Diabetes: Disarming the Silent Killer (Preview) by Sunway University

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Disarming the Silent Killer

Copyright © 2022 by Sunway University Sdn Bhd Published by Sunway University Press An imprint of Sunway University Sdn Bhd No. 5, Jalan Universiti Bandar Sunway 47500 Selangor Darul Ehsan Malaysia press.sunway.edu.my All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, now known or hereafter invented, without permission in writing from the publisher.

ISBN 978-967-5492-19-8

Perpustakaan Negara Malaysia

Cataloguing-in-Publication Data

Chia, YC DIABETES : Disarming the Silent Killer / CHIA YC, OOI PB, HWANG JS, TEOW SY, AHMAD B., PEH SC. ISBN 978-967-5492-19-8 1. Diabetes. 2. Diabetes--Treatment. 3. Diabetes--Complications. I. Ooi, PB. II. Hwang, JS. III. Teow, SY. IV. Ahmad B. V. Peh SC. VI. Title. 616.462

Edited by Hani Hazman, Oileen Chin Designed and Typeset by Rachel Goh Printed by XXX, Malaysia

CONTENTS

Foreword

Preface

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Introduction

About the Editors

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Expert Discourse

1 Human Obesity and Insulin Resistance: Lessons from Human Genetics Stephen O’Rahilly

2 What We Can Do to Prevent Diabetes and Its Complications Khalid Abdul Kadir

3 Prevention of Type 1 Diabetes John Todd

4 Epidemic and Epigenetic Drivers of Diabetes, Obesity and the “Circadian Syndrome” Paul Zimmet

5 Control of Metabolism by the Gut-Brain-Pancreatic Axis Fiona Gribble

6 Exogenous Ketones for Type 2 Diabetes Kieran Clarke

7 New Approaches to Diabetic Complications Mark Cooper

8 Type 2 Diabetes: The Search for Sustainable Solutions Nick Wareham

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Extended Abstracts

1 Cost-Effective Analysis for the Early Initiation of Insulin in Type 2 Diabetes Mellitus Patients in Malaysia Using a Discrete Event Simulation Model Wilson MH, Lee KC, Wu BC & Luh H

2 Prevalence, Diagnostic Criteria, Complications and Potential Biomarkers of Gestational Diabetes Mellitus in the Philippines Pineda-Cortel M, Santiago L, Mamerto T, Anastacio A & Tiongco R

3 Interleukin-2 and Interleukin-6 Play Major Roles in the Global Rheumatoid Arthritis/Type 2 Diabetes Comorbidity Network Liew TO, Rohit M & Chandrajit L

4 Awareness, Knowledge and Prevention of Heart Attacks Among University Staff Martin EC, Ng LF, Jemeela S & Mohammed AJ

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5 Angiotensin II Type 1 Receptor Methylation is Inversely Associated with HbA1c in Non-Diabetic Young Adults Wan Omar WF, Ab Talib N, Mohd Shah AN, Mohd Shah AS & Abdullah A

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6 Fabrication of Oral Nano-Insulin Formulation for Regulating Blood Glucose Level Zaman R, Othman I, Zain AZ & Chowdhury EH

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7 Early Screening of Diabetic Foot Ulcer Using PeDiCare Vikneswaran V, Chong YF & Khaled MH

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8 Prevalence of Diabetes Mellitus Among Urban Population Based on Income Liyanage KL, Neelawala NG & Kumbukgolla WW

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9 Awareness and Risk Perception of University Students Towards Diabetes Mellitus Manoj AM & Ng WN

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Acknowledgements

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Index

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Foreword

Diabetes: Disarming the Silent Killer is a result of the joint collaboration between the University of Cambridge, the University of Oxford, Sunway University, and the Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia. The collaboration served to foster the growing links between the institutions, act as a showcase for the superb educational and clinical facilities of Sunway Medical Centre and the Jeffrey Cheah School of Medicine and Health Sciences, and contribute to the growing reputation of the Malaysian healthcare system for excellence in science-led healthcare. It gives me great pleasure to pen a few lines for the Foreword to this book. This book will focus on what we have presented, discussed, deliberated and shared during the symposium with diabetes mellitus, a chronic disease which is a major and growing cause of premature death and severe disability worldwide, as the main focus. In order to combat this disorder, it is essential that the international community take a multifaceted approach. We need to understand the complexity of diabetes in its different forms and that the interplay of genetic and environmental factors leads to these different subtypes of diabetes. We need to understand the best ways to engage in primary prevention, reduce the incidence of the disease, as well as manage the adverse consequences of the disease. That will require not only improved medications but a better understanding of behavioural factors and improved healthcare delivery. We need better ways of treating the complications once they have started to appear, so that disability is reduced. We have gathered an outstanding group of international researchers who are excited about the opportunity to share their data and views on a broad range of diabetes-related topics, ranging from the aetiology of different forms of

vi Foreword

diabetes, through novel therapies and approaches to the prevention of complications, to the public health aspects of diabetes prevention and management. We are also joined by distinguished learners from Malaysia who will share their results from a local perspective in the book. I hope you find the book informative and that it provides some helpful insights in your research activities.

Professor Sir Stephen O’Rahilly, FRS, FMedSci Professor of Clinical Biochemistry and Medicine University of Cambridge Chairperson of the International Organising Committee

PREFACE

This book evolved from the 3rd Cambridge-Oxford-Sunway Biomedical Symposium held at Sunway Medical Centre on the 26th and 27th of March 2019 in Malaysia. Sunway University and Sunway Medical Centre, in collaboration with the University of Oxford and the University of Cambridge, initiated the inaugural joint symposium in 2016. The first symposium was so well received by not only local participants but also many attendees from the ASEAN region, that the symposium series has since been extended. The second symposium was held in 2017 and, again, it received overwhelming response. The third symposium focused on diabetes, often regarded as the silent killer because of its easy-to-miss symptoms and its link to cardiovascular diseases, the world’s leading cause of death. The focus on diabetes is not only because it primarily causes heart attacks and kidney failure, but because it is a burgeoning problem particularly in Asia where the greatest number of people with diabetes live. It is clear that diabetes, with its devastating complications, is going to be—if not already—a huge problem in Asia. Having world-renowned experts from these institutions share their experiences and know-hows on this major public health problem will help set the stage for further evaluation of the consequences of diabetes. Perhaps, these experts can suggest areas of research needed to help reduce this problem. It was felt that the information presented at this symposium was too valuable to be limited to just the attendees. It was thus decided that the knowledge presented at the symposium should be shared in the form of a book. It was also

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decided that the information would be presented as professional discussions on diabetes by leading experts in the field. A further section of the book contains selected write-ups of extended abstracts presented by researchers at the symposium. It is hoped that this book will not only provide readers with up-to-date information about diabetes, but also stimulate further research to tackle this growing problem and ultimately to disarm this silent killer.

INTRODUCTION

Diabetes affects every country in the world and its prevalence is increasing rapidly. While significant research has contributed to a good understanding of this disease, much remains unknown. For a long while, there were no new discoveries of options to treat diabetes or its complications. More recently, however, new treatment options based very much at the molecular level have become available for raised blood glucose, a hallmark of diabetes. To help prevent and reduce the prevalence of diabetes through groundbreaking discoveries, we require a better understanding of the genetics, epigenetics, predispositions, and factors that contribute to the pathogenesis and emergence of diabetes as a clinical disease. In the Expert Discourse section of this book, leading professionals in the field share their views on and insights into diabetes and how its prevalence and complications can be reduced. Professor Sir Stephen O’Rahilly, Professor of Clinical Biochemistry and Medicine at University of Cambridge, discusses the recent increase in the proportion of the obese population with type 2 diabetes. He points out that the rising incidence of the disorder is attributable to changes in the environment that promotes caloric consumption and impedes energy expenditure. He emphasises the need to understand why some individuals are susceptible to obesogenic influences while others remain resistant. Professor Dato’ Khalid Abdul Kadir, Professor of Medicine at Monash University Malaysia, meanwhile examines the natural history of type 2 diabetes where it progresses from an early asymptomatic stage of insulin resistance to a prediabetes stage and eventually overt diabetes. He shares how the prevention of

insulin resistance and the prediabetes state found in the

metabolic syndrome—one of the main culprits of diabetes development—

x Introduction

is key to preventing the onset of diabetes mellitus. Professor Khalid also discusses several compounds such as glycyrrhizic acid and vitamin E from palm oil that can contribute to reducing the likelihood of diabetes development. Professor John Todd, Professor of Precision Medicine at University of Oxford, reviews and discusses several genetic factors implicated in the development of type 1 diabetes. He talks about how genetic and mechanistic findings point to key biological pathways and environmental factors that underpin the disease. Based on this information, Professor Todd and his team are conducting clinical trials to translate knowledge to practical solutions that can benefit patients. Professor Paul Zimmet, Professor of Diabetes at Monash University, introduces the not-often-heard-of concept of the “Circadian Syndrome”. He discusses how the body clock of the human brain regulates the body’s metabolism and determines the circadian rhythm. The clock coordinates the release of various hormones which may play a big role in the development of obesity and diabetes, two components of the metabolic syndrome. In his discourse, he shares mounting evidence of how disturbances in the circadian rhythm can contribute to the metabolic syndrome. In another discourse, Professor Fiona Gribble, Professor of Endocrine Physiology at University of Cambridge, studies how the elevation of postprandial glucagon-like peptide-1 (GLP-1) levels after bariatric surgery is due to the rapid transit of ingested nutrients to the distal gut. She further discusses a variety of new drugs under development that aim to mimic the gut endocrine consequences of bariatric surgery for the treatment of type 2 diabetes and obesity. Professor Kieran Clarke, Professor of Physiological Biochemistry at University of Oxford, meanwhile talks about the role that diet plays in the pathogenesis of type 2 diabetes. According to her, low-carbohydrate, high-fat (i.e. ketogenic) diets are comparable to or better than traditional low-fat, high-carbohydrate diets in reducing weight and improving diabetic dyslipidaemia and the metabolic syndrome. Professor Clarke describes how she and her team invented a new food group based on ketone metabolism, and found that intake of the new food group normalises fasting blood glucose, triglycerides and cholesterol levels.

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The major cause of morbidity and mortality of diabetes is its complications. Professor Mark Cooper, Head of Department of Diabetes at Monash University, looks into recent therapeutic agents such as sodium-glucose cotransporter-2 inhibitors and GLP-1 and how they have transformed the outlook of diabetic renal and vascular complications. Professor Cooper further describes the pivotal role of glucose and related molecules in modulating epigenetic pathways. Major discoveries could result in new biomarkers and drugs for predicting and treating diabetic complications. In the final discourse by Professor Nick Wareham, Unit Director of the MRC Epidemiology Unit and Professor of Epidemiology at University of Cambridge, he shares how economic costs of dealing with and managing diabetes are a threat to health systems. He opines that translating research interventions into sustainable, practical programmes is met with challenges, stressing the urgent need to develop evidence-based and economical solutions that can bring about long-term changes in public health outcomes. Finally, the Extended Abstracts section in the book shares some of the work done by researchers in the field of diabetes. It is hoped that the findings will encourage and inspire not only doctors, but also scientists and allied health professionals to carry out deeper research into diabetes and its complications, and how they can be alleviated.

Professor Datin Dr Chia Yook Chin, MBBS, FRCP, FAFPM Department of Medical Sciences School of Medical and Life Sciences Sunway University Malaysia

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ABOUT THE EDITORS

Chief Editor

Chia Yook Chin, MBBS, FRCP, FAFPM Professor Datin Dr Chia Yook Chin is Research Professor and Head of Department of Medical Sciences at the School of Medical and Life Sciences, Sunway University, Malaysia. In 1987, she helped build and establish the undergraduate medical curriculum in both primary care medicine and clinical services for the new Department of Primary Care Medicine at the Faculty of Medicine, University of Malaya. She then initiated the Masters in Family Medicine programme, the first of its kind in Malaysia, in University of Malaya in 1989. She was the recipient of the Association of Commonwealth Universities—Senior Medical Fellowship award and spent a year at University of Cambridge, UK, in 1990. Dr Chia holds many leading positions including Director of Postgraduate Diploma of Family Medicine for the Academy of Family Physicians of Malaysia, Honorary Adviser of the Malaysian Society of Geriatric Medicine and International Adviser for Malaysia for the Royal College of Physicians of London, UK.

Chairperson, Local Organising Committee of the 3rd Cambridge-OxfordSunway Biomedical Symposium

Ooi Pei Boon, PhD, KB, PA Dr Ooi Pei Boon obtained her PhD in Guidance and Counselling from Universiti Putra Malaysia in 2016. She is currently a journal reviewer for International Journal of Innovation and Learning and Cyberpsychology, Behavior and Social Networking. She is also a master trainer licensed to coach trainers for Media Heroes—a cyberbullying intervention programme originating from Berlin, Germany—for which she obtained various grants. Her research interests include cyberbullying, online behaviour and cyberbullying prevention

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programmes; mental health and well-being of dialysis patients and students; student experience and internationalisation of higher education institutions; and professional development and self-efficacy of the counsellor.

CONTRIBUTING EDITORS

Badariah Ahmad, MBBS, PhD Dr Badariah Ahmad graduated from Royal College of Surgeons in Ireland in 1997 and completed her MSc (Physio) in 2001 from University College Dublin, Ireland. She returned to Malaysia and joined Monash University Malaysia in 2006 where she became one of the pioneering staff at the Sunway campus. She was awarded a Doctorate from Monash University in 2018. Dr Badariah’s area of expertise includes diabetes education and self-care practices in diabetes. Her main research interest is in type 2 diabetes mellitus, with active research areas in non-communicable diseases, metabolic syndrome, vitamin E and indigenous health. Her academic role includes the planning, development, evaluation and assessment of the Bachelor of Medicine and Bachelor of Surgery curriculum in the Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia. Hwang Jung Shan, PhD Associate Professor Dr Hwang Jung Shan obtained her PhD at University of Melbourne, Australia in 1998. Upon graduation, she received the JSPS Postdoctoral Fellowship and worked on the RNA polymerase of the influenza virus at the Department of Molecular Genetics, National Institute of Genetics, Japan. She spent the next 10 years studying the regeneration of planaria and the gene function of cnidarians, and published in notable journals such as Nature, Proceedings of the National Academy of Sciences USA and Trends in Genetics. She returned to Malaysia in 2010 and joined the Faculty of Applied Sciences, UCSI University, where she was Head of Postgraduate Studies and, later, Deputy Dean. Her line of research focuses on the construction of immunotoxin for the treatment of rheumatoid arthritis by targeting the inflammatory macrophages. She is also working on the genetic polymorphism in rheumatoid arthritis patients who show different responses to anti-rheumatoid arthritis drugs.

About the Editors

Peh Suat Cheng, MD, PhD Professor Peh Suat Cheng joined Sunway University with 40 years of experience in academic medicine. Her impressive research into lymphoma has contributed significantly towards the current understanding of the disease. Besides being published in numerous peer-reviewed journals, she co-authored the World Health Organisation’s reference book, Tumours of the Haematopoietic and Lymphoid Tissues. As a leading Senior Consultant Pathologist in Malaysia, Professor Peh is also a fellow of Royal College of Pathologists in both Australasia and the UK. In recognition of her dedication to academic and service excellence, she has received numerous national and international awards, fellowships and grants. Her extensive experience and research network with various local partners and world-renowned institutions around the world are crucial in championing healthcare development in Sunway City. Teow Sin Yeang, PhD Dr Teow Sin Yeang obtained his PhD in Molecular Virology and Oncology from Universiti Sains Malaysia in 2015. He then pursued his postdoctoral training, first at the Molecular Pathology Unit, Institute for Medical Research, and then at Sunway University in 2016. He is currently Senior Lecturer at Sunway University. His current research interests are in cancer research, particularly colorectal, liver and nasopharyngeal cancer, and virus research on HIV, EBV, HBV and DENV. Dr Teow also works on immunology-related projects such as rheumatoid arthritis and cancer immunology. He is an active reviewer in Tier-1 journals such as Scientific Reports, Bioconjugate Chemistry, Microbial Cell Factories and Biomedicine & Pharmacotherapy. In 2017, he received the MAKNA Cancer Research Award worth RM30,000 for his proposed colorectal cancer biomarker study. In 2018, he was the recipient of the Vice-Chancellor’s Early Career Researcher Award.

About the Editors xvi

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O’Rahilly, Stephen

Tackling Obesity The work of Professor O’Rahilly and his group over the last few decades have been focused primarily on two main areas: the maintenance of energy balance, and the relationship between adipose tissue and insulin action in key target tissues. A key moment in the modern history of obesity research was the discovery by molecular geneticist Jeffrey Friedman and his colleagues at The Rockefeller University; they reported that adipose tissue produced a hormone (now known as leptin) which kept the brain informed of the status of energy stores. This represented a transformative moment in the understanding of obesity. Friedman’s team looked at mice that were genetically engineered to stop producing leptin, and observed how the mice would respond when treated with leptin. The mice that did not produce leptin could not utilise fat properly to generate energy. They would eat more, move less and grow heavier than normal mice. However, simply injecting leptin in a small area of the hypothalamus was sufficient to reverse all of the consequences of deficiencies. “That was a phenomenal discovery,” O’Rahilly enthused. “It was tremendously exciting to me and certainly helped precipitate our interest. In a short space of time, we discovered that the disruption of the leptin-melanocortin axis in humans also resulted in severe obesity. That catapulted us into a new era of research back in the late 1990s at the turn of the century. Joined by our colleagues Sadaf Farooqi, Giles Yeo, and Tony Coll, our group and others started finding many genetic causes of severe obesity in children.” The studies found that most human obesity genes are highly expressed in the brain, especially the hypothalamus. “We did not know when we were looking for the obesity genes that we would find them in the brain. We found that every case is a single gene disruption of the central nervous system. Instead of just finding the gene, we took children to a clinical research facility and measured their food intake and energy expenditure. We found that in almost all the cases, the dominant feature of energy balance was a defect in the ability to induce satiety and to increase appetite, with the children who ate ad libitum meals consuming far more than they required,” O’Rahilly said. He called this a groundbreaking discovery because obesity had been seen as a heritable neurological disorder. “It had metabolic consequences; it was a neuroendocrine disorder in all of these cases.”

Diabetes: Disarming the Silent Killer 5

Approximately 15 years ago, Research Fellow Fiona Gribble took over the leadership of the work in childhood obesity. She recently discovered that disruption of neural guidance molecules, the semaphorins, in the hypothalamus is sufficient to cause severe predisposition to obesity. Many of these defects are attributable to the disruption of pathways engaged by leptin in the hypothalamus. These are all pathways involved in the sensing of how much nutrient is stored. However, there is another set of signalling pathways involving gut hormones that produce a different set of signals. These do not inform how much nutrients are stored. Instead, they reveal what is being eaten or have just been eaten in the immediate past, and provide information to the brain about the amount and the macronutrient content of what is being ingested. However, are all these findings about the brain relevant to common obesity? “Over the last 10 years, there have been work in which we participated that looked at genome-wide genetic variation in hundreds of thousands of people,” O’Rahilly began. “We can look at these studies and simply ask: Where is the genetic variation acting that causes one person to be thin and the other person to be fatter? Where are those genes acting? Using the appropriate bioinformatic tools for the analysis of these data, it is hard to deny that the central nervous system might be important in common obesity. The vast majority of signals that are underpinning differences between individuals are single nucleotide polymorphisms (SNPs) that are affecting gene expression within the brain.” “There are of course other sites where the obesity gene acts, but by far the most dominant site is the central nervous system,” elaborated O’Rahilly. “What are they doing in the central nervous system? Are they affecting appetite or energy expenditure? This is hard to determine because individually, they are all very small sizes of effect. We do know that a common genetic variant in the FTO gene has a dramatic effect on appetite and food intake in children with the risk alleles. They eat more, but the variant has no effect whatsoever on energy expenditure, when measured in over 10,000 people in the unpublished work done by epidemiologist Nick Wareham of University of Cambridge. So, the obesity gene is indeed an appetite gene and not an energy expenditure gene, contrary to some suggestions that have emerged.”

O’Rahilly, Stephen

Obesity-related genetic variants identified through genome-wide association studies show links with appetitive traits, and appetite mediates part of the association between genetic risk and adiposity. Obesity is the result of an interaction between genetic susceptibility to overeating and the exposure to an obesogenic food environment. O’Rahilly explained,“In a family where nobody is obese and there is a limited food supply, only those who are extremely genetically predisposed will become obese. However, when there is an abundance of food, and there is an environment where not much physical activity is expended, then even the modestly genetically predisposed can become obese.” These findings should influence public health policies to make the obesogenic environment less potent and promote healthier diet patterns and portion size.

Therapeutic Challenges and Opportunities in Obesity What then are the therapeutic challenges in tackling obesity? “We know that the brain is the key organ for energy intake and, in part, energy expenditure control,” replied Professor O’Rahilly. “However, the normal function of the brain is poorly understood. It is the most complex organ we have, and neurochemistry is highly spatially compartmentalised. This is illustrated by rimonabant, the endocannabinoid drug which works beautifully to reduce body weight, but by antagonising cannabinoids in other centres of the brain causes severe depression and suicidality. We know that the molecular components of neuronal signalling are used for different functions at different locations. On top of that, some parts of the brain are more difficult to access. There is also a sort of discrimination towards obese people in society, and indeed political perceptions of obesity are unhelpful and pose an obstacle to obesity intervention efforts. Many people feel we should not even be calling it a disease or treating it.” The actions of naturally occurring hormones on the brain that impact energy balance do provide a therapeutic opportunity with a window of safety. O’Rahilly identified three hormonal pathways: (1) the leptin-melanocortin pathway where leptin is the modulator, (2) the entero-endocrine satiety pathway described by Fiona Gribble, and (3) the natural aversive hormonal pathway (such as growth differentiation factor 15 [GDF15]). He explained that if an individual has no leptin due to a broken leptin gene or the absence of fat cells, he or she will become sick; in the former situation, the individual will become very obese as he or she will

Diabetes: Disarming the Silent Killer 7

eat excessively, while in the latter situation, the individual will eat a lot but there will be nowhere for the excess adipose tissue to be stored. Administering leptin to the individual will be therapeutically beneficial, hence the reason why leptin is now a registered drug for the aforementioned indications. Professor O’Rahilly further identified the next agent that is currently being used—the melanocortin-4 receptor agonists. “We can see their potential in rare individuals who have severe obesity associated with proopiomelanocortin deficiency. As these individuals have homozygous mutations in the progranulin gene, they become enormously obese. However, when we give them a selective injection of a melanocortin-4 agonist, they essentially return to normal. This proves that the melanocortin system is critical for the regulation of human body weight. We and others are currently engaged in trials investigating the broader potential use of these agents.” There are also the gut-derived hormones that are being targeted for human obesity therapy. Work on enteroendocrine hormones is not final. Trials on the efficacy and safety of the GLP1 receptor agonist, semaglutide, compared to liragludtide, show that there are substantial weight losses of, on average, 12% or 13% on a tolerable dose. This is a significant advance on previous weightloss drugs that have been made available. It is further clear from the work of researcher Randy Seeley, among others, that the effects of GLP1 on body weight are largely being mediated through receptors in the hindbrain and through glutamatergic neurons. The early results from trials on the efficacy of a GLP1 in patients with type 2 diabetes are impressive.

GDF15 as a Therapeutic Target The mechanism through which GDF15 reduces body weight remained poorly understood until towards the end of 2017, as the receptor for GDF15 could not be found. Four different pharmaceutical companies then reported, almost simultaneously, that GDF15 binds with high affinity to GDNF family receptor alpha-like (GFRAL). The receptor is uniquely expressed in a small number of hindbrain neurons in the area postrema, and possibly in the nucleus tractus solitarius. Professor O’Rahilly’s work shows that the expression is almost exclusively in the area postrema.

O’Rahilly, Stephen

However, why do blood levels of GDF15 go up? What states are associated with high circulating levels of GDF15? O’Rahilly explained that the levels are elevated in a wide range of disease states, such as cancer, renal failure, chronic obstructive pulmonary disease, and cardiac failure. They are particularly high for people with a mitochondrial disorder. They can also be induced by cytotoxic drugs or even by inhaled cigarette smoke. Other stressors include intense exercise, hypoxia, and ageing. They are expressed in a wide range of tissues apart from the brain, especially the liver, kidney, and lung. Professor O’Rahilly went on to form a hypothesis that GDF15 is naturally produced. The exposure to noxious agents or experiences resulting in tissue damage causes the release of GDF15 which travels in the circulation to the target receptor. Action at GFRAL in the area postrema of the brainstem brings about two aversive responses: (1) immediate avoidance behaviour (anorexia, nausea, or reduced movement) that produces the unpleasant sense, and (2) avoidance of future exposure as a result of the unpleasant event being ingrained in the memory. Could it be that GDF15 is an endocrine arm of the integrated stress response? Over the last year, Professor O’Rahilly and his colleagues Anthony Coll and David Savage have been doing a lot of research on GDF15 to determine whether it truly is a stress hormone. Working with senior postdoctoral researcher Satish Patel in the lab, they found that GDF15 expression, like FGF21, is increased by a range of classical integrated stress response inducers. However, GDF15 is produced by the classical cellular integrated stress response pathway in a science somewhat different from FGF21 and other important metabolic hormones. “We got in touch with our colleagues at Pfizer where we had a good set-up to do conditioned taste aversion experiments,” O’Rahilly said. “In the experiments, we gave mice small amounts of GDF15, pairing them with a colour or a taste. Then, we put the mice in a situation of choosing the colour, or the taste, that they had when they were previously exposed. We found that having been exposed to even small doses of GDF15 made these animals avoid the colour or taste like the plague.” It could be concluded that GDF15 is induced by a wide range of stressors and its elevation in circulation results in conditioned taste aversion.

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“We also found that circulating GDF15 rises with overnutritional stress in mice, and that is associated with increased GDF15 being produced in white and brown adipose tissue and in the liver. In humans, data from Professor Matthias Blüher’s research show a strong correlation of GDF15 levels in adipose tissue and in circulation with body mass index.” Does GDF15 play a physiological role in energy homeostasis? At least four of six papers suggest animals lacking GFRAL or GDF15 are susceptible to gaining excess weight on a high-fat diet. From all these studies, it was hypothesised that, unlike leptin which goes up as individuals get fatter but is completely ineffective at stopping them from getting any fatter, GDF15 is one of the signals produced when people get fat and are metabolically stressed. This provides a break on the continuous development of obesity in animals and humans. There is a correlational paper by endocrinologist Dr Hertzel Gerstein which suggests that metformin use is associated with GDF15. He identified GDF15 as a possible biomarker for the use and dosing of metformin in type 2 diabetes. Professor O’Rahilly contacted medical researcher Professor Naveed Sattar in Glasgow about the CAMERA study where they assessed the cardiovascular effects of metformin in 173 non-diabetic individuals with a high cardiovascular risk. It was observed that a non-diabetic individual on metformin, on average, lost approximately four kilograms in weight over the 18 months of study, and there was a sustained and substantial rise in circulating GDF15 throughout the entire period of treatment. While the calculated probability or p-value is not significant, there is a correlation between the change in GDF15 and weight loss. Professor O’Rahilly and his group then gave metformin to mice, and showed that it increases circulating GDF15. Remarkably, however, in response to the metformin doses, there was great GDF15 expression in the lower intestine and the colon. They found that if they gave metformin to wild-type mice on highfat diet over a long term, the mice stopped getting obese. However, if this was done to animals that genetically lacked GDF15, metformin had absolutely no effect. “Thus, all the effects of metformin on body weight require GDF15,” concluded O’Rahilly. “This is not true of the GLP1 receptor or the microbiome. This is, therefore, the dominant mechanism whereby metformin causes body weight loss in animals. It does so by suppressing food intake largely in the wildtype mice, and in the knockout mice, metformin has no effect on the reduction of food intake.”

O’Rahilly, Stephen

These findings were corroborated by the researchers at NGM Biopharmaceuticals. They conducted the same experiment on the receptor knockout animals with the exact same effect.“We also did an experiment where we gave obese animals metformin and then blocked GFRAL gene expression with an anti-GFRAL antibody, reversing the metformin effect in animals who are already obese,” O’Rahilly explained. “We had three independent sets of experiments, showing that metformin was acting in this way.” Metformin has also been reported by Randy Seeley to act on different sets of neurons in the hindbrain compared to GLP1. Unsurprisingly, therefore, there is a synergistic effect of GLP1 and GDF15 on body weight and food intake in animals when metformin, GDF15 and liraglutide are given together. “I think it is still the early days for GDF15,” surmised O’Rahilly.“The first 28 days in a study by the pharmaceutical company Merck was deemed non-successful. While the history of monotherapy for obesity has been miserable, this is by no means over. I believe that GDF15 antagonism in cachexia will be a major effect that we will almost certainly see in the obesity space.”

Adverse Health Consequences of Chronic Overnutrition Why is it that we get sick when we become overweight? Obesity is associated with mechanical abnormalities (such as osteoarthritis of the knee, reflux oesophagitis, and sleep apnoea), cancers (bowel, breast, and oesophageal cancer), and metabolic diseases (including insulin resistance, fatty liver, type 2 diabetes, atherosclerosis, hypertension, and polycystic ovary syndrome). While it is apparent that the mechanical problems result from the gravitational effect on weight, the association between obesity and the development of cancers and metabolic diseases is unclear. “We assume that these conditions are related to obesity but might it be that obesity is a biomarker, and that what is actually going wrong is the imbalance between energy intake and energy expenditure?” questioned Professor O’Rahilly. Over the last 20 years or so, a phenomenon that many scientists have studied and tried to come to grips with is the problem that is most closely related to obesity—the development of insulin resistance. To maintain normoglycaemia, an individual who gets fatter generally needs to produce more insulin. However, at

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any individual degree of body mass index, there is a wide scatter of fasting insulin levels. People of South Asian ethnicity, for example, only need to become slightly overweight to develop much more insulin resistance. How do we get from obesity to insulin resistance in the liver and muscle? “A popular view at the moment is that the culprits are the fat cell and the inflamed adipose tissue,” answered O’Rahilly. “Generally, inflammation and the pro-inflammatory cytokines are the crucial factors for developing insulin resistance. You get insulin resistance in the liver and muscles, while adipose tissue takes up a trivial amount of glucose. This means the adipose tissue somehow ‘talks’ to the liver and muscle, causing insulin resistance there.” Professor O’Rahilly continued, “There is great evidence in mice, but evidence in humans is much less secure for the metabolic inflammation hypothesis. We perhaps have a more secure evidence to support an alternative view that the big fat cell is not the enemy. The big fat cell is by far the safest place to keep positive energy balance because its job is to hold on to adipose tissue storage. It is only when you start reaching the limits of the safe storage in the adipose tissue that nutrients start to be directed to other tissues and induce insulin resistance in those other tissues.” About 10 years ago, David Savage and O’Rahilly set up the United Kingdom national service for people with lipodystrophy, a problem where there is an abnormal distribution of fat in the body. These individuals have severe metabolic syndrome as they cannot expand their adipose tissue due to an inability to produce triglyceride or adipocytes. Each of these individuals has all the features of metabolic syndrome despite them not having big fat cells. Over the past few years, scientists have discovered many of the single gene disorders that cause severe metabolic syndrome. One example comes from the work led by Savage and Corinne Vigoroux, which shows the kind of information that can be understood about a common phenomenon from a rare disease. They identified a novel heterozygous frameshift mutation affecting the C terminus of a protein called perilipin 1 (PLIN1). It is predominantly expressed in white adipose tissue, and sits on the surface of lipid droplets in the white adipose tissue. If it goes into the cytosol for a moment, it is degraded. Patients with lipodystrophy have one normal copy and one defective copy of the gene where the C terminus is mutated to an aberrant sequence.

O’Rahilly, Stephen

Professor O’Rahilly explained how the protein works,“Here you are today, feeling happy after a lunch. What has happened is that the calories you have taken for lunch are now beyond your positive energy balance, and they are being stored in your body. Dietary lipids are transported from the intestines to adipose and other locations of the body in the form of ultra low-density lipoproteins called chylomicrons; they are going round and into your lipid droplets. As triglycerides are being synthesised by the esterification of fatty acids to glycerol, PLIN1— working in concert with another protein, CGI-58, on top of the lipid droplet— inhibits the expression of lipase enzymes that break down the droplets.” “Later in the night,” O’Rahilly continued, “about four hours after you have been asleep, you will have run out of all that food you have been eating but your heart is still beating and requiring free fatty acids. The heart is getting that from your stored fat—three fatty acid molecules that are bonded to each glycerol molecule during triglyceride synthesis. The hormonal changes that occur on the onset of sleep cause phosphorylation changes in PLIN1, which kicks off its partner CGI58, then grabs down adipose triglyceride lipase (ATGL), and brings it onto the surface of the droplet. Adipose triglyceride lipase is the enzyme that catalyses the initial step in triglyceride hydrolysis. On the N terminus, ATGL grabs the next enzyme HSL, an intracellular neutral lipase that is capable of hydrolysing esters, delivering the free fatty acids that your heart needs when you are asleep.” What happens with the lipodystrophy patients? Throughout the day, whether they are fed or have fasted, there is too much CGI-58 for the PLIN1 due to the PLIN1 mutations. It wanders around the droplet, bringing ATGL to the surface of the droplet and effectively infusing the patients with free fatty acids continuously throughout the day. It is quite profound to think that these patients develop severe insulin resistance, diabetes, fatty liver disease, hepatoma, heart disease, and hypertension due to a temporal error in the amount of free fatty acids being delivered into their systems by faulty triglyceride droplets. Hence, a simple abnormality in lipid handling in the adipose tissue can cause a highly penetrant dominant condition of lipodystrophy and all the metabolic consequences.

Diabetes: Disarming the Silent Killer 13

Is this relevant for common diseases? In a study which Professor O’Rahilly described as being “one of the most important pieces of work we have ever done in collaboration with Nick Wareham”, the question that was asked was: What are the insulin resistance genes in the general population? In this integrative genomic study, they identified 53 SNPs that had genome-wide significance. They were predominantly expressed in the adipose tissue. What do they do in the adipose tissue? “We took those SNPs and did a score for insulin resistance and asked: What does a DEXA scan look like in people who are at risk?” O’Rahilly explained. “We found that these people who are at risk have lower fat on their legs and their buttocks; they look like they have a form of lipodystrophy and are unable to store fat in their lower bodies. In another collaborative work led by Luca Lotta, we found that the SNPs that make your bottom smaller are more strongly associated with diabetes.”

“Sodden Bathroom Carpet” Model of Metabolic Disease Professor O’Rahilly went on to describe what he called the “sodden bathroom carpet” model of overnutrition-related metabolic disease that he and his group are currently working on. “We were hoping to be able to move from genes to therapy, from genetic discovery to therapeutic modulation. Just imagine that you are going into a hotel room where someone has left the bathtub running. In a healthy individual, chronic energy intake (water flowing from the tap) is matched by energy expenditure (water flowing out through the plughole). We have a steady state of stored adipose triglyceride (the water does not overflow, and the bathroom carpet is fine). For an individual with obesity and insulin resistance, the energy intake chronically exceeds energy expenditure. We have an energy imbalance, causing the excess nutrients to flow elsewhere (water overfills the bathtub and soaks the carpet). However, not everybody has the same size of bathtub. For individuals with a limited ability to expand adipose storage capacity (a smaller bathtub), even a small excess of energy intake will lead to nutrients being misdirected (overflow of water from the bathtub) and to adverse metabolic consequences such as insulin resistance and diabetes.”

O’Rahilly, Stephen

Pharmacotherapy for Type 2 Diabetes However, what if an individual already has type 2 diabetes by the time he or she has to get the carpet cleaned? Professor O’Rahilly answered, “You can delay glucose absorption from the small intestine with the alpha-glucosidase inhibitors, or exogenous insulin can be administered to help normalise glucose levels. There are all these various therapies that are available.” There are also the insulin sensitisers that work to lower blood sugar by increasing the sensitivity of fat, liver and muscle to insulin. Are there drugs that can improve glycaemia without increasing plasma insulin? “There probably are,” O’Rahilly replied, “but I do not think we actually have anything yet that could truly be called an insulin sensitiser.” First, there are the anti-inflammatory agents. Many of them have been tried, including anti-tumour necrosis factor biologics and algae, but very little progress has been made in breaking the link between overnutrition and insulin resistance using anti-inflammatories. Further, there are PPAR-gamma agonists (thiazolidinedinones). Despite their effectiveness, they have a number of adverse effects, including weight gain, fluid retention, congestive heart failure, and bone fractures. There are also SGTL2 inhibitors, a class of prescription medicines for use with diet and exercise to lower blood sugar. While they have been beneficial, there are still potential problems and side effects. “As for metformin, we know that it is an insulin sensitiser in the liver. However, there is now an emerging, alternative view of its mechanism of action” said Professor O’Rahilly. The weight-loss effect of metformin is potentially mediated entirely by an effect on the colon to act on increasing GDF15 in the brain, therefore suppressing food intake and causing weight loss. Recently, after further research and reading, O’Rahilly thought he would propose an experiment using PET/CT imaging scans due to a growing realisation that metformin effecting an increase in GDF15 in the gut is a powerful stimulus to glucose uptake. He looked at individuals who happened to have PET/CT scans undertaken when they were on metformin, and found that the scans were not able to find anything in the intestine. This is because metformin profoundly increases glucose uptake in the intestine.

Diabetes: Disarming the Silent Killer 15

“That is also true in mice,” O’Rahilly said. “We can see the huge uptake into the gut with metformin that is released only in the distal intestinal epithelial cells and in the colon, and it is barely absorbed into the circulation.” Despite there being hardly any metformin getting into or reaching the liver, kidney or lungs, metformin has a more powerful effect on glucose lowering without the need to get into the body. This information leads O’Rahilly to a hypothesis about metformin action. It is a mitochondrial complex 1 inhibitor, and GDF15 is often induced in intestinal cells under conditions of stress. These cells secrete GDF15, which suppresses appetite and causes weight loss. About 50%, at least, of glucose and insulin-lowering effects can arguably be attributable to that. “It seems that metformin also produces intestinal uptake of glucose directly into the intestine, and that its absorption is not necessary for its action,” he concludes.

Extended Abtracts

Cost-Effective Analysis for the Early Initiation of Insulin in Type 2 Diabetes Mellitus Patients in Malaysia Using a Discrete Event Simulation Model Wilson MH,* Lee KC,* Wu BC* & Luh H‡

ABSTRACT Background The huge economic burden of type 2 diabetes mellitus (T2DM) can be reduced by implementing inexpensive, easy-to-execute interventions such as early initiation of insulin. Aim The objectives of this pioneering pilot study are to utilise novel methods in T2DM modelling using a discrete event simulation (DES)-based approach, and to subsequently evaluate whether early insulin initiation in patients with T2DM is more cost effective compared to later initiation. Method The analysis was performed using a DES model of people with T2DM. The model simulated a cohort of 10,000 patients over a 30-year time horizon. Base-case analysis was conducted for early initiation of insulin where insulin was initiated five years after the diagnosis of T2DM compared to late initiation where insulin was initiated six years after the diagnosis of T2DM. Result When insulin was initiated five years after the diagnosis of T2DM, it resulted in 62,867 diabetes-related complications which incurred a total treatment cost of RM83,779,605. When insulin was initiated six years after the diagnosis of T2DM, it resulted in 16,352 complications which brought the total cost of treatment to RM84,248,196. Comparatively, the total cost incurred for early * Monash University Malaysia, Malaysia ‡ National Chengchi University, Taiwan

Diabetes: Disarming the Silent Killer 71

initiation was lower by RM468,591. There were also more quality-adjusted life years (QALYs) gained for an early initiation, with 543.83 QALYs. The incremental cost-effectiveness ratio (ICER) obtained showed that initiating insulin five years after the diagnosis of T2DM was dominant compared to initiating insulin later at six years after diagnosis. Conclusion This pioneering pilot study has demonstrated that a DES-based modelling is suitable for T2DM modelling, and further research is needed to further develop and establish the model. Keywords T2DM, DES, CEA, insulin, Malaysia

INTRODUCTION Type 2 diabetes mellitus (T2DM) is one of the most common non-communicable diseases in Malaysia. It imposes a large economic burden on the individual and the national healthcare system. While most T2DM patients will eventually need insulin therapy, misconceptions of insulin therapy being required only at the end-stage of the disease often limit the early initiation of insulin therapy, even for patients who are already adequately controlled by oral glucose-lowering drugs. The huge economic burden of T2DM can be reduced by implementing inexpensive, easy-to-use interventions, such as early initiation of insulin. The objectives of this study are to utilise novel methods in T2DM modelling using a discrete event simulation (DES)-based approach, and to subsequently evaluate whether early insulin initiation in patients with T2DM is more cost effective compared to later initiation.

MATERIALS AND METHODS The analysis was performed using a DES model of individuals with T2DM. The model simulated a cohort of 10,000 patients over a 30-year time horizon. Base-case analysis was conducted for early initiation of insulin where insulin was initiated five years after a T2DM diagnosis, compared to late initiation at six years. The software used to generate the model was FlexSim. The flow diagram of the model is illustrated in Figure 1.

Yes

Reach simulation time horizon

7th level complications

Complications progression

2nd level complications

Figure 1 Flow diagram of the discrete event simulation model1

Yes

End simulation

Stop simulation and collect all statistics

Increment in lifespan (years): Update risk factors and utilities costs

1st level complications: Myocardial infarction Stroke Congestive heart failure Ischemic heart diease Blind Renal failure Amputation

Set initial patient baseline, demographics and risk factor profiles

Diabetes Complications

CV death

All-course death

Yes

Patient death

Begin simulation for individual

72 Wilson MH, Lee KC, Wu BC & Luh H

Diabetes: Disarming the Silent Killer 73

RESULTS The final number of patients used for analysis was 8,400; the drop in the number was due to the removal of simulated patients with missing or incomplete data. For the 8,400 simulated patients who were initiated with insulin five years after the diagnosis of T2DM, the total number of diabetes-related complications simulated was 62,867. The most common complication was ischemic heart disease, accounting for 86.2% of all complications. Myocardial infarction was a distant second with 11.8% (Figure 2).

Ischemic heart disease 86.2% Myocardial infarction 11.8% Congestive heart failure 0.7% Blindness 0.6% Stroke 0.5% Amputation 0.1% Nephropathy 0.1%

Figure 2 Percentage of diabetes-related complications for insulin initiation at five years

For the scenario where insulin was initiated six years after the diagnosis of T2DM, the total number of simulated diabetes-related complications was 16,352. The percentage of the complications was more evenly distributed, with ischemic heart disease and myocardial infarction accounting for 46.7% and 45.1% of all complications, respectively (Figure 3). When insulin was initiated five years after the diagnosis of T2DM, the total cost incurred for initiation was RM83,779,605. When insulin was initiated six years after the diagnosis, the total cost was RM84,248,196. In comparison, the cost incurred for an earlier initiation at five years was lower by RM468,591 (Table 1).

Wilson MH, Lee KC, Wu BC & Luh H

Ischemic heart disease 46.7% Myocardial infarction 45.1% Blindness 2.9% Congestive heart failure 2.6% Stroke 1.7% Amputation 0.6% Nephropathy 0.4%

Figure 3 Percentage of diabetes-related complications for insulin initiation at six years

Table 1 Aggregated costs data

Scenario

Total number of complications

Cost of complications (RM)

Outpatient cost (RM)

Insulin cost Total cost (RM) (RM)

Year 5

62,867

74,558,505

3,855,600

5,365,500

83,779,605

Year 6

16,352

75,027,096

3,855,600

5,365,500

84,248,196

There were also more quality-adjusted life-years (QALYs) gained for early initiation at five years compared to six, with 543.83 QALYs. The incremental costeffectiveness ratio (ICER) obtained showed that initiating insulin five years after the diagnosis of T2DM was dominant compared to later at six years (Table 2).

Table 2 Costs, QALY and ICER for base case Insulin initiation

Costs (RM)

QALYs

Year 5

83,779,605

35,416.08

Year 6

84,248,196

34,872.25

-468,591

543.83

Difference

ICER

Dominant

Diabetes: Disarming the Silent Killer 75

DISCUSSION The specific objectives of this pilot study are: (1) to utilise novel methods in T2DM modelling by using the DES-based approach, and (2) to evaluate whether early insulin initiation in patients with T2DM is more cost-effective compared to later initiation. Based on the aforementioned objectives, the main findings are discussed below. With respect to utilising novel methods in T2DM modelling by using the DESbased approach, this study has been successful in terms of generating a feasible model that is able to simulate the complex nature of T2DM. This study has also shown that more work needs to be done to improve the model and make it as robust and realistic as possible. The next steps on what can be done to further improve the functionality of this model are elaborated below. On whether early insulin initiation in patients with T2DM is more cost-effective compared to later initiation, the study has been successful in demonstrating that initiating insulin earlier at five years as opposed to six years after a T2DM diagnosis could save RM468,591. There were also more QALYs gained for earlier initiation at five years with 543.83 QALYs, and the ICER obtained showed that initiating insulin five years after a T2DM diagnosis is dominant compared to six years. These findings are supported by a study called UKPDS 49 which estimated that more than 60% of T2DM patients would require insulin within five years of diagnosis.2 The findings are also consistent with another study involving Malaysian T2DM patients. This particular study showed that initiating insulin therapy is a safe and more effective way to improve glycaemic control in patients who are inadequately controlled with oral monotherapy or oral combination therapy, compared with optimising oral combination therapy alone.3 Based on the main findings above, the implications from this pioneering pilot study are crucial in changing the way T2DM patients are managed in Malaysia. The findings should add on to the many well-established clinical findings that show the efficacy of earlier insulin initiation for T2DM patients.

Wilson MH, Lee KC, Wu BC & Luh H

The findings should also provide evidence in support of the Ministry of Health’s management of T2DM, as seen in the Type 2 Diabetes Mellitus Clinical Practice Guidelines published in 2009. The guidelines recommended earlier use of insulin therapy in T2DM patients with suboptimal glycaemic control either at presentation or with failure of oral anti-diabetic agents. In 2011, the Practical Guide for Insulin Therapy provided a clear and concise approach to all healthcare providers on current concepts in the use of insulin in T2DM, and the updated Type 2 Diabetes Mellitus Clinical Practice Guidelines published in 2015 continues to espouse earlier use of insulin therapy in T2DM patients in Malaysia. The challenges encountered during this pioneering pilot research was the availability of local clinical and cost data in Malaysia. Malaysia has very limited and scattered data with respect to T2DM costs, which makes sourcing for local data to be fed into the DES model challenging. Due to the challenges encountered in data sourcing, the following limitations have been identified: 1. For the haemoglobin A1c (HbA1c) functions, after starting insulin, there is a 0.5% decrease in the HbA1c level during the first year, followed by a 0.2% annual increment until the eighth year. Then, the HbA1c level remains at 7% from the eighth year and beyond due to the treat-to-target insulin regimen used where the dose of insulin is adjusted to maintain the HbA1c levels within the target range set for the patients. In real life, the treat-to-target regimen may not be realistic due to the many confounding factors, such as poor patient adherence and compliance to treatment and treatment inertia among healthcare professionals. 2. Major hypoglycaemia was not assessed as part of the complications as it is assumed that both arms have similar hypoglycaemia outcomes. This is made evident by a clinical study used for the data input, which found no major hypoglycaemia in the entire cohort at end of the study.4 Other important T2DM complications and side effects of insulin treatment, such as acute complications and weight gain caused by insulin treatment, were not included in this analysis. 3. Cost data obtained from the most comprehensive local publication relied upon clinical pathways and estimation by clinical experts and published fee schedules. The cost estimates are a combination of per-episode costs and annual costs. For per-episode costs, the costs for the complications do not involve ongoing costs and are therefore much lower. Only nephropathy

Diabetes: Disarming the Silent Killer 77

has ongoing management costs for dialysis. The follow-up costs for other complications such as myocardial infarction, stroke, heart failure and amputation are not available.5 Considering all of the above, the DES model used for this pioneering pilot study needs to undergo further research to make it an acceptable model to replicate, as closely as possible, the many real-life issues surrounding the complex universe of T2DM. As with other well-established and accepted T2DM health economic models in the world, further research will be needed in the following aspects: 1. Comprehensive literature review and inclusive medical input from expert clinicians in the field of T2DM and experts in the field of healthcare modelling development.6 2. A reassessment of the DES model structure and functionality to incorporate a more holistic representation of T2DM by involving as many real-life Malaysian patient characteristics and parameters as possible, including comprehensive acute and chronic complications, non-diabetes medications and other parameters associated with T2DM management such as selfmonitoring of blood glucose.6 3. A robust validation analysis to evaluate the DES model in terms of performance against real-life T2DM populations, including clinical outcomes and complications.6

CONCLUSION This pioneering pilot study attempted to utilise novel methods in T2DM modelling using a DES-based approach to evaluate whether early insulin initiation in patients with T2DM is more cost-effective compared to later initiation. The research outcome has demonstrated that a DES-based modelling is the way forward for T2DM modelling and further research should be conducted to establish this. The findings also provide evidence that initiating insulin five years after diagnosis is dominant compared to initiating insulin later at six years. This evidence should encourage Malaysia’s Ministry of Health to continue with the recommendation that insulin should be initiated earlier for T2DM patients in the country.

Wilson MH, Lee KC, Wu BC & Luh H

ACKNOWLEDGEMENTS The authors declare no conflicts of interest.

REFERENCES 1. Hsing L. Diabetes complications flowchart. Bandar Sunway: Monash University Malaysia; 2015. 2. Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA. 1999;281(21):2005-12. DOI: 10.1001/jama.281.21.2005 3. Bebakar WMW, Chow CC, Kadir KA, Suwanwalaikorn S, Vaz JA, Bech OM. Adding biphasic insulin aspart 30 once or twice daily is more efficacious than optimizing oral antidiabetic treatment in patients with type 2 diabetes. Diabetes Obes Metab. 2007;9:724-32. DOI: 10.1111/j.1463-1326.2007.00743.x 4. Bender R, Augustin T, Blettner M. Generating survival times to simulate Cox proportional hazards models. Stat Med. 2005;24(11):1713-23. DOI: 10.1002/ sim.2059 5. Feisul IM, Azmi S, Rizal AMM, Zanariah H, Nik Mahir NJ, Fatanah I, et al. What are the direct medical costs of managing type 2 diabetes mellitus in Malaysia? Med J Malaysia. 2017;72(5):271-7. 6. Standfield L, Comans T, Scuffham P. Markov modeling and discrete event simulation in health care: a systematic comparison. Intl J Technol Assess Health Care. 2014;30(2):165-72. DOI: 10.1017/S0266462314000117