AMINO AMSA International Competition 2021: World Diabetes Awareness Month Competition by AMSA-Indonesia

AMINO AMSA-Indonesia Competition Archive

AMSA International Competition 2021

All the works publicized here are the works of AMSA-Indonesia’s member who participated in AMSA International Competition

AMINO | AMSA INTERNATIONAL COMPETITION

FOREWORD

Steven Millenio Widjaja

Secretary of Academic AMSA-Indonesia 2020/2021

The AMSA-Indonesia Competition Archive or AMINO for short is a program by AMSA-Indonesia to facilitate all members to get inspiration on how to make a scientific masterpiece. AMINO acts as an archive where all the works submitted by participants in competitions in AMSA, including Pre-Conference Competition East Asian Medical Students’ Competition (PCC EAMSC), Indonesia Medical Students’ Training and Competition (IMSTC), Pre-Conference Competition Asian Medical Students’ Competition (PCC AMSC) and from AMSA International Competitions, are published. In this series of AMINO, all the scientific masterpieces of AMSA-Indonesia in AMSA International Competition have been compiled, which consists of the following categories: Scientific Paper, Scientific Poster, Public Poster, and Online Social Campaign. We hope that through this volume of AMINO, we are able to further motivate and inspire our members to construct more scientific masterpieces. On behalf of AMSA-Indonesia, I would like to extend my deepest gratitude to personal to all the participants of the AMSA International Competition, the Academic Team of AMSA-Indonesia, the Executive Board of AMSA-Indonesia 2020/2021, and other parties that have contributed to the creation of AMINO. Without each and every single contribution, AMINO would not have been possible. May the release of AMINO increase the academic enthusiasm and ignite the potentials of AMSA-Indonesia members. “Igniting Potentials, Unleashing Possibilities” Viva AMSA!

AMINO | AMSA International Competition 2021

TABLE OF CONTENTS World Diabetes Awareness Month Competition Scientific Paper • First Winner Dissecting the Association of Glycated Albumin with Cardiovascular and Renal Outcomes as An Effort in Putting the Brakes on Diabetic Complications: A Systematic Review and Meta-Analysis

• Second Winner Efﬁcacy and Safety of Insulin Degludec/Insulin Aspart (IDegAsp) in Type 2 Diabetes: 39 Systematic Review of Frequency Adjustment • Third Winner Plasma Glycated CD59 Level as A Novel Predictor of Gestational Diabetes Mellitus and Adverse Outcomes: A Systematic Review and Meta-analysis of Case-control Studies • Entries ■ Serum Uric Acid as A Prognostic Marker in the Early Progressivity of Kidney Function Deterioration in Type 2 Diabetes Mellitus Patients: A Systematic Review ■ FIRST TRIMESTER GLYCATED HEMOGLOBIN (HBA1C) LEVEL AS A NOVEL PREDICTOR OF GESTATIONAL DIABETES MELLITUS: A SYSTEMATIC REVIEW AND META-ANALYSIS OF COHORT STUDIES ■ Potential of Curcumin to Prevent Diabetes Complication: A Systematic Review ■ Effect of Canagliﬂozin on Renal Function in Type 2 Diabetes Mellitus Patients: A Systematic Review ■ Sodium-Glucose Cotransporter (SGLT2) Inhibitors For Prevention of Type 2 Diabetes Mellitus (T2DM) and Its Associated Complications In People At Risk For The Developement of T2DM : Literature Review ■ Corneal Confocal Microscopy As An Early Diagnostic Tool For Diabetic Neuropathy: A Systematic Review ■ Cardioprotective Properties of Glucagon-Like Peptide-1 Receptor Agonist t(GLP-1 RA) in Type 2 Diabetes Mellitus: A Systematic Review

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AMINO | AMSA International Competition 2021 Public Poster • First Winner Healthy Baby Happy Mommy, Diabetes-free BOBA for You and Me

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• Second Winner Prevent Diabetes By Staying In “SHAPE”

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• Third Winner The Ultimate Delight: Prevent diabetes with a hearty piece of cake

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• Entries ■ Type 2 Diabetes Self-Management During Pandemic ■ Fight Against Diabetes Mellitus Type 2 With “COURAGE” ■ Prevent DIABETES as sweet as CUPCAKE ■ Shake Down Diabetes with Insulin ■ “Watch Me” Fight Diabetes: A Skincare Routine ■ Prevent Diabetes with a lot of CREAM ■ Prevent Diabetes with Healthy Lifestyle ■ SUGAR! OUR HERO FOR DIABETES ■ Thwart the Paunch ■ LET’S END DIABETES FIRMLY!

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AMINO | AMSA International Competition 2021 Online Social Campaign • Second Winner Living with Diabetes Mellitus

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• Third Winner Diabetes the Mother of All Diseases

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• Entries Stop Diabetes Through #BeatWithThePITCH

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SCIENTIFIC PAPER

AMINO | AMSA International Competition 2021

Muhammad Alifian Remifta Putra AMSA-Universitas Indonesia 1st Winner of Scientiﬁc Paper Category “Dissecting the Association of Glycated Albumin with Cardiovascular and Renal Outcomes as An Effort in Putting the Brakes on Diabetic Complications: A Systematic Review and Meta-Analysis”

One of the main reasons we joining WDAM is because we're interested to learn and explore more about the topic of Diabetes. In addition, we never try to make a meta-analysis, thus we decided to learn how to make one. Some tips and tricks from me for the first one is that good planning and time management are essential, our team always divides the process of creating paper into 5 main steps; brainstorming for topic, literature search, data processing, writing paper, and finalization. We also have a fixed deadline for each of the steps to keep us on track. Last but not least, we frequently contact a senior to have feedback or whenever we had some confusion in creating our manuscript. Our experience in joining WDAM would be a challenging one, previously we just finished creating two systematic reviews to joining two other competitions. We only have less than two weeks for preparation and we never try to create a meta-analysis. Luckily we had helpful seniors that give a lot of advice and we did our best to use our time by planning on details everything. Good luck to everyone that currently writing their paper!

AMINO | AMSA International Competition 2021

Brenda Cristie Edina AMSA-Universitas Indonesia 2nd Winner of Scientiﬁc Paper Category “Efficacy and Safety of Insulin Degludec/Insulin Aspart (IDegAsp) in Type 2 Diabetes: Systematic Review of Frequency Adjustment”

Submitting a scientific paper to a competition was never my intention in the first place, as I thought scientific writings in competitions never went beyond, rarely contributing to the betterment of scientific community. It was only when I heard of AMSA-International World Diabetes Day competition, I finally decided to give it a try with Lowilius Wiyono and Jeremy Rafael Tandaju. This is because AMSA was once a dear organization in my preclinical life; with whom I trust scientific writings wouldn’t just end in the competition, but beyond that: to increase awareness of the medical community and to cultivate research interest within medical students. To tell you the truth, this was one of my earlier works in systematic review in internal medicine, as I usually researched oncology targetted therapy. However, experiencing this competition firsthand, I earnestly encourage medical students to try scientific writing, specifically systematic review/meta-analysis, as these are the types of research we always needed, which are flexible to be done anywhere anytime; and maybe AMSA competitions are a really good starting step for you! A tip: starting to write, however bad or unconfident you thought your writings were, was always the best step to develop your scientific writing!

AMINO | AMSA International Competition 2021

Gideon Hot Partogi Sinaga AMSA-Universitas Indonesia 3rd Winner of Scientiﬁc Paper Category “Plasma Glycated CD59 Level as A Novel Predictor of Gestational Diabetes Mellitus and Adverse Outcomes: A Systematic Review and Meta-analysis of Case-control Studies”

Diabetes is a major non-communicable disease that causes disability and death worldwide. It can happen to anyone, especially pregnant women which known as gestational diabetes (GDM). GDM is frequently diagnosed late in the second or third trimester, and the pandemic COVID-19 exacerbates the problem. As a result, one of my motivations for participating in this competition is to share ideas in academic writing and scientific review in the hopes of becoming a solution during these difficult times. I will not say that writing this paper has been an easy task. Despite the fact that I have some experience with academic writing, the majority of my work is for scientific posters competition. As a result, this is my first scientific paper competition. Nonetheless, with the help of God and my teammates, we can overcome these obstacles and be given the opportunity to take place on the podium. When it comes to tips and tricks, one of my best advice is to get started right away and not procrastinate. Try to write it in simple and clear English; your ideas do not need to be complicated.

Dissecting the Association of Glycated Albumin with Cardiovascular and Renal Outcomes as An Effort in Putting the Brakes on Diabetic Complications : A Systematic Review and Meta-Analysis ABSTRACT Introduction: Complications arising from diabetes are some of the major challenges and a leading cause of mortality in diabetic patients. HbA1c is currently used as the gold standard to monitor diabetic patients, but its accuracy and validity have been questioned recently for cases where erythrocyte lifespan is affected. Studies have demonstrated that glycated albumin (GA) is a potential biomarker that could overcome the concerns and limitations of HbA1C. Additionally, previous studies also demonstrate the utility of GA in predicting outcomes related to diabetic complications. This meta-analysis aims to investigate the association between GA and cardiovascular and renal outcomes as major macrovascular and microvascular complications in diabetic populations. Methods: We systematically searched through PubMed, Ovid EMBASE, EBSCOhost, Scopus and Web of Science from inception to October 2020. Critical appraisal of included studies were performed using the Newcastle-Ottawa Scale to assess the quality of the studies. Random effects model was used to analyse the pooled estimates of HR and OR for cardiovascular and renal outcomes based on higher and lower GA. Result and Discussion: 20 peer-reviewed studies were included in the meta-analysis, with a total of 7235 diabetic patients that were followed-up to a maximum of 20 years. Higher GA was associated with an increased risk of cardiovascular outcomes (HR: 1.64; 95%CI: 1.23-2.18; P=0.0007) and cardiorenal outcomes (OR: 1.28, 95%CI: 1.10-1.47; p=0.0009). The same trend was also found for renal outcomes (HR: 1.98; 95%CI: 0.89-4.37), however, this was found to be statistically insignificant (p=0.09). Conclusion: Increased serum GA is associated with a higher risk of cardiovascular, renal and cardiorenal complications in diabetic patients, with the exception of renal outcomes which did not reach statistical significance. Keywords: glycated albumin, cardiovascular outcomes, renal outcomes, cardiorenal outcomes

1. INTRODUCTION Diabetes mellitus is one of the most common metabolic diseases due to inadequate insulin secretion and/or impaired action on the target tissues, which is characterized by hyperglycemic state.1-3 According to the American Diabetes Association, diabetes is classified into four main categories, namely type 1 diabetes, type 2 diabetes, gestational diabetes mellitus, and specific types of diabetes due to other causes.2 Collectively, diabetes has emerged as a major burden for the healthcare system worldwide, attributing to the serious health-related and socio-economical impacts.1,3 As estimated by the International Diabetes Federation in 2015, there were 415 million people suffering from this non-communicable disease worldwide.1,3 By 2040, it is predicted to reach 642 million with the majority of increase in type 2 diabetes (T2DM).1,3 The pathophysiology of diabetes is complicated, beginning from the Triumvirate to the Ominous Octet, until recently the concept of Egregious Eleven has been introduced.1,4,5 Moreover, diabetesrelated complications have affected multi organs and contribute essentially to morbidity and mortality of the disease.6 These long term complications cause diabetes to become an extremely costly disease.1,3,6 Cardiovascular and renal complications have been the most representative ones for macrovascular and microvascular complications respectively. In order to prevent the complications, experts focus on good glycemic control which has been proven to be yielding better clinical outcomes.1,3,6 Hemoglobin A1c (HbA1c) that reflects average glucose level for 120 days, is currently used as the standard monitoring method in clinical practice. Despite the benefits, some experts have questioned its validity and utility in the settings of anemia, diabetic nephropathies, and patients presenting with cardiovascular complications, which would influence the erythrocyte turnover.1,7 In contrast, glycated albumin (GA) may more accurately resemble the glycemic control in the aforementioned settings since it is unaffected by erythrocyte lifespan.7-9 Given that there have been a number of studies supporting the predictive value of GA level7-9, the authors were intrigued to further explore regarding the utility of GA as one of the current state-of-the-art issues in the field of endocrinology. Therefore, this meta-analysis intends to summarize current evidence regarding

the association between glycated albumin with renal and cardiovascular-related outcomes as two most representative body systems contributing to microvascular and macrovascular complications. 2. MATERIALS & METHODS 2.1 Search Strategy For this study, the authors performed a literature search based on the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA).10 To retrieve relevant studies, we applied the following keywords: “glycated albumin” AND “cardiovascular event” OR “cardiovascular mortality” AND “albuminuria” OR “diabetic retinopathy”, along with the synonyms and applying the Mesh Terms whenever possible. The search strategy was applied in 5 databases namely PubMed, Ovid EMBASE, EBSCOhost, Scopus, and Web of Science for peer-reviewed studies published up to 1 October 2020. Details on keywords used for each database are elaborated further in Appendix Table 1. 2.2 Inclusion and Exclusion Criteria In creating this review, the authors applied some exclusion and inclusion criteria. The inclusion criteria were such follows: (1) study design, mainly observational studies which include cohort, case-control, and cross sectional studies; (2) peer-reviewed studies that were published before October 2020; (3) study outcomes, Glycated Albumin (GA) level, renal outcomes, cardiovascular (CV)-related outcomes; (4) studies published in English or Bahasa Indonesia. The exclusion criteria that were applied are: (1) types of articles: commentaries, conference abstracts, letters; (2) studies with irretrievable full text; (3) studies with unobtainable or unextractable data despite having contacted the corresponding author; (4) studies published in languages other than English or Bahasa Indonesia. 2.3 Data Extraction, Study Outcomes, and Risk of Bias Assessment 2.3.1 Data Extraction Two independent reviewers performed the data extraction, with discrepancies adjudicated by the consensus with a third investigator. The details of information that were extracted from the

included article were as follows: (1) authors and year of publication; (2) study characteristics, including the recruitment period, study design, country of origin, glycated albumin, type of diabetes; (3) subject characteristics, including the sample size, mean or median age, gender proportion, and comorbidities. 2.3.2 Study Outcomes The main outcomes of interest observed in this review were renal outcomes and cardiovascularrelated outcomes: (1) The renal outcomes include microalbuminuria development; any increased progression to chronic kidney disease (CKD), defined as estimated glomerular filtration rate < 60 ml/min/1.73m2; and progression to end-stage renal disease (ESRD) that requires hemodialysis. (2) The cardiovascular outcomes include cardiovascular events or progression namely coronary artery disease, myocardial infarction, ischemic heart disease, heart failure, arrhythmia, hypertensive crisis, peripheral vascular disease, stroke, transient ischemic attack; and deaths due to cardiovascular diseases. 2.3.3 Risk of Bias Assessment Newcastle-Ottawa Scale (NOS) was utilized in conducting the assessment of methodological quality in terms of risk of bias, which was subsequently judged to be showing good, fair, or poor quality when converted to the Agency for Healthcare Research and Quality (AHRQ) standards.11 The NOS tool consists of 3 main domains, each addressing specific parameters or domains to identify potential bias in the studies, namely selection, comparability, and outcome/exposure with maximum points of 4, 2, 3 respectively. This was applied in accordance to the protocol for cohort and case control studies. As for cross-sectional studies, adapted NOS was used with maximum 5 points for the selection domain.11 It was then subsequently judged as very good, good, satisfactory, or unsatisfactory studies. The assessment was performed by three independent investigators, with conflicts being resolved through consensus of all authors. 2.4 Data Synthesis and Statistical Analysis The quantitative analysis was performed using the software Review Manager version 5.4. Hazard ratios (HRs) and odds ratios (ORs) were extracted from the studies and pooled separately using the DerSimonian and Laird method (random effects model).12 The heterogeneity was assessed

using Tau-square, Cochrane Chi-square as well as I2. Heterogeneity is said to be substantial when the value of I2 is greater than 50%. Thus, considering the heterogeneity of the data, the random effects model was preferred over the fixed effects model, using the inverse variance method. For each pooled HR and its 95% CI, z test was performed to find out the overall effect and the p value to see the statistical significance. A p-value of less than 0.05 is considered to be statistically significant. For cardiovascular outcome, subgroup analysis was conducted by country (United States, China, Germany) and by type of cardiovascular outcome (Death due to Cardiovascular Disease and Cardiovascular Events/Progression). Whereas for renal outcome, subgroup analysis was also conducted based on country (United States, Japan, Germany, China) and type of renal outcome (Microalbuminuria Development, Increase Progression to Chronic Kidney Disease, Progression to End-Stage Renal Disease). Furthermore, we performed sensitivity analysis as a way to assess robustness of pooled estimates and to identify whether a study could greatly influence the heterogeneity/pooled estimate (Appendix Table 4). The sensitivity analysis was done to explore 3 different factors. First of all, the sample size, by which we removed those studies with less than 100 subjects. Secondly, the risk of bias according to the NOS scale (Appendix Table 2), by excluding studies which have an overall NOS score of less than 7. Lastly, we analysed the effect of study design by excluding studies with non-cohort designs (case-control and cross-sectional studies). From the sensitivity analysis, the authors deduced that the aforementioned factors did not have a significant influence on the overall result. In addition, we evaluated the publication bias using funnel plots by visual inspection of the symmetry of the plots. However, this was only performed for cardiovascular outcomes as the other outcomes did not have sufficient data for a funnel plot. Should there be any asymmetry, the Egger test would be conducted.13

3. RESULTS 3.1 Study Selection, Study Characteristics, and Quality Assessment The authors identified 1384 records upon initial search. After removing 23 duplicates, the authors performed the preliminary filtering by screening the records through the titles and abstracts and found 109 articles that were further assessed on a full-text level. Ultimately, we found 20 studies that were included in this review after excluding 89 studies (of which 24 have unretractable data, 35 showed different outcomes, 17 have inappropriate study protocols, 10 have irretrievable fulltext, 2 pilot studies, and 1 retracted study). The detailed systematic search process to select the 20 included studies is depicted in Figure 1. All 20 studies consisted of 16 cohort studies, 1 case-control, and 3 cross-sectional studies were quantitative synthesis. These studies were performed in various countries; 6 were conducted in Japan, 5 in the United States, 4 in China, 2 in South Korea, 2 in Germany and 1 in Egypt. These articles were published between 2007 and 2020 and the provided data that were collected between 1992 and 2015, with a follow-up duration that varied across the studies, ranging from months upto 20 years. Among the included studies, there were 7235 diabetic patients, with over half of them having type 2 diabetes mellitus. Eligible subjects were mostly adults, with mean age ranging from 42.3 to 67 years old. Most patients have comorbidities, including but not limited to, obesity, hypercholesterolemia, hypertension. Regarding the parameter itself, glycated albumin, 8 studies further classified it into categories including tertiles, quartile, and percentile based on their respective cut-off. The baseline characteristics are shown in details in Table 1. The quality and risk of bias assessment of the included studies are depicted in Appendix Table 2A-C. In general, most of the studies showed a predominant fair-to-good quality with details of 6 fair and 12 good quality studies. In addition, one very good and one poor quality study was found.

Figure 1: PRISMA Flowchart10

Table 1: Baseline Characteristics of Included Studies

3.2 Study Outcomes Table 2A & B illustrates the summary of study outcomes from the total of 20 studies that have been acquired from a rigorous process of study selection. The major outcomes that are presented on this table were Glycated Albumin (GA) levels, cardio-renal outcomes of diabetic patients as previously mentioned (Section 2.3). Firstly, for the GA levels, the data that were acquired are mean GA (%) in the blood of diabetic patients along with Standard Deviation (SD) or median and Interquartile Range (IQR) of GA levels. Secondly, for the renal outcomes, authors included ranges of complications that might occur in diabetic patients as follows: microalbuminuria development, increase progression to chronic kidney disease (CKD), and progression to End-Stage Renal Disease (ESRD). Thirdly, for the cardiovascular outcomes, authors focused on cardiovascular events/progression and cardiovascular fatality/mortality. In addition, the risk of developing cardiovascular and/or renal complications from diabetic patients was expressed in the form of a Hazard Ratio (HR) or Odds Ratio (OR) along with 95% CI and p-values. Variables that were adjusted for in each study were also presented.

3.2.1 Association of Glycated Albumin level (Higher/Lower) with Renal Outcomes - HR, Cardiovascular Outcomes - HR, and Cardiorenal Outcomes - OR Figure 2 shows the forest plots depicting the association between levels of GA and cardiovascular and renal outcomes based on pooled HR and cardiorenal outcomes based on pooled OR. In total, there were 5 studies analysing renal outcomes, with a pooled HR of 1.98 [95% CI: 0.89 to 4.37]; p=0.09. There is a significant heterogeneity as shown by an I2 value of 94% (Figure 2A). Furthermore, there were 10 articles that analysed the cardiovascular outcomes as depicted in Figure 2B. The pooled HR shows that a higher GA is associated with an increased risk of developing cardiovascular outcomes in diabetic patients (pooled HR estimates: 1.64 [95% CI: 1.23 to 2.18]; p=0.0007). Likewise, there was also a substantial heterogeneity between these 10 studies (I2=94%). Additionally, 6 studies investigated cardiorenal outcomes by using OR (Figure 2C). The forest plot shows that the pooled HR estimates (1.28, 95%CI: 1.10 to 1.47) were significantly higher (p=0.0009) for higher GA as compared to low GA. The heterogeneity was lower than the previous two but remains substantial as it is above >50% (I2=77%)

Table 2A. Study Outcomes (Renal Outcomes)

Table 2B. Study Outcomes (Cardiovascular-related Outcomes)

Figure 2. Forest Plot: Association of Glycated Albumin level (Higher/Lower) with Renal Outcomes - HR (A), Cardiovascular Outcomes - HR (B) and Cardiorenal Outcomes – OR (C)

3.2.2 Subgroup Analysis of Glycated Albumin level (Higher/Lower) for each Renal Outcomes - HR, and for each Cardiovascular Outcomes - HR The subgroup analyses were performed based on each type of renal and cardiovascular outcomes, as presented in Figure 3. The renal outcomes are divided into 3 subgroups: microalbuminuria development (Hallsacher C et al22), increase progression to CKD (Selvin et al19, Hasslacher et al22, Wang et al16) and progression to ESRD (Freedman et al30, Hasslacher et al22, Yajima et al17). For increase progression to ESRD, the subgroup analysis shows a pooled HR of 2.14 (95%CI: 0.53 to 8.65; p=0.28) while for progression to ESRD, it has a pooled HR of 0.18 (95%CI: 0.69 to 1.56, p=0.86). The test for overall effect gives a z score of 2.04 (p=0.04) and a low heterogeneity (I2=0%) is shown in the test for subgroup differences (Figure 3A) Figure 3B illustrates the subgroup analysis for cardiovascular outcomes. The first outcome is Death due to Cardiovascular Diseases (5 studies namely, Okada et al, Fukuoka et al, Shafi et al, Isshiki et al, Chen et al) with a pooled HR estimate of 1.09 (95%CI: 0.93 to 1.28; p=0.29). The second outcome is Cardiovascular Event (7 studies: Okada et al32, Murea et al27, Shen et al28, Shafi et al26, Hasslacher et al22, Selvin et al, Mihara et al14) which has a pooled HR estimate of 1.84 (95%CI: 1.12 to 3.03; p=0.02). Lastly, the test for overall effect has a z score of 2.94 and is statistically significant (p=0.003). There is also a substantial unexplained heterogeneity (I2=74%/) as shown by the test for subgroup differences.

Figure 3: Subgroup Analysis of Glycated Albumin level (Higher/Lower) for each Renal Outcomes - HR (A), and for each Cardiovascular Outcomes - HR (B) 17

3.2.3 Subgroup Analysis of Glycated Albumin level (Higher/Lower) with Renal Outcomes HR, and Cardiovascular Outcomes - HR based on the Country Figure 3 shows us the subgroup analysis of GA with renal outcomes (Figure 3C), and cardiovascular outcomes (Figure 3D) based on which country the studies are being conducted. First and foremost, in subgroup analysis of GA with renal outcome, there are several countries where the studies were conducted such as the two studies (Freedman BI et al30, and Selvin E et al24) coming from the United States, one study (Yajima et al17) from Japan, one study (Hasslacher C et al.22) from Germany and one study (Wang N et al.16) from China. Overall, due to the very limited amount of studies existing in each country, heterogeneity tests cannot be applied except for studies from the US with I2 of 98%. Not only that, the test for overall effect is also being conducted but for four subgroups available, only one subgroup from China that has a statistically significant Z score (2.35, p=0.02). All in all, the test for subgroup differences shows the Chi2 of 9.99 with a final I2 of 70%, which imply good heterogeneity between studies. In regards to subgroup analysis of GA with cardiovascular outcomes, there are several countries that are included in this subgroup in which four studies come from Japan (Okada T et al32, Fukuoka K et al31, Isshiki K et al21, Mihara A et al14), three studies come from the United States (Murea M et al27, Shafi T et al26, Selvin E et al24), one study from China (Shen Y et al28), and two studies (Hasslacher et al22, Chen CW et al15) from Germany. From four subgroups, only 2 subgroups that produced Z-score tests that are statistically significant are the subgroup of Japan (Z = 2,15, p =0.003), and the subgroup of China (Z=4.39 p<0.0001). All of the subgroups produce a good heterogeneity score and this inline with the result subgroup differences test of I2=53.4% that is still regarded as studies with a good heterogeneity (>50%). (Figure 3)

Figure 3 continued: Subgroup Analysis of Glycated Albumin level (Higher/Lower) with Renal Outcomes - HR (C), and Cardiovascular Outcomes - HR (D) based on the Country

3.2.4 Subgroup Analysis of Glycated Albumin level (Higher/Lower) with Cardiorenal Outcomes-OR divided into Renal and Cardiovascular Outcomes - HR Subgroup analysis was performed for the association between GA with cardiorenal outcomes by dividing it into two main outcomes, which are renal and cardiovascular. In the subgroup of renal outcomes, it consists of two studies (Sany D et al25, Yoon HJ et al20), while for the cardiovascular outcomes includes four studies (Pu et al33, Song SO et al29, Norimatsu K et al23, and Ma X et al18). Only the subgroup of cardiovascular outcomes that produced good heterogeneity (I2=78%), but both renal and cardiovascular outcomes subgroups have statistically significant Z scores (3,47 with p=0.0005 and 2.45 with p=0.01). All in all, the test for subgroup differences shows a good heterogeneity with Chi2 of 4.46 and I2 of 77.6% (p=0.02) (Figure 3E) 3.2.5 Subgroup Analysis of Glycated Albumin level (Higher/Lower) with Cardiorenal Outcomes - OR divided based on the Country Subgroup analysis was also performed based on country of origin for cardiorenal outcomes (presented with OR) as an attempt to explain heterogeneity in Figure 2C. We found an OR of 1.31 [0.82-2.09] among diabetic patients with higher GA living in South Korea (I2=84%). The heterogeneity seemed to decrease when the studies from South Korea and China were combined with the ones from Egypt and Japan, reducing the pooled heterogeneity to 77%. The details are shown in Figure 3F.

Figure 3 continued: Subgroup Analysis of Glycated Albumin level (Higher/Lower) with Cardiorenal Outcomes-OR divided into Renal and Cardiovascular Outcomes (E) and Subgroup Analysis of Glycated Albumin level (Higher/Lower) with Cardiorenal Outcomes - OR divided based on the Country (F) 21

3.2.6 Sensitivity Analysis The conducted sensitivity analysis showed only very subtle changes following the applied restrictions to cohort study in renal outcomes and cardiovascular outcomes, partly due to the predominance of this type of study design (Appendix 4 A & B). The same phenomenon happened when restricting the sensitivity analysis to only studies with >100 sample size for both outcomes (Appendix 4 C & D). Similarly, when the analysis was restricted to only studies with NOS score >6, slightly higher pooled estimate was demonstrated, indicating that higher HR was demonstrated when excluding study with score <7 (Appendix 4 E & F). As for cardiorenal outcomes represented with OR, the sensitivity analysis was restricted to study design (i.e. only cohort studies) and sample size >100 studies demonstrated in Appendix 4 G & H respectively with only slight changes shown. To summarize, the results of sensitivity analysis after applying the restrictions based on study design, sample size, and NOS score generally remained consistent, indicating robust pooled estimates.

4. DISCUSSION 4.1 Diabetes and Its Complications Diabetes is a highly pressing threat to public health which can cause devastating complications on patients' conditions. It is recorded that 102 million total population had diabetes in 1980, and 4 decades since then, the number has quadrupled to 422 million.1,3,34 These tremendous increases were contributed by various factors such as population growth, aging along with the increase of global prevalence in obesity and overweight. If not well controlled, diabetes can cause dangerous complications such as heart attacks, stroke, kidney failure, and also other complications that not imminently cause death but give a tremendous impact on life, for instance, lower limb amputation, and blindness.1,3,34 Firstly, in regards to cardiovascular events, diabetic adults were historically found to have a two to three times higher chance to have cardiovascular disease (CVD).35 This risk is proportionally increased with the rising of fasting plasma glucose.36 Secondly, based on the collective data of 54 countries, at least 80% of ESRD occurrences are predominantly caused by diabetes, and hypertension, or the combination of both. Diabetes alone contributes to 12-55% of the ESRD occurrence in patients, and there is a 10 times higher chance for diabetic patients to develop ESRD compared to non-diabetic ones.37 Thirdly, diabetic retinopathy became one of the major causes of global blindness by contributing to 2.6% of the total proportion in 2010.37 Studies also suggest that diabetic patients have over 35% prevalence to have proliferative (vision-threatening) conditions, while retinopathy itself is 7%.38 Last but not least, diabetes also causes a dramatic increase in risk (10-20x) for lower extremity amputation in diabetic patients compared to non-diabetic ones. This is mainly caused by non-healing, infected foot ulcers in which based on the records, amputation has been done with the rate of 1.5-3.5 events per 1000 persons each year in the population of diabetic patients.39 Overall, diabetic complications are commonly divided into macrovascular (destruction to larger blood vessels) and microvascular (damage to small blood vessels). The demarcation line that differentiates the pathogenic mechanisms between macrovascular and microvascular complications of diabetes itself is still not fully elucidated. Diabetes may induce the microvasculature changes which further trigger extracellular matrix protein synthesis, along with

thickening of the capillary basement membrane, in which both are the pathognomic features for diagnosing diabetic microangiopathy. Also, other processes that took place are the rise of advanced glycation end products, an increase of oxidative stress, low-grade inflammation, and vasa vasorum neovascularization which ultimately lead to macrovascular complications. Thus, hyperglycemia not only plays an important role in microvasculopathy, but also becomes the principal cause of macrovasculopathy progression.40 Initially, researchers believe that there is a sort of intersection between macro and microvascular complications, however recent updates suggest that both complications are strongly interconnected. Starting with microvascular complications that support atherosclerosis using hypoxia and vasa vasorum changes, that finally lead to macrovascular diseases. Therefore, it is essential to discover and understand the markers that can signify the progression for both micro and macrovascular changes.41 4.2 Available Glycemic Markers as Useful Monitoring Tools Attaining and maintaining blood sugar levels in the good threshold is a cornerstone in the prevention of diabetes complications. Since then, several glycemic markers have been developed to evaluate the efficacy of glycemic control in diabetic patients. Currently, glycated hemoglobin (Hb1Ac) has become the most common marker and has traditionally been used to diagnose patients with diabetes, and also to observe its progression despite its biological and analytical limitations.42 Other alternate glycemic markers that are still not fully elucidated on its full potency and usage are fructosamine (FA), 1,5-anhydroglucitol (1.5AG), and glycated albumin (GA).8,43 4.3 Current Challenges and Why Action is Needed Now Given the availability of various glycemic measures for monitoring glucose control, to summarize, two main problems are commonly faced, namely (1) duration-concerned limitation, how certain marker reflects the glycemic condition; and (2) site-concerned limitation, how certain marker lifespan is affected by its site (i.e. erythrocytes or red blood cells/RBC in this context). For the first issue, three glycemic indices, namely fasting plasma glucose (FPG), 2 hour- postprandial glucose (2h-PG), and glycated hemoglobin (HbA1c) are useful, yet could not overcome the obstacle. Shortterm lifestyle changes done by patients (in preparation for examination) may affect or mask the FPG and 2h-FPG parameters, giving good impression to clinicians due to short duration the two

indices can reflect, whereas HbA1c could only reflect long duration for around 2-to-3 months preceding the examination.8,44-46 For the second issue, HbA1c is further limited when patients experience conditions affecting the RBC such as in anemia, attenuated kidney function, hemoglobinopathies, gestational diabetes, blood transfusion, and other cardiovascular complications that affect the lifespan which may cause false results. With these in mind, there is a need for an index which could overcome the obstacles duration-and site-wise. Glycated albumin (GA) has received attention, attributing to its ability as intermediate glycemic index (reflecting 2-to-3 weeks duration preceding the test) and unaffected by RBCs lifespan. Additionally, GA was shown to be useful for patients with wide glucose variability, as a complementary measure other than the ones mentioned earlier, especially in those special circumstances.32,33,44-46 Studies have reported significant association between elevated GA levels (but not HbA1c) with stiffening of carotid arteries, coronary heart disease, development of CVD among Asian population.14,32,33,45,46 This indicated that studies have attempted to touch the issue upon GA level as a predictive monitoring index not only in nephropathies, but also in cardiovascular diseases. This hooked the authors to revisit the utility of GA, especially in diabetic conditions which are more prone to cardiorenal complications so that by knowing the likelihood of having the outcomes sooner, clinicians could intervene by putting the brakes to diabetic complications through optimal therapeutic management. 4.4 Tracing A Line between The Current Findings and Molecular Aspects After including different types of population, our study has shown increased risk of having cardiovascular and renal outcomes as well as cardiorenal outcomes when GA is uncontrolled (i.e. higher GA group) amongst diabetic patients. The pooled estimates mostly showed significant findings, with exemption for renal outcomes. The plausible explanation is that microalbuminuria and progression of severity as the outcomes of interest were relatively meticulous to be reflected significantly by higher GA. Nevertheless, the trend still showed increased likelihood in higher GA groups for the renal outcomes. As for cardiovascular and cardiorenal ones, both significantly showed higher risk, adding to the growing body of literature that the trend was also observed for other populations.

Discussing the molecular mechanism on the increased risk from the pooled estimates of our present review, several studies have suggested underlying possible mechanisms. In hyperglycemic state, the increased GA in diabetic patients was demonstrated to enter the glomerulus and affects the glomerular capillary structurally and functionally leading to diabetic nephropathies. Molecularwise, Gan T et al. suggested that GA stimulates the TGF-β system leading to expansion of mesangial areas which cause reduced filtration units and basement membrane thickening.47 GA also displays proatherogenic potentials in endothelial and vascular smooth muscle cells. A combination of upregulation of vascular endothelial growth factor and augmentation of oxidative stress exerted by GA collectively contribute to structural changes that are prone to cellular activation, plaque formation, and atherogenesis which ultimately affects the cardiovascular system.48 4.5. Implications in Clinical Practice Incorporating the novelty of our findings, we then understand that higher GA levels increase risk of both renal and cardiovascular-related outcomes in diabetic populations. This underrated biomarker, glycated albumin, has been shown to be useful in numerous settings, when intermediate duration-wise index is needed and where the erythrocyte lifespan could be affected. Hence, we encourage its measurement to monitor glycemic control on those circumstances as well as appreciating its predictive role in alerting the clinicians on the likelihood of patients developing cardiorenal outcomes, both of which are representatives of macro and microvascular complications in DM. 4.6. Study Limitations and Strengths We acknowledge that this study has several limitations. First of all, different researchers have different thresholds for higher and lower GA which might impact comparability. In addition, we used different statistical parameters such as HR and OR to analyse the association between higher GA and cardiorenal outcomes, thus caution should be taken when interpreting the results. Another limitation is there is variation in the duration of follow-up with some studies having a shorter follow-up duration than others.

Although there are limitations, this study has some key strengths as well. First of all, through the NOS risk of bias assessment, we found that the majority of the included studies have a good score with a very minimal number of fair and poor studies. Also, most of our studies are cohorts, indicating that most studies have tested the longitudinal effects of GA monitoring. Another strength is the variation of the countries where the studies were conducted, which is globally representative. In addition, there was an extensive process of study search and data analysis, including subgroup and sensitivity analysis.

CONCLUSION

To sum up, this comprehensive meta-analysis demonstrates that glycated albumin is a superior marker to predict the risk of both cardiovascular and renal complications in patients with diabetes. In the end, GA can accurately reflect the glycemic control and helps to monitor and prevent the occurence of microvascular and macrovascular diabetic complications. 5.1 Future Recommendations We recommend that future studies examine larger sample size especially those looking for renal outcomes. The index of GA/HbA1c ratio may also be considered since some studies suggest its utility in circumstances where both HbA1c and GA are affected. Studies could also touch upon the issues of comparability between indices to determine a case-based approach since not every condition would be suitable to be measured with certain indices. Future therapeutic interventional trials in reducing GA level could also be performed to observe any evidence-based benefits that might be obtained when the index is well controlled.

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APPENDIX Appendix 1. Table of Keywords Details

Appendix 2. Newcastle-Ottawa Quality Assessment Scale

Appendix 3. Funnel Plot: Association of Glycated Albumin level (Higher/Lower) with Cardiovascular Outcomes (Figure 2B)

Appendix 4. Forest Plot: Sensitivity Analysis

Appendix 4 continued. Forest Plot: Sensitivity Analysis

Efficacy and Safety of Insulin Degludec/Insulin Aspart (IDegAsp) in Type 2 Diabetes: Systematic Review of Frequency Adjustment Abstract Introduction: Type 2 diabetes mellitus is a prevalent metabolic disease requiring tight glycemic control of basal and post-prandial glucose levels. Treatment intensification using separate basal and bolus injections increased the number of injections and cost-effectivity, leading to decreased compliance and failure of glycemic control. Insulin Degludec/Insulin Aspart (IDegAsp), a novel premix of basal and bolus insulin, is one of potential treatments reducing the number of injections. However, its efficacy and safety has not been reviewed clearly. Therefore, this systematic review aims to compare the efficacy and safety of IDegAsp with standard basal and basal plus bolus insulin regimen. Methods: A systematic review of four databases (Pubmed, Scopus, Science Direct, Proquest) was conducted using the PRISMA guideline. Search results were screened by eligibility criteria, critically appraised by Oxford CEBM tool and Cochrane Risk Bias Assessment tool. Results and Discussion: Out of 132 search results, 10 studies were reviewed. IDegAsp once daily administration was proven beneficial in reducing HbA1c levels and nocturnal hypoglycemia incidences, while IDegAsp twice daily administration was proven beneficial in lowering hypoglycemia incidence and nocturnal hypoglycemia incidence. Conclusion: IDegAsp once daily with stepwise titration on the largest meal of the day achieved most benefits with minimal risks. Keywords: IDegAsp; Diabetes Mellitus Type 2; Insulin; Systematic review Introduction Diabetes mellitus is a metabolic disease suffered by 422 million people globally (2014) and a direct cause of 1,6 million mortalities (2016) due to its complications.1 Type 2 diabetes mellitus, a subtype of Diabetes Mellitus more prevalent in adults, is characterized by impaired glucose metabolism, insulin resistance, and progressive insulin deficiency. Changes in glucose homeostasis in type 2 diabetes mellitus create a continuous state of hyperglycemia in blood plasma. If glycemia is not controlled through the course of disease, chronic hyperglycemia may lead to

various long-term complications (macrovascular and microvascular), which leads to poor quality of life, increased morbidity, and mortality.2,3 Based on the clinical guideline from the American Diabetes Association and European Association for the Study of Diabetes, glycemic control of type 2 diabetes mellitus is done through combining lifestyle changes and pharmacological intervention through a step-wise approach. First line pharmacological treatment of type 2 diabetes mellitus is oral hyperglycemic agents. However, in cases of progressive beta cell destruction and insulin deficiency where glycemic control could not be adequately achieved by only using oral anti-glycemic agents, treatment is intensified by adding basal Insulin therapy or GLP-1 agonist. One of the challenges of basal insulin therapy is control of post-prandial glucose levels. When post-prandial glucose levels still spike even after constant basal insulin therapy, post-prandial or bolus insulin injection may be added to treatment regimens.2,3 The use of basal and post-prandial insulin may be effective in controlling blood glucose levels, however it requires more daily injections and increased cost of treatment. These drawbacks may be inconvenient for most patients, as injections are uncomfortable for most. Aside from the inconveniences, increased number of injections leads to reduced treatment compliance, thus hampering the effectiveness of glycemic control. Patients may come to the hospital even more morbid than before their treatment was intensified, only because they missed most of their insulin injections.2,3 As a solution to this matter, several pre-mixed or self-mixed insulin solutions were innovated. Although most of the time co-formularity of basal and bolus insulin are impossible due to substances incompatibility, some long-acting and rapid acting insulin combination has been formulated. One of them is insulin degludec/insulin aspart (IDegAsp), a soluble co-formulation consisting 70% basal insulin degludec and 30% post-prandial insulin aspart.2,3 IDegAsp is a potential type 2 diabetes mellitus treatment due to its glycemic coverage and reduced number of injections. However, up to this day there has not been any comparison of IDegAsp with standard treatments (basal insulin or basal and bolus insulin) stratified by its frequency. A review of IDegAsp’s efficacy and is needed in order to give a clear risk and benefit consideration for clinical practitioners in prescribing insulin therapies. Therefore, we created a systematic review comparing the efficacy and safety of IDegAsp to basal insulin regimen and basal plus bolus insulin regimen, stratified by its frequency, once daily or twice daily.

Methods We conducted a systematic review complying the PRISMA guideline in order to determine the efficacy and safety of IDegAsp in the management of type 2 diabetes mellitus (Type 2 DM).4 The search strategy was conducted by three independent reviewers to ensure the reviewers’ objectivity. The search was conducted through PubMed, ProQuest, Scopus, and ScienceDirect on 29 October 2020. Every difference in search result was discussed further between reviewers to make a decision. We also conducted hand searching in various databases to look for literature on IDegAsp and type 2 diabetes mellitus. The search was conducted using search queries and keywords of (“Type 2 Diabetes Mellitus” OR “Type 2 DM”) AND “IDegAsp” in every database. A Mesh Term is used if it is available in the selected databases. Moreover, we have contacted experts and researchers from the field and also searched clinical trials in clinicaltrial.gov to look for the latest publication on IDegAsp and Type 2 DM. We selected and screened the studies using inclusion and exclusion criteria which made preceding the research. We included (1) randomized clinical trial; (2) studying population of Type 2 DM in any age; (3) using IDegAsp as intervention or independent variable; (4) using another insulin as controlled variable; (5) Analyze the outcome of IDegAsp use in Type 2 DM, such as HbA1C changes and hypoglycemia events which compared with the control insulin; (6) written in English. We also did citation alerts from existing systematic review or meta-analysis to increase the sensitivity of the acquired studies. However, we exclude editorial/review articles and case report/case series as it is not suitable for this review. All acquired studies were then assessed for its quality using Tools for Critical Appraisal by Center for Evidence-Based Medicine (CEBM) of University of Oxford.5 We also conducted a risk of bias assessment using Cochrane’s tool for risk of bias on seven different aspects of bias.6 The critical appraisal and risk of bias assessment was conducted by three independent reviewers with any disparities and differences discussed properly to make a final decision which could be seen in Table B and C. Out of the selected studies, we extracted the information of study author, year, design, location, age of samples, sample size, intervention, control, aim of study, primary endpoint, level of evidence (based on CEBM level of evidence 2011)7, and their notable outcomes.

Results According to search strategy, we found ten studies eligible for analysis which could be seen on Figure 1. There are three studies comparing once daily administration of IDegAsp to once daily administration of insulin Glargine (IGlar), one study comparing once daily administration of IDegAsp and once daily administration of IGlar and IAsp, five studies comparing twice a day administration of IDegAsp to twice a day administration of biphasic insulin aspart (BIAsp), and one study comparing twice a day administration of IDegAsp to twice a day administration of IDeg and IAsp.2-3,8-15 All studies were randomized controlled studies, with some done in phase III.9,11-13, 15

There were seven multinational and intercontinental studies done.3,8,10-12,15 All studies involved

patients aged 18 years old and above with sample size more than 100 for each study with complete characteristics could be seen on Table 1.2-3, 8-15

Figure 1. PRISMA diagram of study search.

Table 1. Study characteristics. Age (years Sample Author

Year Design Location

old)

size

Objective

Primary

Level of Length

Endpoint

Evidence (Weeks)

IDegAsp OD compared to IGlar OD Croatia, France, India,

Kumar S, et al

2016 RCT

Poland, South Africa,

HbA1c mean change, FPG

South Korea, Sweden,

change, SMPG 9 point,

Turkey, The United

overall prandial glucose

HbA1c mean

increment

change

States

>18

465

26 + 26

HbA1c change, FPG change,

Kumar A, et al

2016 RCT

Austria, India, Poland,

PPG increment SMPG,

Russia, South Korea,

number participants normal

Spain, Turkey, The

HbA1c, hypoglycemic

HbA1c

episodes

change

United States

>18

413

HbA1c change, FPG change, SMPG nine-point, total daily Onishi Y, et al

RCT

insulin dose, hypoglycemic

Phase

episodes, body weight

2013 III

Japan

>20

296

HbA1c change

Age (years Sample Author

Year Design Location

old)

size

Objective

Primary

Level of Length

Endpoint

Evidence (Weeks)

IDegAsp OD compared to IGlar + IAsp OD HbA1c mean change, FPG Tsimikas A, et al

2019 RCT

Algeria, Czech, India,

change, proportion of normal

Russia, Serbia, Turkey,

HbA1c, SMPG profile, total

HbA1c

daily insulin dose

change

The United States

>18

532

IDegAsp BID compared to BIAsp BID HbA1c change, FPG change, Kaneko S, et al

Fulcher

2015 RCT

Hong Kong, Japan,

nine-point SMPG, body

Malaysia, South Korea,

wright, proportion achieving HbA1c

Taiwan

>18

424

normal HbA1c

change

Australia, Denmark,

HbA1c change, FPG change,

Finland, India,

SMPG profile, proportion

RCT

Malaysia, Poland,

achieving normal hbA1c,

Phase

Sweden, Taiwan,

hypoglycemic episodes, body HbA1c

GR, et al 2014 IIIa

Thailand, Turkey

>18

447

weight, insulin dose

change

Age (years Sample Author

Taneda S, et al

Year Design Location RCT

Hong Kong, Japan,

Phase

Malaysia, South Korea,

2016 III

Taiwan

old)

size

178

Objective

Primary

Level of Length

Endpoint

Evidence (Weeks)

HbA1c change, FPG change after 26 weeks, nocturnal Yang W, et al

RCT

hypoglycemia, body weight

Phase

change, response without

HbA1c

hypoglycemic episodes

change

2019 III

China

>18

543

Franek et al

HbA1c 2016 RCT

Europe

>18

371

Safety & efficacy of IDegAsp change

IdegAsp BID compared to IDeg + IAsp BID HbA1c mean change, FPG Rodbard

RCT

Algeria, Austria,

change, proportion of normal

Phase

France, Norway, The

HbA1c, SMPG profile, total

HbA1c mean

daily insulin dose

change

HW, et al 2015 III

United States

>18

274

Abbreviations: IDegAsp (insulin degludec/insulin aspart); IDeg (insulin degludec); IAsp (insulin aspart); IGlar (insulin glargine); OD (one dose); BID (bis in die, latin for twice a day); FPG (fasting plasma glucose); HbA1c (glycated hemoglobin); SMPG (self-measured plasma glucose); RCT (randomized controlled trial)

We found out that nine studies were excellent in terms of validity and applicability (Table 2).5,8,11 Only one study did not state equal treatment of samples in the trial, thus concluded as unclear.12 Based on Cochrane risk of bias assessment, ten studies were clear of selection bias, attrition bias, reporting bias, and other bias (Table 3).6,8,12 However, blinding of all studies were unclear as these study have objective measure, thus blinding was not necessary. Table 2. Critical appraisal results. Validity

Treatment effect

Internal validity

Patient similarity

et al

Yes

Unclear

Yes

Onishi Y, et al

Yes

Unclear

Yes

Tsikimas A, et al

Yes

Unclear

Yes

Yang W, et al

Yes

Unclear

Yes

Franek E, et al

Yes

Unclear

Yes

Rodbard HW, et al

Yes

Unclear

Yes

Double-blind

Kumar A,

analysis

Yes

Follow up and

Yes

intention-to-treat

Equal treatment

Unclear

Similar

Yes

characteristics

Yes

Sample

Yes

randomization

et al

Applicability

Yes

Study Kumar S,

Importance

Treatment effect

Internal validity

Patient similarity

Yes

Unclear

Yes

Unclear

Yes

Other bias

Selective reporting (reporting

Rodbard HW, et al

bias)

Franek E, et al

Incomplete outcome data

Yang W, et al

(attrition bias)

Tsimikas A, et al

Blinding of outcome assessment

Onishi Y, et al

(detection bias)

Kumar A, et al

Blinding of participants and personnel (performance bias) Allocation concealment (selection bias) Random sequence generation (selection bias) Kumar S, et al

analysis Follow up and intention-to-treat Equal treatment Similar characteristics Sample randomization

Study

Double-blind

Unclear

et al

Yes Taneda S,

Yes et al

Yes Fulcher G,

Yes Study

Applicability Importance Validity

Table 3. Risk of bias assessment results.

Other bias

Selective reporting (reporting

bias)

Incomplete outcome data

(attrition bias)

Blinding of outcome assessment

(detection bias)

Blinding of participants and

personnel (performance bias)

Allocation concealment (selection

bias)

Random sequence generation

(selection bias)

Study

Kaneko S, et al Fulcher G, et al Taneda S, et al Interpretation: Green (low risk of bias); Yellow (some concerns); Red (high risk of bias) We found that IDegAsp administration of once a day gave better HbA1c change compared to one study with estimated treatment difference (ETD) of -0.28% (95% CI -0.46; -0.10) compared to IGlar, according to one study as seen in Table 4.9 Two studies shown more patients achieving <7% HbA1c in 26 weeks in the once daily IDegAsp group, with odds ratios of 1.18 (95% CI 0.78; 1.78)8 and 2.21 (95% CI 1.25; 3.92).9 We also found there was lower incidence of nocturnal hypoglycemia in once a day IDegAsp group compared to IGlar group by 75% according to one study.8 However, there are drawbacks of once a day IDegAsp compared to IGlar. It was figured out that there were higher hypoglycemia incidence according to two studies and higher weight gain with ETD of 1.60 kg (95% CI 0.84; 2.36) according to one study.3,8 Comparison between once daily IDegAsp and IGlar for fasting glucose could not be determined by every studies.3,8-9 Once daily administration of IDegAsp compared to once daily IGlar + IAsp showed no significant reduction of HbA1c levels, weight gain, and fasting glucose levels. However, the number of participants reaching normal levels of HbA1c in IDegAsp compared to IGlar + IAsp is significant with an odds ratio of 1.07 (95% CI 0.74; 1.54). The rates of overall hypoglycemic events and nocturnal hypoglycemic events were also reduced significantly with RR 0.90 (95% CI 0.67; 1.22) and RR 0.55 (95% CI 0.34; 0.90), respectively.2

Twice a day IDegAsp administration showed no inferiority, nor superiority compared to BIAsp in terms of HbA1c reduction.10-14 More patients achieved normal HbA1c levels with bidaily IDegAsp in three out of four studies assessing this outcome, with OR 1.60 (95% CI 0.94; 2.72),11 OR 1.20 (95% CI 0.59; 2.46),12 and OR 2.22 (95% CI 1.47; 3.35).13 Moreover, there were three studies stating lower risk of hypoglycemia incident in twice a day IDegAsp administration with lowest risk ratio of 0.46 (95% CI 0.35; 0.61) fold.11,13-14 There were also four studies reported lower incidence of nocturnal hypoglycemia in IDegAsp administration twice daily with lowest risk ratio of 0.25 (95% CI 0.16; 0.38) fold.11,14 In addition, five study showed that twice a day IDegAsp administration shown more reduction towards fasting glucose compared to BIAsp, with largest margin ETD of -1.50 (95% CI -1.98; -1.01) mmol/l.10,14 Two studies reported there was lower insulin dose of twice daily IDegAsp up to 20% compared to BIAsp by week 26 of administration.11,13 However, comparison of weight gain could not be determined as there are one study mentioned significant superiority and one study mentioned significant inferiority.11,13 IDegAsp administration twice daily showed no significant difference in HbA1c change, hypoglycemia incidence, nocturnal hypoglycemia incidence, and fasting glucose reduction compared to IDeg and IAsp twice daily administration. There was also less proportion of patients achieving target HbA1c in bidaily IDegAsp group compared to IDeg and IAsp, with OR 0.50 (95% CI 0.50; 1.38). However, there was less weight gain in IDegAsp group with ETD of -1.04 (95% CI -1.99; -0.10. In addition, IDegAsp group shown less dosage needed (107 IU vs 131 IU) compared to IDeg and IAsp after 26 weeks of administration.15

Table 4. Outcome of studies. Participants Author

Nocturnal

HbA1c

achieving normal Hypoglycemia hypoglycemia

Change

HbA1c (<7%)

incident

Weight Gain

Fasting Glucose

IDegAsp OD compared to IGlar OD ETD -0.03% Kumar S, (95% CI -

OR 1.18 (95% CI

RR 1.43 (95%

RR 0.80 (95%

ETD 0.33 kg (95% ETD 0.33 mmol/l

et al

0.78; 1.78)

CI 1.07; 1.92)

CI 0.49; 1.30)

CI -0.17; 0.83)

Kumar A, (95% CI -

OR 0.95 (95% CI

TR 1.96 (95%

TR 0.25 (95%

ETD 1.60 kg(95% ETD 0.28 mmol/l

et al

0.66; 1.35)

CI 1.42; 2.44)

CI 0.15; 0.47)

CI 0.84; 2.36)

(95% CI -0.14; 0.69)

Onishi Y, (95% CI -

OR 2.21 (95% CI

RR 0.73 (95%

RR 0.75 (95%

RR 0.75 (95% CI

ETD -0.15 mmol/l

et al

1.25; 3.92)

CI 0.50; 1.08)

CI 0.34; 1.64)

0.34; 1.64)

(95% CI -0.29; 0.60)

0.20; 0.14)

(95% CI -0.11; 0.77)

ETD -0.08% 0.26; 0.09) ETD -0.28% 0.46; -0.10)

IDegAsp OD compared to IGlar + IAsp OD ETD 0.07% Tsimikas

(95% CI -

OR 1.07 (95% CI

RR 0.90 (95%

RR 0.55 (95%

ETD 0.43 (95% CI ETD 0.04 (-0.34;

A, et al

0.06; 0.21)

0.74; 1.54)

CI 0.67; 1.22)

CI 0.34; 0.90)

-0.13; 0.99)

0.42)

Other

Participants Author

Nocturnal

HbA1c

achieving normal Hypoglycemia hypoglycemia

Change

HbA1c (<7%)

incident

Weight Gain

Fasting Glucose

Other

IDegAsp BID compared to BIAsp BID ETD 0.05%

ETD -1.06 mmol/l

Kaneko S, (95% CI -

OR 0.94 (95% CI

RR 1.00 (95%

RR 0.67 (95%

ETD -0.38 kg (95% (95% CI -1.43; -

et al

0.61; 1.44)

CI 0.76; 1.32)

CI 0.43; 1.06)

CI -0.96; 0.21)

0.10; 0.20)

0.70) Lower insulin

ETD -0.03%

ETD -1.14 mmol/l

dose (RR =

Fulcher

(95% CI -

OR 1.60 (95% CI

RR 0.68 (95%

RR 0.27 (95%

ETD -0.62 kg (95% (95% CI -1.53; -

0.89; 95% CI

GR, et al

0.18; 0.13)

0.94; 2.72)

CI 0.52; 0.89)

CI 0.19; 0.41)

CI -1.15; -0.10)

0.83; 0.96)

ETD -0.13%

0.76) ETD -1.50 mmol/l

Taneda S, (95% CI -

OR 1.20 (95% CI

RR 1.63 (95%

RR 0.44 (95%

ETD -0.14 kg (95% (95% CI -1.98; -

et al

0.59; 2.46)

CI 0.66; 4.06)

CI 0.20; 0.99)

CI -1.01; 0.74)

0.31; 0.04) ETD -0.08%

1.01) ETD -1.42 mmol/l

Yang W,

(95% CI -

OR 2.22 (95% CI

RR 0.57 (95%

RR 0.53 (95%

ETD 0.61 kg (95% (95% CI -1.74; -

Lower insulin

et al

0.20; 0.05)

1.47; 3.35)

CI 0.42; 0.77)

CI 0.33; 0.87)

CI 0.15; 1.08)

dose of 20%

ETD 0.02%

ETD -1.00 mmol/l

Franek et (95% CI al

0.12; 0;17)

1.10)

RR 0.46 (95%

RR 0.25 (95%

ETD 0.79 kg (95% (95% CI -1.40; -

CI 0.35; 0.61)

CI 0.16; 0.38)

CI -0.03; 1.61)

0.60)

Participants Author

Nocturnal

HbA1c

achieving normal Hypoglycemia hypoglycemia

Change

HbA1c (<7%)

incident

Weight Gain

Fasting Glucose

Other

IdegAsp BID compared to IDeg + IAsp BID Lower total daily insulin dose (107 U ETD 0.18% Rodbard

(95% CI -

HW, et al 0.04; 0.41)

vs 131U) OR 0.50 (95% CI

RR 0,82 (95%

RR 0.80 (95%

ETD -1.04 kg (95% ETD -0.31 mmol/l

0.50; 1.38)

CI 0.61; 1.07)

CI 0.50; 1.29)

CI -1.99; -0.10)

after 26

(95% CI -0.97; 0.34) weeks

Abbreviations: IDegAsp (insulin degludec/insulin aspart); IDeg (insulin degludec); IAsp (insulin aspart); IGlar (insulin glargine); OD (one dose); BID (bis in die, latin for twice a day); HbA1c (glycated hemoglobin); ETD (estimated treatment difference); CI (confidence interval); RR (risk ratio); TR (treatment ratio) Discussions Once daily IDegAsp administration gave better HbA1c reduction compared to once daily IGlar, which could not be explained clearly by twice daily IDegAsp administration.9-14 It was similar to one study that there were HbA1c elevation in first three months of once daily basal insulin administration (8.70%±1.00%; p<0.05) and HbA1c reduction in first three months of changing into once daily IDegAsp (8.28%±1.10%; p<0.05) with significant effect up to six months of administration.16 However, there was a study which stated that IDegAsp administration was not linked with difference of HbA1c in insulin-naive patients, but same study stated there was reduction

of fasting plasma glucose by 1.0 mmol/l (p<0.05), which could not be determined in all studies included.8 These mechanisms could be explained by the fact that IDegAsp is consisted of IDeg dihexamers and IAsp hexamers. IDeg di-hexamers creates a pool of soluble multi-hexamers which continuously formed into monomers, thus slowly dissociating. Meanwhile, IAsp hexamers dissociate swiftly to monomers. IDeg has half life of 25.3 hours with duration of action up to 42 hours, while IAsp acts rapidly in 10-15 minutes of onset and reaches peak action in 90 minutes.8,17 Due to its sustainability and bioavailability, once daily IDegAsp was proven enough to lower HbA1c level. Once daily IDegAsp was neither superior nor inferior to twice daily IDegAsp in the number of patients achieving normal HbA1c levels compared to only basal or only bolus insulin, as majority of studies showed more proportion of patients reaching physiologic HbA1c on 26 weeklong IDegAsp therapy.3,9,11,12-13 However, co-formulation of bidaily IDegAsp is not superior to separate bidaily IDeg + IAsp in the proportion of patients achieving HbA1c target.15 This may be due to the flexibility of dosing and titration in separate IDeg + IAsp. In premixed IDegAsp, the proportion of IDeg and IAsp is always fixed to 30:70, leaving less room for individualized treatment.10 Meanwhile separate regiments, though inconvenient in nature, is more personalized to the patients’ individual fluctuations of fasting and point glucose levels.10 Treatment period also affected the course of treatment, as similar studies eventually reach superior results in 52 weeks of treatment.10 Even though IDegAsp was a long acting insulin, it was proven to have great safety measure. IDegAsp long acting trait did not improve risk of nocturnal hypoglycemia as we saw that there are reduction of nocturnal hypoglycemia in one study.8 The same risk difference of nocturnal hypoglycemia incidence reduction was found in both once daily and twice daily administration of IDegAsp.8,11-14 This was contributed by the stability of IDeg di-hexamers so that impact of rapid and slow acting insulin were clearly separated. It is known by the same study that IDegAsp metabolism and excretion were not impaired by renal or liver impairment at any level.18 Therefore, there was lower risk of IDegAsp-related toxicity. However, there was higher risk of hypoglycemia in once daily administration of IDegAsp according to two studies.3,8 It was stated that hypoglycemic events were peaked at evening, between 20:00 and 24:00 with majority of subjects taking once daily IDegAsp post-evening meal. In contrast, once daily IGlar administration postevening meals showed hypoglycemic effects between 04:00 and 08:00.3 Those phenomena were

linked with onset activity of IDegAsp and IGlar, which were different. IDegAsp showed peak glucose-lowering effect on four hours after administration and slown up to 24 hours after administration.19 Therefore, to achieve reduction of HbA1c using once daily IDegAsp without risking hypoglycemia, it is recommended to give initial dose at largest meal time with tapering on if needed. It has been proven that hypoglycemia incidence was significantly reduced by IDegAsp administration on the largest meal of the day. It also gave better fasting plasma glucose reduction after 26 weeks.8 Hypoglycemia also could be reduced by using stepwise titration scheme.20 As an alternative, three studies suggested that twice a day IDegAsp administration could lower risk of hypoglycemia based on lower dose, which could be reduced to 80% of basal insulin dose according to two studies.11,13,14 Twice a day IDegAsp administration also showed greater effect in fasting glucose plasma reduction according to once daily administration, according to five studies.10-14 However, there was study stated inconvenience of twice daily insulin that contributed to 6% of non-adherence to insulin administration protocol.21 Therefore, twice daily administration of IDegAsp should be re-evaluated even though there are lower risk of hypoglycemia compared to once daily administration. Relation between IDegAsp administration, both once daily and twice daily, and weight gain could not be determined. There were studies stating both positive and negative significance of IDegAsp administration towards weight gain.8,11,13 This finding correlated with other two studies which found weight gain in both arms of IDegAsp and basal insulin.9,14 One study mentioned before stated weight gain as an adverse effect of IDegAsp administration with high dose on patients with higher risk of hypoglycaemia.8 Therefore, there was a relation between dosing and weight gain in IDegAsp administration, both once daily and twice daily, with other types of insulin showing similar weight gain effect. This is a systematic review that positioned various frequencies of IDegAsp administration among other established insulin administration in terms of efficacy and safety. However, this study involved some RCT done in phase III study, thus considered by writers not eligible for quantitative review. Therefore, high-quality of RCT on efficacy and safety of IDegAsp on certain populations should be done to provide more data for meta-analysis in-order to produce pooled variables of IDegAsp’s efficacy and safety.

Conclusion IDegAsp once daily administration was proven more beneficial in terms of HbA1c reduction and lower nocturnal hypoglycemia incidence, but not hypoglycemia incidence and weight gain. On the other hand, IDegAsp twice daily administration was not yet proven in HbA1c reduction and reduced weight gain, but proven in lowering hypoglycemia incidence and nocturnal hypoglycemia incidence. Therefore, considering compliance and convenience, we suggest IDegAsp once daily administration with stepwise titration scheme on the largest meal of the day to achieve benefit with minimizing risk. In addition, we would like to suggest more RCT performed in-order to provide more data for quantitative analysis of efficacy and safety. Acknowledgement There were no conflict of interest nor funding in the process of making this systematic review. References 1. Global reports on diabetes. 1st ed. Geneva: World Health Organization. 2016; p. 46-61. 2. Tsimikas A, Astamirova K, Gupta Y, Gita EG, Nielsen AM, Demir T, et al. Similar glycaemic control with less nocturnal hypoglycemia in 38-week trial comparing the IDegAsp co-formulation with insulin glargine U100 and insulin aspart in basal insulintreated subjects with type 2 diabetes mellitus. J Diabres. 2019;147(10):157-65. 3. Kumar S, Jang H, Demirag N, Skjoth T, Endahl L, Bode B. Efficacy and safety of oncedaily insulin degludec/insulin aspart compared with once-daily insulin glargine in participants with Type 2 diabetes: a randomized, treat-to target study. Diabetic Medicine. 2016;34(2):180-8. 4. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009; 6(7): e1000097. 5. Critical appraisal of prognostic studies [Internet]. Oxford Center for Evidence-Based Medicine. Available from: http://www.cebm.net/wp-content/uploads/2014/04/cebmprognosis-worksheet.pdf 6. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane collaboration’s tool for assessing risk of bias in randomized trials. BMJ. 2011; 343: d5928.

7. Howick J, et al. “The Oxford Levels of Evidence 2”. Oxford Centre for Evidence-Based Medicine.

Available

from:

https://www.cebm.ox.ac.uk/resources/levels-of-

evidence/ocebm-levels-of-evidence 8. Kumar A, Awata T, Bain SC, Ceriello A, Fulcher GR, Unnikrishnan G, et al. Clinical use of co-formulation of insulin degludec and insulin aspart: review article. Int J Clin Pract. 2016 Aug; 70(8): 567-67. 9. Onishi Y, Ono Y, Rabol R, Endahl L, Nakamura S. Superior glycaemic control with oncedaily insulin degludec/insulin aspart versus insulin glargine in Japanese adults with type 2 diabetes inadequately controlled with oral drugs: a randomized, controlled phase 3 trial. Diabetes, Obesity, and Metabolism. 2013 March; 15(9): 826-832. 10. Kaneko S, Chow F, Choi DS, Taneda S, Hirao K, et al. Insulin degludec/insulin aspart versus biphasic insulin aspart 30 in Asian patients with type 2 diabetes inadequately controlled on basal or pre-/self-mixed insulin: A 26-week, randomised, treat-to-target trial. Diabetes Research and Clinical Practice. 2015; 107(1): 139-147. 11. Fulcher GR, Christiansen JS, Bantwal G, Muszynska MP, Mersebach H, Andersen TH, et al. Comparison of Insulin Degludec/Insulin Aspart and Biphasic Insulin Aspart 30 in Uncontrolled, Insulin-Treated Type 2 Diabetes: A Phase 3a, Randomized, Treat-to-Target Trial. Diabetes Care. 2014 Aug; 37(8) :2084-90. 12. Taneda S, Winge JH, Gall MA, Kaneko S, Hirao K. Insulin degludec/insulin aspart versus biphasic insulin aspart 30 twice daily in insulin‐experienced Japanese subjects with uncontrolled type 2 diabetes: Subgroup analysis of a Pan‐Asian, treat‐to‐target Phase 3 Trial. Journal of Diabetes. 2016 Apr; 9: 243-47. 13. Yang W, Ma J, Hong T, Liu M, Miao H, Peng Y, et al. Insulin degludec/insulin aspart (IDegAsp) twice daily (BID) vs biphasic insulin aspart 30 (BIAsp 30) BID - A randomized trial in chinese patients with type 2 diabetes. Diabetes Obes Metab. 2019 Jul; 21(7): 165260. 14. Franek E, Haluzik M, Varzic SC, Sargin M, Macura S, Zacho J, et al. Twice-daily insulin degludec/insulin aspart provides superior fasting plasma glucose control and a reduced rate of hypoglycemia compared with biphasic insulin aspart 30 in insulin-naive adults with type 2 diabetes. Diabet Med. 2016 Apr; 33(4): 497-505.

15. Rodbard HW, Cariou B, Pieber TR, Endahl LA, Zacho J, Cooper JG. Treatment intensification with an insulin degludec (IDeg)/insulin aspart (IAsp) co-formulation twice daily compared with basal IDeg and prandial IAsp in type 2 diabetes: a randomized, controlled phase III trial. Diabetes Obes Metab. 2016 Mar; 18(3): 274-80. 16. Jang HN, Yang YS, Lee SO, Oh TJ, Koo BK, Jung HS. Favorable glycemic control with once-daily insulin degludec/insulin aspart after changing from basal insulin in adults with type 2 diabetes. Endocrinology and Metabol. 2019 Dec; 34(4): 382. 17. Kalra S, Latif ZA, Cornlekci A, Galvez GG, Malik R, Pathan MF, et al. Pragmatic use of insulin degludec/insulin aspart co-formulation: a multinational consensus statement. Indian J Endocrinol Metab. 2016 Jul-Aug; 20(4): 542-5. 18. Unnikrishnan AG, Singh AK, Modi KD, Saboo B, Garcha SC, Rao PV. Review of clinical profile of IDegAsp. J Assoc Physicians India. 2015 May; 63(5): 15-20. 19. Haahr H, Fita EG, Heise T. A review of insulin degludec/insulin aspart: pharmacokinetic and pharmacodynamic properties and their implications in clinical use. Clin Pharmacokinet. 2017; 56(4): 339-54. 20. Gerety G, Bebakar WM, Chaykin L, Ozkaya M, Macura S, Herslov ML, et al. Treatment intensification with insulin degludec/insulin aspart twice daily: randomized study to compare simple and stepwise titration algorithms. Endocr Pract. 2016 May; 22(5): 546-54. 21. Doggrell SA, Chan V. Adherence to insulin treatment in diabetes: can it be improved?. Journal of Diabetes. 2015; 7: 315-21.

PLASMA GLYCATED CD59 LEVEL AS A NOVEL PREDICTOR OF GESTATIONAL DIABETES MELLITUS AND ADVERSE OUTCOMES: A SYSTEMATIC REVIEW AND META-ANALYSIS OF CASE-CONTROL STUDIES

Background: Gestational diabetes mellitus (GDM) are common metabolic problems during pregnancy that can cause severe complications to the mother and to the baby. It is reported that 1 out of 6 pregnant women are affected by diabetes and 86,4% of them are affected by gestational diabetes mellitus. The main adverse outcome of GDM is known to be large for gestational age neonates (LGA). Screening for GDM is compulsory to lower the risk of getting unpreferred GDM outcomes. Plasma glycated CD59 (pGCD59) is a novel biomarker that has a promising role to help the diagnosis of GDM. Objective: The primary aim of this systematic review and meta-analysis is to assess the performance of pGCD59 to identify women with GDM in week 24-28 pregnancy. The secondary aim is to assess the association of pGCD59 with Large at Gestational Age and potentially others adverse neonatal outcomes linked to GDM. Method: This review selects case-control studies on four databases (PubMed, Scopus, ProQuest, and ScienceDirect) systematically using the PRISMA guideline. Search results were screened by previously determined inclusion and exclusion criteria. Critical appraisal and risk of bias was conducted using STROBE checklist for case-control studies. Results and Discussion: This review yielded 3 studies with a total of 2,507 subjects. From the 3 studies reviewed, quantitative analysis shows the mean serum concentration level of pGCD59 was found to be significantly higher in pregnant women with GDM compared to control subjects (MD:2.94; 95% CI: 2.83-3.06; P<0.001). Based on our included studies, adverse outcomes that are sufficient for quantitative analysis is LGA. Our meta-analysis resulted in maternal levels of pGCD59 positively associated with increased odds of LGA (OR:1.60; 1.291.99). Heterogeneity analyses revealed negligible heterogeneity in mean difference of pGCD59 serum level and substantial heterogeneity with LGA as adverse outcomes. Conclusion: Plasma GCD59 can be a clinically useful novel biomarker to detect gestational diabetes in mothers during pregnancy. The use of pGCD59 is preferable than the other current tests because it is a non-fasting test, and it does not require a lot of time. Besides diagnosing GDM, pGCD59 can also be used to detect the several adverse outcomes such as LGA, congenital malformation, and neonatal hypoglycemia. Keywords: Gestational diabetes mellitus, Plasma glycated CD59, Large at Gestational Age, Prediction

Introduction

hypoglycemia, cardiovascular diseases, and

Gestational

Diabetes

congenital malformations.1

Mellitus

(GDM) is one of the major public health

In order to lower the risk of getting

challenges which is defined as glucose

GDM complications, screening for GDM

intolerance of variable degree with onset or

should be done by the mother.1 Although

first recognition during pregnancy.1 A

the tests used in screening are still

report from the International Diabetes

debatable, the oral glucose tolerance test

Federation (IDF) shows that 1 in 6

(OGTT) is known to be a useful test for

pregnancies are affected by diabetes, where

screening GDM. However, in the current

the majority of the case, around 86.4%, is

situation of the Coronavirus disease 2019

affected by gestational diabetes mellitus.2

(COVID-19)

The global prevalence of GDM is not

anecdotal evidence suggests an increase in

known yet, but it is believed to be high

the unwillingness of both pregnant women

because of the increasing number of type 2

and health professionals to undergo the

diabetes globally. Especially for Asian

OGTT. Besides that, the usual clinical

women, who are ethnically prone to suffer

setting for GDM diagnosis, which needs

glucose intolerance, the prevalence is

multiple visits, gives exposure risks to the

between 3.05% to 21.4%.3 It is known that

patient during this COVID-19 pandemic.

GDM can cause severe complications

This situation hinders pregnant mothers to

which affect not only the mother but also

screen for possible GDM. The mother may

the

suffer from undiagnosed GDM, which

predisposing diabetes and obesity to the

increases the risk of the baby becoming

fetus which then, can cause the fetus to

LGA due to high and uncontrolled blood

grow larger than normal size or large for

glucose flow from the mother through the

gestational age newborns. Large for

placenta.4

fetus.

increases the

risk

pandemic,

widespread

gestational age or LGA is defined as birth

Due to this current COVID-19

weight above the 90th percentile of

pandemic situation, some countries like

gestational age. This can later give

Canada and the UK change their guidelines

complications to the mother, which is a

about GDM diagnosis by using HbA1c

caesarean section to deliver the baby.

concentration in early pregnancy. This

Besides that, there are other complications

change was made to reduce the need for

of GDM that can be harmful to the baby

OGTT during pregnancy and postpartum

such as dystocia, trauma, preterm birth,

follow up. HbA1c was known to represent mean glycemia over time. HbA1c also has

the practical advantage of being a non-

gestational age (LGA) newborns, as the

fasting test, which makes it a quick test that

main adverse neonatal outcomes linked to

pandemic.

GDM, as secondary aims. It also aimed to

However, HbA1c has a weak relation with

support the third Sustainable Development

pregnancy

OGTT.

Goals (SDG) of the United Nations which

Furthermore, the HbA1c test can leave

targeted reduction by one-third premature

GDM women to be undiagnosed and

mortality from non-communicable diseases

untreated. Since HbA1c is not able to fully

through prevention and treatment by 2030.6

face the problem, a novel biomarker of

This study is also aimed to encourage

plasma glycated CD59 (pGCD59) is

Indonesia, as the place where this study is

currently the most promising alternative to

conducted, to release urgent statements of

help diagnose women with GDM. The

advice/guidance for modification of GDM

pGCD59 test is also a non-fasting test so it

diagnostic pathways during the COVID-19

is preferred during this pandemic.4

pandemic.

preferred

during

outcomes

this

than

Plasma GCD59 is a soluble form of glycated CD59 which is shed from a cell

Materials and Methods

membrane. CD59 itself is a complement

This systematic review and meta-

regulatory protein that protects the cell

analysis were conducted based on Preferred

from complement-mediated damage. In

Reporting Items for Systematic Reviews

diabetes, it is inactivated by non-enzymatic

and Meta-Analyses (PRISMA) Statements’

glycation and produces the glycated CD59

flow diagram and checklist to improve

or GCD59. The soluble form, which is the

quality of reporting. It is a four-phased flow

pGDC59, can be measured in human blood

diagram, and the checklist consists of 27

plasma using a very sensitive and specific

items

ELISA. It has shown a high sensitivity and

systematic

specificity for GDM diagnosis at the

including the title, abstract, introduction,

pregnancy age of week 24-28.5

methods, results, discussion, and funding.

Based

current

pertaining review

the

and

content

meta-analysis,

knowledge,

importance, and urgency, this systematic

Search strategy

review and meta-analysis is anticipated to

A comprehensive literature search

assess the performance of pGCD59 as a

was performed by three independent

predictor of GDM in early pregnancy as

reviewers

primary aims and explored the association

databases, such as PubMed, Scopus,

of pGCD59 with the prevalence of large for

ProQuest, and ScienceDirect up to 25th

with

multiple

electronic

October 2020. The keywords used in the pursuit were “Plasma Glycated CD59” OR “pGCD59”, “Gestational Diabetes”, and “Oral Glucose Tolerance Test”, which was modified based on each database’s search terms and conditions.

Study eligibility criteria Studies were screened according to the following inclusion and exclusion criteria. Inclusion criteria were: (a) Casecontrol studies, (b) assessed pGCD59 serum levels, (c) compared with OGTT as the gold standard, (d) assessed odds ratio towards adverse outcomes linked with GDM. Case-control studies were chosen due to its ability to identify biomarkers and risk factors for a disease, and novelty upper hand in which it did not require large resources of time and effort to have sufficient power to draw conclusions, unlike cohort studies.7

Figure 1. Diagram flow of literature

Moreover, the exclusion criteria were:

(a)

non-English

journals,

search strategy

(b)

incomplete or inaccessible text, and (c) publication

years.

Each included study was assessed

Duplications were removed and criteria

using Strengthening the reporting of

were

reviewers

observational studies in epidemiology

independently. Any disagreements are

(STROBE) statement checklist designed

discussed together and resolved within

for case-control studies. This tool consists

three authors to reach agreements. Holistic

of quality and risk of bias assessment based

process of literature research could be seen

on every section of the included studies

in figure 1.

including title and abstract, introduction,

fitted

older

than

three

Quality assessment

methods, result, discussion, and funding

delivering a large for gestational age (LGA)

with a total score of 22. Studies with higher

infant. Fixed effect meta-analysis was

STROBE score indicates better quality of

chosen because of the rather similar

studies which showed that the study has

population and method used in primary

lower risk of bias. The quality assessment

research.

was done by three reviewers assessed all

All the studies were also assessed

studies respectively, which each other are

using the Cochrane’s chi-squared test and

blinded on others’ scoring, then discussed

the Higgins I-squared statistical test in

further after scoring was done.

terms of heterogeneity of the included studies. If the p-value of the chi-squared

Summary measures and data analysis Evidence-based

analysis

test results is greater than 0.05 and Iwas

squared statistic is over 50%, the study will

conducted in this systematic review and

be considered as heterogeneous. All forms

meta-analysis. Outcome assessment was

of statistical tests of this study including

done by three reviewers independently,

heterogeneity were tabulated and analyzed

then discussed further into a table. Data was

into a forest plot using Review Manager

extracted from the included studies based

(RevMan) v5.3.

on following aspects: author, publication year, study design, study location, total of

Results

participants of case and control, and

Literature

outcomes.

Characteristics of included studies

The results for the primary aim of

Initial

and

from

General

PubMed,

the study, a comparison was made between

Scopus, ProQuest, and ScienceDirect using

the serum level of pGCD59 in the two

the search strategy mentioned above

groups of pregnant women with GDM and

resulted in a total of 251 studies. Among

normal glucose tolerance using mean

them, 22 were duplicated, while the other

differences with 95% confidence intervals

222 were excluded after screening the titles

(CIs). For the secondary aim, adverse

and abstracts in terms of pGCD59 studies.

outcomes that are sufficient for quantitative

In addition, 4 studies were further excluded

analysis are admitted for meta-analysis.

since 2 did not assess pGCD59 serum level,

Odds ratio with a 95% CI and p-value

1 were editorial paper, and lastly 1 were

below 0.05 was used to determine the

non-English journal. The search yielded in

association between maternal pGCD59

a final three studies, consisting of all case-

serum level with increased odds of

control studies to be included in qualitative

(n=1). The sensitivity and specificity of

and quantitative synthesis.

pGCD59 to identified GDM were assessed

The

data

extracted

and

using respective areas under the ROC curve

characteristics of included studies are

(AUROC). The AUROC ranges from 0.86

shown in Table 1. Overall, this review

to 0.92 indicating that pGCD59 accurately

included a total of 2,507 subjects across two

predicted the diagnosis of GDM in

continents: America (n=2) and Europe

pregnancy weeks 24-28.

Case Author,

Study

year

design

Study location

Partici pant

Ghosh et

Case-

United

al, 20178

control

States

Case-

United

control

States

Halperin et al, 20189 Ma et al,

Case-

20205

control

England

500

267

207

Control

Mean serum level 3.23 ± 1.43

3.4 ± 2.7

3.9 ± 3.3

Partici pant

500

547

486

Mean

AUROC

p-value

[95% CI]

serum

Odds Ratio of LGA [95% CI]

level 0.33 ± 0.19

0.3 ± 0.21

0.7 ± 0.2

p<0.001

0.92

2.24

(0.87- 0.96)

(1.4-3.59)

0.90 (0.86–

3.4

0.93)

(1.14-10.10)

0.86

1.4

(0.83-0.90)

(1.1-1.8)

AUROC: area under the ROC curve. LGA: Large for gestational age Table 1. Summary of study characteristics

Quantitative

analysis

pGCD59

value of pGCD59 serum level in detection

contributing to GDM

of GDM (P=0.27). The heterogeneity

The mean serum concentration level

between the studies was considered as not (I2=23%;

of pGCD59 was found to be significantly

important

higher in pregnant women with GDM

Furthermore, we chose a fixed effects

compared to normal glucose tolerance

model to pool the data, and the results

subjects (Mean Difference (MD) = 2.94;

showed stableness. Forest plot is presented

95%

in Figure 2.

CI:

2.83-3.06;

P<0.001).

publication bias was found in evaluating the

P<0.00001).

Quantitative

analysis

pGCD59

our

associated to LGA

study

considerable

Based on our included studies, only

P<0.0001).

consists

studies

(I2=59%;

heterogeneity According

with

this

meta-

LGA as adverse outcomes that is sufficient

analysis, high pGCD59 serum level was

enough for quantitative analysis. Our meta-

associated with 1.6 times increased odds of

analysis resulted in maternal levels of

LGA in pregnant women with GDM

pGCD59 positively associated with higher

(OR:1.60; 1.29-1.99). A fixed-effect model

prevalence of LGA infants and met

was

minimum requirements for meta-analysis

stableness. Forest plot is presented in

according to Cochrane handbook, although

Figure 3.

used,

and

the

results

showed

Figure 2. Forest plot presenting mean difference of pGCD59 serum level in GDM patients

Figure 3. Forest plot presenting association of increased pGCD59 serum level with LGA

Publication Bias

indicates the lower risk of bias of the study.

Critical appraisal was conducted

From our systematic review and meta-

using STROBE for case-control study

analysis, the highest STROBE score was

criteria which were given in the appendix

obtained by Ma et al5 with the score of 21.8

on the last part of this paper. This tool is

and the lowest was obtained by Halperin et

used to assess the quality of each study and

al9 with the score of 16.1. The average

risk of bias assessment with the maximum

STROBE score for those 10 studies is 19.1,

score of 22. The higher STROBE score

which indicated that this review included

using funnel plot demands at least 10

relatively good studies.

studies to present sufficient power for meta-analyses

studies heterogeneity.10 Therefore, this

concerning pGCD59 serum level and LGA

study is still subject to publication bias

were proven homogenous in the funnel plot

which is limited to the amount of

and statistical examination, in which

publication. Despite all limitations, this

expressed no significant publication bias

study is still currently applicable as it

(Figure 4). However, Cochrane handbook

included all studies available at the

suggests that heterogeneity examination

moment, thus applicable in clinical settings.

All

our

Figure 4. Funnel Plot Assessment of Included Studies (a) mean difference of pGCD59 serum level in GDM patients, (b) association of pGCD59 serum level with LGA

Discussion Gold standard for detecting GDM

before blood is taken, followed by a glucose

GDM is one of the major problems

solution and additional blood tests every

in pregnancy because it increases the risk

hour for three hours. These tests are time

for the maternal and fetal health. Currently,

consuming, inconvenient for patients, and

the gold standard for detecting GDM is

have

largely based on a two-step approach. The

reproducibility. Moreover, OGTT cannot

first step is the Glucose Challenge Test

recognize the association between maternal

(GCT), which blood sugar is tested one

hyperglycemia and abnormal pregnancy

hour after the glucose solution has been

outcomes. This current gold standard was

given. If a woman has a positive GCT test,

done in week 24-28 of pregnancy. Since the

the OGTT is considered a second test. The

timing of the test is in the late phase of

OGTT requires women to fast overnight

pregnancy, there is not much intervention

been

reported

have

low

that can be done.8 Other tests that measure

would be a noticeable increase of pGCD59

HbA1c or fructosamine are not sensitive

level in gestational diabetes mellitus.12

and are therefore not routinely used to

Furthermore, a study by Ghosh et al

screen and diagnose GDM during prenatal

stated that pGCD59 value was 10-fold

care. Issues related to GDM screening and

higher in patients with GDM. Besides that,

diagnosis underline the need for a more

this study also stated that pGCD59 can

reliable, simplified, and patient friendly

independently predict the response to the

GDM test.

current gold standard diagnostic tools, OGTT.8 Higher serum level of pGCD59 is

pGCD59 serum level and GDM

detected in a woman with GDM than in

The Complement systems have a major

role

gestational

the

pathogenesis

diabetes

complications.

This

and

pregnancy as stated by Ma et al.5

several

pathogenesis and current literature, in

formation of the cytotoxic, pore-forming

which if compared with control, the GDM

membrane attack complex (MAC) which is

patients resulted in significantly increased

the main effector of complement-mediated

pGCD59 serum level (MD 2.94; 95% CI:

tissue damage. This mechanism caused

2.83-3.06; P<0.001), with AUROC ranges

many diabetic organ complications. On the

from 0.86 to 0.92 indicating that pGCD59

other hand, CD59 acts as a complement

accurately predicted the diagnosis of GDM

regulatory

in pregnancy weeks 24-28.

which

leads

Our meta-analysis is coherent with

protein

system

non-GDM women at less than 20 weeks of

specifically

inhibits MAC formation and protects the cells

from

complement-mediated

pGCD59 serum level and adverse outcomes

damage.11 CD59 is anchored to the external

GDM is a condition that can affect

surface of the membrane by a lipid tail. It is

fetal safety and future. The detection of

exposed to the extracellular fluid and the

GDM as early as possible will give a doctor

glucose levels.12

time to give the optimal treatment to

diabetes

patients,

the

minimize the adverse outcome for the

complement regulatory function of CD59 is

maternal and fetal. CD59 is one of the

reduced. The reduction of CD59 expression

factors that protects the fetus from maternal

is caused by non-enzymatic glycation of a

immune response in pregnancy. Therefore,

Lys residue within the active site of CD59

regarding pregnancy complications of

that produces functionally inactive plasma

diabetes, the glycation-inactivation of

glycated CD59 (pGCD59). Thus, there

placental CD59 increases complement-

mediated placental damage contributing in

standard, OGTT, which didn’t predict

part to the multiple complications seen in

GDM or abnormal neonatal outcomes.9

women with GDM.12 The most well studied complication

Feasibility

is large for gestational age (LGA). A study

and

Potential

for

Implementation

by Ma et al stated that the risk of delivering

The OGTT is a current cornerstone

an LGA infant was associated with higher

of the diagnosis of GDM that has the

maternal levels of pGCD59. A woman who

possibility of needing two visits and

delivered LGA infants had a mean pGCD59

requires a long test time up to three hours.

level 0.3 standard peptide units (SPU)

In addition, in this COVID-19 pandemic,

higher than a woman who delivered non-

both clinician and pregnant women are

LGA infants. Several studies also stated

trying to reduce the contact as minimum as

that one SPU increase in maternal pGCD59

possible to reduce travel, multiple visits,

level was associated with 30% to 36%

and reducing time needed in the hospital. In

increased odds of delivering a LGA

fact, the diagnosis of GDM requires

infant.5,9 The odds ratio (OR) between the

multiple visits to health care service for

increase in maternal pGCD59 level and

education,

delivering LGA infants was 1.4.5 This

ultrasonography. This activity will increase

literature is in line with our meta-analysis

the risk for the doctor and patient,

which proved that increased level of

especially

pGCD59 did increase the risk of LGA by

countries like the UK and Canada change

1.6 times (OR=1.60; 95% CI=1.29-1.99).

their

monitoring,

the

guidelines

fetal.

and

fetal

Consequently,

using

HbA1c.

In other adverse outcomes, a study

Meanwhile, HbA1c is not strongly related

by Halperin et al also stated that one unit

to adverse pregnancy outcomes than

increase in maternal pGCD59 level was

OGTT. Furthermore, in the Hyperglycemia

associated with 60% higher odds of

and Adverse Pregnancy Outcome (HAPO)

delivering an infant

with congenital

cohort study, testing using this HbA1c

malformations, neonatal hypoglycemia, or

threshold alone would thus reduce GDM

both. The OR between the increase in

frequency from 17.8% to around 1% using

pGCD59 level and delivering infants with

International Association of Diabetes and

congenital malformation was 3.4. These

Pregnancy

results indicated that detection of pGCD59

criteria. This condition makes the majority

can potentially replace the current gold-

of women considered to have GDM would

Study

Groups

(IADPSG)

remain undetected and untreated.4

In Indonesia, as the place where this

analysis as trusted-minimum according to

study is conducted, screening with OGTT

Cochrane’s handbook, is present in this

was done in all pregnant women at baseline

study. However, results showed reliable

and would be reevaluated at 26-28 weeks of

mean difference, OR and 95% CI, which

gestation if the first evaluation is normal.

are important.

OGTT requires the patient to fast and during the examination, patients should

Conclusion

remain seated.13 This test may become lesspreferred

due

patient

Plasma GCD59 can be a clinically

possible

useful novel biomarker to detect gestational

inconvenience. Therefore, validation and

diabetes in mothers during pregnancy. The

regulatory approval of new, non-fasting

use of pGCD59 is preferable than the other

biomarkers, of which glycated CD59 is

current tests because it is a non-fasting test,

currently the most promising, would be

and it doesn’t require a lot of time. Besides

welcomed by both clinicians and pregnant

diagnosing GDM, pGCD59 can also be

women.4

used to detect the several adverse outcomes such as LGA, congenital malformation, and

Strength and Limitation

neonatal hypoglycemia.

This study is the first meta-analysis for the potential use of single measurement

Reference

of plasma GCD59 as a simplified method to identify women at higher risk of GDM.

1. Dirar AHM, Doupis J. Gestational

This study showed that a novel biomarker

diabetes from A to Z. World J

pGCD59 may be a new gold-standard and

Diabetes. 2017;8(12):484–511.

more effective alternative from the current

2. Egan AM, Dunne FP. Epidemiology of

screening tools, OGTT. Furthermore, this

gestational and pregestational diabetes

study may perform as a base for future

mellitus. In: Frontiers in Diabetes

multi-center study to confirm the clinical

[Internet]. S. Karger AG; 2020 [cited

utility of pGCD59 levels, including the

2020 Oct 27]. p. 1–10. Available from:

clinical cut-off values and the potential for

https://www.karger.com/Article/FullT

early pregnancy use.

ext/480161

This study is limited to English only

3. Guo Y, Han Z, Guo L, Liu Y, Li G, Li

journals due to writers’ capability. The

H, et al. Identification of urinary

possibility of publication bias, in which no

biomarkers for the prediction of

aspect collected 10 studies or more for

gestational diabetes mellitus in early

second trimester of young gravidae

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based on iTRAQ quantitative

trimester) gestational diabetes.

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Bogdanet D, Desoye G, Dunne F,

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Halperin JA. Plasma glycated CD59

https://onlinelibrary.wiley.com/doi/abs

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11. Ghosh P, Sahoo R, Vaidya A, Cantel

Clin Endocrinol Metab. 2020 Apr

S, Kavishwar A, Goldfine A, et al. A

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specific and sensitive assay for blood

6. World Health Organization. SDG 3:

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12. Bogdanet D, O’Shea Pm, Halperin J,

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7. Choudhury KR, Barboriak D. Case

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Serum Uric Acid as A Prognostic Marker in the Early Progressivity of Kidney Function Deterioration in Type 2 Diabetes Mellitus Patients: A Systematic Review Andro Pramana Witarto, Grace Manuela Nurhadi, Bendix Samarta Witarto

ABSTRACT Introduction: Type 2 diabetes mellitus (T2DM) is one of the most common chronic metabolic diseases with diabetic nephropathy (DN) as one of its microvascular complications. About 50% of diabetic patients will progress to DN after more than 20 years of diabetes which is caused by progressive endothelial dysfunction and chronic inflammation in the kidney vascular system. DN is mainly diagnosed based on the incidence of unusual albuminuria. Current methods in diagnosing DN are still not ideal due to some non-diabetic factors that contribute to the development of renal disease and in some cases, a decrease in GFR may occur when urinary albumin is still normal. Currently, uric acid is thought to have an important role in the pathogenesis of DN and the development of CKD in diabetic patients. Therefore, this study aims to evaluate serum uric acid (SUA) as one of the potential markers in detecting the progressive deterioration of kidney function in T2DM. Methods: A systematic review was conducted using two electronic databases, including PubMed and Scopus, searching for observational studies that analyze the SUA levels in the different groups of albuminuria in T2DM patients. The risk of bias of the included studies was then assessed using the Newcastle-Ottawa Scale (NOS). Results: The search yielded four case-control studies and five cross-sectional studies with a total of 3,555 T2DM patients. SUA was significantly correlated to the urinary albumin-tocreatinine ratio (UACR) in 7 out of 9 observational studies. Furthermore, in 8 out of 9 studies, SUA was found to be consistently increased from normoalbuminuria to macroalbuminuria. Conclusion: SUA increases significantly from normoalbuminuria to macroalbuminuria in relation to UACR and represents the progressivity of kidney function deterioration in T2DM patients.

Keyword: Serum uric acid, type 2 diabetes mellitus, albuminuria, kidney function, diabetic nephropathy

INTRODUCTION Type 2 diabetes mellitus (T2DM) is one of the most common chronic metabolic diseases with its microvascular and macrovascular complications which may increase the morbidity and mortality of diabetic patients. One of its microvascular complications is diabetic nephropathy (DN). It is associated with the glomerular lesion, pathological excretion of albumin in urine, and a decrease in glomerular filtration rate (GFR).1 DN is considered to be the major cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD).2 About 50% of diabetic patients will progress to DN after more than 20 years of diabetes. 1 Several factors have also been associated with the development of DN in T2DM, along with poor glycemic control, increased urinary albumin secretion, longer duration of DM, dyslipidemia, hypertension, smoking, and advanced age.3 All of the stated factors may take a basic part in the development of DN due to endothelial dysfunction and inflammation induction.4 Eventually, renal function assessment in T2DM could contribute to the reduction of its mortality and morbidity.5

The diagnosis of DN is based on unusual albuminuria. However, in some cases, a decrease in GFR may occur when urinary albumin is still normal. 1 Many studies have focused on finding the appropriate ways for early diagnosis of DN, yet it seems that current methods in diagnosing DN are still not ideal, due to non-diabetic factors that contribute to the renal disease, which cannot be identified from DN.6,7 Currently, uric acid is thought to have an important role in the pathogenesis of DN and the development of CKD in diabetic patients.8 Other literature showed that uric acid is an inflammatory factor, 9 and has a role in endothelial dysfunction which may act as a mediator of the DN development.10 Therefore, we propose that uric acid evaluation in the serum or referred to as serum uric acid (SUA) may become one of the potential markers to detect the progressivity of DN or kidney function in T2DM.

MATERIALS AND METHODS Search strategy This systematic review was conducted based on PRISMA statement. Records were searched in two medical electronic databases, including PubMed and Scopus. No specific time restriction is applied to this study. The literature search was limited to English language only. Keywords used were based on MeSH terms and listed as follows: ((“uric acid”) OR (“urate”)) AND (“albuminuria”) AND ((“diabetes mellitus”) OR (“type 2 diabetes”)) AND (“adult”) AND (“patients”). Further details on the search strategy are shown in Fig. 1.

Figure 1. PRISMA flowchart.11 PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-analyses.

Eligibility criteria Inclusion criteria used in this study were (1) observational study design, case-control and crosssectional studies; (2) study population, type 2 diabetes mellitus (T2DM) patients with measurement and classification of albuminuria based on Albumin-to-Creatinine Ratio (ACR), which divided into normoalbuminuria with ACR <30 mg/g, microalbuminuria with ACR 30300 or 30-<300 mg/g, and macroalbuminuria with ACR >300 or ≥300 mg/g, and with no use of drugs that potentially affect the serum uric acid (SUA); and (3) indicator, measurement of SUA levels. Exclusion criteria were (1) irrelevant topics; (2) irrelevant study design; (3) no English full-text available; (4) non-human studies; (5) involvement of estimated Glomerular Filtration Rate (eGFR) in albuminuria classification; and (6) SUA level correlation among albuminuria groups not reported.

Data extraction and risk of bias assessment The following data from the included studies were extracted: (1) author and year of publication; (2) study location; (3) study design; (4) number of patients in control, normoalbuminuria, microalbuminuria, and macroalbuminuria groups; (5) age of patients; (6) Serum Uric Acid (SUA) levels in control, normoalbuminuria, microalbuminuria, and macroalbuminuria groups;

and (7) outcomes as expressed in p-value in each study. The quality of included studies was assessed using the Newcastle-Ottawa Scale (NOS) for observational studies, specifically casecontrol and cross-sectional studies. The risk of bias assessment was provided in Table 1 and Table 2. Quality assessment using NOS score in case-control studies were classified into goodquality studies (score 7-9), moderate-quality studies (score 4-6), and poor-quality studies (score 0-3), while in cross-sectional studies, NOS score was classified into very good studies (score 9-10), good studies (score 7-8), satisfactory studies (score 5-6), and unsatisfactory studies (score 0-4).

Result Study selection The literature search process is illustrated in Fig. 1. The initial search of this study from PubMed and Scopus databases yielded a total of 253 studies (53 and 200 studies, respectively). Of those, 45 studies were excluded due to duplicate publications, 163 studies were excluded due to irrelevant titles and abstracts, and 45 studies were assessed for the eligibility criteria. Of 45 studies in the full-text assessment, 36 studies were not eligible to be included in this study and 9 other studies were included which consisted of 4 case-control studies12–15 and 5 crosssectional studies.16–20

Study characteristics and outcomes Table 3 presents the characteristics and outcomes of the included studies. All studies were conducted in the Asia region. Overall, this study included a total of 3,555 T2DM patients with albuminuria from all 9 studies and 280 healthy patients as control groups from 4 case-control studies. The mean age of all T2DM patients with albuminuria was 58.34 ± 6.87 years. Outcomes of these studies were expressed in p-value. Non-significant p-values (p > 0.05) were found in two studies and both comprised low number of study participants. Even though no studies showed SUA levels higher than normal, the important findings of this study were the increased trends in SUA levels from normoalbuminuric T2DM patients to macroalbuminuric T2DM patients.

Table 1. Quality assessments of the included case-control studies based on the Newcastle-Ottawa Scale (NOS).

Table 2. Quality assessments of the included cross-sectional studies based on the Newcastle-Ottawa Scale (NOS).

Table 3. Study Characteristics and Results.

Table 3 (cont.). Study Characteristics and Results.

Discussion Assessment of renal function in T2DM has become one of the most important points in reducing mortality and morbidity. 5 Renal function can be assessed using either estimated glomerular filtration rate (eGFR), creatinine serum, urinary albumin, or urinary albumin-tocreatinine ratio (UACR).21 The two most common tests were eGFR and UACR.5 In advanced, GFR alteration does not describe early functional kidney changes, but further functional kidney alteration. This is due to its estimation based on creatinine levels, which have biological variation and imprecision that influence the estimation of GFR. 22 In clinical practice, microalbuminuria can be used as a marker to detect early functional kidney alteration. Nevertheless, some kidney impairment occurs in a non-albuminuric state or before the onset of microalbuminuria. In some cases, as stated before, a decrease in GFR may also occur when urinary albumin is normal. Other studies also state that in advanced DN, microalbuminuria can regress into normoalbuminuria.1,23 To sum these statements, the progression of DN cannot necessarily represent urinary albumin level, but only initial reversible kidney damage. Therefore, there should be other markers to detect early kidney function deterioration in T2DM. Uric acid may play an important role in the development of kidney disease in T2DM. 17 A study by Wang et al.24 showed that there is a significant positive and independent association between higher blood uric acid and an increased risk of a reduced estimated glomerular filtration rate (eGFR) among T2DM patients. As an inflammatory factor, uric acid can elevate oxidative stress and support the activation of the Renin-Angiotensin-Aldosterone System (RAAS).25,26 Therefore, uric acid can be a lead marker in detecting early kidney disease occurrence and the development of DN,27,28 as inflammation also takes a basic part in the development of DN. 4

Our study showed that SUA levels were significantly correlated to UACR in 7 out of 9 observational studies and appeared to be progressively higher from normoalbuminuria to macroalbuminuria. These were due to several pathophysiological mechanisms. SUA may cause impairment in nitric oxide (NO) production and release when it is transported into vascular smooth muscle, inducing kidney vascular endothelial dysfunction. 10 Excessive uric acid in the serum may also lead to an increase in reactive oxygen species (ROS) and induce the inflammation process in the blood vessels. 29 A study by Jalal et al.30 mentioned that ROS is a byproduct of xanthine oxidase (XO) while generating uric acid. Both excessive uric acid and ROS will together cause further inflammatory cascade initiation and cytokine activation. 30,31

Furthermore, uric acid is commonly found elevated in patients with declining renal function due to its excretion through the kidney.8 This excretion rate may be evaluated using SUA. Uric acid levels in serum may reflect the balance of uric acid production and excretion. 9 The latter process may increase the transportation of uric acid into vascular smooth muscle and further cause renal impairment. These two important mechanisms may potentially be a vicious circle for T2DM patients with kidney dysfunction, especially its relation to uric acid as a potential kidney disease progression marker. In addition, some randomized controlled trials (RCTs) even showed that lowering SUA levels in diabetic patients could suppress the progression of chronic kidney disease (CKD).31

To the extent of our knowledge, this is the first systematic review assessing the relation between SUA levels and UACR to improve the early detection of kidney function impairment in T2DM patients. All of the assessed studies also have good to very good quality of studies. Hence, clinicians could consider using SUA levels to evaluate the kidney function of T2DM patients in a condition with limited resources. This study may also serve as a reference for other researches in investigating similar issues. However, this study also has some limitations, such as the exclusion criteria on incompatible language related to the authors’ comprehension and observational studies included were only case-control and cross-sectional studies.

Conclusion In conclusion, based on this systematic review, SUA increases significantly from normoalbuminuria to macroalbuminuria in relation to urinary albumin-to-creatinine ratio (UACR) and reflects the progressivity of kidney function deterioration in T2DM patients. All of the associated drugs that potentially affect SUA levels have also been screened and evaluated by each study. The authors hope that this assessment of SUA levels could help the clinicians to detect the early decline in kidney function of T2DM patients. This study may serve as an early warning in reducing the mortality and morbidity in T2DM associated with impaired kidney function.

References 1.

Razi F, Nasli-esfahani E, Bandarian F. Association of serum uric acid with nephropathy in Iranian type 2 diabetic patients. J Diabetes Metab Disord. 2018;17:71–5.

Aldukhayel A. Prevalence of diabetic nephropathy among Type 2 diabetic patients in some of the Arab countries. Int J Health Sci (Qassim). 2017;11(1):60–3.

Tziomalos K, Athyros VG. Diabetic Nephropathy: New Risk Factors and Improvements in Diagnosis. Rev Diabet Stud. 2015;12(1–2):110–8.

Lim AKH, Tesch GH. Inflammation in Diabetic Nephropathy. Mediators Inflamm. 2012;2012:1–12.

Narva AS, Bilous RW. Laboratory Assessment of Diabetic Kidney Disease. Diabetes Spectr. 2015;28(3):162–6.

Soleymanian T, Hamid G, Arefi M, Ganji MR, Amini M, Hakemi M. Non-diabetic renal disease with or without diabetic nephropathy in type 2 diabetes : clinical predictors and outcome type 2 diabetes. Ren Fail. 2015;37(4):572–5.

Unsal A, Koc Y, Basturk T, Akgun AO, Sakaci T, Ahbap E. Risk factors for progression of renal disease in patient with diabetic nephropathy. Eur Rev Med Pharmacol Sci. 2012;16:878–83.

Giordano C, Karasik O, King-morris K, Asmar A. Uric Acid as a Marker of Kidney Disease: Review of the Current Literature. Dis Markers. 2015;2015:1–6.

Kushiyama A, Tanaka K, Hara S, Kawazu S. Linking uric acid metabolism to diabetic complications. World J Diabetes. 2014;5(6):787–95.

10. Yan D, Tu Y, Jiang F, Wang J, Zhang R, Sun X, et al. Uric Acid Is Independently Associated with Diabetic Kidney Disease : A Cross-Sectional Study in a Chinese Population. PLoS One. 2015;10(6):e0129797. 11. Altman D, Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, et al. The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses of Studies That Evaluate Health Care Interventions: Explanation and The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interv. J Clin Epidemiol. 2009;62(2009):e1–34. 12. Shao Y, Ren H, Lv C, Ma X, Wu C, Wang Q. Changes of serum Mir-217 and the correlation with the severity in type 2 diabetes patients with different stages of diabetic kidney

disease.

Endocrine

[Internet].

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http://dx.doi.org/10.1007/s12020-016-1069-4 13. Chang Y, Lin K, Wang C, Hsieh M. Elevated serum retinol-binding protein 4 concentrations are associated with renal dysfunction and uric acid in type 2 diabetic patients. Diabetes Metab Res Rev. 2008;24:629–34. 14. Abdella N, Akanji AO, Mojiminiyi OA, Assoussi A Al. Relation of serum total sialic acid concentrations with diabetic complications and cardiovascular risk factors in Kuwaiti Type 2 diabetic patients. Diabetes Res Clin Pract. 2000;50(2000):65–72.

15. Elsheikh M, Elhefnawy KA, Emad G, Ismail M, Borai M. Zinc alpha 2 glycoprotein as an early biomarker of diabetic nephropathy in patients with type 2 diabetes mellitus. J Bras Nefrol. 2019;41(4):509–17. 16. Tseng C-H. Correlation of uric acid and urinary albumin excretion rate in patients with type 2 diabetes mellitus in Taiwan. Kidney Int. 2005;68(2005):796–801. 17. Yan L, Xiao-mu L, Xin G. Cross-sectional association of serum C-reactive protein and uric acid with albuminuria in Chinese type 2 diabetic patients. Chin Med J (Engl). 2013;126(21):4023–9. 18. Gul CB, Yildiz A, Gul OO, Hartavi M, Cander S, Eroglu A, et al. Serum uric acid is not associated with diabetic nephropathy in patients with type 2 diabetes. Acta Medica Mediterr. 2015;31:1153. 19. Fukui M, Tanaka M, Shiraishi E, Harusato I, Hosoda H, Asano M, et al. Serum uric acid is associated with microalbuminuria and subclinical atherosclerosis in men with type 2 diabetes mellitus. Metab Clin Exp. 2008;57(2008):625–9. 20. Al-Rubeaan K, Siddiqui K, Al-Ghonaim MA, Youssef AM, AlNaqeeb D. The Saudi Diabetic Kidney Disease study (Saudi-DKD): clinical characteristics and biochemical parameters. Ann Saudi Med. 2018;38(1):46–56. 21. Shahwan MJ, Abdul N, Shaheen RA. Diabetes & Metabolic Syndrome: Clinical Research & Reviews Assessment of kidney function and associated risk factors among type 2 diabetic patients. Diabetes Metab Syndr Clin Res Rev [Internet]. 2019;13(4):2661–5. Available from: https://doi.org/10.1016/j.dsx.2019.07.025 22. Badrick T, Turner P. The Uncertainty of the eGFR. Ind J Clin Biochem. 2013;28(3):242– 7. 23. Macisaac RJ, Jerums G. Diabetic kidney disease with and without albuminuria. Curr Opin Nephrol Hypertens. 2011;20:246–57. 24. Wang J, Yu Y, Li X, Li D, Xu C, Yuan J, et al. Serum uric acid levels and decreased estimated glomerular filtration rate in patients with type 2 diabetes: a cohort study and meta analysis. Diabetes Metab Res Rev. 2018;34(7):e3046. 25. Filiopoulos V, Hadjiyannakos D, Vlassopoulos D. New Insights into Uric Acid Effects on the Progression and Prognosis of Chronic Kidney Disease. Ren Fail. 2012;34(4):510–20. 26. Chaudhary K, Aroor A, Malhotra K, Sowers J. Uric Acid – Key Ingredient in the Recipe for Cardiorenal Metabolic Syndrome. Cardiorenal Med. 2013;3:208–20. 27. De Cosmo S, Viazzi F, Pacilli A, Giorda C, Ceriello A, Gentile S, et al. Article Serum Uric Acid and Risk of CKD in Type 2 Diabetes. Clin J Am Soc Nephrol. 2015;10:1921–9.

28. Li G, Jiao X, Cheng X. Correlations between blood uric acid and the incidence and progression of type 2 diabetes nephropathy. Eur Rev Med Pharmacol Sci. 2018;22:506– 11. 29. Xiong Q, Liu J, Xu Y. Effects of Uric Acid on Diabetes Mellitus and Its Chronic Complications. Int J Endocrinol. 2019;2019:1–8. 30. Jalal DI, Maahs DM, Hovind P, Nakagawa T. Uric Acid as a Mediator of Diabetic Nephropathy. Semin Nephrol. 2011;31(5):459–65. 31. Campion CG, Sanchez-Ferras O, Batchu SN. Potential Role of Serum and Urinary Biomarkers in Diagnosis and Prognosis of Diabetic Nephropathy. Can J Kidney Heal Dis. 2017;4:1–18.

FIRST TRIMESTER GLYCATED HEMOGLOBIN (HBA1C) LEVEL AS A NOVEL PREDICTOR OF GESTATIONAL DIABETES MELLITUS: A SYSTEMATIC REVIEW AND META-ANALYSIS OF COHORT STUDIES

Abstract Introduction: Gestational diabetes mellitus (GDM) is a severe yet neglected threat to maternal and child health, due to its association with multiple adverse pregnancy outcomes. Latest guideline suggest GDM screening between the 24th and 28th week of gestation. However, this approach has been questioned because of the possible delay in receiving the optimal intervention required to safeguard maternal and child health. On the other hand, glycated hemoglobin (HbA1c) level is one of the most promising predictor of GDM in early pregnancy based on several cohort studies done recently. Objective: This systematic review and meta-analysis aims to evaluate the potency of HbA1c level in first trimester as a novel predictor of GDM. Methods: This review selects cohort studies found by database searching systematically using previously determined inclusion, such as pregnant woman as the subject, assess Hb1Ac level in the first trimester, and assess odds ratio towards (GDM), and exclusion criteria such as assess outcome at postpartum, not assess GDM outcomes, and studies written in languages other than English or Bahasa Indonesia. This review was arranged based on PRISMA guideline. Results and Discussion: This review included seven cohort studies with the pooled OR of 4.36 [95%CI: 3.66-5.20]. Quantitative analysis shows that HbA1c level in the first trimester is a significant risk factor of GDM development (p<0.00001). However, heterogeneity analyses revealed substantial heterogeneity are detected in the pooled studies. Therefore, to understand the significance of HbA1c level and the development of GDM, further studies are needed. Conclusion: This study has proven the potency of first trimester HbA1c level as a novel predictor of gestational diabetes mellitus. Thus, it is necessary to integrate the use of HbA1c level screening as part of antenatal care in the first trimester of pregnancy to reduce the GDM complications prevalence and promote healthy pregnancy.

Keywords: Gestational Diabetes Mellitus, First Trimester, Glycated Hemoglobin (HbA1c), Predictor

Introduction

Furthermore, more than 90% of cases of

Gestational diabetes mellitus (GDM)

gestational diabetes are estimated to occur in low- to middle-income countries.5

is a glucose intolerance condition which is first detected during pregnancy and usually

GDM is diagnosed during antenatal

disappear after giving birth. It is a severe yet

screening, rather than through reported

neglected threat to maternal and child health

symptoms.6

these days.2 Ironically, according to the

Association (ADA) and the American

International Diabetes Federation (IDF),

College of Obstetricians and Gynecologists

there were around 223 million women (20-79

(ACOG) suggested that all pregnant women

years) living with diabetes today and this

should be tested for GDM between the 24th

number is projected to increase to 343 million

and 28th weeks of gestation, and those with

by 2045.3

any risk factors are should get earlier

The

American

Diabetes

screening.7 Nevertheless, late screening for

associated with multiple adverse pregnancy

GDM after the 24th gestational week have

outcomes. Hyperglycemia exposure to babies

been questioned due to the possible delay in

in mother’s womb increase their risk of being

receiving the optimal effects of drugs

overweight or obese, which is associated with

therapy, exercise, and diet to prevent

type 2 diabetes mellitus development. Other

maternal and neonatal complications.8 This

complications related to uncontrolled GDM,

issue leads to the global urge of finding

are spontaneous abortions, major congenital

potential early predictors to establish early

anomalies,

hypoglycemia,

prediction on GDM which aims to prevent

polycythemia,

obstetric

Gestational

excessive

diabetes

neonatal fetal

growth,

mellitus

and

neonatal

complications.

jaundice, stillbirth, and respiratory distress

Furthermore, this approach may help avoid

syndrome.4

prolonged hospital stay, especially in the current COVID-19 pandemic.9,10

The global prevalence of GDM among women (20-49 years) as stated in

Glycated hemoglobin (HbA1c) is a

study by Guariguata et al in 2013, is 16.9%,

result from glucose attachment to the N-

or around 21.4 million live births. However,

terminal valine of the hemoglobin β-chain.

it was found that the South East Asian

HbA1c level is linked to the glucose level in

population are at the highest prevalence

the blood and also the erythrocyte lifetime.11

(25.0%) compared with other population.

HbA1C itself has been known as predictor

and diagnostic test for type 2 diabetes.

Search strategy

However, this test has not been widely

A systematic review and meta-

studied in GDM and moreover, no cutoff

analysis of cohort studies was conducted

point has been defined for HbA1C in GDM.

among global population focusing on the

correlation between Hemoglobin A1C levels Recently, accumulating evidences

and acquired gestational diabetes as its

have shown that glycated hemoglobin

outcome.

(HbA1c) level is a potential predictor of

performed by three independent reviewers

gestational diabetes mellitus in early stage of

with multiple electronic databases, including

pregnancy.

the

PubMed, Scopus, and EBSCOhost up to 28

overwhelming effects of GDM on maternal

October 2020. The keywords used in the

and neonatal health and the urgent need for

early diagnosis and control of maternal

"HbA1c” OR “hemoglobin” OR ”A1c”,

glucose levels, we decided to conduct a

“prediction” OR “marker” OR “predictor”

systematic review and meta-analysis to

and “gestational diabetes”. Where applicable

conclude the potential use of HbA1c as GDM

and available, appropriate advance search

predictor. Our aim is to prove the potency of

techniques were applied to narrow the search.

first trimester HbA1c level as a novel

Study eligibility criteria

Therefore,

considering

Initial

were

literature

"Hemoglobin

A1C”

was

predictor of GDM, thus, it can be integrated

Search results were assessed for

as part of antenatal care in the first trimester

duplicates removal which was performed

GDM

using EndNote X9 software. Moreover,

promote

studies were screened according to the

pregnancy

complications

reduce

prevalence

the and

healthy pregnancy.

following inclusion and exclusion criteria. Our inclusion criteria were (1) cohort studies,

Materials and Methods This

systematic

(2)

woman

among

general

was

population as the subject, (3) assess Hb1Ac

conducted based on the Preferred Reporting

level in the first trimester, and (4) assess odds

Items for Systematic Reviews and Meta-

ratio towards gestational diabetes mellitus

Analyses (PRISMA) checklist which can be

(GDM) prediction as the study outcome.

accessed

Exclusion criteria: (1) assess outcome at

through

review

pregnant

http://www.prisma-

statement.org/

postpartum, (2) not assess GDM outcomes,

(3) Studies that did not have a full-text

which study was assessed based on the broad

version, and (4) written in languages other

perspective

than English or Bahasa Indonesia were

comparability of the groups, and the

excluded from this review. Furthermore,

ascertainment of either the exposure of

screening of titles and abstracts of studies

interest. The quality assessment was done by

was carried out according to criteria of

three reviewers with each other blinded on

accessibility by three independent reviewers.

others’

Any disagreements were discussed into

consensus was reached. 13

consensus.

Summary measures and data analysis

The

planned

procedure

illustrated in Figure 1.

including

scoring,

then

Evidence-based

Quality assessment

study

selection,

discussed

analysis

until

was

conducted in this systematic review and

All included studies were assessed

meta-analysis. Outcome assessment was

using Newcastle-Ottawa Scale designed for

done by three reviewers independently, then

Cohort Studies (NOS-Ottawa) which then

discussed further into a table. Data was

converted

Healthcare

extracted from the included studies based on

Research Quality (AHRQ) standard into

following aspects: author and year of

good, fair, or poor quality, which is shown in

publication, study location, study design,

Table 2. This tool consists of quality and risk

participants, study period, and outcomes

of bias assessment based on “star system” in

stated in HbA1c cut off value with its

into

Agency

respective odds ratio and p-value. The results of the study were stated as not correlated and correlated using odds ratio (p<0.05). Odds ratio (OR) with a 95% confidence interval and p-value below 0.05 was used to determine the association between high glycated hemoglobin (HbA1c) serum level at first trimester and incident prediction in gestational diabetes patients. Factors were put as study code, log of odds ratio, and standard of error which will be calculated for study weight, fixed odds ratio,

Figure 1. Literature search strategy

and its 95% confidence interval (CI) which

Results

will be presented in forest plot. Studies were

Search results and study selection

also assessed using the Cochrane’s chi-

Comprehensive literature searches

squared test and the Higgins I-squared

from PubMed, Scopus, and EBSCOhost

statistical test in terms of heterogeneity of the

databases using search strategy mentioned

included studies. If the p-value of the chi-

above resulted a total of 1,466 studies.

squared test results is <0.05 and I-squared

Among them, 678 were deduplicated.

statistic is over 50%, the study will be

Moreover, 432 were excluded after screening

considered as heterogeneous. Thresholds for

the titles and abstracts in terms of gestational

the interpretation of I-squared referred to

diabetes mellitus prediction studies. In

Cochrane Handbook for Systematic Reviews

addition, 327 studies were filtered based on

of Interventions is as follows: 0% to 40%

inclusion and exclusion criteria which

considered as not important; 30% to 60%

resulted into 29 studies to be assessed by full-

represent moderate heterogeneity; 50% to

text reading. Subsequently, 22 studies were

90% represent substantial heterogeneity;

further excluded since 3 were case-control

75%

studies, 1 was qualitative study, 3 were

100%

considered

strong

heterogeneity.14 All forms of statistical tests

studies

of this study including heterogeneity were

outcomes, 5 studies assess only beta score as

carried out using Review Manager (RevMan)

its outcomes, 6 studies with outcome other

v5.3.

than GDM, and lastly 4 were not english

with

non-glycated

hemoglobin

Furthermore, sensitivity analysis was

written. Finally, the search yielded in 7

conducted through Duval and Tweedie’s

studies, consisting of all cohort studies to be

trim-and-fill analysis which are specific for

included in qualitative and quantitative

situations that the heterogeneity is too large.

synthesis.

This method was conducted to re-ensure the pooled effect size after removing any studies

Study characteristics and design

to minimize the publication bias.14 However,

The data extracted and characteristics

we did not conduct further subgroup analysis

of included studies are shown in Table 1.

due to similar characteristics of each studies

Overall, this review included a total of 13,930

indicated in study characteristics table which

subjects. Study locations varied across three

is shown in Table 1.

Table 1. Characteristics of selected studies Study Characteristics Studies, year

Kansu-Celik et al, 2019

Location Ankara, Turkey

Design

Participants

Range/Mean age (year)

Study Period

HbA1c Cutoff Value

Odds ratio (95% CI)

P-value

Retrospective cohort

608

31.11 ± 6.93

Jan 2010 – Jan 2018

HbA1c ≥ 5.6%

4.69 [2.66–8.29]

<0.001

Pezeshki et al, 2019

Zanjan, Iran

Prospective cohort

356

26.4 ± 4.3

Apr 2015 – Apr 2016

HBA1c ≥ 5.3%

9.73 [3.85 – 24.55]

0.001

Punnose et al, 2019

New Delhi, India

Retrospective cohort

2275

28.57 ± 3.76

Jan 2011 – Dec 2016

HbA1c ≥ 5.6%

2.6 [1.486-4.547]

<0.001

Chen et al, 2018

Washington, USA

Retrospective cohort

7020

Normal: 31 ± 5.1 Prediabetic: 32.5 ± 5.2

Jul 2011 – Dec 2014

HbA1c 5.76.4%

7.723 [5.91610.081]

<0.05

Kumru et al, 2016

Istanbul, Turkey

Prospective cohort

333

28.6 ± 4.6

Jan 2011 – Jan 2013

1.11 [0.22–5.57]

<0.05

Osmundson Palo Alto, et al, 2016 California, USA

Retrospective cohort

2812

34.2 ± 4.3

Jan 2011 – Dec 2012

HbA1c 5.76.4%

2.194 [1.572– 3.064]

<0.001

Long Fong et al, Beach, 2014 California, USA

Retrospective cohort

526

28.8 ± 6.4

Jan 2011 – Jan 2013

HbA1c 5.76.4%

2.38 [1.01-5.63]

0.048

NR = Not reported

Table 2. Quality assessment of selected studies.1,2

Studies, year

Selection

Comparability

Outcome AHRQ Standard Good

Kansu-Celik et al, 2019

1 a(*)

2 a(*)

3 a(*)

4 a(*)

1 b(*)

1 a(*)

2 a(*)

3 b(*)

Pezeshki et al, 2019

a(*)

b(*)

a(*)

b(*)

Good

Punnose et al, 2019

a(*)

b(*)

a(*)

Good

Chen et al, 2018

a(*)

b(*)

a(*)

Good

(*)

Good

Kumru et al, 2016

Osmundson et al, 2016

a(*)

b(*)

(*)

a(*)

b(*)

Fong et al, 2014

1Assessment 2 Study

a(*)

Good

a(*)

(*)

Good

form and complete version of AHRQ grading calculation are located in appendix 1.

is considered: Good: 3 or 4 stars in selection domain AND 1 star in comparability domain AND 2 or 3 stars in outcome domain.

Fair: 2 stars in selection domain AND 1 star in comparability domain AND 2 or 3 stars in outcome domain.

Poor: 0 or 1 stars in selection domain AND 0 star in comparability domain AND 0 or 1 stars in outcome domain. given for each of study aspect.

b(*)

(*) Stars

continents: Asia (n=4) and America (n=3).

with all respective study weight. According

Mean age of all included studies distributed

from 22 to 39 years. All studies enrolled

hemoglobin (HbA1c) serum level increases

assess and reported HbA1c cut-off value at

the chance of having gestational diabetes

first trimester which involved in GDM

mellitus by 4.36 (3.66-5.20) times. Forest

prediction, except Kumru et al which did not

plot is presented in Figure 2. Nevertheless, p

report HbA1c cut-off value at first trimester.

value for the overall effect test (z=16.41) is p

<0.00001

Quantitative analysis of High HbA1c Level

association between two factors.

this

meta-analysis,

which

high

shows

glycated

significant

and GDM prediction Our meta-analysis resulted that high

Heterogeneity and sensitivity analysis

glycated hemoglobin (HbA1c) serum level at

Pooled included studies showed that

first trimester was significantly associated

the p-value of chi-square test was < 0.00001

with gestational diabetes mellitus incident as

and the I-square test was 87%. Those are

it is a predictive factor and met minimum

indicating significant heterogeneity studies.

requirements for meta-analysis according to

According to Cochrane handbook, included

Cochrane handbook although our study

studies in this meta-analysis is considered as

consists

considerable

substantial

heterogeneity.16 This meta-analysis has also

sensitivity

showed the cumulative fixed odds ratio of

Tweedie’s trim-and-fill analysis revealed that

each study after calculated with its weight

one study is an outlier study. After removal

and presented the final odd ratio of analysis

of Chen et al study on sensitivity analysis, the

studies

with

heterogeneity. analysis

using

Furthermore, Duval

Figure 2. Forest plot presenting the association of HbA1c level in the first trimester of pregnancy and the occurence of GDM

and

outcome

was

OR=

2.81

(2.22-3.55),

thus applicable in clinical settings.

P<0.000001; I2=63%.17 This event could be due to larger samples used in this study

Discussion

compared to other included studies and due

The Development of Gestational Diabetes

to variability in the diagnostic measurement

Mellitus and The Increasing of HbA1c Level

criteria since this study was part of larger

As gestation occurs, the human body

research project evaluating clinical outcomes

makes few adaptations for preparing the

associated with the new GDM Guideline,

growth of the fetus, one of them is metabolic

IADPSG’s guideline.

adaptation. During early gestation, insulin sensitivity increases in order to increase

Publication Bias

glucose uptake by various tissues to fulfill

Critical appraisal was conducted

energy demands for the entire pregnancy. In

using Newcastle-Ottawa Scale for cohort

the

study criteria which transformed into AHRQ

decreases due to influence from various

criteria. Detailed critical appraisal was given

hormones, such as leptin, cortisol, estrogen,

in the appendix on the last part of this paper.

progesterone,

From our systematic review and meta-

placental growth hormone. This mild degree

analysis, all included studies shows good

of resistance will also increase glucose

quality studies based on AHRQ standard,

production by the liver and the breakdown of

which indicated that this review included low

fat stores in the tissues, further increasing the

risk of bias studies. However, according to

blood glucose level and free fatty acids

Cochrane

concentration.18 However, increased degree

handbook,

heterogeneity

later

insulin

placental

resistance

sensitivity

lactogen,

and

examination using funnel plot demands at

least 10 studies to present sufficient power

compensatory pancreatic β-cells hyperplasia

for studies heterogeneity.16 Therefore, funnel

can results in gestational diabetes mellitus.19

plot analysis assessing publication is not

The dysfunction of pancreatic β-cells causes

performed in this study. Thus, this study is

the impaired response of increasing blood

still subject to publication bias which is

glucose level. Prolonged increasing in blood

limited to amount of publication. Although,

glucose level will decrease tissue insulin

this study is still currently applicable as it

sensitivity in order to divert excess energy

included all studies available at the moment,

uptake to other tissues.20,21 In GDM, the

insulin

gestation,

impaired

insulin-induced glucose uptake decreased by

before pregnancy or in early pregnancy as the

54% compared to normal pregnancy.22 Once

insulin sensitivity in that period should be

β-cells dysfunction occurs, the vicious cycle

higher. The HbA1c level is expected to drop

of it, hyperglycemia, insulin resistance, and

by at least 0.5% as a result of higher insulin

further β-cells dysfunction is established.

sensitivity

Progression of GDM involves many insulin

erythrocytes

signaling pathways and involves many

HbA1c level in the first trimester may

organs throughout the body, such as

indicate

neurohormonal system, adipose tissue, liver,

maternal glycemic control which may result

skeletal muscle, placenta, and gut.18

from poor dietary pattern. This supports the

and

shorter

during

lifespan

pregnancy.24

preconception

dysfunction

of High

Glycated hemoglobin (HbA1c) is a

study by Zhang that improvement in

hemoglobin that has glucose attached to the

glycemic function before pregnancy decrease

N-terminal valine of its β-chain. It can

the risk of developing GDM.25

reliably reflect the blood glucose level for the preceding 8-12 weeks as the lifespan of

The Utility of HbA1c Level Screening

range.11,23

Our review proved that high HbA1c

Measuring the HbA1c level within the first

level is a statistically significant risk factor of

trimester of pregnancy can provide the

the development of GDM. HbA1c level can

estimation of maternal glycemic condition

also predict the occurrence of GDM

erythrocytes

within

that

Figure 3. Organs involved in the pathophysiology of gestational diabetes mellitus

complication. A study by Osmundson stated

history

that high HbA1c level is associated with the

cardiovascular disease. As soon as being

increased risk of excessive gestational weight

delivered, neonates born from mother with

gain, caesarean delivery, and large for

GDM are at risk of hypoglycemia as a result

gestational age, although was statistically

of fetal hyperinsulinemia. Children born

significant only for the weight gain.26 Study

from mother with GDM also have higher risk

by Mañé stated that HbA1c ≥ 5.9% is a

of childhood insulin resistance, which may

statistically

result in obesity, T2DM, and cardiovascular

significant

risk

factor

p=0.028]

predispose

them

disease.18

macrosomia [OR=3.114; 95% CI 1.1278.063;

also

and

preeclampsia

The use of HbA1c level as a risk

1.086-11.532;

factor screening is recommended as it is a

p=0.036].27 Macrosomia results from the

simple and quick test therefore the prolonged

increase in glucose, fatty acids, and amino

hospital stay is not required. Risk factor

acids through the placenta due to GDM,

screening during early pregnancy, including

stimulating the production of insulin and

risk for GDM, is heavily required, especially

IGF-1. Macrosomia is also a risk factor of

in low-income countries, where the access to

shoulder dystocia which will obstruct the

adequate antenatal care is still limited, and in

labor process.18 It is believed that GDM and

the current COVID-19 pandemic era, when

preeclampsia

[OR=3.539;

95%

from

pregnancy

the hospital visit should be limited. Early

endothelial

detection of risk factors of pregnancy

dysfunction, angiogenic imbalance, which

complications can lead to healthier maternal

result from high anti-angiogenic factors such

lifestyle and healthy pregnancy.

maladaptation,

result such

as sFlt-1 and sEng and low pro-angiogenic factors such as PGF, oxidative stress, and

Strengths and Limitations

dyslipidemia. Studies have proven that

Our review has several strength and

patients with GDM have low pro-angiogenic

limitations. To our knowledge, this is the first

factors and high anti-angiogenic factors.28

systematic review and meta-analysis to

Women with the previous history of GDM

assess the HbA1c level in the first trimester

have higher risk of developing type 2

as a risk factor of gestational diabetes

diabetes mellitus (T2DM) later in life. The

mellitus. Our meta-analysis also yielded a

altered vasculature in women with GDM

significant pooled odds ratio and was

statistically

significant,

proving

the

increase glycemic control during pregnancy

significance of its correlation with the

therefore decreasing the prevalence of

development of GDM. All of the studies

pregnancy complications due to GDM and

included in this review is cohort studies,

having a healthy pregnancy. We also

which is the main type of studies in assessing

encourage women in the reproductive age to

risk factors. The main limitation of our study

maintain their glycemic function to prepare

was the high heterogeneity from the meta-

healthy pregnancies by consuming healthy

analysis. This may be caused by the variation

diet and maintaining active lifestyle.

of cutoff value of the HbA1c used and other variables such as the gestational age when the

Acknowledgement

HbA1c level was measured. This review also

We have nothing to declare.

consisted of a low number of eligible studies

Conflict of Interest

since the study about this topic is still scarce.

We declare that we have no competing

The publication bias analysis using funnel

intention for completing this review.

plot cannot be made because of the limited number studies. Furthermore, this review also included only studies written in English.

Conclusion and Recommendation In conclusion, this systematic review and meta-analysis has proven the potency of HbA1c level in the first trimester as a novel predictor of gestational diabetes mellitus in pregnant patients. Thus, it is necessary to integrate the use of HbA1c level screening as part of antenatal care in the first trimester of pregnancy, especially in Southeast Asian country (e.g. in Indonesia), due to the high prevalence; however, further research should be done. Early detection of GDM risk factor using HbA1c level in the first trimester could

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Appendix 1. Newcastle-Ottawa scale A Newcastle-Ottawa Quality Assessment Form for Cohort Studies Note: A study can be given a maximum of one star for each numbered item within the Selection and Outcome categories. A maximum of two stars can be given for Comparability.

Selection 1)

Representativeness of the exposed cohort a) b) c) d)

Truly representative (one star) Somewhat representative (one star) Selected group No description of the derivation of the cohort

Selection of the non-exposed cohort a) Drawn from the same community as the exposed cohort (one star) b) Drawn from a different source c) No description of the derivation of the non exposed cohort

Ascertainment of exposure a) b) c) d) e)

Secure record (e.g., surgical record) (one star) Structured interview (one star) Written self report No description Other

Demonstration that outcome of interest was not present at start of study a) Yes (one star) b) No

Comparability 1)

Comparability of cohorts on the basis of the design or analysis controlled for confounders a) The study controls for age, sex and marital status (one star) b) Study controls for other factors (list) (one star) c) Cohorts are not comparable on the basis of the design or analysis controlled for confounders

Outcome 1)

Assessment of outcome a) b) c) d) e)

Independent blind assessment (one star) Record linkage (one star) Self report No description Other

Was follow-up long enough for outcomes to occur

a) Yes (one star) b) No Indicate the median duration of follow-up and a brief rationale for the assessment above: 3)

Adequacy of follow-up of cohorts a) Complete follow up- all subject accounted for (one star) b) Subjects lost to follow up unlikely to introduce bias- number lost less than or equal to 20% or description of those lost suggested no different from those followed. (one star) c) Follow up rate less than 80% and no description of those lost d) No statement

E-17

100

Thresholds for converting the Newcastle-Ottawa scales to AHRQ standards (good, fair, and poor): Good quality: 3 or 4 stars in selection domain AND 1 or 2 stars in comparability domain AND 2 or 3 stars in outcome/exposure domain Fair quality: 2 stars in selection domain AND 1 or 2 stars in comparability domain AND 2 or 3 stars in outcome/exposure domain Poor quality: 0 or 1 star in selection domain OR 0 stars in comparability domain OR 0 or 1 stars in outcome/exposure domain

101

Potential of Curcumin to Prevent Diabetes Complication: A Systematic Review Intan Qanita1, Ghina Mardhatillah2

Abstract Introduction: Diabetes mellitus is one of the most common metabolic disorders. Regardless the availibity of diabetes medicine, diabetes and its complication are increasing and still became a major problem. This study aims to review potential of curcumin to prevent diabetes mellitus complication on human. Method: A systematic search was conducted across four databases (PubMed, ScienceDirect, Cochrane and Taylor and Francis). 417 articles identified from database searching. Articles were selected based on the inclusion and exclusion criteria apllied. The final articles that used in this review are six articles with clinical trial studies in period 2015-2020, written in English and conducted to diabetic patient with curcumin intervention. Result: 4 research shows that there are significant effect on decreasing body weight, 3 research shows significant effect on decreasing FBG, 2 research shows effect on decreasing HbA1c, 1 research shows significant reduction in the left brachial–ankle PWV, and 1 research shows curcumin able to repress inflammation, and reduce U-mAlb excretion. Conclusion : Curcumin intake with its antioxidant and anti-inflammatory properties has significant role to prevent the developing of cardiovascular, neurological, and nephrological complication in diabetic patient through improving lipid profile, vascular stiffness, inflammation and oxidative stress. Keywords: Diabetes mellitus type 2, curcumin, complication, prevention Introduction Diabetes mellitus is one of the most common metabolic disorders and it is include as a major challenge in public health [1]. The prevalence of diabetes increase drastically from 1980 with 108 million people to 422 million people in 2014 and rising more rapidly in low to middle income countries than in high-income countries. Diabetes mellitus is a chronic diasease that caused by inadequate insulin production by pancrease or the body cannot use the insulin effectively. In 2016, diabetes caused 1.6 million deaths and became the major cause to heart attack, kidney failure, stroke, blindness, and lower limb amputation. [2] Regardless the availibity of diabetes medicine, diabetes and its complication are increasing and still became a major problem. Several experiments conducted on health plants

102

have shown anti-diabetic and anti-hiperlydemic benefits and have been reported to treat diabetes from all over the world. [3] Curcumin longa (turmeric) is a herbaceous plants which found widely in South Asia. Curcumin commonly use as spices in Asian dishes and is well known as antioxidant, anticancer, anti-inflammatory, antiseptic, and antimicrobial properties. [4]. Curcumin based on recent research shows many pharmacological actions. Curcumin may be effective in reducing the development and complication of diabetes because it has antioxidant properties and prevents the formation of oxygen free radicals. [5] The previous researches has been showed the effect on animal trial or in vitro models as anti-inflammatory, blood lipid, and sugar-reducing in turmeric [5]. This study aims to review relevant previous journal articles with clinical trial as the research design to see the potential of curcumin to prevent diabetes mellitus complication on human. The participant object of this systematic review are patient who diagnosed with Diabetes Mellitus and age between 18-85 years old. Methods A sytematic review was performed using the PubMed, ScienceDirect, Taylor and Francis, and Cochrane Databases following PRISMA guidelines for published studies in English language over the period 2015-2020. The following terms were used to generate a search : Type 2 Diabetes Mellitus, Complication, Prevention, and Curcumin. Articles found then were selected with inclusion and excluion criteria. Articles included in this systematic review were clinical trial performed on human, studying about curcumin effects on preventing complications in type 2 diabetes mellitus patients and allow full-text access. Studies on pediatric or adolescent patients, animal studies, and studies in different focus (e.g., type 2 diabetes prevention) are excluded. Further information on study identification, inclusion and exclusion criteria is detailed in Figure.

103

PubMed 2015-2020 (n=64)

Cochrane 2015-2020 (n=191)

ScienceDirect 2015-2020 (n=37)

Taylor and Francis 2015-2020

(n=117) Total records identified through database searching (n=417) Total records included base on inclusion criteria (n=19)

Exclusion Criteria Applied

13 Articles Exluded

6 Articles Included

Result Age Group of Clinical Trials From 6 selected clinical trials there are 2 kinds of age group. Adolesent to elderly. Clinical trial from Panahi et al were recruting people from adolscent to elderly, meanwhile the rest are recruting Diabetes Mellitus patients from adult to elderly. Study Design This review has selected 6 studies that only use research and clinical trial on patient with Diabetes Mellitus with the comparison between Curcumin and placebo or only curcumin. 4 articles shows that there are significant effect on decreasing body weight, 3 articles shows significant effect on decreasing FBG, 2 articles shows effect on decreasing HbA1c, 1 article shows significant reduction in the left brachial–ankle PWV. 1 article shows curcumin able to repress inflammation. The result will be shown in Table

104

Publication

Participant

Variable

Outcome

Summary of Findings

Adab Z, Eghtesadi S,

30-70 y.o

Turmeric

BMI, HbA1c, insulin, and

Turmeric

Vafa M-R, Heydari I,

Hyperlipedemic

powder

HOMA-ir decreased not

showed

Shojaii A, Haqqani

Diabetes Type 2 and

significantly in

effect on decreasing

H, et al., 2019 [5]

N=40 for

intervention group and

FBG and body weight.

placebo

intervention,

increased insignificantly in

N=40 for

placebo group. FBG and

placebo

body weight decreased

powder significant

significantly in intervention and increased significantly in placebo. Adibian M, Hodaei

40-70 y.o

Curcumi

Body weight in

Curcumin

capsule

H, Nikpayam O,

Diabetes

n capsule intervention group reduced showed

Sohrab G,

Mellitus Type 2

and

significantly compare with

impact on lowering

Hekmatdoost A,

N=21 for

placebo

placebo. FBG decreased

FBG,

Hedayati M., 2019

intervention,

significantly in

body weight. It also

[1]

N=23 for

intervention, and increased

increase

placebo

in placebo. TG level

adinopectin

significant

hs-CRP,

and

serum

decreased in intervention and placebo. hs‐CRP concentrations have a significant decrease in intervention and no effect in placebo. Serum adinopectin increased in both groups. Asadi S, Gholami

30-60 y.o

Nanocur

HbA1C and FBG was

Curcumin

MS, Siassi F,

Diabetes

cumin

decreased significantly on

significant effect on

Qorbani M,

Mellitus and

capsule

intervention group

decreaing

Khamoshian K,

diagnosed with

and

compare to placebo group.

FBG, Bs2hp level, and

Sotoudeh G., 2019

Distal

placebo

Significant reduction on

reduce the severity of

[10]

symmetric

severity of polyneuropathy

polyneurophaty

105

shows

HbA1c,

polyneuropathy

in intervention group.

(DSPN) caused

Bs2hp level had more

by DM. N=35

reduction on intervention

for intervention

group than placebo.

and N=37 for placebo Panahi Y, Khalili N,

18-65 y.o

Curcumi

Body weight and BMI

Curcuminoids showed

Sahebi E, Namazi S,

Diabetes

noids

were significantly

significant effect on

Reiner Ž, Majeed M,

Mellitus Type 2

capsule

decreased in intervention

decreasing body weigh

et al., 2017 [9]

patients. N=50

and

group and increased in

and BMI.

for intervention

placebo

placebo group. Serum TG

and N=50 for

has not shown significant

placebo

different on both group.

Srinivasan A,

30-65 y.o

Curcumi

Intervention groups, shows Intervention

Selvarajan S,

Diabetes

n longa

significant reduction in the

shows

Kamalanathan S,

Mellitus Type 2

capsule

left brachial–ankle PWV,

reduction in the left

Kadhiravan T,

patients. N=60

and

aortic augmentation

brachial–ankle PWV,

Prasanna Lakshmi

for intervention

placebo

pressure, aortic

aortic

NC, Adithan S., 2019 and N=54 for

augmentation index, and

pressure,

aortic

[4]

aortic augmentation index

augmentation

index,

(at heart rate 75) compare

and

aortic

to the placebo

augmentation index

placebo

Yang H, Xu W, Zhou 47-85

y.o Curcumi

Z, Liu J, Li X, Chen Diabetes L, et al., 2015 [11]

Curcumin

groups, significant

augmentation

intervention Curcumin intervention

dramatically reduces U- can

Mellitus Type 2

mAlb excretion without inflammation

patients. N= 4

affecting

patient

control. It also reduces

diagnosed with

plasma MDA and LPS

DKD, N= 3 with

level

pre DKD, and

inflammatory.

the others are T2D

with

106

metabolic

and

represses

reduce

normal U-mAlb excretion

Note. BMI: body mass index; HbA1c: hemoglobin A1c; HOMA-ir: homeostatic model assesmentof insulin resistence; FBG: fasting blood glucose; TG: triglyceride; hs-CRP: high sensitivity C-reactive protein; Bs2hp: blood sugar after 2 hours; PWV: pulse wave velocity; U-mAlb: urine-microalbumin; MDA: Malondialdehyde; LPS: Lipopolysaccharides.

Discussion Cardiovascular Complications Insulin resistance in type 2 diabetes mellitus will cause in persistent high level of blood sugar circulating and later will lead to dyslipidemia in diabetic patient. ‘Diabetic dyslipidemia’ is the term that use to describe lipid abnormalities in patients with diabetes. It is characterized by high total cholesterol, high triglycerides, low high density lipoprotein cholesterol and increased levels of small dense low density lipoprotein particles [6]. Diabetes Mellitus is associated with a 2 to 4-fold increased mortality risk from heart disease [7]. This mortality risk is associated with dyslipidemia, inflammation and oxidative stress that are the major risk factors of atherosclerosis and cardiovascular disease in diabetic patient [5]. Turmeric or Curcuma longa has been used in many countries as spice since ancient times. Many researches on this plant show numerous benefit especially as antioxidant, antiinflammatory, blood lipids and sugar-reducing properties [8] A study was conducted to 80 hyperlipidemic type 2 diabetic patients with consumption of 2100 mg of turmeric for 8 weeks cause significant decrease in body weight and BMI. In the same population, turmeric also caused significant decrease in serum triglycerides and LDL-c and prevented the increase in serum total cholesterol [5]. Several mechanisms has been studied on how turmeric improves lipid profile that it can increase cholesterol catabolism, inhibiting the synthesis of cholesterol and fatty acid, and affects LDL-c receptors and inhibits absorption of dietary cholesterol [5]. A double-blind randomized clinical trial on 44 patients with type 2 diabetes also indicate that curcumin consumption may reduce diabetes complications through decreasing triglyceride level as well as indicators of inflammation [1]. This study also showed increased concentration of adiponectin in a group with curcumin intervention. Adiponectin is an inflammatory cytokine produced and secreted by adipose tissue that has inverse association with insuline resistance, dyslipidemia and cardiovascular disease [1]. Result from a randomized double-blind placebo-controlled trial of type 2 diabetic patient with intervention of curcuminoid plus piperin after 12 weeks showed reduction of serum lipoprotein and increase in HDL-c concentration compared with placebo group [9]. This discovery that curcumin effects on increasing HDL serum levels is essential as its much more problematical than lowering LDL serum [9]. Cardiovascular complication of type 2 diabete mellitus also characterized by increased central arterial stiffness and endothelial dysfunction. A randomized controlled trial in 136 type

107

2 diabetes patient given 3 months treatment of curcuma longa show significant reduce in arterial stiffness. Parameter use in this study is pulse wave velocity (PWV) of carotid-femoral, and left branchial-ankle as the gold standard of measuring arterial stiffness [4]. Neurologic Complication Diabetes mellitus also cause complication in nerve damage as in diabetic sensorimotor polyneuropathy (DSPN). This disease is a common complication that affects feet, legs, hand and arms. Chronic hyperglicemia in diabetic patient induce systematic oxidative stress and generate diabetic neuropathy. As mentioned before that curcumin has benefit in antioxidant and anti-inflammatory effect a double-blinded randomized placebo-controlled clinical trial was conducted on 80 diabetic patient and showed a significant reduction in severity of DSPN, total reflex score, and temperature in curcumin group. Researche believed curcumin inhibits production of pro-inflammatory cytokines including TNF-α, Interleukin-1 (IL-1) and also prevents synthesis of Nitric Oxide. This antioxudants and anti-inflammatory effects of curcumin can be useful in the treatment of diabetes and its complication such as neuropathy [10]. Nephrologic Complication Chronic hyperglicemia in diabetes is major causal factor in metabolic abnormality that induce oxidative stress. This oxidative stress will damage renal tissue and its function and become pathological mechanism that cause diabetic kidney disease (DKD). A study performed in type 2 diabetes mellitus patients with curcumin intervention by oral intake at dose of 500 mg/day for a period of 15-30 days to see the effect of curcumin in preventing hyperglycemiamediated oxidative stress and blocking inflammatory activation. Parameter to assess inflamation was lipopolysachharide content and protein in blood lymphocytes. This study showed an inhibiting effect of curcumin on inflammatory signaling and apoptotic proteins in blood lymphocytes. This leading to a new mechanism of curcumin the treatment of DKD by reducing LPS absorption and blocking LPS-induced renal inflammation and damage. The study also came to term that curcumin can prevent DKD and attenuates DKD by inflammation pathway [11]. Conclusion Diabetes as the most common metabolic disorder in the world relates to many complications and chronic impairment of multiple organs and systems. Those complications including microvascular and macrovascular is associated with chronic hyperglicemia, oxidative stress and inflammation. This will lead to cardiovascular disease, neurologic disease and nephrologic disease. Turmeric or Curcuma longa, a plant that commonly used as spice happens to have antioxidant anti-inflammation, and many other pharmacological actions. Several studies includes animal studies and clinical trial has been conducted to find curcumin effects as complementary medicine or supplement in preventing type 2 diabetes and its complications. This systematic review intended to find curcumin role in preventing type 2 diabetes cardiovasuclar, neurologic and nephrologic complications. We conlude that curcumin

108

has significant effects in preventing those complication through improving lipid profile, vascular condition , and inflammatory marker in diabetic patient. We suggest further research to find better understand in this topic especially regarding the efficacy and bioactivity of curcumin intervention in diabetic patient. Limitation Although this review highlighted the potential of curcumin to prevent diabetes complications, the literature included are limited to English article though Curcumin is widespread mostly in non-English speaking countries. Therefore, valuable research article in different languange could not be included. Additionally, there are only several studies clinical trial that have been done on human and only small number of research could be searched initially due to limited database that could be used by authors. To explore a deeper understanding about this association, further research on similar topic with abundant resources of database must be conducted. Acknowledgments None Conflict of Interest No declared References 1.

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Aronson D, Edelman ER. Coronary artery disease and diabetes mellitus. Cardiol Clin. 2014 Aug;32(3):439-55. doi: 10.1016/j.ccl.2014.04.001. Epub 2014 Jun 10. PMID: 25091969; PMCID: PMC4672945.

Ray, A. B., Chansouria, J. P. N., & Hemalatha, S. (2010). Medicinal plants: Antidiabetic and hypoglycaemic activities (first ed.) (pp. 130–133). India: IBDC Publishers.

Panahi Y, Khalili N, Sahebi E, Namazi S, Reiner Ž, Majeed M, et al. Curcuminoids modify lipid profile in type 2 diabetes mellitus: A randomized controlled trial. Complement Ther Med. 2017;33:1–5.

10.

Asadi S, Gholami MS, Siassi F, Qorbani M, Khamoshian K, Sotoudeh G. Nano curcumin supplementation reduced the severity of diabetic sensorimotor polyneuropathy in patients with type 2 diabetes mellitus: A randomized double-blind placebo- controlled clinical trial. Complement Ther Med. 2019;43:253–60.

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Effect of Canagliflozin on Renal Function in Type 2 Diabetes Mellitus Patients: A Systematic Review Kelvin Kohar1, Syailendra Karuna Sugito1, Ariestiana Ayu Ananda Latifa1 1

Faculty of Medicine, Universitas Indonesia, Depok, Indonesia

ABSTRACT Background: Type 2 diabetes mellitus (T2DM) is a significant health issue worldwide. Currently, Metformin, as approved first-line therapy, unexpectedly showed deleterious effects on renal function. Moreover, renal problems or diabetic nephropathy is a common complication that happens in T2DM patients. Diabetic nephropathy will also progress to end-stage renal disease which patients will require dialysis to survive. On the other hand, Canagliflozin (sodium glucose-cotransporter receptor inhibitor) may show some promising effects on renal and heart in T2DM patients in many studies. Objective: This systematic review will investigate the protective effect of canagliflozin in renal function.

Methods: Relevant studies from PubMed, Scopus, and ProQuest databases were screened, searching for randomized clinical trials (RCT) which analyze the effects of canagliflozin on renal

function in type 2 diabetes mellitus. Studies were assessed for bias risk with Cochrane risk-of-bias tool. Result: The search yielded 5 RCTs consisting of 16,759 patients in total. Administration of canagliflozin shows positive effect on eGFR and albumin levels in the urine. Discussion: Canagliflozin acts as SGLT1 and SGLT2 inhibitor thereby causing reduction in blood glucose level by inhibiting absorption of glucose in renal tubules and intestines. Canagliflozin provides renoprotective effects from several mechanisms such as glycemic control, reduction of glomerular hyperfiltration, diuretics effects, anti-inflammatory and oxidative stress, improvement of endothelial function, inhibition of sympathetic nerve activity, mild ketosis, and production of erythropoietin. Conclusion: Canagliflozin has some renoprotective effects by causing significant decrease in eGFR declining per year in T2DM patients.

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Recommendation: We suggest canagliflozin to become a candidate for first line therapy for T2DM. Further studies should investigate about the side effects and contraindications for the drug. Keywords: canagliflozin, type 2 diabetes mellitus, T2DM, renal function

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INTRODUCTION Diabetes mellitus (DM) is a chronic metabolic disease indicated by persistent hyperglycemia. Generally, this disease can be classified into type 1 and type 2 diabetes mellitus. Type 2 diabetes mellitus (T2DM) is the most common problem characterized by insulin resistance. The recent fact showed that T2DM was responsible for approximately 90% of the disease. Nowadays, T2DM is increasingly seen in children until younger adults because of physical inactivity and obesity. Patients with DM usually encounter many symptoms, such as fatigue and lack of energy, urination increase, infection, and delayed wound healing.1 Until now, this disease still becomes one of the major issues concerned by the World Health Organization (WHO). According to the International Diabetes Federation (IDF) in 2019, there were about 463 million, which means 1 in 10 people lived with diabetes. Every year, this disease is responsible for more than 1.3 million deaths. From the numbers, Indonesia was the 6th highest contributor among countries in the world. Furthermore, IDF also predicts this number will rise to 700 million people by 2045.2,3 In addition, T2DM is a comorbid disease that can cause many life-threatening complications, such as neuropathy, nephropathy, retinopathy, atherosclerosis, angina, foot damage, and depression. Diabetic kidney disease or diabetic nephropathy was reported as a common complication in 40% of patients.4 Globally, T2DM patients' management depends on metformin. Some studies showed that first-line therapy drug (Metformin) shows a positive correlation with deleterious effect on renal function by decreasing the estimated glomerular filtration rate (eGFR) in T2DM patients.5,6 Moreover, diabetic nephropathy has become the most prevalent cause of end-stage renal disease requiring dialysis to survive. Canagliflozin, which was just accepted by Indonesia's National Food and Drug Agency (BPOM) on 18 September 2020, may become a solution to this problem. It showed some promising renal and heart protective effects that also can be used in T2DM patients with chronic kidney disease.7 Based on current knowledge, urgency, and importance of T2DM management, we decided to conduct a systematic review of Canagliflozin and its role as therapy and renal protective function in T2DM patients. It also correlates with the 3rd Sustainable Development Goals (SDG) by United Nations to reduce premature death from non-communicable diseases, including diabetes.8

114

METHODS Research Strategy The article exploration was conducted from PubMed, Scopus, and ProQuest on 28 October 2020. The main keywords are ("canagliflozin") AND ("diabetes mellitus") AND ("nephropathy") and modified based on each database's terms and conditions. The research is limited only to English, published within 5 years, and full-text publication. Additional records were identified through manual searches and bibliographies from other studies not identified in electronic searches. The study selection process follows the PRISMA Statement flow diagram--i.e. identification, screening, eligibility test, and inclusion of studies--and is managed using Mendeley. Duplicates removed and the retrieved articles undergo Abstract/Title screening to eliminate papers with irrelevant topics and objectives.9 The selection continues to go on the full-text screening according to our inclusion and exclusion criteria. To reduce the risk of bias in selecting, the screening was done by one reviewer and approved by the other two.

Figure 1. PRISMA Statement Diagram.9

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Inclusion and Exclusion Criteria This review focused on randomized clinical trial articles investigating the eGFR changes in properly diagnosed TM2D patients given canagliflozin treatment. Exclusion criteria were: journals that observe the effect of several drugs combination; preclinical studies; type 1 diabetes, non diabetic, or special form of diabetes; research with outcome measurements other than eGFR (e.g hormones); patients with comorbidities that may alter the outcome (diagnosed by chronic kidney disease. acquired kidney transplant, etc); and inaccessible articles. Quality Assessment The Cochrane criteria were used to assess the quality of the included studies after selecting qualified articles for the review. The evaluation of each study was as follows: randomized generation, allocation concealment, double blindness of the performers and participants, blinding of outcomes, selective reporting, and any other sources of biases.10

116

RESULT Study Characteristics

Author

Study Design

Study Location

Randomize Multicenter Vlado P, et d clinical 34 al11 (2019) trial countries

Takenaka Randomize T, et al12 d clinical (2017) trial

Heerspink Randomize HJL, et d clinical al13 (2017) trial

Neal B, et al14 (2017)

Bode B, et al15 (2015)

Tokyo, Japan

Sydney, Australia

Randomize 667 centers d clinical in 30 trial countries

Randomize 90 centers d clinical in 17 trial countries

Sample size

Mean ± SD/median (range) Treatment age in years

4401

Canaglifloz 63.0 ± 9.2 in and placebo

1450

10142

714

55 ± 2

Dose

100mg daily

canagliflozi Canaglifloz n (100mg in or daily) or luseoglifloz luseoglifloz in and in (5mg placebo daily)

HbA1c

eGFR (ml/min/1. 73 m2)

N/A

Canaglifloz in: 56.3±18.2 Placebo: 56.0±18.3

N/A

N/A (eGFR were reduced after treatment for 3 months)

56.2

Canaglifloz in or glimepiride uptitrated to 6–8 mg

Canaglifloz Canaglifloz in (100 in 100 mg mg): 3.3 (-0.82%) Canaglifloz 100 mg and Canaglifloz in (300 300 mg in 300 mg mg): 0.5 daily (-0.93%) Glimepirid Glimepirid e (6-8 mg): e (-0.81%) 0.9 (per year)

63,3

Canaglifloz in (N: 5795), Placebo (N: 4347)

Canaglifloz in: 76.7±20.3 Placebo: 76.2±20.8

N/A

Canaglifloz in and placebo

Table 1. Study Characteristics.

117

100 mg daily

100 mg, 300 mg

N/A

Canaglifloz Canaglifloz in (100 in 100 mg mg): 77.6 ± (-0.32%) 17.0 Canaglifloz Canaglifloz in 300 mg in (300 (-0.43%) mg): 78.7 ± Placebo 16.4 (0.17%) Placebo: 76.1 ± 16.3

Risk of Bias Assessment Vlado P, et al (2019)11

Takenata T, et al (2017)12

Heerspink HJL, et al (2017)13

Neal B, et al (2017)14

Bode B, et al (2015)15

Random sequence generation

Allocation concealment

Blinding of participants and personnel

Blinding of outcome assessment

Selective reporting

Other bias

+ = low risk of bias; - = low risk of bias; ? = unclear risk of bias

Table 2. Risk of Bias Assessment.

From 1493 articles founded from the search strategy, 5 articles are included in the study based on inclusion and exclusion criteria which presented a huge number of samples. Three out of five articles included are a multicenter study performed on more than 15 countries each with a total number of samples exceeding 14000 participants.11,14,15 Whilst, the other two studies were conducted in Japan and Australia which may provide group variants in our study. All studies practiced on the elder population as their sample (mean 55-63 yo).12,13 Studies conducted by Vlado et al, Neal et al, and Bode et al presents a significant decrease in eGFR declining per year.11,14,15 In a 10.142 number of samples study, the canagliflozin treated group shows a higher rate of eGFR (76.7±20.3) than the placebo group (76.2±20.8).14 The higher dose of canagliflozin demonstrates a more beneficial outcome for its renoprotective effect. A study conducted by Bode et al explains that canagliflozin (given 300 mg daily) shows a significant decrease in declining of eGFR in TM2D patients than the lower dose (given 100 mg daily).15 Succeeding, Heersprink et al proceed with a correlated result on the effect of high dose canagliflozin.13

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DISCUSSION Pharmacodynamics of canagliflozin in T2DM Canagliflozin (Invocana®) is a sodium glucose-cotransporter (SGLT) receptor inhibitor that acts on SGLT-1 and SGLT-2. Canagliflozin has 250-fold selectivity for SGLT-2 than SGLT-1. SGLT-2 is a high-capacity and low-affinity transporter located in the proximal tubule. This transporter is found more effective during glucose reabsorption in T2DM patients.15 Canagliflozin acts by blocking SGLT-2 to decrease reabsorption of filtered glucose responsible for 90% of total body glucose. Furthermore, this drug also works in SGLT-1 that is also expressed in the proximal tubule but concentrated in the distal brush border membrane surface of villi in the small intestine lumen.16,17 Canagliflozin will block SGLT-1 to prevent glucose reabsorption in the small intestine that accounts for 10% of total body glucose. These mechanisms cause an elevation in urinary glucose excretion (UGE) and reduce in plasma glucose patients.17,19 Renoprotective mechanism of canagliflozin Canagliflozin provides renoprotective effects from several mechanisms such as glycemic control, reduction of glomerular hyperfiltration, diuretics effects, anti-inflammatory and oxidative stress, improvement of endothelial function, inhibition of sympathetic nerve activity, mild ketosis, and production of erythropoietin.20 Inflammation and chronic hyperglycemia are main causes of kidney tissue damage in diabetes mellitus.21 Inhibition of glucose reabsorption in renal tubules and glucose absorption in the small intestine due to inhibition of SGLT1 and SGLT219 result in modest reduction of blood glucose level thereby reducing the risk of glucotoxicity in various organs including kidneys by reducing renal growth, inflammation and injury.22 One of the disorders that occurs in the kidneys in diabetic kidney disease is glomerular hyperfiltration. It is mainly caused by activation of renin-angiotensin-aldosterone system (RAAS) induced by hyperglycemia. Persistent glomerular hyperfiltration could cause kidney injury.20 SGLT2 is a transporter protein that cotransports glucose and sodium ion (Na+)24 therefore inhibition of SGLT2 also results in increased excretion of Na+ in the urine. Increased level of Na+ in the urine causes increase in urine volume due to osmotic pressure. Increased urine production will reduce extracellular fluid (ECF) volume and blood pressure. These will reduce atrial natriuretic peptides (ANP) levels thereby causing vasoconstriction of afferent arterioles.

119

Increased sodium level in the urine also causes macula densa to activate tubuloglomerular feedback by inhibiting renin secretion from juxtamedullary cells causing vasodilation of efferent arterioles. Both vasodilation of efferent arterioles and vasoconstriction of afferent arterioles will reduces intraglomerular pressure and hyperfiltration.22,23 This will also reduce albumin filtration and tubular transport work thereby reducing renal oxygen consumption.22 Increased glucose excretion via urine also contributes to modest decrease in body weight. Reduction of blood pressure together with modest decrease in body weight will result in reduced renal and cardiovascular burden.22 Inhibition of SGLT2 is also associated with increase in glucagon level and decrease in insulin level. Increase in glucagon level leads to vasodilation therefore increases renal plasma flow, GFR, and electrolyte excretion. On the other hand, decrease in insulin level will induce lipolysis and gluconeogenesis. These mechanisms causes mild ketosis that have potential protective effects on kidneys.22 Other promising effects of Canagliflozin Canagliflozin also shows some benefits for the cardiovascular system. A systematic review conducted in 2013 showed that this drug was able to reduce blood pressure by about 4.5 mmHg compared with other antidiabetic agents.24 Furthermore, Canagliflozin Cardiovascular Assessment Study (CANVAS) program enrolling over 10,000 patients showed a reduction in hospitalizations for heart failure in T2DM patients. It also showed a decrease in death numbers due to cardiovascular causes, such as myocardial infarction and stroke.25 Studies hypothesized these effects could happen due to some mechanism. SGLT-2 inhibitor acts as a natriuretic or diuresis that can reduce preload and afterload. Moreover, it also inhibits SGLT-1 that is expressed in the cardiac sarcolemma and Na+/H+ exchanger in the myocardium to reduce cardiac injury, fibrosis, hypertrophy, remodeling, and systolic dysfunction.26,27 Current treatment and downsides of canagliflozin Generally, the current first line treatment for type 2 diabetes mellitus (T2DM) is metformin. Metformin is known for its effectiveness on lowering A1C, low hypoglycemia risk, and low cost.29 Although canagliflozin has some protective effects on cardiac and renal function, it has some downsides. Canagliflozin is relatively new and still costs much. Moreover,

120

canagliflozin also has some side effects such as increased frequency of urination and the risk of genitourinary infections which is consistent with its mechanism of action.23,29 STUDY STRENGTH AND LIMITATION The strength of our review is that this review only includes RCTs and consists of a large total sample from various study locations across different countries, thus indicating strong evidence.19 On the other hand, there are some limitations to our review, such as limited data provided by the evidence. CONCLUSION In conclusion, canagliflozin causes a significant decrease in eGFR declining per year in T2DM patients. Canagliflozin has some renoprotective effects because of its mechanism in blocking SGLT1 and SGLT2 thus lowering blood glucose. These mechanisms lead to reduction in intraglomerular pressure, blood pressure, body weight, and glue toxicity in renal tissue thereby providing renoprotective effects. Moreover, canagliflozin also has other promising beneficial effects especially on cardiovascular function. However, canagliflozin has some limitations due to its higher cost and some complication as increase in urination in risk of genitourinary infection. RECOMMENDATION The result of this systematic review may suggest canagliflozin as a potential candidate for the new first line treatment for T2DM patients due to its effectiveness in lowering blood glucose and protective effects on renal and cardiovascular function. Even so, it remains to be further investigated regarding the side effects and contraindications of this drug.

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10. Johansson GM, Grip H, Levin MF, Häger CK. The added value of kinematic evaluation of the timed finger-to-nose test in persons post-stroke. 2017;1–12. 11. Vlado P, Jardine MJ, Neal B, Severine B, JL HH, M CD, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med [Internet]. 2019 Jun 13;380(24):2295–306. 12. Takenaka T, Kishimoto M, Ohta M, Tomonaga O, Suzuki H. Sodium-glucose co-transporter type 2 inhibitors reduce evening home blood pressure in type 2 diabetes with nephropathy. Diabetes Vasc Dis Res [Internet]. 2017;14(3):258–61. 13. Heerspink HJL, Desai M, Jardine M, Balis D, Meininger G, Perkovic V. Canagliflozin slows progression of renal function decline independently of glycemic effects. J Am Soc Nephrol. 2017 Jan;28(1):368–75. 14. Neal B, Perkovic V, Mahaffey KW, Zeeuw DD, Fulcher G, Erondu G, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. Postgrad Med [Internet]. 2018;130(2):149–53. 15. Bode B, Stenlöf K, Harris S, Sullivan D, Fung A, Usiskin K, et al. Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55-80 years with type 2 diabetes. Diabetes, Obesity and Metabolism. 2015; 17(3): 294–303. 16. Jakher H, Chang TI, Tan M, Mahaffey KW. Canagliflozin review - safety and efficacy profile in patients with T2DM. Diabetes Metab Syndr Obes. 2019;12:209-15. 17. Kumar KMP, Ghosh S, Canovatchel W, Gardoia N, Rajashekar S. A review of clinical efficacy and safety of canagliflozin 300 mg in the management of patients with type 2 diabetes mellitus. Indian J Endocrinol Metab. 2017 Feb; 21(1):196-209. 18. Brocavich SS, Hilas O. Canagliflozin (Invokana), a novel oral agent for type-2 diabetes. P T. 2013;38(11):656-60. 19. Deeks ED, Scheen AJ. Canagliflozin: A review in type 2 diabetes. Adis Drug Evaluation. 2017 Aug 23;77:1577-92. 20. Mima A. Renal protection by sodium-glucose cotransporter 2 inhibitors and its underlying mechanisms in diabetic kidney disease. J Diabetes Complications. Juli 2018;32(7):720–5. 21. Ninčević V, Omanović Kolarić T, Roguljić H, Kizivat T, Smolić M, Bilić Ćurčić I. Renal Benefits of SGLT 2 Inhibitors and GLP-1 Receptor Agonists: Evidence

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Supporting a Paradigm Shift in the Medical Management of Type 2 Diabetes. Int J Mol Sci. 20 November 2019;20(23):5831. 22. Davidson JA. SGLT2 inhibitors in patients with type 2 diabetes and renal disease: overview of current evidence. Postgraduate medicine. 2019 May 19;131(4):251-60. 23. Zelniker TA, Braunwald E. Cardiac and renal effects of sodium-glucose co-transporter 2 inhibitors in diabetes: JACC state-of-the-art review. Journal of the American College of Cardiology. 2018 Oct 9;72(15):1845-55. 24. Vasilakou D, Karagiannis T, Athanasiadou E, Mainou M, Liakos A, Bekiari E, Sarigianni M, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: A systematic review and meta-analysis. Ann Intern Med. 2013 Aug 20;159(4):262-74. 25. Neal B, Perkovic V, Mahaffey KW, Zeeuw DD. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2018;377:644-57. 26. Lam CSP, Chandramouli C, Ahooja V, Verma S. SGLT-2 inhibitors in heart failure: Current management, unmet needs, and therapeutic prospects. JAHA. 2019 Oct 15;8(20). 27. Ropero AG, Delgado APV, Gallego CGS, Badimon JJ. Inhibition of sodium glucose cotransporters improves cardiac performance. Int J Mol Sci. 2019 Jul;20(13):3289. 28. Kelly MS, Lewis J, Huntsberry AM, Dea L, Portillo I. Efficacy and renal outcomes of SGLT2 inhibitors in patients with type 2 diabetes and chronic kidney disease. Postgraduate Medicine. 2019 Jan 2;131(1):31-42. 29. Kluger AY, Tecson KM, Lee AY, Lerma EV, Rangaswami J, Lepor NE, Cobble ME, McCullough PA. Class effects of SGLT2 inhibitors on cardiorenal outcomes. Cardiovascular diabetology. 2019 Dec 1;18(1):99.

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Sodium-Glucose Cotransporter (SGLT2) Inhibitors For Prevention of Type 2 Diabetes Mellitus (T2DM) and Its Associated Complications In People At Risk For The Developement of T2DM : Literature Review ABSTRACT Introduction : In recent years, new classes of antihyperglycemic have appeared. And one of new agent is Sodium-glucose cotransporter 2 inhibitors (SGLT2i), this agent also has approved by Food Drug Administration. SGLT 2 inhibitor, consist of empagliflozin, canagliflozin, dapagliflozin, and the latest addition is remogliflozin.8SGLT2 inhibitors act in proximal tubule of the kidney principally, by inhibiting and blocking reapsorption of filtered glucose, and it can reduce hyperglycemia effectively through reduction of body weight, reduction blood pressure (both systolic and diastolic), cardiovascular and renal protection, decrease disease proression by improving β-cell insulin secretion and insulin sensitivity in peripheral tissues, associated with a reduction in plasma glucose consentration. Besides decreasing plasma glucose, they also induce someweight loss, lower BP and carry a low risk of hypoglycaemia. Some SGLT2 inhibitors also have cardiovascular and renalbenefits. They are generally well tolerated but have several well-recognised adverse effects that should be considered to optimise their risk to benefit ratio. Objective : The study highlights the efficacy of SGLT2 inhibitors for prevention of type 2 diabetes mellitus and its associated complications in people at risk for the developement of T2DM. Conclusion : As for the advantages of SGLT2 inhibitors, namely that it can reduce hyperglycemia effectively through weight loss, decreased blood pressure (both systolic and diastolic), cardiovascular and kidney protection, decreased disease progression by increasing β cell insulin secretion and insulin sensitivity in peripheral tissues, associated with decreased concentration. plasma glucose. Apart from the advantages. The adverse effect of SGLT2i are minor, such as genital mycotic infections, lower urinary tract infections, some cases of diabetic ketoacidosis. So, SGLT2i is recommended as alternative theraphy for the T2DM patients.

Keywords : SGLT2 inhibitors, T2DM, Complication of T2DM

125

I. Introduction

remogliflozin.8SGLT2 inhibitors act in

continues to increase every year. WHO

proximal tubule of the kidney principally,

has estimated about 422 million people in

by inhibiting and blocking reapsorption of

the world have diabetes.1 In additional, IDF has estimated approximately 463 million adults aged 20-79 yaers were living with diabetes in the world. WHO

β-cell

and the prevalence of diabetes has

through

and

renal

protection,8

insulin

secretion

and

insulin

sensitivity in peripheral tissues, associated

continued to increase.1

with a reduction in plasma glucose consentration.10

T2DM occurs when the body becomes resistant to insulin1 with relative insulin

Besides decreasing plasma glucose, they

deficiency.3 In the past three decades the

also induce someweight loss, lower BP

prevalence of type 2 diabetes has risen

and carry a low risk of hypoglycaemia.

dramatically in countries of all income

Some

levels.1In most countries, people with type

glucose

also

have

well-recognised adverse effects that should

developing type 2 diabetes.2T2DM is sensitizers

inhibitors

generally well tolerated but have several

million people have increased risk of

insulin

SGLT2

cardiovascular and renalbenefits. They are

2 diabetes is increasing, it is about 374

be considered to optimise their risk to

benefit ratio.12

absorption

inhibitors and glucagon- like peptide-1

II. Method

receptor agonists.9 years,

effectively

and it can reduce

decrease disease proression by improving

last few decades, both the number of cases

recent

hyperglycemia

cardiovascular

associated to diabetes each year. Over the

pressure (both systolic and diastolic),

estimated about 1,6 million deaths are

secretagogues,

filtered glucose,5,

reduction of body weight,4 reduction blood

with

canagliflozin,

dapagliflozin,7 and the latest addition is

The prevalence of people with diabetes

treated

empagliflozin,

As a literature study, this written consists new

classes

of analysis and synthesis from various

antihyperglycemic have appeared. And

referencesof

one of new agent is Sodium-glucose

obtained. The references of this literature

cotransporter 2 inhibitors (SGLT2i),5 this

study are taken from references which are

agent also has approved by Food Drug

published

Administration.5 SGLT 2 inhibitor, consist

Scholar, PubMed, ProQuest, and Science

126

various

globally

journals

through

which

Google

Direct. The references obtain should fit

which include deaths, the progression of

into inclusion criteria, that is : 1) published

cardiovascular or kidney diasease.5

from 2016-2020; 2) obtain in English

Second-line pharmacotherapy selection for

Language and; 3) fulltext and related to the

patients with T2DM optimized on MET, or

certain. Then, author does the analysis and

with intolerance or contraindication to

synthesis on those references as the

MET, is debated. Experts recommend that

sources of literature.

patient-specific considerations and shared decision-makingshould

III. Discussion Actually,

the

major

treatment

incorporated

into treatment decisions. SGLT2-I are one

and

of promising new classes of diabetes

management for patients with T2DM is

pharmacotherapy.16

the developement in lifestyle intervention, including increasing physical activity,

Sodium-glucose cotransporter-2 (SGLT2)

control weight, and healthy diet. Even, to

inhibitors have emerged as a new class of

control glycemic, just from weight loss.

OHAs, which act by inhibiting renal

But, beside of that, if pharmacotheraphy is

glucose reabsorption mediated by SGLT2

necessary, so the major agent that can use

in the proximal renal tubule, thereby

is metformin, it has been recommended

increasing urinary glucose excretion and

consistently as useful agent in T2DM. But,

reducing blood glucose levels. In addition,

some study show that, some of patients are

these agents are associated with caloric

intolerant

loss, resulting in weight loss as well as a

metformin,

because

adverse effect like diarrhea (10 %) or renal

reduction

disorder, so SGLT2i is recommended as

triglyceride levels.15

alternative theraphy for this patients.

blood

pressure

and

A novel class of anti-diabetic drugs,

Because the available antihyperglicemic

sodium glucose cotransporter type 2

agents are less efficacious and may be

inhibitors

harmful,

as alternative treatment,

convincing glucose-lowering effects but

SGLT2i is have gained popularity.4 In few

also exhibit promising effects on metabolic

years, because of SGLT2 inhibitors, so

disorders such as obesity and insulin

there have been many studies and trials of

resistance.

this new agent, and the outcomes show

therapeutic activity independent of insulin

that the benefit on important clinical result,

action, by facilitating glucose excretion

(SGLT2i)

SGLT2

through the kidney.18

127

not

only

exert

show

their

Beside of improving glycemic control,

Besides reducing glycemia, SGLT2i has

SGLT2i

benefit

also

useful

in reducing

reducing

cardiovascular

glycosylated hemoglobin (HbA1C) about

mortality and renal protection.7 SGLT2i

0,5 until 10 percen. And the important to

also act effectively in individuals with

know that, SGLT is also useful to decrease

long-standing diabetes and has depleted β-

body weight and blood pressure.4

cell reserve, it can also increase in UGE, through reduction in plasma glucose and

Glucose lowering SGLT2 inhibitors have

HbA1c

been studied as monotherapy or in

for

the

management

regimen.9 Insulin

mmol/mol

independent

is the

primary mechanism of action, it

inhibitors achieve a reduction in HbA1c of 12.1

causing

levels was independent of the insulin

hyperglycaemia in type 2 diabetes. SGLT2

4.4–

without

hypoglycemia.8 The decrease in HbA1c

combinationwith other oral agents or insulin

levels,

associated to benefit of SGLT2i in acting

(0.4–1.1%),

to induce glucosuria, so it can effectively

depending on the baseline HbA1c and the

lower blood glucose.11

specific drug and dose used [1–4]. HbA1c is reduced to a slightly greater extent by

During the progress of diabetes,4 T2DM

high-dose canagliflozin (vs other SGLT2

theraphy has many additional use regimens

inhibitors), probably as a result of its

to control hyperglycemia well.5 There is

additional action of inhibiting SGLT1 in

study shows that the teatment for diabetes

the intestine.12

needs 3 agents, for example metformin combine with 2 other agents. This meta

There is study found that dapagliflozin 5

analyses also shows that combination both

mg once daily for 12 weeks for the

of metformin and SGLT2 are more

treatment of T2DM, especially for obese, it

efficacious compared to combinating other

can reduce HbA1c and reduce body weight

antihyperglicemic

significantly.6Some clinical studies also

HbA1C, but increased the risk of agent-

insulin was effective and well tolerated in

related AEs, and it also associated to the

patients with T2DM.9Then, other agent

risk of hypoglycemia.7 SGLT2i might

from SGLT2i is empagliflozin, it can the

complication

This

combination led to significant decreases in

reported that combination of SGLT2iand

reduce

agents.4

similarly decrease glucose utilization,

diabetes

increase

significantly, including both microvascular

fat

oxidation

and

ketone

production and shift the whole body

and macrovascular.11

towards catabolism. However, glucose

128

utilization is restricted in two different

(Jardiance,

Boehringer

ways: a LCHD limits glucose influx from

Approved

fixed-dose

the gut, while SGLT2i enhances urinary

products include canagliflozin/ metformin

glucose disposal. It is presumed that

(Invokamet,

LCHD lowers portal glucose levels and

dapagliflozin/ metformin (Xigduo XR,

diminishes hepatic glucose uptake. In

AstraZeneca),

contrast,

linagliptin

SGLT2is

likely

not

Janssen),

Ingelheim). combination

extended-release

and

empagliflozin/

(Glyxambi,

Boehringer

manipulate portal glucose levels, butmay

Ingelheim) and empagliflozin/ metformin

manipulate metabolic changes in the

(Synjardy,

kidney, such as gluconeogenesis or lipid

Ipragliflozin,

oxidation.18

tofogliflozin has been approved in Japan

Boehringer

Ingelheim).

luseogliflozin,

and

for subjects with type 2 diabetes. SGLT2

The adverse effect of SGLT2i are minor,

inhibitors have various advantages as oral

such as genital mycotic infections, lower

antidiabetic

urinary tract infections, some cases of

agents:

effective

glucose

lowering, low risk of hypoglycaemia as

diabetic ketoacidosis.10

monotherapy

and

when

used

with

A Significant number of efective drugs for

Pioglitazone,

long-term control of high-glucose levels in

Metformin, reduction in visceral fat, long

T2D patients have demonstrated their

durability of action, weight loss, and

effectiveness in reducing microvascular

reduction of systolic blood pressure. 13

complications. Unfortunately, these drugs

DPP-4

inhibitors

The screened 2870 patients; of these 288

have not shown clear benefits in reducing

(10.03%)received

CV adverse events, even few of them may

therapy.

be harmful when administered to patients

SGLT2

Monotherapy

inhibitor

with

SGLT2

inhibitors was present in 21 (6.25%).

with concomitant cardiac disease. The

Metformin was the most frequent AHA

SGLT2i represent a newclass of drug with

(57.29%)

a promising future.17

combined

with

SGLT2

inhibitors. Most patients used at least IV. Result The

2additional different antidiabetic drugs

FDA

has

approved

(46.87%). Co-morbidities were present in

SGLT2

38 (13.19%) patients. Fifty-three (18.40%)

inhibitors for use in adults with type 2 diabetes:

Canagliflozin

(Invokana,

Janssen),

dapagliflozin

(Farxiga,

AstraZeneca),

and

patients

required

insulin.In

the

dapagliflozin group, mean patient age was57.68 ± 11.06 years (range 34 to 82).

empagliflozin

129

According to gen-der, there were 135

(OR 3.17 95% CI[2.63, 3.71]) and men in

(58.69%) women and 95 (41.3%)men.

the treated group was reported.14

HbA1C goals were met in 19.56% of

Conclusion :

patients. Inthe canagliflozin group, 58 cases were included. Meanpatient age was

Sodium-glucose 2 (SGLT2i), have also

58 ± 10.56 years (range 30 to 83). Ac-

been

cording to gender, 28 (50%) patients were

Administration.

men and 28(50%) women. HbA1C goals

consisting of empagliflozin, canagliflozin,

were met in 18.96% of pa-tients. The

dapagliflozin, and the newest addition is

canagliflozin

average

remogliflozin. SGLT2 inhibitors, are the

reductionon the HbAC1 levels from 9.72%

most recently available oral drugs category

to 8.69% and the dapa-gliflozin group

of glucose-lowering drugs, exerting their

from 9.90% to 8.83%.Both therapies

effect

hadsimilar reductions of HbA1C with no

excretion.

significant

group

had

differ-ence

between

them.

that

(19.44%) patients. The combination of

blood

dipeptidyl peptidase 4(DPP4) inhibitors highest

control

plasma

insulin

urinary

tract

reduce

hyperglycemia

pressure

(both

cardiovascular

systolic and

and kidney

glucose.

Apart

from

the

infections, lower urinary tract infections,

severe

infections

can

are minor, such as genital mycotic

some cases of diabetic ketoacidosis. So,

hypoglycemic events, ketoacidosis, and severe

glucose

advantages. The adverse effect of SGLT2i

than non-insulin users (22.13%,P< 0.05, 0.84]).

urinary

associated with decreased concentration.

requirement had poorer control (7.75%)

CI[0.07,

inhibitors,

insulin sensitivity in peripheral tissues,

cant difference between dapagliflozin and

95%

boosting

Drug

by increasing β cell insulin secretion and

(3.2 vs. 2.7 kg,P= 0.657) with no signifi-

with

SGLT

Food

protection, decreased disease progression

regimens. Mild weight loss was reported

Patients

diastolic),

rate

(30.30%/26.55%) compared with other

canagliflozin.

the

effectively through weight loss, decreased

SGLT2 inhibitors with sulfonylureas, and

the

As for the advantages of SGLT2i, namely

Overall HbA1C goals were met in56

had

approved

SGLT2i is recommended as alternative

were

theraphy for the T2DM patients.

reported. However, a higher frequency of urinary tract infections(OR 2.3, 95% CI

More reasearch is needed to evaluate these

[1.81, 2.78])

benefits in clinical settings.

and mycotic

infections

(OR4.02, 95% CI [4.02, 5.18]) in women,

130

and Glucagon Kinetics During

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132

CORNEAL CONFOCAL MICROSCOPY AS AN EARLY DIAGNOSTIC TOOL FOR DIABETIC NEUROPATHY: A SYSTEMATIC REVIEW

ABSTRACT Objective: To evaluate the effectiveness of corneal confocal microscopy, its parameters, and threshold as an early diagnostic method for diabetic neuropathy Method: A systematic review was conducted through PubMed, CENTRAL, and Scopus, searching for studies implementing corneal confocal microscopy (CCM) in patients with diabetes for detecting neuropathy in the early stage. Quality assessment of studies selected were performed using selected risk-of-bias assessment tool. Results: The search yielded 9 studies with a total of 2027 subjects. From the 9 studies reviewed, CCM proved to be a reliable method of diagnosis for diabetic neuropathy with consistent sensitivity and specificity. Fiber length, density, and bead size are the most reliable parameters for diagnosis. Conclusion: Significant correlation between CCM parameters and diabetic neuropathy were found. Therefore corneal confocal microscopy showed promising potentials as an early diagnostic tool for diabetic neuropathy. Keywords: Corneal confocal microscopy, diabetic neuropathy, early diagnosis INTRODUCTION

cardiovascular

Diabetes is a significant metabolic

complication

diseases.3 of

One

common

diabetic

diabetes

condition characterized by inappropriately

peripheral

elevated blood glucose levels. About 422

characterized by loss of sensation, tingling,

million people are affected by diabetes, 1.6

and other types of neuropathic pain on the

million of which died because of the disease.1

lower limbs.4

In Indonesia alone, about 7% of the

neuropathy,

Diabetic

condition

neuropathy occurs when

population are affected by diabetes.2 This is a

there is damage to sensory nerve fibers and

cause of concern as diabetes can lead to

cell death as a result of oxidative stress and

various complications, including blindness,

inflammation.

kidney

resistance, and overall dysregulation of

failure,

limb

amputations,

and

133

Hyperglycemia,

insulin

metabolic pathways are the main causes of

making early and accurate diagnosis difficult.

excessive reactive oxygen species that result

Consequently, a valid and quantifiable

in axonal injury. Consequently, patients with

method of diagnosis is needed to detect

diabetic neuropathy could develop foot

diabetic neuropathy at its earliest stage.7

ulcers, experience pain, and even progress to

There are several instruments that can

the extent of the need for lower limb

be used to diagnose diabetic neuropathy, such

amputation. It is almost definite that the

quality of life will be severely affected by this

Instrument

condition. Currently, treatment for diabetic

Assessment,

neuropathy is limited to supportive care and

Symptom. Despite that, currently there is no

glycemic control, which might be limited in

consensus about which questionnaires are

terms of prognosis. However, early diagnosis

best used for diagnosis or evaluating the

could

further

degree of the disease, and the evaluation

complications, such as foot ulcers and

relies solely on clinical expertise and

amputation, as high-risk patients would

judgement, which might be unreliable in

receive more intensive glycemic control and

some cases.4

vital

preventing

Michigan

Neuropathy

questionnaire and

Screening

and

Diabetic

Physical

Neuropathy

foot care to reduce risk of foot ulcers. Thus,

The gold standard for early diagnosis

prevention and early diagnosis is vital in

is the nerve conduction velocity test. This

implementing management as early as

method exhibits decrease in nerve conduction

possible,

other

velocity and reduction in amplitude of

complications and ensure that the highest

muscle action potential in patients with

quality of life possible can be achieved.5,6

diabetic neuropathy. Its strength relies on the

order

Currently,

prevent

diagnosing

diabetic

fact that it is quantifiable, repeatable, and

neuropathy is still a challenge, proven by

sensitive enough to detect sensory and motor

many cases where it is often diagnosed late

losses when symptoms have not been

where severe consequences, such as foot

apparent, as well as its ability to predict

ulceration, have already manifested. In

ulceration and mortality. However, this

addition, half of the patients with diabetic

method is invasive and painful. Moreover, its

neuropathy are asymptomatic. Even when

utilization requires highly trained specialists,

symptoms are present, many patients have

such that this diagnostic tool is not widely

trouble describing their symptoms clearly,

available in public health units. It is also

134

limited to detecting large nerve fiber

improving the quality of life of diabetic

dysfunction, and not small sensory fiber

patients.

damage, even though this small fiber damage is the earliest manifestation of diabetic

METHODS

neuropathy.4,8 Hence, there is an opportunity

Search strategy

in developing a better diagnostic method.

This systematic review of clinical

Recent studies show that corneal

trials is conducted based on the PRISMA

confocal microscopy (CCM) can be used to

statement. We explored PudMed, Cochrane

detect early diabetic neuropathy. CCM

Controlled Register of Trials (CENTRAL),

detects morphology of corneal nerve fibers in

Scopus databases from the last 5 years up to

sub-basal corneal plexus by illuminating a

17th October 2020 with the following

single point of tissue and reconstructing it

keywords:

into a high resolution, magnified image.

microscopy”, “diabet*”, and “neuropathy OR

Parameters commonly measured are nerve

polyneuropathy”. The search was limited to

fiber density, nerve fiber length, nerve fiber

human participants and the language was

branching, beading, and tortuosity.9 It can be

restricted to Bahasa Indonesia and English,

used to quantify small nerve fibre function,

which were the only languages readable by

thus detecting early diabetic neuropathy. In

the authors. Details of the literature search

addition, it is non-invasive compared to the

strategy are shown on Figure 1.

“cornea*”,

“confocal

current gold standard of diagnosis.10 Therefore, this systematic review aims to evaluate the diagnostic value of CCM for early detection of diabetic neuropathy, along with its parameters and threshold. Through the results of this review, the authors hope to improve guidelines of current diabetic

neuropathy

improving management

early of

diagnosis,

diagnosis diabetic

thereby

and

patients,

risk and

consequently, reducing complications and

Figure 1. Diagram flow of literature search strategy.

135

Inclusion and exclusion criteria

The main characteristics of included

Studies were screened according to the

inclusion

(1)

in Table 1. The initial search yielded 190

study

studies from PubMed, Scopus, and Cochrane

population, involving patients of type II

Controlled Register of Trials (CENTRAL)

diabetes mellitus with or without neuropathy.

databases. Duplicates were removed, titles

Conversely, exclusion criteria were also set:

and abstracts were screened, and finally full-

(1)

(2)

text articles were assessed for eligibility.

unknown and/or inappropriate study types

Fourteen were further excluded due to

and settings, (3) incompatible language

irrelevant

(articles not in English or Bahasa Indonesia).

restrictions, and irrelevant outcomes. This

observational

criteria studies;

irretrievable

as and

full-text

follows:

studies in this systematic review are shown

(2)

articles,

study

designs,

language

resulted in a final of 9 studies to be included Data extraction and risk of bias assessment

in qualitative synthesis, comprising 2 cohort

We extracted data from selected

studies and 7 cross-sectional studies.

studies, which include: author and year of publication, location, study design, study

Study characteristics and outcomes Study characteristics included in this

population, intervention, and outcome. These Newcastle-Ottawa

review are shown in Table 1. Overall, this

Scale, which consists of 9 domains with

review included a total of 2027 patients.

scores of 7-9 classified as good quality, 4-6

Studies were conducted in 6 countries across

as having high risk of bias, and 0-3 as very

the world. Outcomes were associated with

high risk of bias. Risk of bias assessment was

relevance of confocal microscopy assessment

conducted by the three reviewers (NE, PG,

in terms of nerve fiber density (NFD), nerve

and VJ) and any discrepancies were resolved

branch density (NBD), nerve fiber length

by consensus between reviewers. Appendix 1

(NFL), and nerve fiber tortuosity (NFT) to

provides details of risk of bias assessment of

severity

included studies.

corresponding p-values. These also show

were

assessed

using

neuropathy

with

their

relevant thresholds for which diabetic neuropathy can be diagnosed.

RESULTS Study selection

Based on quality assessment, the majority of the studies fulfilled more than 7

136

Table 1. Characteristic of studies No Author; Year Location of Publication 1 Hafner J et al; Vienna, 201917 Austria

Study design

Study population

Prospective, 94 type 2 DM cross-sectional • 68 no DR study • 48 NPDR •

Assessment •

41 PDR •

•

Andersen ST et al; 201818

Denmark

Crosssectional study

144 type 2 DM 25 controls

Imaging with Heidelberg Spectralis OCT for macular and peripapillary neuroretinal layer thicknesses Confocal microscopy for evaluating NFL, NFD, and NBD Skin punch biopsy and lower limb inspection using 2 validated scores: Utah Early Neuropathy Scale (UENS) and Michigan Neuropathy Screening Instrument (MNSI)

DPN defined according to Toronto criteria for confirmed DPN

137

Results •

↓NFL and NFD in NPDR and PDR compared to no DR; and PDR compared to NPDR

•

Similar NFD and NFL for eyes with PDR and no DR

•

↓IENFD in NPDR (p<0.001) and PDR (p<0.001) compared to no DR

•

Loss of statistical significance for the differences in NFD between PDR and no DR during secondary sensitivity analysis

•

Low negative correlation of intraepidermal and corneal fiber loss with UENS and MNSI (p<0.05)

•

Moderately significant positive correlation between stage of DR and UENS (p<0.001) and MNSI (p<0.001) score

•

↓NFD in patients with confirmed DPN (p=0.04) and without DPN (p=0.01) compared to controls

•

No significant difference between NFL (p=0.06) and NBD (p=0.29) between groups

Yan A et al; 201922

Manchester, UK

Crosssectional

•

NFD associated with age, height, total- and LDL cholesterol

•

57 type 2 DM patients

•

DPN assessed by Toronto consensus criteria

•

↓CNFD in diabetic patients compared to healthy controls (P<0.001)

•

26 healthy controls

•

54 type 1 DM as disease control group

Neuropathy severity assessed by TNS, vibration sensibility (128 Hz tuning fork), pinprick sensibility (Neurotip)

↓CNBD and CNFL in type 2 DM patients (CNBD: P<0.001; CNFL: P<0.001)

•

↓IWL in type 2 DM patients (P<0.001)

•

In vivo CCM conducted bilaterally and image analysis were conducted using the fully automated nerve analysis software ACCMetrics.

•

28% difference in IWL (P=0.009); 22% difference in CNFL (P=0.02); CNBD was 29% lower in DPN+ (P=0.02); CNFD was 18% lower (P=0.03)

•

8 images representing the central cornea dan 5 images representing inferior whorl were identified

•

Corneal nerve variables quantified were CNFD, CNFL, CNBD, and IWL

138

Xiong Q et al; 201725

Shanghai, China

Crosssectional, observational study

128 type 2 DM patients: • 49 no DSPN •

43 mild DSPN

•

36 moderateto-severe DSPN

24 age-matched controls

•

• •

•

139

DSPN assessed using Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes in 2009 dan Consensus Statement of the joint 8th International Symposium CCM performed using HRT II microscope with RCM Examination sites were the central cornea dan part of the cornea 2 mm inferior to the limbus From 100 singles images captured during each examination, 5 nerve fiber images were selected were selected to be processed using Fiji imaging analysis software Parameters assessed were CNFL, CNBD, and CNFD

•

↓CNFL in type 2 DM patients compared to healthy control (no, mild, and moderate-to-severe DSPN) (P=0.012, P=0.003, and P<0.001 respectively)

•

↓CNFL in patients with moderate-tosevere DSPN compared to patients with no DSPN (P<0.001) or mild DSPN (P=0.004)

•

↓CNBD in type 2 DM patients compared to healthy control (P=0.036,P=0.016, and P<0.001 respectively)

•

↓CNBD in patients with moderate-tosevere DSPN compared to patients with no DSPN (P<0.001 for both)

•

Neither CNFL nor CNBD decreased significantly between patients with no or mild DSPN.

•

CNFD was similar among the four groups (Healthy control, no, mild, or moderate-to-severe DSPN)

Ishibashi F, 201627

Japan

Crosssectional

•

Ishibashi F, 201728

Hiroshima, Japan

Crosssectional

•

162 type 2 DM patients, with or without clinical evidence of diabetic neuropathy 45 healthy control subjects

•

103 subjects with diabetes type 2, with or without clinical evidence of diabetic neuropathy 42 agematched control

•

• • •

140

DPN assessed with electrophysiology and nerve conduction velocity (NCV) studies Clinical evaluation of neuropathy using the Neuropathy Disability Score (NDS) CCM for evaluating NFD, NFL, NBD, tortuosity, and bead size

CCM to measure NFD, NFL, NBD, NBL, frequency of beading, and bead size Pupillary light reflex Clinical evaluation of neuropathy with DNSGJ criteria Electrophysiology and nerve conduction velocity studies at left medial malleoulus to assess DPN

•

↓CNFD, CNFL, CNBD, and BF in diabetic patients (P<0.0001)

•

Further reduction in patients with moderate and severe neuropathy Significant difference of CNFD and BS between patients with and without neuropathy (P=0.02, P=0.03) TG and BS in diabetic patients Significant correlation between HbA1c and all CNF parameters except TG and BF. NDS was associated with CNFD and CNFL inversely and with BS positively ↓CNFD and BF in diabetic patients without clinical signs of neuropathy TG and BS compared with those of the control subjects Neurophysiological test results in the patients without neuropathy were not different from those of the control subjects

• • •

Dehghani C, 201629

Queensland, Prospective Australia cohort

•

55 year old Caucasian male with type 2 DM

•

Annual assessments comprised of HbA1c, lipid profile and blood pressure DPN assessed using neuropathy disability score (NDS), quantitative sensory testing (QST) of thermal and vibration perception, nerve conduction studies (NCS) Corneal nerve parameters measured using IVCCM

•

NFL quantification and electrophysiological examination

•

AUC and diagnostic thresholds derived and validated in randomly selected samples using ROC analysis

Derivation AUC for NFL was 0.77 in type 1 DM (p<0.001) and 0.68 in type 2 DM (p<0.001), and reproduced in validation set

•

Optimal threshold for automated NFL was 12.5 mm/mm2 in type 1 and 12.3 mm/mm2 in type 2

•

In total cohort, lower threshold value below 8.6 mm/mm2 to rule in DSP and upper value of 15.3 mm/mm2 to rule out DSP associated with 88% specificity and 88% sensitivity

•

Perkins BA et al; 201830

Manchester, UK

Multicenter cohort study

998 from 5 centers 516 type 1 DM 482 type 2 DM

141

•

Rapid decline in CNFD, CNBD and fiber length (CNFL) before development of foot ulcer No significant deterioration of other measures (NDS, QST, NCS)

Tummanapalli Sydney, SS et al; Australia 31 2019

Prospective 38 type 1 DM and cross-sectional 32 type 2 DM patients

•

DPN assessed using Toronto consensus criteria

•

Neuropathy severity assessed using TNS, vibration sensibility (128 Hz tuning fork), pinprick sensibility (Neurotip)

•

Bilateral CCM examination

•

8 central and 3 to 4 IW images were selected and quantified for CNFD, CNFL, CNBD, CTBD, CNFrD, IWL, and IWNFrD

•

Images analysed using fully automated analysis software ACCMetrics

142

•

↓ all corneal nerve parameters in DPN+ patients compared to DPNpatients (P<0.050), except IWL (P=0.190)

•

CNFL had the highest AUC (0.809, P<0.003) with an optimum diagnostic threshold ≤ 13.64 mm/mm2 (81% sensitivity, 81% specificity), followed by CNFrD (0.777, P=0.007), CNBD (0.764, P=0.011), CNFD (0.762, P=0.012), and IWNFrD (0.734, P0.024)

•

AUC for IWL was not significantly different from the reference line (0.617, P=0.258)

of the criteria, indicating that the studies were

However,

there

are

various

of low bias risk and therefore relatively good

limitations to these approaches. Aside from

qualities.

being known to be painful and invasive, due to their nature, these approaches can only

DISCUSSION

detect large nerve fibers dysfunction, even

Gold standard for diagnosing diabetic

though most of the peripheral nerves (70-

neuropathy

90%) are classified as small. This means that

It has long been established that the

diabetic neuropathy can only be detected in

gold-standard for the diagnosis of diabetic

its severe form, despite the need for early

neuropathy is nerve conduction studies

detection that is a prerequisite for improving

(NCS). NCS is able to quantify conduction

early

velocity and amplitude of nerve action

enhancing quality of life. This is a great

potential. Both velocity and amplitude

disadvantage as late diagnosis prevents early

correlates strongly with neuropathy, as

risk factor management, which could impact

reduced amplitude imply axonal loss and

neuropathic sequelae.12 NCS and EMG also

slowing of conduction velocity imply axon

require specialized doctors and equipment

injury and demyelination. Meanwhile, EMG

which are not typically available in public

is able to record muscle electrical activity by

settings, further highlighting the need for a

using an insertional electrode. Abnormal

better

spontaneous activity such as sharp waves and

neuropathy in its early stage.11,12

prevention

approach

progression

diagnose

and

diabetic

fibrillation potential could suggest active denervation,

while

chronic

axonal

Corneal confocal microscopy and diabetes

neuropathies can be characterized by long

As the most densely innervated tissue

duration and large amplitude of motor unit

in the human body and being mostly

potentials,

axons

transparent, the eye provides a non-invasive

innervate denervated muscle fibers. As a

visual access to nerve fibers beneath, thus

result, EMG is not only valuable in

becoming a unique potential marker of

determining location of nerve lesion, but also

neurodegenerative changes. Recent studies

show that there is a strong relationship

determining

uninjured

the

motor

chronicity

neuropathy.11

between

corneal

nerve

structure

and

morphology with neuropathy.13 Corneal

143

confocal microscopy (CCM) is an in vivo,

and require specialized expertise, such as

non-invasive, novel technique to study the

NCV and EMG, or simply not objective

internal structure of cornea cellular structure.

enough, such as questionnaires.15

It is able to provide imaging comparable to in vitro histochemical technique. As a result,

Nerve fiber density, nerve fiber length, and

this technique has the potential as a marker

nerve branch density

for peripheral nerve damage.14

One

the

most

common

CCM is able to provide images for

microvascular complications of type 2

various layers of the cornea, from the

diabetes is diabetic neuropathy. In its early

epithelium, the Bowman’s membrane, the

development,

stroma, and finally the corneal endothelium.

neurodegeneration may be present before any

In studying nerve structure and morphology,

visible

the Bowman’s layer becomes the focus of

diabetes is a systemic disease, progression of

study as it shows nerve bundles of the sub-

ocular neurodegenerative change could be

basal nerve plexus.14 Parameters commonly

associated with neuropathic changes in other

observed are corneal nerve fiber length

organs. Hyperglycemia results in decreased

(NFL), corneal nerve fiber density (NFD),

oxygen and nutrient supply to small corneal

corneal nerve branch density (NBD), and

fibers, leading to changes in NFD, NFL, and

corneal

(NFT),

NBD. Similarly, due to high blood sugar

other

levels, vascularity of the eyes may become

nerve

although

fiber

recent

parameters

that

tortuosity

studies are

also

show

sensitive

also

provides

microvasculopathy

occurs.

of As

altered, leading to proliferative ocular

diagnosing neuropathy.13,14 CCM

manifestation

neurodegeneration.16 objective,

Hafner et al discovered that NFL and

quantifiable, and reproducible results. With

NFD were significantly decreased in eyes

the advancement of technology, there are

with

already several automated software to

diabetic retinopathy (PDR and NPDR) in

quantify the results of corneal nerve fibers, so

comparison to those without retinopathy. The

operators' expertise would not cause bias or

threshold values in this case were 14,7/mm2

interfere with results. This further support

for NFD and 14,6mm/mm2 for NFL.

CCM’s advantages over current methods of

Similarly, intraepidermal nerve fiber density

diagnosis, which are either invasive, painful,

(IENFD) in NPDR and PDR also decreased

144

proliferative

and

non-proliferative

compared to no DR. However, NBD is

been found that Aδ and C fibres were

deemed not as reliable as NFL and NFD in

susceptible to injury in patients with diabetes

diagnosing neuropathy. Despite measuring

due to the lack of of protection and nutrition

diabetic retinopathy, there is also strong

supply usually provided by Schwann cells.24

correlation

with

peripheral

Similar results were also found in a study by

neuropathy

have

similar

Xiong Q in which NFL, along with NBD and

complications

and

NFD, were reduced in type 2 DM patients

diabetic both

microvascular pathomechanism.17

with neuropathic symptoms compared to those without neuropathic symptoms.25

In line with that, Andersen et al’s study revealed significantly lower NFD in

Similar studies by Ishibashi et al

confirmed

diabetic

support CCM diagnostic value.26,27 In one

without

diabetic

study, it is observed that there is strong

polyneuropathy compared to controls.17 This

correlation between both NFL and NFD and

discovery is in line with previous studies

the severity of neuropathy. Although there is

which evaluate NFL and NFD as the most

no difference in neurophysiological tests

reliable

diabetic

between control and the subgroup without

polyneuropathy.19-21 Similarly, this study

neuropathy, there is a significant difference

also found that NBD is less reliable in

in NFL, NFD, and NBD.26 A different study

diagnosing neuropathy compared to other

by Ishibashi et al supported this, as there is

parameters.18

steady decrease of NFL, NFD, and NBD with

patients

with

both

polyneuropathy

and

markers

for

early

Another study by Yan et al also

increasing severity of diabetic neuropathy.27

proved that NFL showed the strongest

However, compared to NCV as gold standard

negative correlation with the severity of

of testing, NFL and NFD had the strongest

neuropathy, which is in line with previous

correlation,

studies conducted by Ahmed A et al and

although

Petropoulos et al.22,23 This study also shows

correlation.26

significant

decline

corneal

while still

NBD

shows

statistically

weak,

significant,

nerve

In a cohort study following a type 2

parameters in type 2 diabetes patients without

diabetic patient over a 7 year period, it is

clinical neuropathy. This finding supports the

further proven that NFL, NFD, and NBD is a

use of CCM for the early diagnosis of

reliable marker of diabetic neuropathy. These

neuropathic in diabetic patients.22 It has also

parameters rapidly decline in relation to the

145

severity of neuropathy, and especially before

altering the size of beads. In diabetic rats, it

the development of further complications

is observed that motor protein involved in

such as foot ulcer. In comparison, other non-

axonal transport of mitochondria is changed,

corneal parameters such as blood pressure,

resulting

lipid profile, neuropathy disability score

distribution. In addition, patients with

(NDS), and quantitative sensory testing

diabetic neuropathy usually have high

(QST) showed no deterioration, and even

mitochondrial accumulation of glycogen

showed improvement in QST. Therefore, it

particles. Alterations of these components

can be concluded that CCM is a reliable

might contribute to the changes in density

diagnostic

and size of bead.26

tool

for

neuropathy,

its

progression, and severity.28

changes

mitochondria

From a diagnostic point of view, corneal nerve bead size seems to be the most

Other parameters for diagnosis Aside

stated

parameters of CCM. Expansion of bead size

parameters, a study has also shown that

can be observed in patients without clinical

corneal nerve fiber bead size and nerve fiber

evidence of DPN, and gets larger with the

tortuosity (NFT) is a good indication of

severity of the neuropathy. It also has a good

diabetic

other

association with NCV of the median nerve,

parameters, bead size and NFT correlate

thus increasing potential for CCM as a

negatively with diabetic neuropathy, which

predictive tool for neuropathy in type 2

means that with increasing severity of

diabetes patients.26

neuropathy,

from

sensitive and specific compared to other

previously

neuropathy.

these

Unlike

parameters

increase. Threshold, specificity, and specificity

Altered beading structures have strong correlation with loss of nerve fiber density

On a larger scale, a multicenter study

and branches, while tortuosity is related to

by Perkins et al analyzed the receiver

nerve fiber length, therefore verifying further

operating

that NFL, NFD, and NFB is altered in

generated from CCM of type 2 diabetic

diabetic neuropathy patients.26,27

patients. Both manual and automated corneal

characteristic

(ROC)

curves

While the exact mechanism has not

nerve quantification revealed that CCM had

elucidated,

that

diagnostic validity for diabetic sensory

mitochondria dysfunction plays a role in

polyneuropathy, particularly through NFL as

been

predicted

146

the most optimal variable. In fact, the value

was already reduced compared to the healthy

of area under the curve was 0.68. These were

controls of similar ages.30

reproduced in the validation set. In the total

Similarly, in a study by Ishibashi et al,

cohort, a lower threshold value of below 8.6

NFL and NFD have high sensitivity and

mm/mm2 to rule in polyneuropathy and an

specificity, at 63% and 65% for NFL

upper value of 15.3 mm/mm2 to rule out

(p=0.071), and 66% and 54% for NFD

polyneuropathy was associated with 88%

(p=0.02). The threshold value between

specificity and 88% sensitivity.29

healthy subjects and diabetic patients is

Another study by Tummanapali et al

11.6mm/mm2 for NFL and 23.1/mm2 for

which analyzed the ROC curve also proved

NFD. Bead size also show consistent results

that in the diagnosis of DPN in type 2, NFL

at 65% sensitivity and 53% specificity, with

was the most optimal parameters with a value

threshold at 9.76µm2 (p=0.031). In addition,

of 0.809 (P < 0.003) for the AUC and an

there is strong correlation between NFL and

optimum diagnostic threshold value of ≤

NFD to NCV as gold standard of testing.26

13.64 mm/mm2, which is associated with

In comparison to neurophysiological

81% sensitivity and 81% specificity. This

assessment,

was followed by NFrD (nerve fractal

correlation. CCM findings were compared to

dimension) with an AUC value of 0.777 (P =

polyneuropathy assessment via the Utah

0.007), NBD with 0.764 (P = 0.011), NFD

Early

with 0.762 (P = 0.012), TBD (total branch

Michigan Neuropathy Screening Instrument

density) with 0.762 (P = 0.012), and IWNFrD

(MNSI). Low negative correlation of intra-

(inferior whorl nerve fractal dimension) with

epidermal and corneal fiber loss with UENS

0.734 (P = 0.024). This study also showed

and MNSI (p<0.05) was found, while

that IWL (inferior whorl length) was not a

moderately significant positive correlations

reliable parameter to discriminate patients

between stage of DR and UENS (p<0.001)

with diabetic neuropathy from those without,

and MNSI (p<0.001) score were also

as the AUC value of 0.617 (P = 0.258) is not

revealed. These showed the applicability of

significantly different from the reference line

CCM in evaluation of polyneuropathy

of 0.500. This may be because in type 2

severity.17

diabetic patients without DPN, the IWL value

CCM

Neuropathy

also

Scale

shows

strong

(UENS)

and

Therefore, in comparison to other markers for neuropathy, specificity and

147

sensitivity of CCM can be considered

researches are needed to confirm the possible

adequate or even superior. In fact, diagnosis

implementation of CCM in the official

via clinical signs revealed poor accuracy,

guideline

ranging from 25-85%.30 This particularly

neuropathy.

for

diagnosis

diabetic

leads to large proportions of underdiagnosis and misdiagnosis of diabetic neuropathy in

Limitations

clinical practice, such that CCM is a better

This study is not without limitation

reproducible option for diagnosis. CCM also

due to the exclusion of the studies not written

has superior specificity to the gold standard

in English or Indonesian, which are the

NCS, which has a value of 62.1%. The

languages readable by the authors. Another

sensitivity of CCM is lower than NCS (94%),

limitation is that most studies in this review

but since NCS can only detect large fiber

were conducted outside Asia. This indicates

neuropathies in the later stage, this difference

that more research on the use of CCM for the

can be ignored.31,32

diagnosis of diabetic neuropathy in Asia, specifically Indonesia, is needed in order to

Future application and research

develop the possibility of using this method

This review provides further evidence

as one of the diagnostic tools for diabetic

of the use of CCM as a marker of patients

neuropathy in this region in particular.

with diabetic neuropathy and that there is a possibility that this method can be used as

CONCLUSION

one of the main diagnostic tools for diabetic

Diabetes is one of the most common

neuropathy in the future. CCM has shown a

metabolic condition with possible severe

superior

adequate

complications including diabetic neuropathy,

sensitivity compared to nerve conduction

commonly diagnosed at a later stage. The

studies as the current gold standard in

invasive nature and late-stage detection by

diagnosing diabetic neuropathy. Moreover,

nerve conduction study as the current gold

the

early

standard prompts the need for another

polyneuropathy, along with its established

method which is as effective but less

feasibility and reproducibility, means that

invasive. This review has shown that the non-

CCM can potentially be one of the tools to

invasive CCM can be a more suitable method

diagnose

in order to diagnose diabetic neuropathy,

specificity

ability

and

CCM

diabetic

detect

neuropathy.

Future

148

with evidence from various studies that prove

consistency

the high sensitivity and specificity of CCM.

Furthermore, these parameters can be used to

With increasing severity of neuropathy,

gauge the severity of neuropathy. Further

NFD, NBD, and NFL decrease in value,

studies, especially in Asia, are needed to

while NFT and bead size increases with

investigate the possibility of implementing

consistency, even in early stages. This means

this method in the guideline for diagnosis of

that these parameters can be reliable

diabetic neuropathy and to further confirm

diagnostic

which parameters are the most reliable to be

markers

neuropathy,

although

for

early for

diabetic

NBD,

the

still

controversial.

used for diagnosis.

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153

APPENDICES Table 2. Bias assessment of the included studies Categories

Selection

Item No.

Quality assessment criteria

Perkins BA et al; 2018

Representativeness of the intervention cohort

✓

Selection of the non-intervention cohort

✓

Ascertainment of intervention

Andersen ST et al; 2018

Hafner J et al; 2019

Tumman apalli SS et al; 2019

Yan A et al; 2019

Xiong Q et al; 2017

Ishibashi F et al, 2016

Ishibashi F et al, 2017

Dehghan i C et al, 2016

✓

154

Selection (for case-control studies)

✓

5 Is the case definition adequate? 6

Comparability

Demonstration that outcome of interest was not present at start of study

Representativeness of the cases

Selection of controls

✓

Definition of controls

Study controls for one most important factor

✓

155

Comparability (for casecontrol studies)

Outcome

Study controls for any additional factor

✓

Study controls for one most important factor

✓

Study controls for any additional factor

Assessment of outcome

✓

Was follow-up long enough for outcomes to occur?

✓

Adequacy of follow up of cohorts

✓

156

Exposure (for case-control studies)

Ascertainment of exposure

Same method of ascertainment for cases and controls

✓

Non-response rate ✓

Overall Quality Score (Maximum = 9)

157

Cardioprotective Properties of Glucagon-Like Peptide-1 Receptor Agonist (GLP-1 RA) in Type 2 Diabetes Mellitus: A Systematic Review

ABSTRACT Introduction Cardiovascular diseases contribute as the cause of mortality in T2DM patients with prevalence of 52%. GLP1-RAs medication has proved to exhibit cardiovascular benefits which may be advantageous to reduce mortality in T2DM patients. Therefore, we reviewed the existing studies, focused on analyzing cardiovascular outcomes in GLP-1RAs medications. Method A computerized data searching was conducted through JSTOR, PubMed, Scopus, EBSCohost, and CENTRAL. We screened all related studies assessing the use of GLP-1 RAs in T2DM patients compared to control. Any cardioprotective properties were obtained for the outcomes. The quality assessment is conducted to minimize the risk of bias using JADAD score and Newcastle-Ottawa Scale depends on study design. Result We reviewed 6 studies, with various models and methods. The duration therapy of each study varied from 7.5 months to 3.2 years. These studies used either liraglutide or exenatide. GLP1 RA was combined with various OAD and two studies excluded patients with history of GLP-1 RA treatment. Moreover, these studies found that GLP-1 RA significantly caused weight loss and improved cardiac functional capacity through increasing LVEF and reducing end-systolic & enddiastolic LV volume. It also caused improvement on myocardial blood flow without affecting myocardial glucose uptake. However, these studies did not demonstrate GLP-1 RA effects in reducing blood pressure and improving lipid profile. Conclusion These studies demonstrated cardioprotective benefits of GLP-1 RA through reducing body weight, improving & preserving cardiac functional capacity, and elevating Myocardial Blood Flow. However, these studies failed to demonstrate several effects of GLP-1 RA, which are reducing blood pressure and improving lipid profile.

Keywords: T2DM, GLP-1 RA, cardioprotective

158

INTRODUCTION Based on WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD), 52% of deaths in type 2 diabetes mellitus (T2DM) were caused by cardiovascular disease (1). T2DM patients have increased risk of developing cardiovascular disease. Thus, to avoid untimely demise, cardiovascular disease in T2DM patients must be well managed.

Glucagon-like peptide-1 receptor agonist (GLP-1 RA) is a class of T2DM medication in adults, that mimics GLP-1, with various effects including enhances insulin production, induces satiety, and inhibits gastric acid & glucagon production (2). According to American Diabetes Association (ADA) Standard of Medical Care 2020, GLP-1 RA is proven to exhibit cardiovascular benefit (3). Compared to insulin, it has a lower risk of developing hypoglycemia and is also beneficial for weight loss. ADA also recommends GLP-1 RA to be combined with metformin in T2DM patients with established atherosclerotic cardiovascular disease (ASCVD) (3). Several clinical trials show various results on the cardiovascular benefit of GLP-1 RA therapy. However, to the best of our knowledge, there is no systematic review that comprehensively assess the cardioprotective capacities regarding GLP1-RA treatment. Therefore, this study aimed to evaluate and assess thoroughly about the cardioprotective capacities of GLP-1 RA therapy in T2DM patients.

METHOD Data Searching Strategy This systematic review was done according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement and based from Cochrane Handbook for Systematic Review of Interventions (4,5). Several databases including JSTOR, PubMed, Scopus, EBSCohost, and CENTRAL. We reviewed all relevant studies from inception to October 2020 with search keywords ((((GLP 1 receptor agonist[MeSH Terms])) OR (glucagon like peptide 1[MeSH Terms])) AND (cardioprotective agents[MeSH Terms])) AND (type 2 diabetes mellitus[MeSH Terms]). Boolean operators were applied to broaden and narrow the search results.

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Eligibility Criteria The search was limited to human participants with language restriction to English and Bahasa Indonesia. Subsequently, the inclusion criteria of our study were as follows: i) observational and interventional study either randomized or non-randomized, ii) adult patients (> 18 years old) and diagnosed with T2DM with GLP-1 RA therapy, iii) metformin or other standard oral antidiabetic drugs were used as the comparison. Any measured outcomes majorly including but not limited to cardiovascular events. In addition, exclusion criteria were also set: irrelevant title, irretrievable full-text articles, inappropriate study type, incompatible language (English or Bahasa Indonesia), and wrong PICO settings.

Data extraction and quality assessment Two investigators (WW and AC) conducted the data screening and extraction from eligible studies including: author and year of publication, study design and setting, sample size, mean or range of sample age, duration of therapy, type of GLP1-RA, and outcomes. Finally, to minimize the risk of bias, quality assessment of the eligible studies were performed through Newcastle-Ottawa Scale (NOS) for observational study and JADAD score for interventional study (6,7). The quality assessment was conducted by two reviewers (WW and AC) collaboratively, disagreement between investigators were adjudicated by third investigators (DN).

Result

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Table 1. Characteristic of Study No

Study

(risk of bias

Study Design

Country

Sampl

Duration of

Age

e Size

Therapy

(year

(months)

old)

7,5 (mean)

n/a

assessment) 1.

Varanasi et

Retrospective

al., 2012 (NOS score:

New York

110

Analyzed Variable

Type of GLP-1 RA

BMI, HbA1c, SBP,

Liraglutide

cross-sectional

CRP, fasting lipid

(titrated from

study

concentrations

0,6 mg/day,

9/9)

1,2 mg/day, 1,8 mg/day every 2 weeks)

Gejl et al.,

Randomized,

2012

double-blinded,

(JADAD score: 3/5)

Denmark

8"*

n/a

58,3

Myocardial Blood

Exenatide IV

Flow (MBF),

0,066

placebo-

Myocardial Glucose

pmol/kg.min

controlled

Uptake (MGU)

(mean)

crossover study 3.

Arturi et al.,

Single center,

2016

randomized,

(JADAD score: 3/5)

New York

32*

59,5

Gender, age, BMI,

Liraglutide

SBP, DBP, HR,

(uptitrated

parallel-group,

FPG, HbA1c, serum

from 0,6 mg,

pilot study

creatinine, ProBNP,

1,2 mg, 1,8

total cholesterol,

mg every

HDL, LDL,

week)

(mean)

161

amylase, lipase, calcitonin 4.

Bizino et al.,

Randomized,

2019

double-blind,

(JADAD

assessor-blinded,

score: 5/5)

placebo-

Netherlands

6,5

controlled,

Mean

LV diastolic and

Liraglutide

liraglutide systolic function,

(uptitrated

gorup:

BP, body weight,

from 0.6mg,

60; Mean

HbA1c, LVEDV,

1.2mg, and

LVESV, LVM,

1.8mg in

LVMI,

each week).

placebo

single-center

group: 59

clinical trial

LVMI/LVEDVI, creatinine, NTproBNP.

Bethel et al.,

Randomized ,

United

2020

double-blind,

Kingdom

(JADAD

placebo-

score: 3/5)

controlled

Raparelli et

Multiple center

al., 2020

cohort study

14.752

38,4

60 (mean) MACE, ACM

(median)

Exenatide 2mg once per week

Rome

167.25

59 (median)

Major cardiovascular

(NOS score:

events: AMI,

9/9)

unstable angina, heart failure, stroke.

*All subjects are Caucasian with T2DM. "All subjects are male.

162

n/a

Table 2. Study outcomes characteristic No. Study Evaluated Characteristic BMI Previous Medical History Consumption of (kg/m2) Diabetes Other Drugs Treatment 1. Varanasi 38,2 insulin/ Obese, antihypertensive and et al., metformin/ uncontrolled antilipidemic drugs 2012 sulfonylurea/ hyperglycemia, thiazolidinediones/ sitagliptine. 2.

Gejl et

31,9 +

al., 2012

1.0

Arturi et

< 45

al., 2016

Bizino et al., 2019

≥ 25

Insullin-naive, combined with metformin or sulfonylurea.

Non-smoker and without coronary arteries disease

metformin and/ or sulfonylurea.

Acute myocardial infarction and NYHA class II/ III and/ or LVEF <

insulin or metformin.

45%

Statins, sulfonylurea, angiotensin II antagonists, ACE inhibitors, and CaCB. ACE inhibitors and/ or ARB, beta blocker, aldosterone agonists, diuretics and/ or digoxin.

Stable BP <150/85 mmHg for at least 1 month.

antilipidemic agent or antihypertensive drugs.

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Cardiovascular Outcomes

Reduction in mean body weight, mean HbA1C, CRP, TG concentration, and SBP. Significant relationship between the reduction of TG &HbA1C and the reduction of CRP & HbA1c. Exenatide stabilized GLUT transport in patients with low insulin sensitivity. Exenatide significantly increased MBF and did not alter MGU. Liraglutide increase LVEF, anterograde stroke volume, and cardiac output. Liraglutide reduce indexed end-systolic & end-diastolic LV volume, mitral regurgitation and was associated with a significant reduction of ProBNP levels. Liraglutide cause reduced early LV diastollic filling and LV filling pressure, indicating its potential ability to postpone the onset HFpEF and concomitant morbidity & mortality.

Bethel et

Excluded patient with previous treatment of GLP1 RA.

Included patient with any prior CV risk and coronary, cerebrovascular, or peripheral artery event.

aspirin, thienopyridines, antiplatelets, antihypertensive, and antilipidemic agents

n/a

Ongoing use of metformin.

Excluded patient with diagnosis of T1DM, gestational diabetes mellitus, and cystic fibrosis.

antihypertensive, statins, and aspirin.

al., 2020

Raparelli et al., 2020

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EXSCEL-observed HRs for MACE and ACM remained robust after right censoring or application of literature-derived risk reductions, but exenatide versus placebo MACE effect size and statistical significance were increased by IPTW. Women experienced less major cardiovascular event and stronger risk reductions than men who currently treated with GLP-1RA than those treated with sulfonylurea.

Literature Search From the database search, we found 102 literatures

total.

After

removing

duplicates, we found 94 studies and we screened through the title and abstracts and found 8 eligible studies to be reviewed, but 2 must be removed because those two studies did not focus on the cardiovascular outcomes of GLP-1RA medications. Finally, we found one retrospective study(8), one multi center cohort study(9), and four randomized control studies(10–13) ranging from 2012 to 2020 involving 182.205 participants. The quality assessment using JADAD score and NOS score for the included studies resulted in all of the six studies with low risk of bias.

Characteristic of Study Sample of studies Two studies conducted in New York and the others are conducted in the United Kingdom, Denmark, Netherlands, and Rome. The sample of each study varied between 8 to 167.254 participants. In general, the mean age of the samples varied from 58.3-60 years old, but the study of Raparelli et al (2020) only revealed the median age of their sample, which is 59 years old.

Duration of Therapy The duration of therapy from each study varied between 7.5 months to the longest duration was 3.2 years. One study by Gejl et al (2012) did not state the duration of therapy of their study.

Type of GLP-1 RA Three studies used Liraglutide for their studies, while the other two used Exenatide, and the last study by Raparelli et al (2020) did not state the drugs used in their study. Study by Varanasi et al (2012) uptitrated the Liraglutide from 0.6mg/day, 1.2mg/day, and 1.8mg/ day every two weeks.

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Study by Arturi et al (2016) and Bizino et al (2019) also uptitrated the Liraglutide in the same dose but for every one week. Study by Gejl et al (2012) used intravenous Exenatide 0.066 pmol/kg.min and study by Bethel et al (2020) used Exenatide 2mg for once per week.

Medical History All of the studies included obese patient with body mass index (BMI) above 25 kg/m 2. Study by Gejl et al (2012) included only non-smoker patients and excluded those with coronary artery diseases or other significant diseases. Study by Arturi et al (2016) stated a more specific criteria(s) for their study. They included patients with history of previous acute myocardial infarction and NYHA class II/ III and/ or LVEF < 45%. In addition, they excluded patients with CHF due to or associated with uncorrected thyroid disease, clinically active cardiovascular disease, conventional myocardial revascularization procedure, hospitalization for acute heart failure, uncontrolled hypertension, history of malignancy, history of alcohol or drug abuse, liver or kidney failure, and any drug use that may disturb the glucose metabolism, and known or suspected hypersensitivity to trial or related products. Study by Bizino et al (2014) had the criteria of stable BP <150/85 mmHg for at least 1 month prior to the experiment and excluded those with history of renal, hepatic, or cardiovascular disease; history of gastric bypass surgery; pancreatitis; and pregnant or lactating women. Different from Gejl et al (2012), study by Bethel et al (2020) included patients with any degree of prior cardiovascular risk and also prior coronary, cerebrovascular, or peripheral artery events. Other than that, Bethel et al (2020) also excluded patients with history of two or more episodes of severe hypoglycemia in the last 12 months, end stage kidney diseases, personal or familial history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2, and a baseline calcitonin level >40ng/L. Finally, study by Raparelli et al (2020) excluded patients with gestational diabetes, type 1 diabetes mellitus, and cystic fibrosis.

Previous Diabetes Treatment In the study of Varanasi et al (2012), in total of 110 patients, 65 patients received combined therapy with insulin, 102 combined with metformin, 54 combined with sulfonylurea, 38 combined with thiazolidinediones, and 18 patients combined with DPP-4 inhibitor (sitagliptin). On the contrary, all patients in the study by Gejl et al (2012) were insulin-naive but received metformin therapy. Six out of eight patients received sulfonylurea, but all of these OAD medications were

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discontinued 48 hours prior the study day and other remaining medications were stopped 12 hours before treatment. Study by Arturi et al (2016) only included patients with previous treatment of metformin and/ or sulfonylurea. Additionally, study by Bizino et al (2019) had 6 patients with combined therapy with sulfonylurea and 15 patients combined with insulin. Both studies by Arturi et al (2016) and Bethel et al (2020) excluded patients who had a history of GLP-1 RA medications. The last study by Raparelli et al (2020) selected patients with ongoing use of metformin with criteria at least one prescription in 90 days before cohort entry.

Consumption of Other Drugs All of the studies disclosed their samples’ additional drug consumption beside antidiabetic drugs. Most patients consumed antihypertensive and antilipidemic agents including angiotensin II antagonist, ACE inhibitor, calcium channel blocker, ARBs, beta blocker, aldosterone agonist, diuretic, digoxin, aspirin, fibrate, niacin and statins. Study of Varanasi et al (2012) included 102 patients with antihypertensive; 92 patients with statin; 34 patients with fibrate; 22 patients with niacin; 76 patients with ACE inhibitor; 56 patients with hydrochlorothiazide; 47 patients with beta blocker; and 28 patients with calcium channel blocker. On the other hand, Bizino et al (2019), included 21 patients with antilipidemic agents and 18 patients with antihypertensive agents. Study by Gejl et al (2012) stated that their sample included 3 patients with angiotensin II antagonist, 6 patients with ACE inhibitor, and 5 patients with calcium channel blocker. Study of Bethel et al (2020) included 393 patients with antihypertensive, 300 patients with aspirin, 57 patients with thienopyridines, 333 patients with antiplatelets; 336 with ACE inhibitor or ARB, 236 patients with beta blocker, 123 patients with calcium channel blocker, 336 patients with statin and 355 patients with any lipid lowering agents. Last but not least, a study by Raparelli et al (2020) stated that their samples consumed additional drugs to prevent cardiovascular adverse effects.

Findings Cardiovascular Outcomes From these studies, we listed several parameters that related to cardiovascular disease and its risk factors including BMI, HbA1c, blood pressure, lipid profile, CRP, MBF, MGU, left ventricular function, proBNP, HR, cardiovascular event-free survival.

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Varanasi et al (2012) found that liraglutide caused significant reduction in body weight; 120 + 5 kg to 115 + 3 kg, CRP; 4.7 to 3.2, and HbA1C. Additionally, CRP reduction was dose dependent. Moreover, they also found decreased TG level and mean SBP in the population that received liraglutide therapy. On the other hand, Gejl et al (2012) examined myocardial blood flow (MBF) and glucose uptake (MGU). They revealed that exenatide significantly increased MBF by 24% (0.69 ml/g.min to 0.86 ml/g.min), without altering MGU level. Exenatide also stabilized GLUT transport in patients with low insulin sensitivity.

Moreover, the study of Arturi et al (2016) focused on the cardiac functional capacity of T2DM patients with a history of post-ischemic chronic heart failure. It is found that liraglutide induced significant increase of LVEF and decrease of end-systolic & end-diastolic LV volume. Decrease of end-diastolic LV volume affected significant improvement in anterograde stroke volume.

Study by Bizino et al (2019) found that liraglutide reduced early LV diastolic filling and LV filling pressure, thus postponing the onset of HFpEF and concomitant morbidity and mortality. The use of sulfonylurea derivatives (SUD) was decreased from 26% at baseline to 18% at 26 weeks and the use of insulin also decreased from 70+46 to 54+43 IU/day in the liraglutide group. It is also found that liraglutide reduces weight and NTproBNP level significantly, while there is no significant difference between HbA1c level in liraglutide group and placebo. None of the patients experienced symptoms of heart failure during their study, but one participant in the liraglutide group who started calcium channel blocker medication developed edema.

Study by Bethel et al (2020) observed EXSCEL (EXenatide Study of Cardiovascular Event Lowering) in patients with type 2 diabetes. Patients in this study are allowed to consume up to three oral glucose-lowering agents either alone or in combination with insulin. The MACE (major adverse cardiovascular events) and ACM (all-cause mortality) remained potent after right censoring or application of literature-derived risk reductions, but exenatide versus placebo MACE effect size and statistical significance were increased by IPTW (inverse probability for treatment weighting).

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Finally, a study by Raparelli et al (2020) focused on differentiating the major cardiovascular events between male and female in GLP-1 RA medication. It is found that women experienced less major cardiovascular events than men and the risk reduction was found stronger in women. Other than that, the use of antihypertensive and statins medication also found less frequent among women than men. Unfortunately, women experienced higher adverse events than men, such as urosepsis and genital yeast infection.

DISCUSSION The results are varied between each study and all studies have distinct findings related to cardiovascular outcome and its risks. Generally, all studies showed positive outcomes toward GLP-1 RA therapy in T2DM patients.

Differences in Samples All studies used different types of GLP-1 RA including liraglutide and exenatide, with various therapy duration, between 6 months up to 3,2 years. However, a study by Gejl et al (2012) did not reveal their therapy duration. Two studies by Arturi et al (2016) and Bethel et al (2020) excluded patients with previous history of GLP-1 RA therapy. Besides, most patients received GLP-1 RA therapy in combination with other oral antidiabetics, except Gejl et al that stopped all oral antidiabetic and remaining medications before giving exenatide therapy to their patients.

Previous Diabetes Treatment Previous diabetes treatment plays an important role because poor glycemic control will lead to worse cardiovascular treatments. Currently, it is emphasized to closely monitor and control the glycemic levels of T2DM patients, in order to improve cardiac outcomes (14). In this systematic review, Arturi et al (2016) and Bethel et al (2020) excluded patients with previous history of GLP1 RA treatment. Possibly, the authors used this method to evaluate the effect of initial GLP-1 RA therapy on their samples.

From the current recommendation, GLP-1 RA used as an additional therapy with metformin in T2DM patients with established ASCVD (3). Most patients in these studies previously received either metformin or insulin therapy and would be combined with GLP-1 RA throughout the

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research period. This condition created an ideal therapy regiment that corresponded with the current guideline. When combined with insulin, GLP-1 RA therapy improved glycemic control without increasing the risk of hypoglycemia. Moreover, this combination therapy did not cause any major adverse event besides gastrointestinal events, which was also found in GLP-1 RA monotherapy (15). Hypoglycemia effect from GLP-1 RA only emerged when it is combined with other agents that triggers hypoglycemia (16). In combination with metformin, GLP-1 RA also demonstrated positive outcomes, including more dominant weight loss effect (17) and additive glucose-lowering control (18).

BMI and Weight Loss Study by Varanasi et al (2012) found that liraglutide significantly caused weight loss on their samples. Bizino et al (2019) also found similar results on their study. This weight loss effect from GLP-1 RA also demonstrated by other studies (19–21). Better results were found in exenatide therapy, that significantly reduced body weight, waist circumference, and total body and fat truncal fat mass (22). This effect will be helpful for T2DM patients in reducing the risk of cardiovascular disease, because excess fat accumulation triggered cardiovascular disease through supporting premature atherosclerosis formation in large arteries and causing abnormality in coronary microvasculature. From these studies, we can see that the samples’ BMI varied from 31,9 to 45 kg/ m2, that can be categorized as obese. Thus, the weight loss effect from GLP-1 RA would be beneficial in reducing the risk of developing cardiovascular disease and as well as heart failure in T2DM patients (23).

Consumption of Other Drugs Antihypertensive drugs are known to reduce cardiovascular events risks in patients with T2DM and those with systolic blood pressure (SBP) above 140 mmHg. Almost all participants in studies reviewed in this article also consumed antihypertensive drugs in combination with their antidiabetic drugs. Recent systematic review concluded that the treatment reduced all cause mortality (including myocardial infarction, stroke, and heart failure) if the baseline SBP before treatment was more than 140 mmHg or if SBP with treatment was 130-140 mmHg. However, the treatment was not beneficial for those with SBP below 140 mmHg which increased the

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cardiovascular events risks. This may reinforce the medication for T2DM if those antihypertensive agents are combined with GLP-1RA which have proven to have cardioprotective effects (24).

Several studies also included patients with antilipidemic agents. Lipid profile control in T2DM patients is very important because elevated total cholesterol level, especially triglyceride, can independently become a risk factor for CHD in T2DM patients (25,26). Moreover, in T2DM patients, LDL cholesterols are adjusted into small, dense LDL (sdLDL), which tends to be more atherogenic (27). Studies in this systematic review did not report any drug interaction between anti lipidemic agents and GLP-1 RA. Therefore, GLP-1 RA therapy will be beneficial for T2DM patients in controlling their lipid profile and reducing the risk of developing cardiovascular.

Cardiovascular Outcomes Cardiac Functional Capacity Diabetes mellitus is independently associated with abnormal left ventricular (LV) relaxation (28). This thing happened because advanced-glycation-end products (AGEs) accumulated in the interstitial. This condition contributes to the occurrence of congestive heart failure (CHF). From these studies, Arturi et al (2016) demonstrated that liraglutide therapy results in improved LVEF, and reduced end-systolic and end-diastolic LV volume, without affecting LV mass. Similar results also demonstrated by Bizino et al (2019). Therefore, these effects are beneficial to preserve diastolic function, especially in preventing CHF and HFpEF, which are frequently developed in T2DM patients. However, it is important to be careful with HFpEF patients that are classified into New York Heart Association class III or IV, that have higher E/Ea ratio, because liraglutide therapy may exacerbate heart failure symptoms and decompensation.

Myocardial Blood Flow (MBF) and Myocardial Glucose Uptake (MGU) Based on the study of Gejl et al (2012), Exenatide significantly increased MBF by 24% from 0,69 to 0,86 ml/g.min. It also stabilized GLUT transporters in patients with low insulin sensitivity. However, these effects did not appear in liraglutide therapy (29). Moreover, GLP-1 RA did not alter MGU, but it is originally lower in T2DM patients because low insulin infusion produced a similar condition to fasting state and caused high circulating FFA (30). The MBF boosting effect

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from GLP-1 RA may be beneficial for ischemic heart disease and coronary arterial disease patients.

Blood Pressure Varanasi et al (2012) demonstrated that liraglutide significantly caused systolic blood pressure (SBP) reduction, especially the first three months after treatment initiation. This outcome may be beneficial in improving arterial compliance and reducing arterial stiffness. Similar results also stated by other studies that compared liraglutide to insulin glargine, in addition to glimepiride and metformin (31). However, Arturi et al (2016) found no significant SBP reduction in liraglutide therapy, in addition to sitagliptin. Bizino et al (2019) also did not find any significant blood pressure changes in liraglutide therapy, in addition to metformin or insulin. Different outcomes from these studies happened because each study has different sample characteristics and methods in giving GLP-1 RA to their samples. Thus, further comprehensive investigation should be conducted.

Lipid Profile Based on several studies, GLP-1 RA therapy caused significant changes in lipid profile, with slight reduction of HDL-C (32–34). Varanasi et al (2012) demonstrated similar result, that liraglutide caused mean triglyceride concentration reduction from 173 ± 19 mg/dL to 151 ± 15 mg/dL, but other studies in this systematic review did not find any significant cholesterol level reduction in GLP-1 RA therapy. This thing happened because each study’s sample has different characteristics, with various doses and types of GLP-1 RA. Therefore, the effect of GLP-1 RA in improving lipid profile needs further investigation.

Medical History Studies in this systematic review included patients with various histories and additional risks of cardiovascular disease. However, Gejl et al (2012) and Bizino et al (2019) excluded patients with a history of cardiovascular disease. On the other hand, GLP-1 RA, especially liraglutide, has potential mechanisms that can be used to prevent cardiovascular disease. It increased eNOS activity and reduced ICAM-1 expression, which can be protective against endothelial dysfunction

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(35). These effects may add more benefits in GLP-1 RA therapy, but further investigation should be done to comprehensively understand its mechanism.

Study by Varanasi et al (2012) included obese patients with uncontrolled hyperglycemia into their study. Generally, samples in these studies also had high BMI, that categorized as obese. Indeed, GLP-1 RA, specifically liraglutide, will be more beneficial in obese patients because it had been aprroved as antiobesity medication (15). Moreover, Bethel et al (2020) excluded samples with end-stage kidney diseases or an eGFR at entry <20 ml/min/1.73 m2. Bizino et al (2019) also excluded samples with history of renal-hepatic disease. This decision is really wise, considering that most GLP-1 RA therapy required dose adjustment in patients with lower eGFR (3).

CONCLUSION In conclusion, GLP-1 RA has cardioprotective benefits for T2DM patients through reducing body weight, improving & preserving cardiac functional capacity and elevating MBF without affecting MGU. Though these are some promising outcomes regarding the cardioprotective properties of GLP-1 RA, the studies are still limited. These studies failed to demonstrate several effects of GLP1 RA which are reducing blood pressure and improving lipid profile. Further studies to explore more about these benefits should be conducted in the future.

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Brunström M, Carlberg B. Effect of antihypertensive treatment at different blood pressure levels in patients with diabetes mellitus: Systematic review and meta-analyses. BMJ [Internet]. 2016 Feb 25 [cited 2020 Oct 28];352. Available from:

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Fontbonne A, Eschwège E, Cambien F, Richard JL, Ducimetière P, Thibult N, et al. Hypertriglyceridaemia as a risk factor of coronary heart disease mortality in subjects with impaired glucose tolerance or diabetes - Results from the 11-year follow-up of the Paris Prospective Study. Diabetologia [Internet]. 1989 May [cited 2020 Oct 29];32(5):300–4. Available from: https://link.springer.com/article/10.1007/BF00265546

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PUBLIC POSTER

AMINO | AMSA International Competition 2021

Ade Gautama AMSA-Universitas Indonesia 1st Winner of Public Poster Category “Healthy Baby-Happy Mommy, Diabetes-free BOBA for You and Me!”

World Diabetes Awareness Month is one of the newest themes for the competition held by AMSA International. Before joining WDAM, I usually joined another competition by AMSA International, so joining WDAM is my way to not waste the chance given by AMSA, as this type of competition is open for all AMSA members all over the world. A public poster is a medium to communicate things visually and it also serves as media for direct education. To make a good public poster you have to pick a topic, as in medical fields about health all topics are as important as another topic. Second, you have to determine your public poster’s aim to increase awareness or tips in preventing specific diseases. Then start creating the background of your topic, creating layouts of your poster, and combining colors to make people understand your material and be attracted to read your poster easily. I am attracted to join the public poster competition because it shows that we can convey information through creative ways to do health promotion and prevention. I see this as the future of health promotion because a poster is the most attractive and efficient media to convey information nowadays.

AMINO | AMSA International Competition 2021

Andrea Melynda Panggalo AMSA-Universitas Hasanuddin 2nd Winner of Public Poster Category “Prevent Diabetes by Staying in ‘SHAPE’”

My experience on taking a part of this competition was unforgettable. The time we spent trying to come up with a title, the thrill of racing against the deadline, and the joy of reading the announcement.. It was deﬁnitely unforgettable. I joined WDAM 2020 because I was eager to learn about the process of making a public poster. I like to draw both manually and digitally, but I’d like to try other form of art such as designing and lay outing as well! While making this poster, I learned a lot about diabetes, and it was really helpful when it was brought up to class this semester. I also learned a lot about designing, like how to make a readable, clear yet fun to read designs. I was very hesitant at ﬁrst, but I ended up putting some of my drawings onto my poster. I’m so grateful to have my team mates and mentor with me, they’ve been very supportive and positive about my designs. Not to mention the awesome abstract my team mates come up with. I’m glad that I have joined WDAM 2020, and I hope that it would bring joy and thrill towards others as well!

AMINO | AMSA International Competition 2021

Josephine Passareta Riduvan AMSA-Universitas Hang Tuah 3rd Winner of Public Poster Category “The Ultimate Delight: Prevent Diabetes with a Hearty Piece of Cake”

AMSA is the right organization for me to develop academic skills, social realization, and connections between medical students both at my university and other universities. Being a member of AMSA-UHT, I have participated in several national events, social events, and have the opportunity to take part in several competitions that have been held by both AMSA-Indonesia and AMSA International. Previously, I never thought about participating in an international competition before finally my AMSA friend offered me to join his team so that they could try various competitions held at AMSA together. So, I thought that "why don't I just give it a try?" because honestly we don't know what we will get in the future until we try it. win or lose, I just want to give my best, apply more of what I've just done before, and want to add to the positive experience during my time at FK. My first competition in the international competition was the World AIDS Day public poster from AMSA International and thank God in my first competition, my friends and I were able to bring home the 2nd place or 1st runner up for AMSAUHT.

Healthy Baby Happy Mommy, Diabetes-free BOBA for You and Me Gestational diabetes (GSD), one of the most common pregnancies, are defined as a high blood glucose state during pregnancy. It is listed as one of the emerging worldwide epidemics, but it remains neglected among pregnant women worldwide. Global prevalence studies recently have shown that the 16.9% of pregnant women in the age of productivity (20-49 years), which occur in 21.4 million live births in 2013 worldwide while 90% of them occurred in low-middle income countries. Consequently, It has affected a quarter of the population of pregnant women among Southeast Asia regions as its highest prevalence. In addition, this disease has increased by more than 30 % within one or two decades in a number of countries including developing countries, showing the emergence of tackling this health problem.

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Subsequently, studies have shown that the high prevalence of GSD is due to myth growing among people. The myth among pregnant women is them thinking that gaining more weight would have resulted in healthy bigger babies. Pregnant women also think that while they are pregnant, they are “Eating for two” while in fact, excessive gestational weight gain due to excessive eating can cause complications. Those complications include preeclampsia, preterm labour, severe hypoglycemia, and large size babies or macrosomia. Large size babies can cause several other complications during delivery including trauma to the babies. It also requires the mother to deliver through C-section or Caesarean section, not the natural way.

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Gestational diabetes can also cause the mother and the baby to be included in the group of the population who are at risk to develop type 2 diabetes. This can be a huge problem because the number of people with diabetes is already increasing this last decade, and in 2014 it has reached the number of 422 million. Preventing gestational diabetes can lower the number of diabetes cases in the future because if we prevent gestational diabetes, we can keep the mother and the baby healthy, so they are not at risk of developing diabetes in the future. In order to achieve that, we propose our simple solution “BOBA”. B stands for being active by doing moderate and regular exercise. O stands for obeying doctor’s therapy including blood sugar regular check, medications, and keeping self-health records using books or other media. Another B stands for being careful of weight gain. Lastly, A stands for adopting a healthy diet for eating.

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By doing BOBA before, during, and after pregnancy, mothers can have a healthy pregnancy and prevent the chance of both, the mother and the baby, to develop diabetes in the future. Objectives To increase knowledge and awareness among society about lifestyle which can lead to gestational diabetes To fight the stigma among people about “eating for two” and “more weight more healthy bigger babies”. To reduce the incidence of gestational diabetes, therefore, making better future generations Conclusion Gestational diabetes prevention could be promoted through raising awareness about the diabetes-free BOBA lifestyle. We hope this kind of health promotion will impact society through knowledge improvement and decrease the incidents of gestational diabetes, therefore fighting the stigma and myth in society. References: 1. World Health Organization (WHO). Diabetes [Internet]. WHO; 2020 [cited 2020 Oct 28]. Available from: https://www.who.int/news-room/fact-sheets/detail/diabetes 2. NHS UK. Overview: Diabetes [Internet]. UK: NHS; 2020 [cited 2020 Oct 28]. Available from: https://www.nhs.uk/conditions/gestational-diabetes/ 3. Guariguata L, Linnenkamp U, Beagley J, Whiting DR, Cho NH. Global estimates of the prevalence of hyperglycaemia in pregnancy. Diabetes Res Clin Pract. 2014 Feb;103(2):176-85. 4. Kraschnewski JL, Chuang CH. "Eating for two": excessive gestational weight gain and the need to change social norms. Womens Health Issues. 2014;24(3):e257-e259. 5. Wisely R. Busting ‘Big Baby’ Myths: An OB-GYN Eases Fears with Facts [Internet]. Michigan

Health;

2018

[cited

2020

Oct

28].

Available

from:

https://healthblog.uofmhealth.org/womens-health/busting-big-baby-myths-an-ob-gyneases-fears-facts 6. Alejandro E, Mamerto T, Chung G, Villavieja A, Gaus N, Morgan E et al. Gestational Diabetes Mellitus: A Harbinger of the Vicious Cycle of Diabetes. International Journal of Molecular Sciences. 2020;21(14):5003.

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7. Dirar AHM, Doupis J. Gestational diabetes from A to Z. World Journal of Diabetes. 2017;8(12):489-511. 8. Diabetes and pregnancy. [Atlanta, Ga.]: U.S. Dept. of Health and Human Services, Centers for Disease Control and Prevention; 2010.

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PREVENT DIABETES BY STAYING IN “SHAPE” Andrea Melynda Panggalo; Adem Pratiwi SM; Revina Raissa Gunawan AMSA-Hasanuddin University, Makassar, South Sulawesi

ABSTRACT The estimated prevalence of adult aged 20 – 79 years with diabetes in 2019 was 463 million, and this number would rise to around 700 million by the end of 2045 1. There are approximately 374 million people with a higher risk of developing T2DM, more than 1.1 million children and adolescent living with the type 1 diabetes and more than 20 million live birth are affected by diabetes during pregnancy (gestational diabetes), making diabetes mellitus one of the most horrible uncommunicable disease with the number of deaths reaching 4.2 million in 20191. Diabetes Mellitus is defined as heterogeneous complex metabolic disorder characterized and identified by chronic hyperglycemia and followed by either defects in insulin secretion, insulin action, or both1-3. Furthermore, uncontrolled increase of blood sugar in diabetic patients may lead to many serious long-term damage, dysfunction and failure of the organs3. Diabetes Mellitus can be classified into the following general categories: 1. Type 1 diabetes mellitus (T1DM), characterized by an autoimmune-idiopathic process with β-cell destruction3,5. This process can cause an absolute or near absolute deficient insulin production and thus requires daily administration of insulin until the rest of their life5. 2. Type 2 diabetes mellitus (T2DM) is characterized with inability of the body to utilize insulin which is produced by β-cell in liver. This type of diabetes is also associated with insulin secretion compensatory defect 3,5. Most T2DM patient are cause by obesity and physical inactivity. 3. Gestational diabetes, this classification of diabetes only occurs during pregnancy5. Women with gestational diabetes have higher risk of complication in pregnancy and at delivery also their children have increase risk of T2DM in the future 3. The most common symptoms caused by Diabetes Mellitus are thirst, polyuria, drastic weight loss, blurry vision, slow healing injuries, and decline of immunity that can lead to the

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person being prone to infection. In severe clinical manifestations, the patient may develop ketoacidosis or a non-ketotic hyperosmolar state which can lead to stupor, coma and even death. Some complications due to long term accumulated effects of diabetes mellitus include retinopathy with high risk of blindness, renal failure, nerve damage in the feet that increase the incidence of foot ulcer, infection, and also autonomic dysfunction, such as sexual dysfunction6. This poster aims to reduce the risk of developing Diabetes Mellitus caused by unhealthy lifestyle with staying in “SHAPE”. “SHAPE” is an acronym for Stop smoking, Healthy programmed meals, Active Lifestyle, Preserve ideal weight, and Enough Sleep. 1. S is for Stop smoking. The chemicals in cigarattes cause harm and interfere our body’s cell’s normal function, and thus can cause inflammation, which may decrease the effectiveness of insulin and increase the risk of diabetes7. 2. H is for Healthy programmed meals. In order to keeping track our blood glucose level, it is recommended to eat more fruit and vegetable, reduce eating food with high Glicemic Index(GI) (such as rice and chocolate), eating with plate method (50% non-strachy vegetables, 25% lean protein, and 25% grain or starchy food) 8. 3. A is for active lifestyle. The goal is to do moderate-intensity physical activity, such as walking briskly, doing house work, swimming for at least 150 minutes per week, or 20 to 25 minutes of activity per day. Increasing physical activities can increase the body sensitivity of insulin9. 4. P is for Periodically check blood sugar. Regular blood sugar monitoring help delay and even prevent diabetes. 5. E is for Enough sleep. Sleep affects the body’s hormone level and its ability to regulate and metabolize glucose. People with sleep restriction have 40% lower glucose tolerance on average, which cause their glucose level stay significantly higher than people with enough sleep10.

Finally, the urge to control all the risks of Diabetes will be depend on personal lifestyle choices. In the era where physical inactivity becoming a trend and fast foods are everywhere, we hope that staying in "SHAPE" may help in preventing the society to suffer from Diabetes.

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Bibliography 1 .

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Ninth edition. IDF DIABETES ATLAS [Internet]. Diabetesatlas.org. [cited 2020 Oct 29]. Available from: https://diabetesatlas.org/upload/resources/2019/IDF_Atlas_9th_Edition_2019.pdf

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Who.int. [cited 2020 Oct 29]. Available from: https://apps.who.int/iris/bitstream/handle/10665/66040/WHO_NCD_NCS_99.2.pdf;jse ssionid=9EEEEB1C8ED1AF72BE1F755AC1C29317?sequence=

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Diabetes [Internet]. Who.int. [cited 2020 Oct 29]. Available from: https://www.who.int/news-room/fact-sheets/detail/diabetes

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WHO | About diabetes. 2014 [cited 2020 Oct 29]; Available from: https://www.who.int/diabetes/action_online/basics/en/index1.html

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Solis-Herrera C, Triplitt C, Reasner C, DeFronzo RA, Cersosimo E. Classification of Diabetes Mellitus. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dungan K, et al., editors. Endotext. South Dartmouth (MA): MDText.com; 2018.

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CDCTobaccoFree. Smoking and Diabetes [Internet]. Cdc.gov. 2020 [cited 2020 Oct 29]. Available from: https://www.cdc.gov/tobacco/campaign/tips/diseases/diabetes.html

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CDC. Diabetes Meal Planning [Internet]. Cdc.gov. 2020 [cited 2020 Oct 29]. Available from: https://www.cdc.gov/diabetes/managing/eat-well/meal-plan-method.html

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Get Active! [Internet]. Cdc.gov. 2019 [cited 2020 Oct 29]. Available from: https://www.cdc.gov/diabetes/managing/active.html

1 0 .

Type2diabetes.com. [cited 2020 Oct 29]. Available from: https://type2diabetes.com/diet-nutrition/healthy-weight/

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The Ultimate Delight Prevent diabetes with a hearty piece of cake

Background Diabetes or commonly known as “sugar”, is a noncommunicable disease which impaire glucose metabolism, characterized by the elevation of blood glucose. It has emerged as one of the leading global health issues. The most common type of diabetes is type 2 or better known as diabetes mellitus that usually occure in adulthood. This happens when the human body becomes resistant to insulin or cannot produce an adequate amount of insulin. The number of people with diabetes has dramatically increased in the past few years and is predicted to keep increasing. According to WHO, about 422 million people worldwide have diabetes and 90% of the cases are type 2 diabetes. While becoming one of the leading global health issues, diabetes also contributes to 1.6 million deaths each year worldwide 5. While in Indonesia, 57% of the population got diabetes and 95% of the incidence is type 2 diabetes 1,2,3. Diabetes information is widely available in the social media, but it is hard to know which one is accurate. One of the most well-known myths is that diabetes is mild. However, if it is poorly managed, it can lead to a serious condition and even life-threatening. Diabetes is not that ‘sweet’, since it can cause the patient to have Stinky ulcerated diabetic foot; Weakness, numbness and pain due to Neuropathy; Erectile dysfunction and other sexual disorders; Eye damage dysfunction such as Retinopathy and even Threats of dying prematurely 1. Diabetes is characterized by chronic hyperglycaemia due to defects in insulin secretion, insulin action or even both. Insulin here acts as a hormone that signals the fat cells, muscle and liver to take glucose from the blood and convert it into glycogen and triglycerides to be stored inside the body 6,7. With insulin resistance, glucose metabolism cannot be fulfilled by pancreatic Beta cells. Eventually, this leads to an increase demand of insulin in the body

1,2,3

. The closed

insulin store in the poster represents the pancreas that could not meet the sudden increase of insulin needs in diabetic patients. The most important effort to lower the number of diabetes patients is to widen people’s knowledge on its prevention. This public poster is created to educate, spread awareness and engage the society to prevent diabetes efficiently but still in a simple and affordable way. Type 2 diabetes can be prevented by getting someone’s very own CAKE 5.

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Check blood glucose regularly, can help delay and prevent diabetes complications, such as heart attack, stroke, kidney disease and any other complications. It can also be used as an early diagnosis tool

1,6,7

. Always exercise at least 30 minutes a day per week so that

everyone can Keep ideal body weight. Doing simple aerobic exercise like cycling, jogging or swimming for 30 - 45 minutes at least 3 - 5 times a week can lower body weight and improve insulin sensitivity which lead to a better blood glucose control 8. Enrich the daily intake of fibre and mineral. It is known that fibres slow down the process of carbohydrate conversion into sugar and help control the level of glucose in the blood. As for the mineral, it can help the human body to improve their insulin sensitivity 8. By having a healthy CAKE lifestyle, one can cut diabetes risk by half 5.

Objectives To increase awareness on the importance of implementing a healthy lifestyle as diabetes prevention

Conclusion Diabetes cannot be cured but it can be . But then again, an ounce of prevention is worth a pound of cure. By promoting this CAKE as diabetes prevention, it is hoped that the society will be aware and realize that diabetes is not just a mild disease.

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References 1. Kharroubi A, Darwish H, Abu Al-Halaweh A, Khammash U. Evaluation of Glycated Hemoglobin (HbA1c) for Diagnosing Type 2 Diabetes and Prediabetes among Palestinian Arab Population. 2020. 2. Shaw J, Sicree R, Zimmet P. Global estimates of the prevalence of diabetes for 2010 and 2030. 2020. 3. Li S, Guo S, He F, Zhang M, He J, Yan Y et al. Prevalence of Diabetes Mellitus and Impaired Fasting Glucose, Associated with Risk Factors in Rural Kazakh Adults in Xinjiang, China. International Journal of Environmental Research and Public Health. 2015;12(1):554-565. 4. Lau D, Teoh H. Benefits of Modest Weight Loss on the Management of Type 2 Diabetes Mellitus. Canadian Journal of Diabetes. 2013;37(2):128-134. 5. Diabetes [Internet]. Who.int. 2020 [cited 23 October 2020]. Available from: https://www.who.int/health-topics/diabetes#tab=tab_1 6. Encyclopedia M, ketoacidosis D. Diabetic ketoacidosis: MedlinePlus Medical Encyclopedia [Internet]. Medlineplus.gov. 2020 [cited 25 October 2020]. Available from: https://medlineplus.gov/ency/article/000320.htm 7. Blood Glucose Monitoring [Internet]. Diabeteseducator.org. 2020 [cited 25 October 2020].

Available

from:

https://www.diabeteseducator.org/living-with-

diabetes/Tools-and-Resources/blood-glucose-monitoring 8. Adi Soelistijo S, Lindarto D, Decroli E, Permana H, Sucipto K, Kusnadi Y et al. Pedoman Pengelolaan dan Pencegahan Diabetes Melitus Tipe 2 Dewasa di Indonesia 2019. PB Perkeni; 2019.

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Type 2 Diabetes Self-Management During Pandemic Abstract Covid-19 is global pandemic that affecting almost all the country in this world. Covid19 has various aggravating risk factors, such as NCD, namely Diabetes mellitus. People with diabetes melitus should extra take care of themself during this pandemic and maintaining glycemic control would boost the innate immune system and help prevent from Covid-19. It has recently been found that the elderly with type 2 diabetes mellitus have experienced worsening of glycemic control manifesting as higher fasting blood glucose. This has an impact because of social distancing, quarantine, and lockdown that were implemented during the pandemic. Lockdown and social distancing implied for community control would have limited the physical activities of the people with DM. Limitation in food supplies during the lockdown would have compelled people with DM to modify their dietary habits that were earlier related to great glycemic control. Individuals with diabetes mellitus would not have been able to visit their doctors for schedule clinic check-ups.[1] Hence, diabetes self-management instruction refers to the ongoing process of encouraging the information and capacity essential to successfully oversee the disease. First, always educate patient about social distancing, hand hygiene, cough etiquette, and proper use of masks. Second, elemedicine videos and consults can be used to teach correct insulin injection, use and storage practices. Third, empower patients how to do self-monitoring of blood glucose (SMBG) at home, good glycemic control may also reduce the chances of superimposed bacterial pneumonia. Fourth, give priority to foods with a low glycemic index, less consumption fried food, eat vegetables an fruits, restrain consumption of foods high in sugar, carbohydrates, and fat, avoiding consumption alcohol and smoking. Fifth, do physical activity at least 1 hour a day, you split it into 20-minutes session, for example do walk up and down eight sets of stairs.[2] Sixth, be aware about hypoglycemia sign and symptoms are shaking, anxiety, sweating, chills, clamminess, irritability, confusion, tachycardia, dizziness, hunger, nausea, pallor, drowsiness, malaise, blurred vision, tingling or numbness in the lips, tongue, or cheeks, headache, lack of coordination, nightmares and seizures. Also, be awre with diabetic ketoacidosis are shortness of breath, breath that smells fruity, nausea and vomiting and very dry mouth. If you see people with diabetes has the sign and symptoms, you should contact their healthcare team.[3] Keywords: Type 2 Diabetes, Covid-19, diabetes self-management

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Reference: [1]Banerjee M, Chakraborty S, Pal R. Diabetes self-management amid COVID-19 pandemic. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2020;14(4):351-354. [2] Palui R, Pramanik S, Ray A, Gupta U, Siddhanta S, Dutta D. Managing Diabetes in the COVID-19 Era: Focus on COVID-19 Safe Clinics, Telemedicine, and Diabetes SelfManagement. Journal of Social Health and Diabetes. 2020. [3] Mukona D, Zvinavashe M. Self- management of diabetes mellitus during the Covid-19 pandemic: Recommendations for a resource limited setting. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2020;14(6):1575-1578.

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Fight Against Diabetes Mellitus Type 2 With “COURAGE” Abstract It is estimated that 366 million people had Diabetes Mellitus in 2011; by 2030 this would have risen to 552 million. The number of people with type 2 DM is increasing in every country with 80% of people with DM living in low- and middle-income countries. DM caused 4.6 million deaths in 2011. It is estimated that 439 million people would have type 2 DM by the year 2030. The incidence of type 2 DM varies substantially from one geographical region to the other as a result of environmental and lifestyle risk factors. Diabetes Mellitus (DM) is known as one of the oldest diseases to human. The disease was first reported in Egypt about 3000 years ago, but wasn’t able to be classified as Type 1 or Type 2 until 1988. Type 2 Diabetes Mellitus (T2DM) is the most common form of DM characterized by hyperglycemia, insulin resistance and relative insulin deficiency. The numbers of T2DM increase from time to time as the modernization of the world is rapidly evolving, which leads to people (especially the younger ones) having an “easier life” that they don’t really have to put efforts on daily lives. People living with type 2 DM are more vulnerable to various forms of both short- and long-term complications, which often lead to their premature death. This tendency of increased morbidity and mortality is seen in patients with type 2 DM because of the commonness of this type of DM. Through lifestyle and diet modification. Studies have shown that there was significant reduction in the incidence of type 2 DM with a combination of maintenance of body mass index of 25 kg/m2, eating high fibre and unsaturated fat and diet low in saturated and transfats and glycemic index, regular exercise, abstinence from smoking and moderate consumption of alcohol. Suggesting that majority of type 2 DM can be prevented by lifestyle modification. Patients with type 2 DM should receive a medical nutrition evaluation; lifestyle recommendations should be tailored according to physical and functional ability. Although education alone is not a cure for the disease, the type 2 diabetes patient is not able to achieve metabolic regulation, if does not know the basic principles of nutrition, physical activity, care of the lower extremities, as well as specific skills related to the administration of subcutaneous injection of insulin, control of blood sugar levels, and other necessary parameters.

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This poster contains some information of Type 2 Diabetes Mellitus, from its description to the prevention. The poster also includes abbreviation “COURAGE” that contains seven things to do to prevent Type 2 Diabetes Mellitus. “C” stands for “Control Weight” as for the fact that Type 2 Diabetes Mellitus is closely linked to the epidemic of obesity. “O” stands for “Obtain Medical Checkups” regularly to recognize the risk of Type 2 Diabetes Mellitus by screening or calculate the risk factors. “U” stands for “Upgrade To A Healthier Lifestyle” by consuming fibers and change to healthier options of meals. “R” stands for regular exercise for 30 minutes each day to burn the calories of the body, preventing from the glucose in the blood to rise. “A” stands for “Avoid Smoking” as it takes part in the process of elevated glucose in the blood. “G” stands for “Glucose Intake Limitation” by checking the nutrition facts of the food before we eat due to the fact that having too much sugar in the body will not only increase the risk for Type 2 Diabetes Mellitus but also can lead to other diseases. Last, “E” stands for “Eat Healthy Food” by adjusting to the diet for Type 2 Diabetes Mellitus prevention. To our knowledge, preventing is the best way. By avoiding the causes of Type 2 Diabetes, it also shows that we care for our bodies. The patients with type 2 diabetes are invited to be aware about the information provided, and to incorporate long-term education in their lifestyle, with emphasis on behavioral changes. In addition, the state should realize the financial benefits from the information provided to patients with type 2 diabetes and support such interventional programs.

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Bibliography 1. Olokoba, Obateru, Olokoba. Type 2 Diabetes Mellitus: A Review of Current Trends [cited

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3464757/ 2. Fan, Huang, Tang. Effect of individualized diabetes education for type 2 diabetes mellitus: a single-center randomized clinical trial [cited 2016]. NCBI. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398463/ 3. DeFronzo RA, Ferrannini E. Type 2 diabetes mellitus. Europe PMC. 2015. Available from: https://europepmc.org/article/med/27189025 4. Polikandrioti, M. The role of education in diabetes mellitus type 2 management. Available

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mellitus-type-2-management.php?aid=3572 5. Garcia, Perez. A comprehensive approach to type 2 diabetes mellitus – A recommendation

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Prevent DIABETES as sweet as CUPCAKE Diabetes is a chronic (long-lasting) health condition that affects how body turns food into energy. When there isn`t enough of Insulin, there will be too much blood sugar stays in bloodstream that finally can cause serious health problems. There are 3 main types of diabetes: type 1, 2, and gestational diabetes. (CDC) About 422 million people worldwide have diabetes, the majority living in low-and middle-income countries, and 1.6 million deaths are directly attributed to diabetes each year. Both the number of cases and the prevalence of diabetes have been steadily increasing over the past few decades. (WHO) The global diabetes prevalence in 2019 is estimated to be 9.3% (463 million people), rising to 10.2% (578 million) by 2030 and 10.9% (700 million) by 2045. Just under half a billion people are living with diabetes worldwide and the number is projected to increase by 25% in 2030 and 51% in 2045. (International Diabetes Federation : Diabetes Research and Clinical Practice) There are still many people who still misunderstand about diabetes, here are some myths and facts about diabetes: -

Myth: Diabetes is a death sentence Fact: People with diabetes can live long and healthy lives, free of complications. The management of diabetes is in your hand

Myth: Oral medicines destroy the kidney. So it’s better to delay or avoid the medicines Fact: One of the complications of diabetes is kidney failure, and delay in taking the medicines can inflict further damage and complications. There are diabetes warning signs and symptoms that both women and men have in

common, for example: Urinate (pee) a lot, often at night, Are very thirsty, Lose weight without trying, Are very hungry, Feel very tired, Have very dry skin, Have sores that heal slowly, Have more infections than usual. (CDC) Currently, no one knows how to prevent type 1 diabetes, but it can be managed by following your doctor's recommendations for living a healthy lifestyle, managing your blood sugar, getting regular health check-ups, and getting diabetes self-management education and support. (CDC) Simple lifestyle measures have been shown to be effective in preventing or delaying the onset of type 2 diabetes. To help prevent type 2 diabetes and its complications, people should have a ‘CUPCAKE’:

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Care and have a healthy life style Utilize your free time for exercise at least 30 mins regularly Pick your healty diet Check up your regular health annually Avoid tobacco use Keep control your weight stable Eat fiber-rich food Some women can prevent gestational diabetes (diabetes in pregnancy) by getting enough exercise and changing their diet (NCBI: Institute for Quality and Efficiency in Health Care. InformedHealth.org : What can help prevent gestational diabetes? 2017) Diabetes is a chronic (long-lasting) health condition that affects how body turns food into energy. When there isn`t enough of Insulin, there will be too much blood sugar stays in bloodstream that finally can cause serious health problems. There are 3 main types of diabetes: type 1, 2, and gestational diabetes.

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Reference 1. World Health Organization. Diabetes. [Online].Available from: https://www.who.int/health-topics/diabetes#tab=tab_1 [Accessed 2020 October 24]. 2. Saeedi, P. Diabetes Research and Clinical Practice.[Online]. Available from: https://www.diabetesresearchclinicalpractice.com/article/S0168-8227(19)312306/fulltext [Accessed 2020 October 24]. 3. Centers for disease control and prevention. Diabetes Basics. [Online]. Available from: https://www.cdc.gov/diabetes/basics/index.html[Accessed 2020 October 24]. 4. Centers for disease control and prevention. Diabetes Symptoms. [Online]. Available from: https://www.cdc.gov/diabetes/basics/symptoms.html[Accessed 2020 October 24]. 5. Centers for disease control and prevention. Prevent Type 2 Diabetes. [Online]. Available from: https://www.cdc.gov/diabetes/prevent-type-2/index.html [Accessed 2020 October 24]. 6. World health organization. Diabetes. [Online].Available from: https://www.who.int/newsroom/fact-sheets/detail/diabetes [Accessed 2020 October 24]. 7. Informedhealthorg [internet]. What can help prevent gestational diabetes?. [Online]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441575/[Accessed 2020 October 24]. 8. World health organization. Myths and Facts about Diabetes . [Online]. Available from: http://origin.searo.who.int/entity/world_health_day/2016/myths-and-facts-aboutdiabetes.pdf [Accessed 2020 October 24].

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SHAKE DOWN DIABETES WITH INSULIN

Lately, there have been numerous of ongoing myths around the world about diabetes. Those myths are commonly reported as facts. These misrepresentations of diabetes can be harmful. Information about diabetes is widely available especially on the internet, but not all of it is true. It can be very challenging to know what is true, therefore, this public poster aims to highlight seven facts behind the myths of diabetes diagnosis, prevention, and treatment.

DIAGNOSIS Myth 1 : I don’t need to test for diabetes because I’m healthy. Fact

: Here are the criteria of people recommended for type 2 diabetes routine screening:

People beginning at age 45 without any health issues.

Overweight people over 45 years old.

People over 45 years old with heart disease

People with diabetes risk factors (sedentary lifestyle, a family history of type 2 diabetes, a personal history of gestational diabetes or blood pressure above 140/90 mmHg).

Myth 2 : Diabetes is much more serious than pre-diabetes Fact

: Pre-diabetes is when blood glucose levels are higher than normal but aren’t high

enough for someone to be diagnosed with Type 2 Diabetes. Pre-diabetes increases the risk of developing Type 2 Diabetes and cardiovascular disease. It is possible to reverse pre-diabetes through lifestyle changes such as eating a healthy diet and participating in regular exercise. However, it is estimated that without these changes one in three people with pre-diabetes will develop Type 2 Diabetes. Now, what is the three results you can get and what to do? ·

Normal

: repeat the test every three years.

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Borderline : ask your doctor when to come back for another test.

Diabetes

: do other tests to distinguish between type 1 and type 2 diabetes.

What are the tests used to diagnose type 2 diabetes? 1. Glycated hemoglobin (A1C) test. This blood test indicates your average blood sugar level for the past 2-3 months. - Normal : below 5,7% - Prediabetes: 5,7-6,4% - Diabetes : 6,5% or higher (on two separate tests) 2. Random blood sugar test, fasting blood sugar test, and oral glucose tolerance test (for patients with hemoglobin variant). a. Random blood sugar test : taken anytime, regardless of when you last ate. -

Diabetes

: 200 mg/dL or higher (strengthened symptoms such as frequent

urination and extreme thirst. b. Fasting blood sugar test : taken after an overnight fast. -

Normal : below 100 mg/dL

Prediabetes

: 100-125 mg/dL

Diabetes

: 125 mg/dL or higher (on two separate tests)

c. Oral glucose tolerance test : commonly used for pregnant women. Taken periodically for the next two hours after drinking a sugary liquid after an overnight fast. -

Normal : below 140 mg/dL

Prediabetes

: 140-199 mg/dL

Diabetes

: 200 mg/dL or higher after two hours

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PREVENTION Myth 1 : Exercise should be limited for people with type 2 Diabetes Fact

: People with Type 1 and 2 Diabetes can exercise or participate in sport. Exercise and

sport play a vital role in the management of Diabetes as they help to lower blood glucose (sugar) and reduce the risk of developing chronic complications. Myth 2 : Every people with type 2 Diabetes can’t eat sugar Fact

: Limited portion of sugar consumption is included in dietitian’s method for type 2

diabetes patients. A diet rich in fiber and whole grains and low in saturated fat is associated with reduced risk of obesity and diabetes.

Myth 3 : The use of insulin during pregnancy can have a negative impact on the baby. Fact

: Insulin is safe for the fetus because only a small amount of insulin enters the placenta.

TREATMENT Myth 1 : Acupuncture is an outdated way to treat diabetes. Fact

: Application of acupuncture significantly reduced blood glucose concentrations, and

suggest that this was an effective treatment for type-2 diabetes mellitus. Other study shows that ear acupuncture was an effective intervention for glycemic control. Myth 2 : Blood sugar level increases after eating apples Fact

: Apples contain polyphenols. Polyphenols have been proven to display remedial

benefits by enhancing insulin secretion and insulin resistance. Other than that, polyphenol-rich diets, such as apples, mangoes, strawberries, etc are able to modulate the expression of genes involved in insulin secretion, insulin signalling, and liver gluconeogenesis pathways.

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REFERENCES

Kang GG, Francis N, Hill R, Waters D, Blanchard C, Santhakumar AB. Dietary polyphenols and gene expression in molecular pathways associated with type 2 diabetes mellitus: A review. Int J Mol Sci. 2020;21(1). Nakamura H, Ishigami T, Kawase Y, Yamada A, Minagawa M, Fukuta H, et al. Effects of acupuncture stimulation on blood glucose concentration in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, an animal model for type-2 diabetes mellitus. Med Sci Monit Basic Res. 2014;20:70–5. Paulo S, November B, Vencio S, Bufaiçal N. 21st Brazilian Diabetes Society Congress. Vol. 10, Diabetology & Metabolic Syndrome. 2018. 1-199 p. Galaviz KI, Narayan KMV, Lobelo F, Weber MB. Lifestyle and the Prevention of Type 2 Diabetes: A Status Report. Am J Lifestyle Med [Internet]. 2018 Jan 24;12(1):4–20. Available from: http://journals.sagepub.com/doi/10.1177/1559827615619159

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“Watch Me” Fight Diabetes: A Skincare Routine Fildza Intan Rizkia, Amirah Rana Aqilah, Satria Angga Widitama

Background Diabetes is a chronic, metabolic disease characterized by elevated levels of blood glucose, which leads to serious damage to the heart, eyes, blood vessels, kidneys, and nerves over time (World Health Organization). The most common type of diabetes is type 2 diabetes, which usually occurs in adults when the body becomes resistant to insulin or does not make enough insulin.1 Based on the World Health Organization, diabetes is acknowledged as an important cause of premature death and disability. In the Political Declaration on the Prevention and Control of NonCommunicable Diseases (NCDs) 2012, diabetes is considered as one of the four priorities of NCDs targeted by world leaders.1 Changes in lifestyle patterns such as dietary changes, reduced physical activity, and increasing urbanization give rise to increased rates of obesity, which also contribute to the number of DM. Besides causing severe renal, vascular, and ophthalmic complications, skin may also be compromised by various diseases directly to diabetes or with associations not yet fully proven.2 Between 30 - 70% of patients with DM will present a cutaneous complication at some point during their lifetime. The dermatologic manifestations may vary in severity. It can be benign, deforming, and even life-threatening.3 Even with the life-threatening effect, skin disorders are usually neglected and frequently underdiagnosed. It may increase the risk of important outcomes such as skin lesions, ulcerations, and diabetic foot, which may lead to major complications.4 One of the common dermatologic manifestation, diabetic foot ulcer (DFU), contributes over 90% of nontraumatic lower limb amputations (LLAs), which is more than a million amputations/year and cause prolonged hospital admission.5 The key to most diabetic wound management is proper prevention.6

Objectives Diabetes mellitus (DM) wreaks havoc all over the patient’s body. The skin is not excluded from that attack. Insulin affects the utilization of glucose in the skin and is required for growth and

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differentiation of keratinocytes and fibroblasts.6 These may cause frequent infections, nonspecific pruritus, dryness, etc.7

Through this poster, we aim to increase awareness of one of the complications of diabetes, the skin manifestation. Diabetes causes anyone to develop skin complications easier. These include diabetic dermopathy, necrobiosis lipoidica diabeticorum, diabetic blisters, and eruptive xanthomatosis. However, most of the skin conditions can be prevented if it is well taken care of.8

These are some steps may prevent skin manifestations in diabetic patients: 1.

W - Well-managed blood glucose level8 Based on research, 94% of patients with inadequate glycemic control had some skin disorder, and only 60% of patients with adequate glycemic control had some skin disorder. Therefore, managing blood glucose plays an important role in skin manifestations.4

A - Avoid hot baths and showers8 How baths and showers may inflame the skin, causing itching, redness, and even peeling. It may disrupt the natural balance of skin’s moisture, and increase the chances of infection.9

T - Treat cuts well8 Immediately wash minor cuts with mild soap and water, then cover it with sterile gauze. Consult to a doctor to use an antibiotic cream or ointment.8

C - Clean and dry your skin routinely8 Diabetes mellitus may cause autonomic neuropathy, which may impair patient’s perspiration ability. This may lead to dry skin, skin tears and fissures, and losing viscoelasticity.4

H - Humidify your home8 Based on research, exposure of normal human skin to conditions of low humidity decreases the moisture content of the stratum corneum and leads to trans-epidermal water loss (TEWL). Keeping indoor humidity in a balanced way helps to prevent skin dryness. 10

M - Moisturize skin adequately8 Evidence-based study stated that application of optimal skin care using gentle cleansers and moisturizers daily is one measure that may help improve skin barrier dysfunction, preventing complications by providing early-stage treatment of patients with diabetes.11

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E - Examine your foot daily8 Diabetes, which is not controlled, causes the development of neuropathy and peripheral arteries disease by a complex metabolic pathways. Peripheral ischemia and loss of sensation caused by peripheral neuropathy may lead to foot ulcers and may advance which leads to be amputated. So it is essential to do foot examination daily.12

The usage of TV concept symbolizes a medium that catches people’s eyes, so they can remember the slogan well, “Watch Me”. The design incorporates a blue circle as one of the characters, which is the symbol of diabetes coined by International Diabetes Federation. The circle represents life, health, and also unity. It signifies that the global diabetes community came together to support the United Nations Resolution on diabetes. Blue reflects the colour of the United Nations, as a symbol of unity that we are all together to fight diabetes and reverse the global trends that will impede economic development and premature death. The blue circle is used to present that diabetic patients can win and control the battle against blood glucose inside their body, before they can cause further problems. In this poster, the blue circle is fighting the sugar cube, the embodiment of the blood sugar itself. Therefore, through this poster, we expect that it can raise global community’s awareness regardless of their diabetes status, on the steps to prevent skin manifestation of diabetes. By knowing those steps, it will help reduce a great number of skin manifestations and amputation due to poor diabetic foot care. It also boosts the quality of life of the patients. Therefore, this may enhance their self-esteem since there is no or minimal noticeable skin manifestation to be seen and there is no pain caused by the skin problems.

References: 1.

WHO. Global Report on Diabetes. Isbn [Internet]. 2016;978:6–86. Available from: http://www.who.int/about/licensing/copyright_form/index.html%0Ahttp://www.who.int/a bout/licensing/copyright_form/index.html%0Ahttps://apps.who.int/iris/handle/10665/2048 71%0Ahttp://www.who.int/about/licensing/

Mendes AL. Diabetes mellitus and the skin*. An Bras Dermatol. 2017;92(1):8–20.

Rosen J, Yosipovitch G. Skin Manifestations of Diabetes Mellitus [Internet]. Endotext. MDText.com, Inc.; 2018 [cited 2020 Oct 28]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29465926

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De Macedo GMC, Nunes S, Barreto T. Skin disorders in diabetes mellitus: An epidemiology and physiopathology review. Diabetol Metab Syndr. 2016;8(1):1–8.

Rodrigues BT, Vangaveti VN, Malabu UH. Response to: Comment on “prevalence and Risk Factors for Diabetic Lower Limb Amputation: A Clinic-Based Case Control Study.” J Diabetes Res. 2018;2018.

Nather A, Cao S, Chen JLW, Low AY. Prevention of diabetic foot complications. Singapore Med J. 2018;59(6):291–4.

Baidya A, Halder AK, Datta PK. Spectrum of Cutaneous Manifestations of Diabetes Mellitus: An Observational Study from a Tertiary Care Hospital. J Diabetes Metab. 2018;09(04).

American Diabetes Association. Skin Complications [Internet]. [cited 2020 Oct 28]. Available from: https://www.diabetes.org/diabetes/complications/skin-complications

University of Pittsburgh Medical Center. Is a Hot Shower Really That Bad for Your Skin? [Internet]. 2015 [cited 2020 Oct 28]. Available from: https://share.upmc.com/2015/01/hotshower-bad-skin/

10.

Goad N, Gawkrodger DJ. Ambient humidity and the skin: the impact of air humidity in healthy and diseased states. J Eur Acad Dermatology Venereol. 2016;30(8):1285–94.

11.

Robert S. Kirsner. Diabetic Skin Changes Can Benefit from Moisturizer and Cleanser Use: A Review [Internet]. J Drugs Dermatol. 2019 [cited 2020 Oct 28]. p. 1211–7. Available from: https://jddonline.com/articles/dermatology/S1545961619P1211X

12.

Mishra SC, Chhatbar KC, Kashikar A, Mehndiratta A. Diabetic foot. BMJ [Internet]. 2017 Nov 16 [cited 2020 Oct 28];359:j5064. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5688746/

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Prevent Diabetes with a lot of CREAM Diabetes mellitus (hereafter referred to as “diabetes”) is one of the most common noncommunicable diseases in the world. This disease is a chronic metabolic disorder characterized by an increase in blood sugar levels. The increasing prevalence of diabetes and its complications that cause early morbidity and mortality make diabetes a priority health concern. People with diabetes can experience serious complications such as heart and cardiovascular disease, vision loss, and kidney disease. Currently there are approximately 422 million people in the world who suffer from diabetes with the number of deaths reaching 1.6 million each year. This means that there is 1 person with diabetes for every 11 people in the world (1). There are 2 main types of diabetes : type 1 diabetes and type 2 diabetes. Type 1 diabetes is a condition where the pancreas does not produce enough insulin or even does not produce insulin at all, resulting in an increase of glucose levels in the blood. Type 1 diabetes occurs since childhood / juvenile. Meanwhile, type 2 diabetes usually only develops in adults due to insulin resistance. Type 2 diabetes is the most common type and in the last three decades its prevalence has increased dramatically in countries of all income levels. The majority of people with type 2 diabetes are overweight or obese. Other risk factors that can cause diabetes include physical inactivity, unhealthy diet, age, family history of diabetes (genetic), and high blood pressure (2,3). According to WHO, there is a globally agreed to halt the rise in diabetes and obesity by 2025 (4). Creators proposed an intervention in helping prevent diabetes with five important point that can easily remember called CREAM. First, C is for Control your weight, by losing 5-10% of the current weight may be able to prevent or delay diabetes. It is important because people who are overweight or obese can aggravates insulin resistance. Second, R is for Regularly do exercise. Physical inactivity could led to type 2 diabetes. By exercise regularly, muscles works more often and improves the ability to use insulin and absorb glucose. This could help to lose weight, lower blood sugar levels, and also has many health benefits. Third, E is for Eat healthy. Healthy eating plan by reduce the amount of calories to eat and avoid extra sugar consumption have a big impact to keep the weight and control blood sugar levels. Diet should include plenty of whole grains, fruits, vegetables and healthy fats. Avoid processed meat and limit red meat is also recommended. Fourth, A is for Ask a doctor whether there is anything else you can do to prevent diabetes. Explanation from the health care provider also necessary to see each person’s needs, high risk people may suggested to take diabetes medicines. Fifth,

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M is for Maintain a no-smoking life because smoking can contribute to insulin resistance which can lead to type 2 diabetes (5). This five intervention is shown in the public poster as an idea to help the community to understand more about diabetes especially type 2 diabetic, and hopefully they can give more care to prevent diabetes before it causes more health problems. Let’s prevent diabetes with a lot of CREAM! References : 1.

World Health Organization. Global report on diabetes [Internet]. Geneva; 2016 Apr [cited

2020

Oct

28].

Available

from:

https://www.who.int/publications/i/item/9789241565257 2.

CDC. What is diabetes? | CDC [Internet]. [cited 2020 Oct 26]. Available from: https://www.cdc.gov/diabetes/basics/diabetes.html

World Health Organization. HEARTS D: diagnosis and management of type 2 diabetes [Internet]. Geneva: WHO; 2020 [cited 2020 Oct 28]. 1–35 p. Available from: https://www.who.int/publications/i/item/who-ucn-ncd-20.1

World Health Organization. Diabetes [Internet]. 2020 [cited 2020 Oct 28]. Available from: https://www.who.int/news-room/fact-sheets/detail/diabetes

U.S. National Library of Medicine. How to Prevent Diabetes: MedlinePlus [Internet]. [cited

2020

Oct

28].

https://medlineplus.gov/howtopreventdiabetes.html

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ABSTRACT

Prevent Diabetes with Healthy Lifestyle Author : Megan Janice Nawing, Majesty Patu Buana, Tiara Resky Anugrah Mahmud Hasanuddin University

Background : Type 2 diabetes is a disease that occurs when the body doesn’t make enough insulin or doesn’t use insulin well. Insulin, a hormone made by the pancreas, helps glucose get into your cells to be used for energy. This causes blood glucose, also called blood sugar, is too high. It’s kind of diabetes which accounts for approximately 90% of the total, this rising trend can be attributed to ageing, a rapid increase in urbanisation, and obesogenic environments. Symptoms of type 2 diabetes include increased urination, blurred vision, fatigue, and nausea. The good news is that you can take steps to prevent or delay the development of type 2 diabetes. Healthy lifestyle choices can help prevent type 2 diabetes, and that's true even if you have diabetes in your family. A healthy lifestyle includes more exercise, eat healthy, and avoid smoking. Also, keeping body weight in a normal scale and do medical check up routine.

Objectives : To inform other people about the symptomps, treatment, and how to prevent diabetes type 2. We hope that it can increase society’s awareness of diabetes and make them start a healthy lifestyle.

References : 1. What is Diabetes? | NIDDK [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases. [cited 2020 Oct 27]. Available from: https://www.niddk.nih.gov/healthinformation/diabetes/overview/what-is-diabetes

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2. Diabetes prevention: 5 tips for taking control [Internet]. Mayo Clinic. [cited 2020 Oct 26]. Available from: https://www.mayoclinic.org/diseases-conditions/type-2-diabetes/indepth/diabetes-prevention/art-20047639 3. International Diabetes Federation - Facts & figures [Internet]. [cited 2020 Oct 27]. Available from: https://www.idf.org/aboutdiabetes/what-is-diabetes/facts-figures.html

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SUGAR! OUR HERO FOR DIABETES Author: Michael Pinarto, Vinson Evan Thenardy, Irene Jessica Leonardy AMSA-Hasanuddin University, Makassar, South Sulawesi

ABSTRACT Background: Diabetes is a chronic (long-lasting) health condition that affects how your body turns food into energy. Diabetes is also a major public health problem in worldwide. In 2016 diabetes is in the 7th rank as the deadliest disease in the world. Current global estimates indicate that this condition affect 463 million people and is set to escalate to 700 million by the year 2045. One of the obstacles in the way of seeking health services is the lack of knowledge about the disease in terms of prevention, diagnosis, and treatment. Many people still don’t understand about this disease and don’t have an update information about this disease. This can lead to the spread of wrong information that can cause a misunderstanding in public about diabetes. According to a study in 2012, show that the public has different ideas about diabetes and most of the public give a negative and black image about diabetes. This black image can give a negative impact to people with diabetes. More studies show that the public negative image and a verbal bullying can affect the HbA1c concentration of people with diabetes, which can worsen the patient’s condition. That’s why we want to change this “status quo” about people’s misunderstanding in diabetes. Objective: The aim is to provide knowledge and information to the public about diabetes and also we want to tell the latest update of the disease to the public, so there is no more misunderstanding in the public.

References: 1.

International Diabetes Federation. IDF Diabetes Atlas Ninth Edition. 2019.

The top 10 causes of death [Internet]. [cited 2020 Oct 22]. Available from: https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death

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Abdoli S, Mardanian L, Mirzaei M. How public perceive diabetes: A qualitative study. Iran J Nurs Midwifery Res [Internet]. 2012 Jul [cited 2020 Oct 25];17(5):370–4. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23853650

Storch EA, Heidgerken AD, Geffken GR, Lewin AB, Ohleyer V, Freddo M, et al. Bullying, regimen self-management, and metabolic control in youth with type I diabetes. J Pediatr. 2006 Jun 1;148(6):784–7.

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Thwart the Paunch Muhammad Mikail Athif Zhafir Asyura1, Athaya Shaumi Hermawan1, Aurora Dhea Sitanggang1 1

Faculty of Medicine, Universitas Indonesia

Diabetes is a type of non-communicable disease which is characterized by the increase of blood glucose levels, that in time, if untreated may lead to further complications within the cardiovascular, urogenital, or nervous system.1 In general, there are two types of diabetes; type 2 diabetes or previously called non-insulin dependent diabetes and type 1 diabetes or also known as insulin-dependent diabetes.1,2 The majority of people that has diabetes are more likely to be type 2 due to its etiology being the ineffective use of insulin which is exacerbated by physical inactivity and excess bodyweight.2 On the other hand, type 1 diabetes surface due to the lack of insulin production thus requiring continuous medical intervention in the form of insulin administration.1,2 Despite, diabetes being one of the most highlighted disease worldwide, diabetes remained prevalent and is still very severe. According to the World Health Organisation (WHO), about 422 million people have diabetes and is on the rise. Furthermore, there are about 1.5 million deaths due to diabetes annually and 3.7 million if coupled with hypertension. Combined, diabetes remained a formidable contender for the 7th leading cause of global death, and thus there is an urgency to spread and disseminate information about diabetes to thwart this trend.2 Hence, by creating this poster, we hope that we can clarify certain misconceptions about diabetes and explain they can do to minimise their own risk of developing diabetes. From our poster title “Thwart the Paunch”, we used the word thwart to emphasise on prevention and to strike attention on the viewers. The word paunch is a synonym to a protruding abdomen, which is a characteristic of type 2 diabetes patients.1 From the title alone, we aim to instil understanding on the viewers that by reading this poster, they would know about how to prevent diabetes. Fundamentally, prevention of a disease would be less effective if there are still major misconceptions surrounding that disease. Hence, in the first part of the poster, we chose to dedicate it to the myths and facts about diabetes. We chose 5 different myths that cover diabetes holistically.3,4 Firstly, we want to emphasise that sugar alone would not cause diabetes.3 This point is further supplemented by the candies and sweets being strategically placed around the poster. In type 2 diabetes, it is caused by a problem in how our body processes diabetes, and note sugar intake alone. Next, we want to convey that despite many claims about traditional alternatives, to this date, there are still no cure to diabetes, and

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prevention should be the best call of action.3 Furthermore, in the next point, we want to clarify that everyone is at risk of developing both types of diabetes and both are equally serious. Despite their different etiologies, both types of diabetes still contribute to the mortality rate equally.3,4 Finally, we want to emphasise once more on how serious diabetes as a global disease.3,4 Next, after getting a better understanding about diabetes, we would like to share about certain methods to prevent its development. We decided to use the pseudonym THWART to make it easy for viewers to remember. The first letter, T stands for talk. In this context, talk translates to talking with one’s healthcare providers in case one realises and is worried that one might have diabetes. Secondly, the letter H stands for healthy diet. By avoiding too much sugars and saturated fats we hope that could prevent obesity which is associated with diabetes. Thirdly, the letter W stands for weight. Similar to H, by maintaining one’s weight, certain risk factors of diabetes can be prevented. Fourthly, the letter A stands for avoid tobacco and alcohol. Smoking has remained one of the most contributing risk factors toward diabetes as it increases the chance of developing diabetes by 50%. Next, the letter R stands for regular exercise. As mentioned before, we hope that by exercising frequently, this may help in maintaining one’s weight and thus preventing the occurrence of obesity related diabetes. Finally, the letter T stands for timely check-ups. After analysing one’s condition, visiting a doctor regularly may help in ensuring that your health is satisfactory and if needed, future follow ups to ensure good health.5,6 We chose to personify certain gummy bears as a metaphor for diabetic patients. We hope by doing this, the viewer would be psychologically involved by observing the gummy bears trying to prevent diabetes and would be more motivated in doing so. In conclusion, diabetes remained as a globally severe disease. Despite its popularity, there are still certain facts that are misunderstood by the people and the lack of knowledge on how to prevent the disease itself. By doing this poster, we aim to tackle the misconceptions surrounding diabetes and to provide certain suggestions to prevent diabetes in an attractive medium.

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References: 1. World Health Organisation. Diabetes [internet]. Geneva: WHO; 2020 Jun 8 [cited 2020 Oct 29]. Available from: https://www.who.int/health-topics/diabetes 2. World Health Organisation. Diabetes Overview [internet]. Geneva: WHO; [cited 2020

Oct

29].

Available

from:

https://www.who.int/news-room/fact-

sheets/detail/diabetes 3. Snouffer E. Top 5 greatest myths about diabetes [internet]. 2019 Jul 10 [cited 2020 Oct 29]. Available from: https://diabetesvoice.org/en/advocating-for-diabetes/top5-greatest-myths-about-diabetes/ 4. American Diabetes Association. Myths about diabetes [internet]. USA: American Diabetes

Association;

[cited

2020

Oct

29].

Available

from:

https://www.diabetes.org/diabetes-risk/prediabetes/myths-about-diabetes 5. Harvard School of Public Health. Simple steps to preventing diabetes [internet]. Massachusetts: Harvard School of Public Health; [cited 2020 Oct 29]. Available from: https://www.hsph.harvard.edu/nutritionsource/disease-prevention/diabetesprevention/preventing-diabetes-full-story/ 6. National Institute of Health. How to prevent diabetes [internet]. USA: MedlinePlus; [cited

2020

Oct

29].

https://medlineplus.gov/howtopreventdiabetes.html

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ABSTRACT LET’S END DIABETES FIRMLY! Rifda Hanun Shalihah, Shafira Nur Fauziah

Background Diabetes, considered as one of the major health threats in the 21st century, is a group of metabolic disorders, mostly characterized by hyperglycemia, that is found in every region in the world. WHO estimates that there were about 422 million adults suffering from diabetes in 2014. In Indonesia itself, the prevalence of people with diabetes rose by 0.5% to 2% in a span of 4 years. Diabetes caused around 1.5 million deaths in 2012, making a total of 3.7 million deaths with those who had cardiovascular disease with hyperglycemia. Diabetes can reduce people’s life expectancy by 5 to 10 years, meaning that diabetes is one of the matters of health which we should be more aware of and do something to diagnose, prevent, and treat. Therefore, my friend and I would like to present our idea in the form of a public poster entitled “Let’s END Diabetes FIRMLY!”.

Objectives Our objective is to encourage people to know more things about diabetes within the sentence “Let’s END Diabetes FIRMLY!” consisting two acronyms, ‘END’ and ‘FIRMLY’. END is an acronym of three basic things that people can do to help them diagnose diabetes, consisting that knowing that early detection is important, noticing the signs and symptoms, and doing diagnostic tests, meanwhile FIRMLY is another acronym we made to shortly and simply explain the things that can prevent people from having diabetes also treat people with diabetes, consisting food control, insulin injections, routine exercise, regular monitoring of glucose and medications, lessening of stress, also yoga that has been proven to help people lessen the stress they’re feeling that can indirectly raise the risk of having diabetes or even worsen the condition.

Conclusion As explained previously, diabetes is one of the major health threats to people of any age, and is threatening us by reducing our life expectancy by five to ten years, and that is one thing for us to notice that diabetes is a serious thing for us to deal with. Using this poster, we would like people to know the easy steps of what they could do to detect or diagnose, to prevent, and to treat diabetes, simply put to help all of us firmly end diabetes. Also by doing the preventive

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steps consisted in this poster, we sincerely hope that we can help reduce the number of people with diabetes, and by doing the curative steps, we can help raise the quality of life of those suffering with diabetes.

Reference 1. World Health Organization. Diagnosis and management of type 2 diabetes. Switzerland: World Health Organization; 2020 [cited 2020 Oct 28]. p. 9-17. 2. Kementerian Kesehatan Republik Indonesia. Hasil utama RISKESDAS 2018. Jakarta: Kementerian Kesehatan Republik Indonesia; 2018 [cited 2020 Oct 28]. p. 66-74. 3. Singh VP, Khandelwal B. Effect of yoga and exercise on glycemic control and psychosocial parameters in type 2 diabetes mellitus: a randomized controlled study. Int J Yoga [Internet]. 2020 May - Aug [cited 2020 Oct 28];13(2):144-51. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336951/

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ONLINE SOCI CAMPAIGN

IAL

AMINO | AMSA International Competition 2021

Anastasia Bella Christopilia AMSA-Universitas Kristen Indonesia 2nd Winner of Online Social Campaign Category “Living with Diabetes Mellitus”

Hello people of Tomorrow! My name is Anastasia from AMSA-UKI. I would like to thank AMSA-Indonesia and AMSA-UKI for giving me the chance to join the World Diabetes Awareness Month Competition and to both Agnes and Robert for being amazing teammates in the competition, as well to the volunteers who have supported the campaign. I joined World Diabetes Awareness Month Competition because I wanted to have an experience competing at the International level. From WDAM Competition, I learned to voice my knowledge of diabetes to the public in hopes to prevent diabetes early on. At ﬁrst, it wasn’t easy for me and my teammates working on the online social campaign because the preparation was quite short. We couldn’t believe it when we were going to be on the second place in the competition and we did. Some tips and tricks from me that you can do to start competing are ﬁnding good teammates who have huge motivations and have the same vision as yours. We have to work more creatively so that our campaign will be very meaningful to the community. We invite as many of our friends as possible to join the campaign we have prepared. I’ve learned many lessons during the process. I believe that if you have the motivation and the desire, you should just go and try it!

AMINO | AMSA International Competition 2021

Venna Bella Sabatina AMSA-Universitas Katolik Indonesia Atma Jaya 3rd Winner of Online Social Campaign Category “Diabetes the Mother of All Diseases”

The reason why we want to join the World Diabetes Awareness Month Competition is because we all share similar thoughts regarding diabetes. Diabetes is one of the deadliest yet familiar diseases in our society. However, unfortunately, people's knowledge of the disease is still limited, and they have not been received complete and thorough information about it. As a result, we aim to contribute even more to raise public awareness by participating in the online social campaign branch. This is our ﬁrst time participating in an online social campaign competition and we think there are no speciﬁc tricks. However, the most important lesson that we've learned during this process is that we need to have strong determination and tons of creativity because, honestly, this is not a simple task. There are numerous details that have to be considered. The most interesting part is we have to position ourselves from society's point of view, determining what factors make someone interested in participating in a health campaign and what distinguishes our health campaign from others. Despite the numerous details and preparations that must be completed, the entire process of this health campaign is quite exciting, as it requires a great deal of creativity and many "out of the box" concepts, including some humorous ones that make us chuckle. Furthermore, we are also grateful to create a health campaign that can be useful to society.

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World Diabetes Awareness Month Competition 2020 by AMSA International Asian Medical Students’ Association (AMSA) International

Online Social Campaign Proposal Fight Diabetes and Be Sweet Without Diabetes #BeatDiaBEATes Arranged by: Anastasia Bella Christophilia Lamria Agnes Meilani Robert Kristianto AMSA-UKI Batch 2018 and 2019 Faculty of Medicine Universitas Kristen Indonesia 2020

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Background

Diabetes Mellitus is one of the most common and serious chronic diseases in most countries today. Half of the cases are undiagnosed because the initial phase of Diabetes Mellitus is not accompanied by symptoms until complications occur. Based on the current population growth pattern, it estimated that the number of people with Diabetes Mellitus in the world in 1998 was 140 million. Dr. Hilary King from WHO has predicted that the number of cases will increase by up to 300 million through 2025. That number is more than 150 million in Asia (Cockram, 2000). Indonesia is the fourth most populous country in the world with a population of 237.6 million people in 2010. Indonesia also has the seventh-largest number of diabetes patients (7.6 million), despite its relatively low prevalence (4.8% including type 1 diabetes). and 2 in individuals aged 20-79 years) in 2012. Lifestyle from now on increases the risk of Diabetes Mellitus. Unfortunately, the increasing number of diabetics is not followed by treatment so that continuously Diabetes is a condition that couldn't be cured. Researchers to date are doing recombinant and a lot of research to address this problem. Starting from recombinant DNA and surgery to telemedicine and telehealth to improve the quality of life for a person with risks due to lifestyle, heredity, or already suffering from Diabetes. Rising for our background, we have the desire to plan an online campaign focused on increasing knowledge and awareness to live with Diabetes. The campaign we are doing is “Fight Diabetes and be Sweet Without Diabetes” following by #BeatDiaBEATes.

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II.

Scope of Campaign

Participant of Campaign -

General

: All Social Media Users

Particular

: AMSA International’s Member

Target of Campaign -

General

: All Social Media Users

Particular

: Obesity, Health-Care Workers, Diabetes Patients, and people with risk and families of Diabetes.

Media of Campaign

III.

: Instagram

Basic Theory

A. What is Diabetes

Diabetes mellitus (DM) is a chronic disease in which high blood glucose (BG) levels (hyperglycemia) are not regulated by perfect glucose homeostasis. Diabetes mellitus (DM) can cause hyperglycemia in DM patients. Hyperglycemia in uncontrolled diabetes mellitus can cause disturbances in the body system, especially nerves and blood vessels (World Health Organization, 2018). Prevention that can be done is by changing the patient's lifestyle, such as increasing diet and physical exercise (International Diabetes Federation, 2017).

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B. Types of Diabetes

Diabetes mellitus can be classified into 2, namely: a. Diabetes mellitus type 1: Diabetes type 1 or insulin-dependent diabetes mellitus (IDDM) is characterized by the body's immune system destroying pancreatic β cells, so that β cells are unable to produce the insulin hormone which functions to lower blood glucose levels. b. Diabetes mellitus type 2: Diabetes type 2 or non-insulin-dependent diabetes mellitus (NIDDM) begins with a condition of insulin resistance, which is a decreased sensitivity of insulin receptors in the liver, muscle tissue, and adipose tissue so that the insulin hormone is not used properly.

C. Pathophysiology of Diabetes

Pathophysiology is divided based on classification and type, namely: a. Diabetes mellitus type 1 Diabetes mellitus type 1 is autoimmune which is mediated by T cells which damage pancreatic β cells and progress slowly. Impaired immune tolerance occurs due to immune cell abnormalities and changes in β cell antigens. Β cell damage. Β cell damage is caused by genetic and environmental susceptibility factors. The strongest genetic association can be seen in patients with histocompability of the leukocyte antigen (HLA) class II alleles HLA-DQ and HLA-DR. b. Diabetes mellitus type 2 In the pathophysiology of type 2 diabetes mellitus, there are several conditions that play a role, such as: 1. Insulin resistance 2. Pancreatic B cell dysfunction. Type 2 diabetes mellitus is not caused by a lack of insulin secretion, but because insulin target cells fail or are unable to respond to insulin normally. Commonly referred to as "insulin resistance". Insulin resistance mostly occurs as a result of obesity and lack of physical activity and aging. In type 2 diabetes mellitus patient, excessive hepatic glucose

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production can also occur but there is no autoimmune destruction of Langerhans B cells of pancreas. Type 2 diabetes mellitus is only relative and not absolute. In the early development of type 2 diabetes mellitus, B cells show a disturbance in the first phase of insulin secretion, meaning that insulin secretion fails to compensate for insulin resistance. If not handled properly, in the next development there will be damage to the B cells of the pancreas. The progressive damage to pancreatic B cells will often lead to insulin deficiency, so that ultimately the patient requires exogenous insulin. In people with type 2 diabetes mellitus, these two factors are generally found, that is insulin resistance and insulin deficiency. D. Clinical Manifestation of Diabetes

From the pathophysiology we will see a symptom or clinical manifestation of the diabetes classification: a. Diabetes mellitus type 1 The symptoms of type 1 diabetes mellitus are polydipsia, polyuria, polyphagia, weight loss, weaknesses, recurrent infections (e.g. boils, carbuncles, and bladder infections), wounds are difficult to heal, pruritus in the genital area, impaired vision, paresthesia, cardiovascular discharge (for example, chest pain, leg pain, and neurological deficit). b. Diabetes mellitus type 2 The symptoms of type 2 diabetes mellitus are weak, tingling (numbness at the end of the extremity), itching, blurry eyes, erectile dysfunction in men, pruritus vulvae in women, and wounds those are difficult to heal. Supporting Investigation of Diabetes: a. Diabetes mellitus type 1 Temporary blood sugar levels > 200 mg / dL (11.1 mmol / L). In asymptomatic patients, fasting blood sugar levels are found to be higher than normal and the glucose tolerance test is impaired on more than one examination. Fasting blood sugar is considered normal if the blood level in

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venous blood (plasma) is <140 mg / dL (7.8 mmol / L) or capillary blood <120 mg / dL (6.7 mmol / L). C-Peptide measurement can be used to see the function of cell residues, which is a cell that still produces insulin and can be used if it is difficult to distinguish between types 1 and 2 diabetes. HbA1c examination is performed, routine every 3 months. Benefits of HbA1c can measure blood glucose levels over the past 120 days (according to erythrocyte age), assess changes in therapy 8-12 weeks before, assess control of DM disease to prevent diabetes complications. Glycosuria not specific for DM needs to be confirmed by checking blood sugar. Type 1 diabetes mellitus contains 70-80% autoantibodies (ICA, IAA) so it is not an absolute requirement for diagnosis. b. Diabetes mellitus type 2 On the supporting examination of Diabetes mellitus 2, namely: •

Fasting Blood Sugar

•

Blood Sugar 2 hours Post Prandial

•

Urinalysis

E. Treatments of Diabetes

The type 1 diabetes only can be treated by insulin but the type 2 diabetes can be treated by oral medicine for the initial phase.

F. Complication of Diabetes Mellitus

a. Acute complication The acute complication that can be happened to people with Diabetes is an extreme hyperglycemia that can cause Ketoacidosis Diabetic and Hyperglicemic Hyperosmolar State or it can be hypoglycemia. b. Chronic Complication

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The chronic or the effect of the prolonged Diabetes is diabetic foot ulcer, heart attack, peripheral neuropathy, diabetic neuropathy, peripheral arterial disease, diabetic retinopathy, glaucoma, cataracts, and stroke.

IV.

Campaign Plan TITLE: Fight Diabetes and Be Sweet Without Diabetes

HASTAG: #BeatDiaBEATes #WDAM2020 #WorldDiabetesAwarenessMonth #VivaAMSA TIMELINE INSTAGRAM (@amsa_intl) DAY POST 1

STORY

Greetings People of Tomorrow!

Prevalence of Diabetes

With this post, AMSA International proudly announce the online social campaign for the World Diabetes Awareness Month online campaign with the title “Fight Diabetes and Be Sweet Without Diabetes” that is focused on which focuses on raising awareness about diabetes and improving public health through campaigns. Greetings People of Tomorrow!

Mellitus

Caption for the Post (incl. hastag)

World Diabetes

World Diabetes Day (WDD) was created in 1991 by IDF and the World Health Organization in response to growing concerns about the escalating health threat posed by diabetes. WDD are celebrated on November 14 so on the World Diabetes Awareness Month (WDAM) held on November.

Awareness Month

The blue circle is the global symbol for diabetes awareness. It signifies the unity of the global diabetes community in response to the diabetes epidemic. 3

Mortality of

This or That

Diabetes

#BeatDiaBEATes

Mellitus

Greetings People of Tomorrow! Diabetes Mellitus is one of the most common causes of death from the chronic disease today. Increasing the mortality rate from this disease is related to the complications it causes. However, if we look back, Diabetes Mellitus is a disease that can be prevented. How?

Prediabetes

Greetings People of Tomorrow!

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Fact Prediabetes means you have a higher than normal blood sugar level. If you have prediabetes, the long-term damage of diabetes — especially to your heart, blood vessels, and kidneys — may already be starting. There's good news, however. Progression from prediabetes to type 2 diabetes isn't inevitable. Are you can be normal after being prediabetes? Let's see. 5

Type of

Greetings People of Tomorrow!

Diabetes

Mellitus

Diabetes mellitus has various types with different etiologies. However, the major types belonging to diabetes mellitus are type 1 diabetes (IDDM), type 2 (NIDDM), and gestational diabetes.

Prevention of

Greetings People of Tomorrow!

Diabetes The main objective of conducting World Diabetes Awareness Month is to take preventive measures against Diabetes Mellitus. Prevention methods are aimed at making lifestyle changes to be healthier.

Mellitus

Myth or Fact and Discussion

Overview of Design

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References 1. Marsis IO. Panduan Praktik Klinis. Jakarta: IDI; 2017 2. Sudoyo AW, Setiyohadi B, Alwi I, Simadibrata M, Setiati S. Buku Ajar Ilmu Penyakit Dalam Jilid II edisi V. Jakarta: Interna Publishing; 2017. 3. Ridwan A, Astrian R, Barlian A. Pengukuran efek antidiabetes polifenol (Polyphenon 60 ) berdasarkan kadar glukosa darah dan histologi pankreas mencit (Mus musculus L.) S.W. jantan yang dikondisikan diabetes mellitus. Matematika & Sains. 2012;17(2):78- 82

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Online Local Diabe e E en Repor

Living ith Diabetes Mellitus 271

A. Name of the Project The name of the Online Local Diabetes Event (OLDE) is “Living with Diabetes”. B. Platform Platform that we use to do social online local campaign is by Instagram. C. Project Scope Participant of Campaign : 2 organizer and 5 volunteers. Target of Campaign -

General : All Social Media Users

Particular : Obesity, Health-Care Workers, Diabetes Patients, and people with risk and families of Diabetes.

D. Start and End Date and Time The online local campaign will be held in one week (31 October – 5 November 2020).

E. Workload and Position of Every Team Member Anastasia Bella Christophilia

: Create and prepare proposal and campaign materials.

Lamria Agnes Meilani

: Creating an online campaign design.

Robert Kristianto

: Create and prepare proposal and campaign materials.

F. Ground Work At the beginning of the publication of the WDAM AMSA International guideline, we had several ideas consisting of: 1. The latest innovation in examining patients with Diabetes Mellitus. 2. The newest and effective method of treatment to improve the well-being of patients with Diabetes Mellitus.

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3. An outline of Diabetes Mellitus. Because this campaign is aimed at the community, we decided to focus on making the campaign public. We raise several things such as etiology, classification, and education.

G. Summary of the project TITLE: Fight Diabetes and Be Sweet Without Diabetes HASTAG: #WDAM2020 #WorldDiabetesAwarenessMonth #FightDiabetes #BeSweetWithoutDiabetes #LivingWithDiabetes #BeatDiaBEATes #VivaAMSA TIMELINE INSTAGRAM DAY POST 1

Caption for the Post (incl. hashtag above) [World Diabetes Awareness Month] Greetings people of tomorrow! WORLD

DIABETES

AWARENESS

MONTH! There are 500 million people in the world today

with diabetes.

Indonesia with

273

today about "What is Diabetes" to give information about diabetes and this campaign is mediated by Instagram posts. You can follow their campaign on this account itself. We are looking forward to your participants by following our Instagram for joining this campaign. Follow our progress for more info! Thank you! 2

[Diabetes?] Greetings people of tomorrow! WORLD

DIABETES

AWARENESS

MONTH! There are 500 million people in the world today

with diabetes.

Indonesia with

population of 270 million, has about 16 million diabetes, but it estimated that half of diabetes in Indonesia remain undiagnosed, especially young people because of the lack of screening. With this post, AMSA-International proudly announces the World Diabetes Awareness Month online social campaign with the title "Living with Diabetes" that focuses on raising people's awareness and knowledge about diabetes. This campaign will be held in a week, starting from today about "Get To Know Sweet Blood Disease" to give information about diabetes. This campaign is mediated by Instagram posts. You can follow their campaign on this account itself. We are

274

looking forward to your participants by following our Instagram for joining this campaign. Follow our progress for more info! Thank you! 3

[Who Is Most Affected of Diabetes?] Greetings people of tomorrow! WORLD

DIABETES

AWARENESS

MONTH! There are 500 milion people in the world today with diabetes. Indonesia with a population of 270 milion, has about 16 milion diabetes, but it estimated that half of diabetes in indonesia remain undiagnosed, especially young people because of the lack of screening. With this post, AMSA-International proudly announces the World Diabetes Awareness Month online social campaign with the title "Living with Diabetes" that focuses on raising people's awareness and knowledge about diabetes. This campaign will be held in a week, starting from today about "Get To Know Sweet Blood Disease" to give information about diabetes, who is most affected and whom to screen. This campaign is mediated by instagram posts. You can follow their campaign on this account itself. We are looking forward to your participants by following our instagram for joining this campaign. Follow our progress for more info! Thank you!

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[How is the clinical diagnosis of Diabetes and what are the complication of Diabetes]

Greetings people of tomorrow!

WORLD

DIABETES

AWARENESS

MONTH!

There are 500 million people in the world today

with diabetes.

Indonesia with

population of 270 million, has about 16 million diabetes, but it estimated that half of diabetes in Indonesia remain undiagnosed, especially young people because of the lack of screening.

information

about

diabetes.

This

campaign is mediated by Instagram posts. You can follow their campaign on this account itself. We are looking forward to your participants by following our Instagram for joining this campaign. Follow our progress for more info! Thank you!

276

[What is it diabetes mellitus 1 and the causes of diabetes mellitus type 1]

Greetings people of tomorrow!

WORLD

DIABETES

AWARENESS

MONTH!

There are 500 million people in the world today

with diabetes.

Indonesia with

population of 270 million, has about 16 million diabetes, but it estimated that half of diabetes in Indonesia remain undiagnosed, especially young people because of the lack of screening.

With this post, AMSA-International proudly announces the World Diabetes Awareness Month online social campaign with the title "Living with Diabetes" that focuses on raising people's awareness and knowledge about diabetes. This campaign will be held in a week, starting from today about "Diabetes Melitus type 1" to give information about diabetes. This campaign is mediated by instagram posts. You can follow their campaign on this account itself. We are looking forward to your participants by following our instagram for joining this campaign. Follow our progress for more info! Thank you!

277

[What is it diabetes mellitus type 2 and how for Education of Diabetes]

Greetings people of tomorrow!

WORLD

DIABETES

AWARENESS

MONTH!

There are 500 million people in the world today

with diabetes.

Indonesia with

population of 270 million, has about 16 million diabetes, but it estimated that half of diabetes in Indonesia remain undiagnosed, especially young people because of the lack of screening.

With this post, AMSA-International proudly announces the World Diabetes Awareness Month online social campaign with the title "Fight Diabetes and Be Sweet Without Diabetes" that focuses on raising people's awareness and knowledge about diabetes. This campaign will be held in a week, starting from today about "Diabetes Mellitus type 2 and Education" to give information about diabetes. This campaign is mediated by Instagram posts. You can follow their campaign on this account itself. We are looking forward to your participants by following our Instagram for joining this campaign. Follow our progress for more info! Thank you!

278

This project has been implemented once on October 31, 2020. This online campaign has been spread through 7 Instagram accounts. Diabetes Mellitus is the 6th leading cause of death in the world. In 2016, an estimated 1.6 million deaths were directly caused by diabetes. Even so, this disease is a disease that can be prevented. Therefore, the message that can be taken by every community is how to describe the disease and how to prevent Diabetes Mellitus.

H. Impact Analysis of the Event We have implemented an online campaign on the first day and will continue until the sixth day. From this social campaign, we received good feedback, especially from medical students where many asked about this campaign and also wanted to volunteer in this activity. Henceforth, we also want to hold a question and answer session so that social media users other than medical students can find out and be aware of the importance of preventing Diabetes Mellitus.

I. Attendance details In the distribution of social campaigns through Instagram, seven accounts spread online campaigns, namely as follows: agneslms, anastasiaa.bc, dwvighnes_, maesyclarisahutapea, mrchliadjajanto, gretachrstbl28, and sharonlevita1602.

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J. Documentation

280

ABSTRACT

“DIABETES THE MOTHER OF ALL DISEASES”

Diabetes is a growing health problem among non-communicable disease that attacks many people around the world. According to World Health Organization (WHO) there are 422 million people in the world suffering from diabetes and it is also responsible for 1.6 million deaths each year. Other than its serious complications and impairments in the patient’s daily life, diabetes is also a growing concern both for the nations health care and economic condition. World Diabetes Awareness Month which is celebrated every November annually reminds us about diabetes, and more importantly the need to keep improving ways to prevent diabetes. Therefore, we propose our social campaign “Diabetes The Mother of All Diseases” which hopefully can raise awareness about diabetes and together we prevent diabetes from happening. The campaign will be posted online on Instagram, YouTube, Facebook, LINE, WeChat, and KakaoTalk and WhatsApp with the hope to reach more people across countries so we can join hands in spreading the information and encourage many people to prevent diabetes from happening. This campaign will run for seven days and really need the participation of everyone so that this campaign will be successful and impactful. We hope through this campaign, we can inspire many people to start real actions against diabetes because diabetes is the mother of all diseases.

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ONLINE SOCIAL CAMPAIGN PROPOSAL WORLD DIABETES AWARENESS MONTH 2020

DIABETES THE MOTHER OF ALL DISEASES AMSA INTERNATIONAL

ARRANGED BY :

Venna Bella Sabatina Hepyta Valerie Jacky Klemens Owen

2020

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BACKGROUND

World Diabetes Awareness Month is being celebrated annually every November, considering that there are still many people with diabetes around the world. According to WHO there are 422 million people in the world who have diabetes, particularly in low income countries. Diabetes is also responsible for 1.6 million deaths each year, unfortunately the incidence and the prevalence of diabetes is continuously increasing for the few decades.1 Not only deadly, diabetes also affects many aspects of someone’s life, such as it can affect the economic condition, mental health, and social life of a person. The cost needed to treat diabetes patients in 2017 was US $ 327 billion, which is an increase from the previous US $ 245 billion. Due to the high number of diabetes patient care, it is not surprising that the family is also burdened, especially if the affected patient is the backbone of the family, this will certainly have a lot of influence on the family economy situation.2 Diabetes is a disease that not only affects a person's physical condition but can also affect the patient' entire life and people around them. The complications caused can also include systemic complications such as kidney failure, stroke, limb amputation, and many deadly diseases. That is why we named our campaign as “DIABETES THE MOTHER OF ALL DISEASES”.3 This campaign is being made to raise the awareness about diabetes so that more people are educated and can take real action in the form of prevention against diabetes.

II. SCOPE OF CAMPAIGN Project Title: Diabetes The Mother of All Diseases Details of Project: 

Project Aim and Purposes Increase community awareness and knowledge about diabetes and means to prevent it.

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

Project Objectives Publication through social media for 7 days which are massive, interactive, and evidence-based.



Benefits Identification For AMSA : Branding AMSA International for its concern toward Sustainable Development Goals 3 (SDG) 3 from WHO in prevention of non-communicable disease. For the Community : Focus on the major issues of non-communicable disease which is diabetes through popular and interactive approach.



Limits and Exclusions 

This campaign is mainly focused on social media platforms which might result in limitation of participant and audiences.



The informations are limited on the current updates of diabetes until 27th October 2020.



Targets o

Primary : Susceptible groups and adolescent.

Secondary : Young generations and health care workers.

Tertiary : stakeholders and governments.

III. BASIC THEORY a.

What is Diabetes Diabetes is a chronic metabolic disease that happens either because insulin does

not produce enough from the pancreas or when the patient cannot use the insulin significantly. These conditions lead to rise in blood sugar or known as hyperglycaemia, and may lead to catastrophic conditions to the body’s system.1 b. Types of Diabetes There are several types of diabetes based on its pathophysiology. Type 2 diabetes is caused by the body’s inability to use insulin effectively. This is the most common type of diabetes. It can cause obesity and physical inactivity. Sign and symptoms are often not marked, and as the result diagnosis made several years after onset which the complications have already happened.1

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Type 1 diabetes is characterized by inadequate production of insulin and therefore the patient will require administration of insulin. The etiology and how to prevent it remains unkown. The patient experience excessive urination (Polyuria), thirst (polydipsia), hunger, skinny, change in visual, and fatigue.2 c. Symptoms of Diabetes There are several symptoms that can be suspected if the person has diabetes: urinate a lot (often at night), thirsty, lose weight, hungry, numb or tingling on extremity, experience fatigue, ulcer heals slowly, and prone to illness or infections. Additional symptoms for people with type 1 diabetes may have vomiting, nausea, or stomach pain.2 d. Risk Factor There are several risk factors for type 2 diabetes from the genetic and metabolic factor. Ethnicity, familial history of diabetes, obesity, unhealthy diet, physical inactivity and smoking increase the risk for type 2 diabetes. Excess in body fat and physical inactivity is by far the most common risk factors for global diabetes burden. BMI (Body Mass Index) is also associated with increased risk of type 2 diabetes.2 In terms of diet, unhealthy diet including high intake of saturated fatty acid, high total fat intake, and inadequate dietary fiber will lead to unhealthy body weight and there increase the risk for type 2 diabetes. Other than that, high intake of sweet foods increase the risk of being obesed.2 Active smoker is also prone to type 2 diabetes about 10 years after smoking cessation with the highest risk among heavy smokers.2 e. Complications of Diabetes Diabetes has multi-organ complications. Abnormally high blood glucose will trigger conditions such as: Diabetic ketoacidosis (DKA) in types 1 and 2. In the other hand abnormally low blood glucose can happen in all types of diabetes which result in seizure or loss of consciousness. Heart, blood, eyes, kidneys, and nerves are the main target in the complications of diabetes. The most common manifestations is diabetic neuropathy which increases the likelihood of having foot ulcers, infection, and eventually limb amputation. Diabetic retinopathy will also cause blindness and resulting in damage in retina. Diabetes also cause increased risk in cancer.4

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f. Socio-Economic burden Measuring the burden cost can be seen directly from medical cost, and indirectly from productivity loss, premature mortality and its effects on Nations’ Gross Domestic Product (GDP). On a systematic review, the direct cost of diabetes is predicted to be more than US$ 827 billion.5,6 The International Diabetes Federation (IDF) also has estimated that the economic burden of health-care associated with diabetes has tripled over period to 2003-2013 because of the rising number in people with diabetes and per capita diabetes.7 g. Prevention Diabetes can be prevented by some means, but type 1 diabetes cannot be prevented and only by managing its complication. Lifestyle is known to be effective to prevent type 2 diabetes and its complications. These includes: maintain healthy and ideal body weight, physically active with 30 minutes regular, moderate-intensity activity. Eating healthy and balanced diet by avoiding sugar and saturated fats and avoid tobacco use decreases the severity and even prevent diabetes.7

IV. CAMPAIGN TIMELINE Date

Materials

Social Media

08/11/2020 Video Trailer, Diabetes

Facebook, YouTube, Instagram (Feeds

definition, Diabetes

and Story), LINE (timeline and story),

epidemiology, Puzzle

WhatsApp (story), broadcast message via

Fragment day one.

WhatsApp, LINE, WeChat, and KakaoTalk.

09/11/2020 Classification of Diabetes,

Facebook, Instagram (Feeds and Story),

Diabetes symptomps,

LINE (timeline and story), WhatsApp

Crossword Diabetes, Puzzle

(story), broadcast message via

fragment day two.

WhatsApp, LINE, WeChat, and KakaoTalk.

10/11/2020 Causes of Diabetes, Diabetes

Facebook, Instagram (Feeds and Story),

Risk Factor, How many % do

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LINE (timeline and story), WhatsApp

you get ?, Puzzle Fragment

(story), broadcast message via

day three.

WhatsApp, LINE, WeChat, and KakaoTalk.

11/11/2020 Myth and Facts answer about

Facebook, Instagram (Feeds and Story),

Diabetes, Myth and Facts

LINE (timeline and story), WhatsApp

Challenge, Puzzle Fragment

(story), broadcast message via

day four.

WhatsApp, LINE, WeChat, and KakaoTalk.

12/11/2020 Complication Matching,

Facebook, Instagram (Feeds and Story),

Impact of Diabetes, Puzzle

LINE (timeline and story), WhatsApp

Fragment day five.

(story), broadcast message via WhatsApp, LINE, WeChat, and KakaoTalk.

13/11/2020 Diabetes Prevention, Help me

Facebook, Instagram (Feeds and Story),

to lift this weight Challenge !,

LINE (timeline and story), WhatsApp

Puzzle Fragment day six.

(story), broadcast message via WhatsApp, LINE, WeChat, and KakaoTalk.

14/11/2020 What you can do about

Facebook, Instagram (Feeds and Story),

Diabetes?, to do list challenge, LINE (timeline and story), WhatsApp Puzzle Fragment day seven.

(story), broadcast message via WhatsApp, LINE, WeChat, and KakaoTalk.

For

detailed

campaign

plan,

please

https://tinyurl.com/DetailPost Caption [WORLD DIABETES AWARENESS MONTH 2020] Hello, People of Tomorrow !

6 287

kindly

check

this

link

November is coming and guess what else is coming? Yes, WORLD DIABETES AWARENESS MONTH ! Maybe you are wondering, why should we care about this disease? Isn't diabetes a common disease and many people knowing? In fact, more than 422 million people in the world who have diabetes comes from low income countries. It is also responsible for 1.6 million deaths each year, and unfortunately the incidence and the prevalence of diabetes is continuously increasing for the few decades. Unfortunately, it turns out that many people know about this disease, but do not take real prevention of diabetes. Isn’t that scary? And how about you? I believe you are not the same. Stay focused, because DIABETES IS THE MOTHER OF ALL DISEASES #DiabetesTheMotherofAllDiseases #WorldDiabetesAwarenessMonth #vivaAMSA V. ATTACHMENT DAY ONE 1.1 Video Trailer ( YouTube, IGTV, Facebook, Broadcast message via WhatsApp, LINE, WeChat, and KakaoTalk)

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1.2 Diabetes Definition and Diabetes Epidemiology (Instagram Feeds, LINE TIMELINE, Facebook)

1.3 Puzzle fragment day one (Instagram Story, WhatsApp Story)

DAY TWO 2.1 Classification of Diabetes and Diabetes Symptomps (Instagram Feeds, LINE TIMELINE, Facebook)

2.2 Crossword Diabetes, Puzzle Fragment day two (Instagram Story, WhatsApp Story, broadcast message via WhatsApp, LINE, WeChat, and KakaoTalk)

DAY THREE 3.1 Causes of Diabetes and Risk Factor of Diabetes TIMELINE, Facebook)

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(Instagram Feeds, LINE

3.2 How many % do you get?, Puzzle Fragment day three (Instagram Story, WhatsApp Story, broadcast message via WhatsApp, LINE, WeChat, and KakaoTalk)

DAY FOUR 4.1 Myth and facts answer (Instagram Feeds, LINE TIMELINE, Facebook)

4.2 Myth & facts Challenge and Puzzle Fragment two (Instagram Story, WhatsApp Story, broadcast message via WhatsApp, LINE, WeChat, and KakaoTalk)

DAY FIVE 5.1 Impact of Diabetes (Instagram Feeds, LINE TIMELINE, Facebook)

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5.2 Complication Matching and Puzzle Fragment day five (Instagram Story, WhatsApp Story, broadcast message via WhatsApp, LINE, WeChat, and KakaoTalk)

DAY SIX 6.1 Diabetes Prevention (Instagram Feeds, LINE TIMELINE, Facebook)

6.2 Help me to lift this weight Challenge !, Puzzle Fragment day six (Instagram Story, WhatsApp Story, broadcast message via WhatsApp, LINE, WeChat, and KakaoTalk)

DAY SEVEN 7.1 What can you do about Diabetes ? (Instagram Feeds, LINE TIMELINE, Facebook)

7.2 To do List challenge, Puzzle Fragment (Instagram Story, WhatsApp Story, broadcast message via WhatsApp, LINE, WeChat, and KakaoTalk)

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REFERENCE: 1. Diabetes [Internet]. Who.int. 2020. Available from: https://www.who.int/healthtopics/diabetes#tab=tab_1 2. The Cost of Diabetes | ADA [Internet]. Diabetes.org. 2020. Available from: https://www.diabetes.org/resources/statistics/costdiabetes#:~:text=Conclusion,billion%20(in%202012%20dollars). 3. Diabetes - long-term effects [Internet]. Betterhealth.vic.gov.au. 2020. Available from: https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/diabeteslong-term-effects 4. Global Report on Diabetes. France; 2016. 5. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4*4 million participants.

Lancet

2016;

published

online

April

http://dx.doi.org/10.1016/S0140-6736(16)00618-8. 6. Seuring T, Archangelidi O, Suhrcke M. The economic costs of type 2 diabetes: A global systematic review. PharmacoEconomics. 2015; 33(8): 811–31. 7. IDF Diabetes Atlas, 6th ed. Brussels, International Diabetes Federation; 20

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ONLINE LOCAL DIABETES EVENT WORLD DIABETES AWARENESS MONTH 2020

DIABETES: SAVE YOUR LOVE ONES AMSA INTERNATIONAL

ARRANGED BY:

Vennaa Bella Sabatina Hepyta Valerie Jacky Klemens Owen

2020

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REPORT 1. Venue / platform •

Instagram

•

LINE

•

2. Project level / scope •

Social media user especially teenager and young adults across Instagram, LINE, and Whatsapp

3. Start and end date and time •

Start date: Wednesday, 28th October 2020 (09.00 WIB) (GMT+7)

•

End date: Thursday, 29th October 2020 (12.00 WIB) (GMT+7)

4. Workload and position of every team member No 1.

Position Organizator

Name

Workload

Venna Bella

The event’s initiator, providing ideas and concepts

Sabatina

for the event, looking for material, giving feedback on the design, and helping gather people for posting the information.

Organizator

Hepyta

The event’s initiator, helping to create and edit

Valerie

designs also post-event videos, providing feedback on material content and concepts and helping gather people for posting the information

Volunteer

Jacky

Helping in arranging the campaign's concept and

Klemens

material, giving feedback about the design, helping

Owen

gather people for posting the information also LINE.

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Volunteer

Louis Fabio

Giving feedback to the design and publication via

Jonathan

Instagram.

Kezia

Giving feedback to the design and publication via

Adelize

WhatsApp.

Junus 6.

Volunteer

Jeremy

Designing the contents and providing ideas for the

Menajang

content.

Jennifer

Design and brainstorm ideas for the content.

Sutanto

5. Ground work In determining the event topic, we highlighted the fact that many people still have not known about how to prevent and focus too much on a large scale. The truth is we believe that the prevention should start from the smallest group as possible, our loved ones, including: family, friends, and others that we care about. After deciding the topic, we brainstormed the contents that would be shared including the information and how to deliver them in interactive ways. Then we decided on which platform we would deliver them. Because of the COVID-19 outbreak in Indonesia, we planned to share this event through online platforms. On the execution date, we share through social media: Instagram, Facebook, LINE about the post that we made and also through Google Forms asked feedback from the participant about our campaign and then evaluating our event.

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6. Summary of the project Our campaign focus on raising awareness and holistic approach about diabetes and wanted to give message that diabetes should be prevented, especially for our love ones. We aimed to target people across all ages and all conditions to care about diabetes as a way to save their love ones. We chose to post on social media (LINE, Whatsapp, and Instagram) because it is one of the largest platform to share and the impact can be massive. Adding to that, we can also reach people across the globe with this social media. A total of 254 participants posted our campaign in the span of 2 days from Wednesday, 28th October 2020 to Thursday, 29th October 2020. The preparations came long before that and finally, on the execution date, everything is going well. We posted some Only some people having minor problem regarding the mechanism of posting in their social media. Then, we asked them to fill our feedback form. 99,6% want to share this material to family and friends, 80,7% think that this campaign is very useful, and 80,3% think that this campaign is very interesting. Aside from the feedback form, we also gained some appreciation by people feeling that this helps them to get closer and care more about their love ones just as our campaign tagline. We really happy to have done this project.

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7. Impact analysis of the event After doing the event, here are some impact analysis of the event. Our participant reached 254 people from those who shared through Instagram, Whatsapp, and LINE. We also asked their feedbacks and most say that this campaign open their eyes on how to care with people they love by preventing diabetes. Moreover, most of them say that it is a good campaign and should be continued for its good message about preventing diabetes. The participants said most of them learn more about the components of diabetes and also important facts about diabetes. Moreover, now they know that to prevent diabetes is not impossible tasks rather of a loving journey to save their love ones. They also said that the material are appealing and easy to understand which increase their engagement with the material.

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We posted our campaign on LINE, Whatsapp, and Instagram and the insights are quite amazing, in fact that every Instagram user has their own insights, and moreover we also share to many groups and personal chat on LINE and Whatsapp. For future event, we think that it would be better to do some more activities rather than just posting online materials. We can organize a webinar to give more info about more holistic approach on prevention of diabetes while also partnering with other GO/NGO that also concern about diabetes. Focused group discussion (FGD) can also be done to explore more about people’s mindset and to be more personalized, and other means to reach more people through online platforms. We can also open donation to help those suffering from diabetes and giving their family support to care more about family member. By doing that, we hope to give better information and help more people to care about their love ones.

Here are some feedbacks that we documented. For full recap, kindly check: https://tinyurl.com/FeedbacksDiabetes

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8. Documentation (picture, links, videos) INSTAGRAM FEEDS, LINE, WHATSAPP

CAPTION

[CAPTION] Hello, People of Tomorrow! November is coming and guess what else is coming? Yes, WORLD DIABETES AWARENESS MONTH! Maybe you are wondering, why should we care about this disease? Isn't diabetes a common disease and many people knowing? In fact, more than 422 million people in the world who have diabetes comes from low income countries. It is also responsible for 1.6 million deaths each year, and unfortunately the incidence and the prevalence of diabetes is continuously increasing for the few decades.

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Unfortunately, it turns out that many people know about this disease, but do not take real prevention of diabetes. Isn’t that scary? And how about you? I believe you are not the same. So, let’s take part in our campaign about diabetes and #SaveYourLoveOnes #WorldDiabetesAwarenessMonth #vivaAMSA STORY

By including hastag #WDAM #SaveYourLoveOnes

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World Diabetes Awareness Month Competition 2020 By AMSA International

Online Social Campaign Proposal Stop Diabetes Through #BeatWithThePITCH Arranged By : Yolanda Anisa Marlin Dhea Anisa Yuri Lubis AMSA-UNJA Faculty of Medicine and Health Sciences Universitas Jambi 2020

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Title : Stop Diabetes Through #BeatWithThePITCH I. Background World Diabetes Awareness Month was created by International Diabetes Federation (IDF) and World Health Organization (WHO) in 1991, in response to the increasing both of the number of cases and the prevalence of diabetes, so it can reduce the quality of health in world wide. In 2006, World Diabetes Awareness Month became an official United Nations, which celebrated every year on 14 November. Diabetes is a disease that can found in all populations, even in all regions of the world. The prevalence of people with diabetes continues to increase every year. WHO has estimated about 422 million people in the world have diabetes, the particularly in low and middle income countries compared to high income countries. [1] In additional, IDF Diabetes Atlas 9th edition has estimated approximately 463 million adults aged 20-79 yaers were living with diabetes in the world. [2] WHO estimated about 1,6 million deaths are associated to diabetes each year. Over the last few decades, both the number of cases and the prevalence of diabetes has continued to increase. [1] In additional, IDF also estimated that diabetes has caused 4,2 million deaths, and also caused at least USD 760 billion dollars in health spending in 2019 and 10 % on adults. [2] In most countries, people with type 2 diabetes is increasing, it is about 374 million people have increased risk of developing type 2 diabetes. And type 1 diabetes also attack more than 1,1 million children and adolescents group.Without interventions to stop the increase of diabetes, there will rise to 700 million people living with diabetes by 2045. [2] Diabetes is not only individual health problem, but also become one of the largest public health problems in the world. Diabetes, not only effects to the quality of life, but also results in death significantly. So, it’s important to make the strategy of diabetes prevention. Evidence from international studies, which from Finland, Sweden, USA, China, India, and Japan have proven that prevention of diabetes through lifestyle interventions can delay and even can stop the occurence of diabetes in people who are at high risk. Lifestyle interventions are the key to prevention of diabetes, which include weight control and physical activity.[7] There is also study acknowledge that apart from lifestyle interventions, the major strategies that has been evaluated for reduce the occurence of diabetes is pharmacotheraphy.[4]

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Rising from our background, we have desire to plan an online campaign focused on preventing

diabetes.

The

campaign

are

doing

isStop

Diabetes

Through

#BeatWithThePITCH (P)harmacotherapy if necessary (I)ncrease physical activity (T)ake control of weight (C)heck Blood Sugar Levels (H)ealthy Eating Plans II. Scoup of Campaign Participant of Campaign -

General

: All Social Media Users

Particular

: AMSA International’s Members

Target of Campaign -

General

: All Social Media Users

Particular

: People who have risk factors for diabetes

Media of Campaign

: Instagram (fun fact, true and false, diabetes risk factor checklist, food

connect game, instagram filter challenge, poster, myth and fact, do’s and dont’s) and Line/ WhatsApp (announcement and invitation). III. Basic Theory a. What is Diabetes Diabetes is a chronic [1] and heterogenous metabolic disorder[4] characterized by elevated levels of blood glucose[1] or the presence of hyperglycemia due to impairment of insulin secretion, defective insulin action or both[4]. The chronic hyperglicemia of diabetes is associated with the long term microvascular complications, which can lead serious damage to the heart, blood vessels, eyes, kidneys and nerves[4]. b. What is Types of Diabetes

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Diabetes can be classified into some types: 1. Type 1 diabetes : once known as juvenile diabetes or insulin-dependent diabetes, [1] it is primarily a result of beta cell destruction[5] which the pancreas produces a little or no insulin by itself. [1] This form includes cases due to autoimmune process and those for which the etiology of beta cell destruction is unknown. [5] 2. Type 2 diabetes : The most common is type 2 diabetes usually in adults, which occurs when the body becomes resistant to insulin [1] with relative insulin deficiency. [5] In the past three decades the prevalence of type 2 diabetes has risen dramatically in countries of all income levels. [1] 3. Gestational diabetes: It is diagnosed in the second or third trimester of pregnancy. [7] 4. Specific types of diabetes due to other causes : Such as monogenic diabetes syndromes, disease of the exocrine pancreas, drug or chemical-induced diabetes, or cause of organ transplantation. [7] c. What is Risk Factorsof Diabetes Some studies show that the incidence of diabetes increases in female, while the highest prevailing age group is between 41 to 55 years. Diabetes has some risk factors including hyperglycemia, irregular fat profiles, changes in seditious mediators and clotting. [5] IDF also state that the obesity is a major risk factor for diabetes, especially in low and middle income countries.[2] Beside of that, previous study also stated that there is positive relationship between diabetic family history nad prevalence of diabetes, and there is also positive relationship between drug consumption and diabetes.[5] Other study also stated that the risk factors can be classified into modifiable and non-modifiable risk factors. Modifible risk factors consist overweight and obesity, sedentary lifestyle, metabolic syndrome, hypertension, dislipidemia, dietary factors, drugs such as corticosteroids or diuretics, inflammation, previously identified impaired glucose tolerance (igt) and impaired fasting glucose (ifg). [2] [3]

d. What is Clinical Symptom of Diabetes Type 1 diabetes has symptoms include excessive thirst and dry mouth, frequent and abundant urination, lack of energy, extreme tiredness, tringling or numbness in hands and feet, recurrent fungal infections in the skin, slow healing wounds, and blurred vision. [2]Type 2 diabetes is caused by the excess body weight and physical inactivity. Symptoms may be

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similar with type 1 diabetes, but often asimptomatic. Because of that, type 2 diabetes may be diagnosed several years after onset, and after complications have arisen. Recently, this type was seen in adults and children. [2] In both type 1 and type 2 diabetes, varies genetic and environmental factors can result in the progressive loss of beta cell mass that manifests clinically as hyperglicemia and in this condition, the patients are at risk for developing chronic complication. [6] e. How to diagnose of Diabetes ? Criteria for the diagnosis of diabetes [6] FPG ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h. OR 2-h PG ≥200 mg/dL (11.1 mmol/L) during OGTT. The test should be performed as described by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water. OR A1C ≥6.5% (48 mmol/mol). The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay. OR In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dL (11.1 mmol/L).

f. How to Prevent the Diabetes? From an epidemiological perspective, prevention of diabetes can be done at various levels : -

Primary prevention : Prevention of onset of diabetes.

Secondary prevention : Prevention of progression of diabetes and the onset of complication.

Tertiary prevention : Prevention of progression of diabetes-related complications and the prompt management including rehabilitation. [3]

Two major strategies have been evaluated for reducing the incidence of diabetes, which include lifestyle interventions and pharmacotheraphy.[3] In additional, a series of cost effective interventions can improve people outcomes. These interventions include blood

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glucose control, through combination of physical activity, healthy diet, medication if necessary, control of blood pressure and lipids to reduce complication. [1] g. What is Outcomes from Diabetes Prevention ? Recently, some studies of trials attempt prevention of diabetes in people at high risk through lifestyle intervention and pharmacotheraphy declared with considerable success and favourable results. So, this strategy is useful to control the risk factors for developement of diabetes. [3] IV. Campaign Plan TITLE :Stop Diabetes Through #BeatWithThePITCH HASHTAG : #BeatWithThePITCH #WorldDiabetesAwarenessMonth #VivaAMSA TIMELINE DAY

INSTAGRAM

LINE and WhatsApp

Story

Post

Fun Fact of Diabetes

What is Diabetes

Announcement of World Diabetes Awareness Month

True and FalseGame

Instagram Filter Challenge

Myths and Facts about

Invitation to join True

Diabetes

and False Game

Knowing Clinical

Invitation to join

Symptoms

Instagram Filter Challenge

Diabetes Risk Factors

Knowing the Risk Factors

Invitation to Join

Checklist

of Diabetes

Diabetes Risk Factors Checklist

Stop Diabetes Through #BeatWithThePITCH

Food Connect Game

Do’s and Dont’s

Invitation to join Food Connect Game

Games and Challenge Winner Announcement

339

Overview of Design Stories

340

Post

341

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Massages for Line and WhatsApp Day 1 Greetings People of Tomorrow! With this post, we are announcing to AMSA International about World Diabetes Awareness Month online campaign entitled “Stop Diabetes Through #BeatWithThePITCH” that focuses on preventing diabetes to control the risk factors for developement of diabetes. This campaign will be held in a week, starting from today. Mediated by intagram @beatwiththepitch, and distributed widely and publicly through personal line and whatsapp account. We are looking forward for your participation in this campaign by following our instagram account and joining our challenges and games competition on your instagram, line, and whatsapp account. Thank you, AMSA International! VivaAMSA! Day 2 Greetings People of Tomorrow! With this post, we are announcing to AMSA International aboutWorld Diabetes Awareness Month online campaign entitled “Stop Diabetes Through #BeatWithThePITCH” by joining the games competition of True and False Gameson instagram story. It can be downloaded in this link: ... Attached with this link is the proposal of the campaign. Thank you, AMSA International! VivaAMSA! Day 3 Greetings People of Tomorrow! With this post, we are announcing to AMSA International aboutWorld Diabetes Awareness Month online campaign entitled “Stop Diabetes Through #BeatWithThePITCH” by joining

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challenge competition of Instagram Filter. The filter can be taken from intagram of @beatwiththepitch. ... Attached with this link is the proposal of the campaign. Thank you, AMSA International! VivaAMSA! Day 4 Greetings People of Tomorrow! With this post, we are announcing to AMSA International aboutWorld Diabetes Awareness Month online campaign entitled “Stop Diabetes Through #BeatWithThePITCH” by joining to fill the checklist of Diabetes Risk Factors on instagram story. It can be downloaded in this link: ... Attached with this link is the proposal of the campaign. Thank you, AMSA International! VivaAMSA! Day 6 Greetings People of Tomorrow! With this post, we are announcing to AMSA International aboutWorld Diabetes Awareness Month online campaign entitled “Stop Diabetes Through #BeatWithThePITCH” by joining the games competition of Food Connect on instagram story. It can be downloaded in this link: ... Attached with this link is the proposal of the campaign. Thank you, AMSA International! VivaAMSA!

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References 1. World Health Organization. Diabetes [Internet]. 2020 [Cited 2020 Oct 20] Available from : https:///www.who.int/health-topics/diabetes#tab=tab_1 2. International Diabetes Federation. Diabetes [Internet]. 2020 [Cited 2020 Oct 20] Available from : https://idf.org/52-about-diabetes.html 3. American Diabetes Association. Cardiovascular Disease and Risk Management : Standards of Medical Care in Diabetes. USA : ADA. 2020 Jan;43. 4. Punthakee Z, Goldenberg R, Katz P. Definition, Classification and Diagnosis of Diabetes, Prediabetes and Metabolic Syndrome. Canadian Journal of Diabetes. 2018 Apr;42. 5. Liyanage L. Diabetes Mellitus and Its Risk Factors. Epitome : International Journal of Multidisiplinary Research. 2018 Sep;4. 6. American Diabetes Association (ADA). Classification and Diagnosis of Diabetes : Standards of Medical Care in Diabetes. USA : ADA. 2020 Jan;43.

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World Diabetes Awareness Month Competition 2020 By AMSA International

Report of Local Diabetes Event Stop Diabetes Through #BeatWithThePITCH Arranged By : Yolanda Anisa Marlin Dhea Anisa Yuri Lubis AMSA-UNJA Faculty of Medicine and Health Sciences Universitas Jambi 2020

369

Name of the project / event : TALKSHOW Entitled Stop Diabetes Through #BeatWithThePITCH Venue/ platform : Instagram live @amsaunja Project level/ scope : 

Participant of Talkshow : All Instagram Users



Target of Talkshow : All Instagram Users



Media of Talkshow : Instagram (Talkshow)

Start and end date and time : 

Date : 31 October 2020



Start time : 13.15 WIB



End time : 14.30 WIB

Workload and position of every team member : 

Yolanda Anisa (Master of Ceremony)



Marlin (reporter)



Dhea Anisa Yuri Lubis (infocom)

Ground work The title of our project is Stop Diabetes Through #BeatWithThePITCH, it is taken from the title of our online social campaign. This project became a pre-event of our social campaign. The materials of campaign are taken from the materials of our online social campaign, which consists of (outline of material) : 

What is Diabetes



What is Types of Diabetes



What is Risk Factors of Diabetes



What is Clinical Symptom of Diabetes



How to diagnose of Diabetes ?

370



How to Prevent the Diabetes?

The project is in the form of a talkshow, which is guided by MC, so both of MC and speaker are discussing through the questions that have been provided. This project consist of two organizer (Team of social campaign competition and AMSAUnja), and 5 volunteers outside of our team. The volunteers are from Community Outreach team of AMSA-Unja. The volunteers are contributed in the process of preparation of this project, which consists of : 

Assist in making the questions for talkshow



Assist in the promotion process (distributing project poster)



Assist in the process of finding presenter/ speaker

The timeline of preparation : Making the materials and outline of talkshow Making the questions for talkshow (collaboration with the volunteers) Making poster as invitation, and making the sertificate 30 October 2020

for speaker Finding the speaker of talkshow (dr.Intan Karnina Putri) (collaboration with the volunteers) The distribution of poster invitation for talkshow The Day of Talkshow

31 October 2020

Summary of the project : This project is implemented as pre-event of the online social campaign, which aims to educate the people/ instagram users about diabetes (including the outline of material). This talkshow make the participant (who watch live) understand about the diabetes so it can increase the awareness of diabetes. Impact analysis of the event 

Participant count : 100 participants



Feedback : for the next event, maybe the preparations can be in advence

371



Message learn : Increasing awareness to the society about diabetes is extremely important to make the strategy of diabetes prevention. And one of way to achieve it through giving the education to the society. Because of the pandemic, so it can be implemented through webinar or talkshow.



Donation acquired : -



Media coverage : live instagram



Opportunities : as pre event of our online social campaign, so it can introducing the online social campaign to the participant of talkshow. The participant can get the knowledge about diabetes so they can aware and prevent diabetes.

Attendance details Participants of talkshow :

@yolandaanisa @ifebriyanti_ @kennedyarthasasta_ @dhea_lubis @afifahamn @ganhsc @alasari04 @naufalzar12 @mirzafathurrohman @oshattaa @erikendiansah @anisaismiyanti @ilham_lubis @imakedokteranunja @nurulyulita @ayushiagenerosa @marlin08_ @tarahariyono @fadilaputri28 @silviaryfriskaa @maulana24434 @maydiniaamanda @anggamguna @hanaazkia @_nyemnyem @nadhilahap @husnanhidayat @saniarahman @mazizradef @rizkydvndy @nisacakee @meitridiyah @hannayaputri @farhanriyadhil_ @ayu_ro @fauzanhanif @firdausasham @zaa.a02 @lutfiananda @firrahndyam @dndgustin @dhey.niss @ss.bila @andinimutiara @gilbertsitrait @mfadiln71 @albashirferiohadi @adityaariaa @sitipuanazizah @rika_367 @raytoma @mufrhan @aullianisa @fadlansaputraa @rossekhairul @hairondhq @imamwan @rizaqadafi @meyonice_ @fajarfadlany @marisaaprafita @albertprabono @ruxandranurul @arialariel @ameliaminarfah @saffanahsiti @talithaargani_t

@nyoman.krisna

@ratinurulh

@chelsa.ta

@fani.nadila

@farhanmiyadi

@amer1carolatte @pandela_gt @mashuri_alqois @seruninasution @nblaazka @shafirarmdhania @ridosapu

@rifaimuhammad

@ardy_butut

@fadhel_mahfuzd

@dr_sandi_perdana28

@fadli_muhammad16 @tsugii @amsa.umm @s.girl8848 @tiwilstr @tengbengs @ubicilembuuw @ftriiah @faisalafghn @amsajember @annisya_puspitasari @raaqaanasta @riddoks @fanny_alfia @ayyuhumahamalia @agungprasetioo @amsauaj

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Documentation

Link (video of documentation) : https://drive.google.com/file/d/1mqyCokkT_eDFay1ygDFh5K0dRYjv1Xvj/view?usp=sharin g

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Check all the campaign material for online social campaign masterpieces through : http://bit.ly/CampaignMaterialAMSA