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RNI NO. - 71334/99

ISSN 0972-7043

The Asian Journal of

Diabetology VOLUME VOLUME13, 16,NUMBER NUMBER24

January-March October-December 20132013

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Insulin Management of Type 2 Diabetes Mellitus 82.5% (141)

17.5% (30)

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Effectiveness and Tolerability of Vildagliptin xxxxxxxxxxxxxxxxxxxxxxxx in Indian Patients with Type 2 Diabetes Mellitus: Results from EDGE−A Real-World Observational Study

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Prevalence and Pattern of Dyslipidemia Among Type 2 Diabetic Patients at a Rural-Based Hospital in Gujarat, India Patients without dyslipidemia

Patients with dyslipidemia

xxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxx ADA Releases Revisions to Recommendations for Standards of Medical Care in Diabetes

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Dr Vijay Viswanathan Editor

Dr KK KK Aggarwal Aggarwal Dr Group Editor-in-Chief Group Editor-in-Chief

The Asian Journal of

DIABETOLOGY

IJCP Group of Publications

Volume 16, Number 4, October-December 2013

Dr Sanjiv Chopra Prof. of Medicine & Faculty Dean Harvard Medical School Group Consultant Editor Dr Deepak Chopra Chief Editorial Advisor Padma Shri and Dr BC Roy National Awardee

FROM THE DESK OF GROUP EDITOR-IN-CHIEF

KK Aggarwal

Dr KK Aggarwal Group Editor-in-Chief Dr Veena Aggarwal MD, Group Executive Editor Anand Gopal Bhatnagar Editorial Anchor

IJCP Editorial Board

REVIEW ARTICLE

IJCP Editorial Board Obstetrics and Gynaecology Dr Alka Kriplani Dr Thankam Verma, Dr Kamala Selvaraj Cardiology Dr Praveen Chandra, Dr SK Parashar Paediatrics Dr Swati Y Bhave Diabetology Dr CR Anand Moses, Dr Sidhartha Das Dr A Ramachandran, Dr Samith A Shetty ENT Dr Jasveer Singh Dr Chanchal Pal Dentistry Dr KMK Masthan Dr Rajesh Chandna Gastroenterology Dr Ajay Kumar Dr Rajiv Khosla Dermatology Dr Hasmukh J Shroff Dr Pasricha Dr Koushik Lahiri Nephrology Dr Georgi Abraham Neurology Dr V Nagarajan Dr Vineet Suri Journal of Applied Medicine & Surgery Dr SM Rajendran, Dr Jayakar Thomas Orthopedics Dr J Maheshwari Advisory Bodies Heart Care Foundation of India Non-Resident Indians Chamber of Commerce & Industry World Fellowship of Religions

6

Insulin Management of Type 2 Diabetes Mellitus

Allison Petznick

ORIGINAL STUDY 14 Effectiveness and Tolerability of Vildagliptin in Indian Patients with Type 2 Diabetes Mellitus: Results from EDGE−A Real-World Observational Study

Subhash K Wangnoo, Giovanni Bader, Apurva Gawai, Shradhanand Singh

CLINICAL STUDY 22 Prevalence and Pattern of Dyslipidemia Among Type 2 Diabetic Patients at a Rural-Based Hospital in Gujarat, India

Hetal Pandya, JD Lakhani, J Dadhania, A Trivedi

PRACTICE GUIDELINES

Published, Printed and Edited by Dr KK Aggarwal, on behalf of IJCP Publications Ltd. and Published at E - 219, Greater Kailash, Part - 1 New Delhi - 110 048 E-mail: editorial@ijcp.com

30 ADA Releases Revisions to Recommendations for Standards of Medical Care in Diabetes

Mara Lambert

Printed at New Edge Communications Pvt. Ltd., New Delhi E-mail: edgecommunications@gmail.com Š Copyright 2013 IJCP Publications Ltd. All rights reserved.

The copyright for all the editorial material contained in this journal, in the form of layout, content including images and design, is held by IJCP Publications Ltd. No part of this publication may be published in any form whatsoever without the prior written permission of the publisher.

LIGHTER READING

Editorial Policies The purpose of IJCP Academy of CME is to serve the medical profession and provide print continuing medical education as a part of their social commitment. The information and opinions presented in IJCP group publications reflect the views of the authors, not those of the journal, unless so stated. Advertising is accepted only if judged to be in harmony with the purpose of the journal; however, IJCP group reserves the right to reject any advertising at its sole discretion. Neither acceptance nor rejection constitutes an endorsement by IJCP group of a particular policy, product or procedure. We believe that readers need to be aware of any affiliation or financial relationship (employment, consultancies, stock ownership, honoraria, etc.) between an author and any organization or entity that has a direct financial interest in the subject matter or materials the author is writing about. We inform the reader of any pertinent relationships disclosed. A disclosure statement, where appropriate, is published at the end of the relevant article.

32 Lighter Side of Medicine

Note: Asian Journal of Diabetology does not guarantee, directly or indirectly, the quality or efficacy of any product or service described in the advertisements or other material which is commercial in nature in this issue.

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FROM THE DESK OF GROUP EDITOR-IN-CHIEF Dr KK Aggarwal

Padma Shri and Dr BC Roy National Awardee Sr. Physician and Cardiologist, Moolchand Medcity, New Delhi President, Heart Care Foundation of India Group Editor-in-Chief, IJCP Group and eMedinewS National Vice President, IMA Member, Ethics Committee, MCI Chairman, Ethics Committee, Delhi Medical Council Director, IMA AKN Sinha Institute (08-09) Hony. Finance Secretary, IMA (07-08) Chairman, IMA AMS (06-07) President, Delhi Medical Association (05-06) emedinews@gmail.com http://twitter.com/DrKKAggarwal Krishan Kumar Aggarwal (Facebook)

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Rosiglitazone: US FDA has reversed restrictions placed in 2010 on the use of rosiglitazone for the treatment of type 2 diabetes.1 There had been concerns about cardiovascular safety with this drug. However, the RECORD study, published in 2009 and designed as a noninferiority study comparing rosiglitazone with metformin or sulfonylurea with the premise that rosiglitazone would be beneficial for cardiovascular disease, found no difference in cardiovascular hospitalizations or mortality.

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Combination ACE inhibitor and ARB therapy in diabetic nephropathy: Combination therapy with an ACE inhibitor plus an ARB should not be used in patients with diabetic nephropathy. The VA NEPHRON-D trial randomly assigned 1,448 patients with diabetic nephropathy to lisinopril or placebo; all patients also received losartan.2 The trial was discontinued early (after a median of 2.2 years) because of safety concerns. The primary event rate (a 50% or 30 mL/min/1.73 m2 decline in estimated GFR, end-stage renal disease or death) occurred with similar frequency in both groups, while acute kidney injury requiring hospitalization or occurring during hospitalization was significantly more common with combination therapy (18.0 versus 11.0 percent), as was severe hyperkalemia (9.9 vs 4.4%).

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Oral antihyperglycemic therapy for gestational diabetes: American College of Obstetricians and Gynecologists endorsed the use of oral antihyperglycemic agents as an alternative to insulin for treatment of gestational diabetes mellitus (GDM).3 Glyburide may be given to women with GDM who fail nutritional therapy and refuse to take, or are unable to comply with, insulin therapy.

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Fluoroquinolones and dysglycemia in diabetic patients: Fluoroquinolones have been associated with both hypoglycemia and hyperglycemia, which led to the withdrawal of gatifloxacin from the market in 2006. In a population-based cohort study of diabetic patients, oral fluoroquinolones (moxifloxacin, levofloxacin, ciprofloxacin) were associated with a modest but statistically significant increased risk of dysglycemia; the risk of both hypoglycemia and hyperglycemia appeared to be highest for moxifloxacin.4 The absolute risk of hyperglycemia per 1,000 persons was 6.9 for moxifloxacin, 3.9 for levofloxacin, 4.0 for ciprofloxacin, compared with 1.6 for macrolides.

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JNC 8: Expert Panel want BP cuffs loosened: The long-awaited update to guidelines for the management of hypertension, from the panel appointed to the Eighth Joint National Committee (JNC 8), raises the recommended blood pressure threshold to determine the need for drug therapy in many patients. For most hypertensive individuals 60 or older, pharmacologic treatment should be started when the systolic pressure is 150 mmHg or higher or the diastolic pressure is 90 mmHg or higher, with the goal of achieving readings below those cutoffs. For younger hypertensive patients and for those with chronic kidney disease or diabetes regardless of age-treatment should be initiated when the systolic pressure is 140 or higher or the diastolic pressure is 90 or higher.

REFERENCES 1. http://www.fda.gov/Drugs/DrugSafety/ucm376389.htm (Accessed on December 02, 2013).

2. Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013;369:1892.

3. American College of Obstetricians and Gynecologists. Practice bulletin no. 137: Gestational diabetes mellitus. Obstet Gynecol 2013;122:406.

4. Chou HW, Wang JL, Chang CH, et al. Risk of severe dysglycemia among diabetic patients receiving levofloxacin, ciprofloxacin, or moxifloxacin in Taiwan. Clin Infect Dis 2013.

Asian Journal of Diabetology, Vol. 16, No. 4, October-December 2013

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REVIEW ARTICLE

Insulin Management of Type 2 Diabetes Mellitus ALLISON PETZNICK

ABSTRACT Insulin therapy is recommended for patients with type 2 diabetes mellitus and an initial A1C level greater than 9 percent, or if diabetes is uncontrolled despite optimal oral glycemic therapy. Insulin therapy may be initiated as augmentation, starting at 0.3 unit per kg, or as replacement, starting at 0.6 to 1.0 unit per kg. When using replacement therapy, 50 percent of the total daily insulin dose is given as basal, and 50 percent as bolus, divided up before breakfast, lunch, and dinner. Augmentation therapy can include basal or bolus insulin. Replacement therapy includes basal-bolus insulin and correction or premixed insulin. Glucose control, adverse effects, cost, adherence, and quality of life need to be considered when choosing therapy. Metformin should be continued if possible because it is proven to reduce all-cause mortality and cardiovascular events in overweight patients with diabetes. In a study comparing premixed, bolus, and basal insulin, hypoglycemia was more common with premixed and bolus insulin, and weight gain was more common with bolus insulin. Titration of insulin over time is critical to improving glycemic control and preventing diabetes-related complications.

Keywords: Insulin therapy, type 2 diabetes mellitus, augmentation therapy, replacement therapy, glycemic control

I

nsulin is secreted continuously by beta cells in a glucose-dependent manner throughout the day.

It is also secreted in response to oral carbohydrate loads, including a large first-phase insulin release that suppresses hepatic glucose production followed by a slower second-phase insulin release that covers ingested carbohydrates.1,2 Type 2 diabetes mellitus is associated with insulin resistance and slowly progressive beta-cell failure.

By the time type 2 diabetes is diagnosed in patients, up to one-half of their beta cells are not functioning properly.3 Beta-cell failure continues at a rate of about 4 percent each year.4 Therefore, patients with type 2 diabetes often benefit from insulin therapy at some point after diagnosis.

CONCERNS ABOUT INSULIN THERAPY Pain, weight gain, and hypoglycemia may occur with insulin therapy. Pain is associated with injection therapy and glucose monitoring, although thinner and shorter needles are now available to help decrease pain.

Weight gain associated with insulin therapy is due

ALLISON PETZNICK, DO, is a family physician at Firelands Regional Medical Centers in Sandusky, Ohio. She is also a family physician and diabetologist with Northern Ohio Medical Specialists in Sandusky.

Source: Adapted from Am Fam Physician; 2011;84(2):183-190.

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Asian Journal of Diabetology, Vol. 16, No. 4, October-December 2013

to the anabolic effects of insulin, increased appetite, defensive eating from hypoglycemia, and increased caloric retention related to decreased glycosuria. In the U.K. Prospective Diabetes Study, patients with type 2 diabetes who were taking insulin gained an average of 8 lb, 13 oz (4 kg), which was associated with a 0.9 percent decrease in A1C level compared with patients on conventional therapy.5 Hypoglycemia may occur from a mismatch between insulin and carbohydrate intake, exercise, or alcohol consumption. Hypoglycemia has been associated with an increased risk of dementia and may have implications in cardiac arrhythmia.6,7 All patients should be instructed on the symptoms and treatment of hypoglycemia. American Diabetes Association (ADA) guidelines recommend that the blood glucose level be checked if hypoglycemia is suspected (glucose level lower than 70 mg per dL [3.89 mmol per L]), then treated with a fast-acting carbohydrate, such as juice or glucose tablets. The blood glucose level should be rechecked after 15 minutes to make sure it has normalized.8 An epidemiologic study has raised concern about cancer risk with glargine and other insulin therapies.9 Glargine is theoretically more likely to cause cancer because of its high affinity for insulin-like growth factor I receptor. A consensus statement by the ADA indicates that this possible risk needs further research but should not be a limiting factor in treatment

REVIEW ARTICLE choice.10 Finally, it is important to note that there have been no randomized controlled trials demonstrating reduced all-cause mortality or cardiovascular events with insulin augmentation in patients with type 2 diabetes.

compared with human insulin.17 Analogue insulin usually causes less postprandial hyperglycemia and delayed hypoglycemia.18,19 In a recent meta-analysis, glycemic control was not improved with analogue insulin compared with human insulin, but nocturnal hypoglycemia was reduced.17

INITIATING APPROPRIATE INSULIN THERAPY

An industry-funded cost-effectiveness analysis found that the increased cost of medication is more than offset by the reduction in hypoglycemic events.20 However, the analysis assumed a cost differential of 14 percent, which is inconsistent with current pricing ($119 for a 10-mL vial of glargine insulin compared with $73 for a 10-mL vial of NPH insulin, a 63 percent difference).20,21 Cost-effectiveness analyses have differed regarding the long-term cost savings of using analogue insulin in patients with type 2 diabetes, with industry-sponsored studies finding reduced cost22 and government-sponsored studies finding no cost reduction.23 Measures of adherence and quality of life have been improved with analogue insulin compared with human insulin.24,25

The American College of Endocrinology and the American Association of Clinical Endocrinologists recommend initiation of insulin therapy in patients with type 2 diabetes and an initial A1C level greater than 9 percent, or if the diabetes is uncontrolled despite optimal oral glycemic therapy.11 Insulin may be used alone or in combination with oral medications, such as metformin. This recommendation is based on expert opinion, and not on the results of randomized controlled trials comparing different approaches in patients with an initial A1C level greater than 9 percent.

In the U.K. Prospective Diabetes Study, early intensive glucose control starting with a sulfonylurea, then metformin, then insulin was associated with a 25 percent reduction in microvascular complications and a 12 percent risk reduction in any diabetesrelated end point, but was not associated with a reduction in all-cause mortality.5 A subgroup of patients randomized to intensive therapy with metformin alone had a 36 percent reduction in all-cause mortality.12 This supports current ADA guidelines that recommend using metformin as first-line pharmacologic therapy; however, additional therapies need to be added if diabetes is not controlled with metformin alone.

Recent trials have shown that intensive glucose control (i.e., an A1C target of less than 6.0 or 6.5 percent) does not improve, and may worsen, clinical outcomes.13-15 Older patients with a limited life expectancy and patients with a high risk of hypoglycemia, previous cardiovascular disease or advanced microvascular disease, longer diabetes duration, or multiple comorbid conditions may benefit from less stringent glucose control.16 ANALOGUE VERSUS HUMAN INSULIN Glucose control, adverse effects, cost, adherence, and quality of life need to be considered when choosing a type of insulin. In general, analogue insulin is similar to human insulin in controlling diabetes, although some trials have found higher mean A1C levels in patients taking analogue insulin

CHOOSING THE CORRECT TYPE OF INSULIN Insulin regimens should be tailored to the patient’s needs and lifestyle. One of the most important considerations is the pharmacokinetics of different insulin preparations26 (Table 1).26,27 Table 2 defines commonly used terms in insulin therapy.

Augmentation Only In one study, patients who had uncontrolled type 2 diabetes and were taking a sulfonylurea and metformin were randomized to receive premixed, bolus, or basal analogue insulin. Median A1C levels were similar among the groups, but hypoglycemia was more common in the premixed and bolus groups, and weight gain was more common in the bolus group.28 The results of this study suggest that adding basal insulin to oral antihyperglycemics is similarly effective but has fewer adverse effects compared with adding premixed or bolus insulin.

The goal of basal insulin is to suppress hepatic glucose production and improve fasting hyperglycemia. If basal insulin is titrated too high, it will also partially cover meals and lead to hypoglycemia during the night or if a meal is missed. Long-acting analogue insulin may be administered once or twice daily, depending on the dose. Lower doses may not last 24 hours, whereas higher doses may impede insulin absorption. NPH may be administered one to three times daily. NPH is

Asian Journal of Diabetology, Vol. 16, No. 4, October-December 2013

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REVIEW ARTICLE Table 1. Pharmacokinetic Profiles of Insulin Therapies

Table 2. Commonly Used Terms in Insulin Therapy

Insulin type

Duration

Term

Augmentation Use of either basal or bolus insulin to help improve glucose control in patients with partial beta-cell failure

Onset

Peak

Long-acting Detemir

3 to 4 hours

6 to 8 hours

6 to 23 hours

Glargine

90 minutes

None

24 hours

Intermediate-acting NPH

1 to 2 hours

4 to 10 hours 14 or more hours

Aspart

15 minutes

1 to 3 hours

Glulisine

15 to 30 minutes 30 to 60 minutes

4 hours

Lispro

15 minutes

3 to 5 hours

Regular

30 to 60 minutes 2 to 4 hours

5 to 8 hours

NPH/lispro or aspart

15 to 30 minutes Dual

14 to 24 hours

NPH/regular

30 to 60 minutes Dual

14 to 24 hours

30 to 90 minutes

Mixed*

*NPH/regular: Humulin 70/30, Novolin 70/30, Humulin 50/50; NPH/ lispro or aspart: Humalog 75/25, Novolog 70/30, Humalog 50/50.

often used during pregnancy and in patients who are unable to afford the up-front cost of analogue insulin.

Bolus insulin may also be used for augmentation. Shortacting insulin is administered before meals to cover the carbohydrate load. Short-acting analogue insulin is given up to 15 minutes before a meal to maintain two-hour postprandial glucose levels. Taking insulin after meals increases the risk of early postprandial hyperglycemia followed by delayed hypoglycemia.29 Regular insulin may be used instead and is given 30 to 45 minutes before meals.

Replacement Replacement therapy includes basal-bolus insulin and correction or premixed insulin; an insulin pump may be used, but is beyond the scope of this article.

Replacement should be considered for patients with type 2 diabetes that is uncontrolled with augmentation therapy and who are able to comply with such a regimen or who desire tighter control.

Bolus insulin should be added to basal insulin if fasting glucose goals are met but postprandial goals are not.

When blood glucose levels are above predefined targets, additional short-acting insulin may be added to the bolus

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Asian Journal of Diabetology, Vol. 16, No. 4, October-December 2013

Calculation 0.3 unit per kg

Replacement

0.6 to 1.0 unit Use of basal and bolus per kg insulin to control blood glucose when endogenous insulin production is minimal or absent

Carbohydrate ratio

The number of units of insulin needed to cover for a certain number of grams of carbohydrates ingested

500 divided by total daily insulin (usually about 1 unit per 10 g)

Correction (sensitivity)

How much 1 unit of insulin is expected to decrease the patient’s blood glucose level; when the blood glucose level is above predefined targets, shortacting insulin may be added to the bolus dose or given separately between meals

1,500 divided by total daily insulin (usually about 1 unit per 25 g)

Short-acting 3 to 5 hours

Definition

dose before meals. For example, a patient takes 40 units of glargine daily and 12 units of lispro (Humalog) before each meal, and has a correction factor of 1 unit for every 20 mg per dL (1.11 mmol per L) above 120 mg per dL (6.66 mmol per L). If the blood glucose level at breakfast is 160 mg per dL (8.88 mmol per L), the patient would take 12 units of lispro for the meal plus an additional 2 units for correction before eating.

Premixed insulin similarly reduces A1C compared with basal-bolus insulin.30 NPH is combined with regular insulin or short-acting analogue insulin and is administered two or three times daily. Fewer injections are needed, but patients are more restricted in their eating habits and schedule. Patients must eat breakfast, lunch, dinner, and possibly midmorning and bedtime snacks to prevent hypoglycemia. If used, correction insulin must be administered separately with a short-acting insulin. This may increase the number of injections compared with basal-bolus therapy.

INITIATION, TITRATION, AND FOLLOW-UP The initial dosage of insulin is individualized based on the patient’s insulin sensitivity. Insulin therapy

REVIEW ARTICLE Table 3. American Diabetes Association Blood Glucose and A1C Goals for Patients with Diabetes Mellitus Measurement General population

Pregnant women

Fasting blood glucose

60 to 100 mg per dL (3.33 to 5.55 mmol per L)

90 to 130 mg per dL (5 to 7.21 mmol per L)

Postprandial < 180 mg per dL blood glucose (9.99 mmol per L)

100 to 130 mg per dL (5.55 to 7.21 mmol per L)

A1C

< 6.0 percent

< 7.0 percent

Note: Recent studies have found no cardiovascular benefit with A1C targets of 6.0 or 6.5 percent compared with targets between 7.0 and 8.0 percent. Some microvascular benefit has been associated with A1C targets of 6.0 or 6.5 percent.

Table 4. Treat-to-Target Trial’s Titration Schedule for Basal Insulin in Patients with Diabetes Mellitus Fasting glucose level

Increase in basal insulin

120 to 140 mg per dL (6.66 to 7.77 mmol per L)

2 units

141 to 160 mg per dL (7.83 to 8.88 mmol per L)

4 units

161 to 180 mg per dL (8.94 to 9.99 mmol per L)

6 units

> 180 mg per dL (9.99 mmol per L)

8 units

may be started with a set dosage, such as 10 units of glargine daily, or by using weight-based equations.

Equations to estimate augmentation, replacement, carbohydrate ratio, and correction therapy are listed in Table 2.

When using replacement therapy, 50 percent of the total daily insulin dose is given as basal and 50 percent as bolus, divided up before breakfast, lunch, and dinner. For example, a 120-kg (265-lb) patient requiring basal-bolus and correction insulin would need 36 units of basal insulin (0.3 unit per kg); 12 units of short-acting insulin before each meal (0.3 unit per kg divided among three meals); and, for correction, 1 unit of a short-acting insulin for every 25 mg per dL (1.39 mmol per L) above the set glucose target.

Titration of insulin over time is critical to improving glycemic control and preventing diabetes-related complications.5,31 Current ADA goals for glucose control are outlined in Table 3.16 Fasting glucose readings are used to titrate basal insulin, whereas both preprandial and postprandial glucose readings are used to titrate mealtime insulin.1 Physicians may

increase or decrease basal and/or bolus insulin by 10 percent based on the patient’s home glucose readings.

Some physicians have adopted the Treat-to-Target Trial’s titration schedule for basal insulin (Table 4).31 It is also safe and effective to give patients autonomy to adjust insulin on their own.32 Typically, insulin is increased or decreased by 2 to 3 units every three to seven days if the patient’s blood glucose level is not within set targets.

Patients should go to the physician’s office for followup at least every three to four months. The frequency of communicating insulin titration via clinical contact, telephone, e-mail, or fax is highly correlated with improvement of A1C levels.33,34 INSULIN INJECTION TECHNIQUE Insulin is effective only if administered appropriately.

Injections may be given in the abdomen, outer thigh, back of the arm, and flank/buttocks region. The needle should be placed at a 90-degree angle to the skin and held in place for five to 10 seconds after injection to prevent insulin leakage.8 Rotation of injection sites is important to prevent lipohypertrophy (i.e., scar tissue from repeated injections in the same area). Lipohypertrophy leads to poor insulin absorption and depot formation, which may randomly release insulin, causing early postprandial hyperglycemia and/or delayed hypoglycemia.35 Insulin is available in pens and vials. Benefits of insulin pens include the convenience of storing at room temperature for 28 days after opening and ease of use for patients with visual or dexterity problems. Patients with visual difficulties may listen to the “clicks” of the insulin pen to count the number of units. Patients should be instructed to prime the insulin pen before every use. Priming consists of drawing up 1 or 2 units of insulin and injecting into the air to allow the insulin to fill the needle.

USING INSULIN WITH ORAL MEDICATIONS Many oral medications are safe and effective when combined with insulin therapy. To maximize benefit without causing significant adverse effects, it is important to consider the mechanism of action for different therapies.

Insulin sensitizers have been proven safe and effective when combined with insulin therapy.36,37 Metformin is usually continued indefinitely after the patient starts insulin therapy because it reduces cardiovascular

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REVIEW ARTICLE risk in overweight patients with type 2 diabetes.12 Metformin combined with insulin is also associated with decreased weight gain, a lower insulin dosage, and less hypoglycemia compared with insulin alone.38 Thiazolidinediones improve insulin sensitivity but may increase weight gain, fluid retention, and risk of congestive heart failure when combined with insulin.36 Thiazolidinediones also have not been shown to reduce macrovascular complications or all-cause mortality.

Alpha-glucosidase inhibitors delay absorption of carbohydrates in the gastrointestinal tract to decrease postprandial hyperglycemia. These medications are safe and effective when combined with insulin.39 Insulin secretagogues (sulfonylureas and glitinides) can be combined with insulin, especially when only basal augmentation is being used. However, there is a possible increased risk of hypoglycemia that needs to be monitored closely. Usually by the time insulin is required for meals, insulin secretagogues are not effective or necessary. However, it is recommended to continue oral medications while starting insulin to prevent rebound hyperglycemia.40 After the diabetes is controlled, the patient may be weaned off of oral medications.

Incretin therapies include dipeptidyl-peptidase IV inhibitors (sitagliptin and saxagliptin) and glucagon-like peptide-1 agonists (exenatide and liraglutide). Sitagliptin is currently the only one of these medications that is approved by the U.S. Food and Drug Administration for combination therapy with insulin. This combination is associated with improved fasting and postprandial glucose control.41 Exenatide combined with insulin has been associated with improved glycemic control, weight loss, and no increased risk of hyperglycemia.42 As with thiazolidinediones, glucagon-like peptide-1 agonists and saxagliptin have not been shown to reduce macrovascular events or all-cause mortality.

NOTE: For complete article see: www.aafp.org/afp

REFERENCES

Prospective Diabetes Study (UKPDS) Group [published correction appears in Diabetes. 1996;45(11):1655].

Diabetes. 1995;44(11):1249-1258.

5. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):837-853.

6. Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP Jr, Selby JV. Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA. 2009;301(15):1565-1572.

7. Lindström T, Jorfeldt L, Tegler L, Arnqvist HJ. Hypoglycaemia and cardiac arrhythmias in patients with type 2 diabetes mellitus. Diabet Med. 1992;9(6):536-541.

8. American Diabetes Association. Insulin administration.

Diabetes Care. 2004;27(suppl 1):S106-S109.

9. Jonasson JM, Ljung R, Talbäck M, Haglund B, Gudbjörnsdòttir S, Steineck G. Insulin glargine use and short-term incidence of malignancies—a populationbased follow-up study in Sweden. Diabetologia.

2009;52(9):1745-1754.

10. Giovannucci E, Harlan DM, Archer MC, et al. Diabetes and cancer: a consensus report. Diabetes Care. 2010;33(7): 1674-1685.

11. Jellinger PS, Davidson JA, Blonde L, et al. Road maps to achieve glycemic control in type 2 diabetes mellitus: ACE/ AACE Diabetes Road Map Task Force. Endocr Pract. 2007; 13(3):260-268.

12. UK Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group [published correction appears in Lancet. 1998;352(9139):1558]. Lancet. 1998;352(9131):854865.

13. Gerstein HC, Miller ME, Byington RP, et al.; Action to Control Cardiovascular Risk in Diabetes Study Group.

Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545-2559.

14. Patel A, MacMahon S, Chalmers J, et al.; ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-2572.

2. Diabetes Education Online. University of California, San Francisco. http://www.deo.ucsf.edu. Accessed December 10, 2010.

15. Duckworth W, Abraira C, Moritz T, et al.; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes [published corrections appear in N Engl J Med. 2009;361(10):1028 and N Engl J Med. 2009;361(10): 1024-1025]. N Engl J Med. 2009;360(2):129-139.

3. Gastaldelli A, Ferrannini E, Miyazaki Y, Matsuda M, DeFronzo RA. Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study. Diabetologia. 2004;47(1):31-39.

16. American Diabetes Association. Standards of medical care in diabetes—2010 [published correction appears in Diabetes Care. 2010;33(3):692]. Diabetes Care. 2010; 33(suppl 1):S11-S61.

4. U.K. Prospective Diabetes Study 16. Overview of 6 years’ therapy of type II diabetes: a progressive disease. U.K.

17. Singh SR, Ahmad F, Lal A, Yu C, Bai Z, Bennett H. Efficacy and safety of insulin analogues for the management of

1. Ritzel RA, Bulter PC. Physiology of glucose homeostasis and insulin secretion. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker;2002:61-72.

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REVIEW ARTICLE diabetes mellitus: a meta-analysis. CMAJ. 2009;180(4): 385-397.

a noninferiority intensification substudy of the DURABLE trial. Clin Ther. 2010;32(5):896-908.

18. Ross SA, Zinman B, Campos RV, Strack T; Canadian Lispro Study Group. A comparative study of insulin lispro and human regular insulin in patients with type 2 diabetes mellitus and secondary failure of oral hypoglycemic agents. Clin Invest Med. 2001;24(6):292-298.

31. Riddle MC, Rosenstock J, Gerich J; Insulin Glargine 4002 Study Investigators. The Treat-to-Target Trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care.

2003;26(11):3080-3086.

19. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. The DECODE study group. European Diabetes Epidemiology Group. Diabetes epidemiology: collaborative analysis of diagnostic criteria in Europe. Lancet. 1999;354(9179):617-621.

20. Bullano MF, Al-Zakwani IS, Fisher MD, Menditto L, Willey VJ. Differences in hypoglycemia event rates and associated cost-consequence in patients initiated on longacting and intermediate-acting insulin products. Curr Med Res Opin. 2005;21(2):291-298.

21. Drugstore.com. http: //www.drugstore.com. Accessed January 9, 2011.

22. Brändle M, Azoulay M, Greiner RA. Cost-effectiveness and cost-utility of insulin glargine compared with NPH insulin based on a 10-year simulation of longterm complications with the Diabetes Mellitus Model in patients with type 2 diabetes in Switzerland. Int J Clin Pharmacol Ther. 2007;45(4):203-220.

23. Cameron CG, Bennett HA. Cost-effectiveness of insulin analogues for diabetes mellitus. CMAJ. 2009;180(4):400-407.

24. Howorka K, Pumprla J, Schlusche C, Wagner-Nosiska D, Schabmann A, Bradley C. Dealing with ceiling baseline treatment satisfaction level in patients with diabetes under flexible, functional insulin treatment. Qual Life Res. 2000;9(8):915-930.

25. Fritsche A, Schweitzer MA, Häring HU; 4001 Study Group. Glimepiride combined with morning insulin glargine, bedtime neutral protamine hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes.

A randomized, controlled trial. Ann Intern Med. 2003; 138(12):952-959.

26. Endotext.org. The management of type I diabetes. http: // www. endotext.org/diabetes/diabetes17/diabetesframe17. htm. Accessed December 6, 2010.

27. Hirsch IB. Insulin analogues. N Engl J Med. 2005;352(2): 174-183.

28. Holman RR, Farmer AJ, Davies MJ, et al.; 4-T Study Group.

Three-year efficacy of complex insulin regimens in type 2 diabetes [published correction appears in N Engl J Med. 2010;363(21):2078]. N Engl J Med. 2009;361(18):1736-1747.

29. Cobry E, McFann K, Messer L, et al. Timing of meal insulin boluses to achieve optimal postprandial glycemic control in patients with type 1 diabetes. Diabetes Technol Ther. 2010;12(3):173-177.

30. Miser WF, Arakaki R, Jiang H, Scism-Bacon J, Anderson PW, Fahrbach JL. Randomized, open-label, parallelgroup evaluations of basal-bolus therapy versus insulin lispro premixed therapy in patients with type 2 diabetes mellitus failing to achieve control with starter insulin treatment and continuing oral antihyperglycemic drugs:

32. Ligthelm RJ. Self-titration of biphasic insulin aspart 30/70 improves glycaemic control and allows easy intensification in a Dutch clinical practice. Prim Care Diabetes. 2009;3(2):97-102.

33. Kennedy L, Herman WH, Strange P, Harris A; GOAL A1C Team. Impact of active versus usual algorithmic titration of basal insulin and point-of-care versus laboratory measurement of HbA1c on glycemic control in patients with type 2 diabetes: the Glycemic Optimization with Algorithms and Labs at Point of Care (GOAL A1C) trial.

Diabetes Care. 2006;29(1):1-8.

34. Swinnen SG, Devries JH. Contact frequency determines outcome of basal insulin initiation trials in type 2 diabetes.

Diabetologia. 2009;52(11):2324-2327.

35. Johansson UB, Amsberg S, Hannerz L, et al. Impaired absorption of insulin aspart from lipohypertrophic injection sites. Diabetes Care. 2005;28(8):2025-2027.

36. Berhanu P, Perez A, Yu S. Effect of pioglitazone in combination with insulin therapy on glycaemic control, insulin dose requirement and lipid profile in patients with type 2 diabetes previously poorly controlled with combination therapy.

Diabetes Obes Metab. 2007;9(4):512-520.

37. Avilés-Santa L, Sinding J, Raskin P. Effects of metformin in patients with poorly controlled, insulin-treated type 2 diabetes mellitus. A randomized, double-blind, placebocontrolled trial. Ann Intern Med. 1999;131(3):182-188.

38. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405-412.

39. Kelley DE, Bidot P, Freedman Z, et al. Efficacy and safety of acarbose in insulin-treated patients with type 2 diabetes. Diabetes Care. 1998;21(12):2056-2061.

40. Riddle MC, Schneider J. Beginning insulin treatment of obese patients with evening 70/30 insulin plus glimepiride versus insulin alone. Glimepiride Combination Group.

Diabetes Care. 1998;21(7):1052-1057.

41. Vilsbøll T, Rosenstock J, Yki-Järvinen H, et al. Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes. Diabetes Obes Metab.

2010; 12(2):167-177.

42. Sheffield CA, Kane MP, Busch RS, Bakst G, Abelseth JM, Hamilton RA. Safety and efficacy of exenatide in combination with insulin in patients with type 2 diabetes mellitus. Endocr Pract. 2008;14(3):285-292.

Asian Journal of Diabetology, Vol. 16, No. 4, October-December 2013

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ORIGINAL STUDY

Effectiveness and Tolerability of Vildagliptin in Indian Patients with Type 2 Diabetes Mellitus: Results from EDGE−A Real-World Observational Study SUBHASH K WANGNOO*, GIOVANNI BADER**, APURVA GAWAI†, SHRADHANAND SINGH‡

ABSTRACT Objective: To assess the effectiveness and tolerability of vildagliptin in combination with another oral antidiabetic drug (OAD) versus any other two-agent OAD combinations in Indian patients with type 2 diabetes mellitus (T2DM) in a real-world setting. Study design: This was a post hoc analysis of a multicenter, prospective, 1-year, observational EDGE study for patients enrolled in India. The primary efficacy endpoint of the study was proportion of patients achieving glycosylated hemoglobin (HbA1C) reduction of >0.3% without peripheral edema, hypoglycemic event, discontinuation due to a gastrointestinal event or weight gain. One of the secondary efficacy endpoints was proportion of patients achieving HbA1C <7% without hypoglycemia and weight gain. Results: The mean age, bod y mass index, HbA1C and duration of T2DM were 51.8 years, 26.6 kg/m2, 8.6% and 4.3 years, respectively. The proportion of patients achieving the efficacy endpoints was significantly higher in the vildagliptin cohort compared with the comparator cohort (p < 0.0001). The vildagliptin cohort showed a numerically greater reduction in HbA1C than the comparator cohort (1.4 vs 1.1%; analysis not pre-specified). Adverse events were comparable in both groups (4.2% vs 4.9%). Conclusion: In India, in a real-world setting, vildagliptin showed better overall clinical benefits compared with comparator OADs in patients with T2DM. Keywords: Dipeptidyl peptidase-4 inhibitor, dual combination, India, oral antidiabetic drug, real-world, type 2 diabetes, vildagliptin

T

ype 2 diabetes mellitus (T2DM), a major lifestyle disorder, has transitioned from being a class disease to a mass epidemic and poses a rapidly emerging global threat to public health with a worldwide prevalence of 366 million.1 India, once known as the “diabetes capital of the world”,2 was home to 61.3 million patients with T2DM in 2011 and this figure is expected to rise to 101.2 million by 2030.1

*Senior Consultant Endocrinologist and Diabetologist Apollo Centre for Obesity, Diabetes and Endocrinology (ACODE) Indraprastha Apollo Hospital, Sarita Vihar, New Delhi **Principal Medical Scientific Expert, Global Medical Affairs - Diabetes, Novartis Pharma AG, Postfach, Switzerland †Medical Advisor ‡Clinical Research Medical Advisor Novartis Healthcare Private Limited, Worli, Mumbai Address for correspondence Dr Apurva Gawai Medical Advisor Novartis Healthcare Private Limited, Sandoz House, 7th Floor, Shivsagar Estate Dr Annie Besant Road, Worli, Mumbai - 400 018 E-mail: apurva.gawai@novartis.com

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Asian Journal of Diabetology, Vol. 16, No. 4, October-December 2013

Various phenotypic and genotypic characteristics in Indians may lead to increased insulin resistance, lower adiponectin, greater abdominal adiposity (higher waist circumference despite lower body mass index [BMI]) and a higher prevalence of impaired glucose tolerance; all of these factors contribute to a higher risk of developing T2DM at a comparatively young age.3 Physical inactivity, changes in dietary habits, a carbohydrate rich diet, urbanization and environmental factors also add to this risk.4 In addition, patients and healthcare professionals in India face challenges such as clinical inertia (failure to initiate or intensify the treatment) in achieving glycemic control, inadequate treatment follow-up and lack of disease awareness among patients.4 Guidelines suggest the use of combination therapies including diverse oral antidiabetic drugs (OADs), acting via multiple mechanisms, to effectively manage hyperglycemia, while dealing with the challenges of the progressive nature of T2DM and monotherapy failure.5 Vildagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor improves pancreatic α- and β-cell responsiveness

ORIGINAL STUDY to glucose, and consequently provides improved glycemic control as monotherapy, or as a component of combination therapy, without weight gain and hypoglycemia.6-8 Pragmatic real-world observational studies are designed to provide a closer look into routine clinical practice.9 EDGE (Effectiveness of Diabetes control with vildaGliptin and vildagliptin/mEtformin) was a prospective, 1-year, observational study conducted across 27 countries from Europe, Central and Latin America, Asia and Middle East to evaluate the efficacy, safety and tolerability of vildagliptin in combination with another OAD versus all other two-agent OAD combinations in real-world settings.10 In these post hoc analyses, we assessed the effectiveness and tolerability of vildagliptin combination versus all other two-agent OAD combinations in patients enrolled from India in the EDGE study.

SUBJECTS AND STUDY DESIGN Of the 45,868 patients enrolled in the EDGE study,10 11,057 were enrolled across 472 sites in India. Patients with T2DM, aged ≥18 years, who had inadequate glycemic control, while receiving OAD monotherapy with a sulfonylurea (SU), metformin, thiazolidinedione, glinide or α-glucosidase inhibitor were eligible. Patients receiving DPP-4 inhibitors other than vildagliptin, incretinmimetics/analogs or insulin, requiring three or more OADs, or who had a history of hypersensitivity to study drugs were excluded.

Physicians chose antidiabetic treatment for their patients at their own discretion. To avoid physician bias for a particular choice of treatment, patients were asked for informed consent and enrolled in the study only after the treatment decision was made (Fig. 1).

The term index therapy was used to represent the combination treatment initiated at enrolment. Further details of the subjects and study design are reported elsewhere.10 MATERIALS AND METHODS

Efficacy Endpoints The primary efficacy endpoint of the study was the proportion of patients responding to the treatment (reduction in glycosylated hemoglobin [HbA1C] >.3% from baseline to 12 months) with no intolerability findings (peripheral edema, hypoglycemic event, discontinuation due to a gastrointestinal event or weight gain ≥5%). One of the secondary efficacy

endpoints was the proportion of patients with baseline HbA1C ≥7% who achieved target HbA1C <7% without hypoglycemia and weight gain ≥3%. Change in HbA1C from baseline to study endpoint was also evaluated in these post hoc analyses (an analysis not pre-specified in the protocol). Hypoglycemia was defined as symptoms suggestive of hypoglycemia that resolved promptly on administration of oral carbohydrate (including mild and severe events).

Statistical Analysis Descriptive statistics were used for these post hoc analyses. Inference is provided for primary and secondary efficacy endpoints. The per protocol (PP: Patients who completed the study without any major protocol deviation) population was used for analyses of the efficacy endpoints. Data were censored if patients changed index therapy. The probability of success was analyzed for the efficacy endpoints using a binary logistic regression model to calculate odds ratios (ORs) with 95% confidence intervals (CIs). The OR expresses odds in favor of success with vildagliptin combinations relative to odds in favor of success with comparator OADs. Patients whose outcomes could not be categorized as a success or failure (e.g., due to missing HbA1C or body weight data at the 12-month endpoint) were considered nonevaluable. These nonevaluable patient data were considered failures in calculation of the OR for success. Only unadjusted ORs were reported for the primary and secondary efficacy endpoints in these post hoc analyses. HbA1C drop was adjusted with baseline value by using an analysis of covariance (ANCOVA) model.

RESULTS Of the 11,057 patients enrolled from India in the EDGE study, 365 patients (198 in the vildagliptin and 167 in the comparator cohort) were excluded due to inadequate source documentation or problems with quality or accuracy of data entry. The remaining intention-to-treat (ITT) population received newly prescribed vildagliptin (5,621) or a nonvildagliptin OAD (5,071) added to prior monotherapy (Table 1).

The PP population, a subset of the ITT population comprising 5,606 patients in the vildagliptin cohort and 5,070 patients in the comparator cohort, was used for the analyses of efficacy endpoints.

The demographic and baseline characteristics of patients in the ITT population are summarized in Table 2. Overall, 61.4% patients were male. The mean

Asian Journal of Diabetology, Vol. 16, No.4, October-December 2013

15

ORIGINAL STUDY Table 1. Patient Populations and Flow Enrolled*

11,057

No cohort assignment

0 Vildagliptin cohort

Comparator cohort

5,819

5,238

198

167

ITT**

5,621

5,071

Patients completed

5,418

4,874

203

197

7

3

5,606

5,070

Assigned No adequate source documentation at site; lack of quality and accuracy of data entry

Patients discontinued Patients with ≥1 protocol deviation Per protocol

†

*The enrolled population includes all patients who gave documented informed consent. **The intention-to-treat (ITT) population is a subset of the enrolled population and includes all patients who were assigned to new treatment at study start. †The

per protocol (PP) population is a subset of the ITT population, who completed the study without any major protocol deviation; it was used for the analyses of effectiveness endpoints.

Table 2. Demographic and Patient Baseline Characteristics (ITT Population) Characteristic

Vildagliptin (n = 5,621)

Comparator (n = 5,071)

Total (n = 10,692)

51.7 ± 9.94

52.0 ± 9.95

51.8 ± 9.95

Male

3,459 (61.5)

3,102 (61.2)

6,561 (61.4)

Female

2,162 (38.5)

1,969 (38.8)

4,131 (38.6)

Age (years) Gender, n (%)

(kg/m2)

26.8 ± 4.16

26.4 ± 3.93

26.6 ± 4.06

Baseline HbA1C (%)

8.6 ± 1.12

8.5 ± 1.09

8.6 ± 1.11

Duration of T2DM (years)

4.4 ± 4.29

4.1 ± 3.89

4.3 ± 4.11

BMI

Data are mean ± standard deviation unless specified otherwise.

BMI = Body mass index; ITT = Intention-to-treat; SD = Standard deviation; T2DM = Type 2 diabetes mellitus.

Table 3. Index Medication (ITT Population) Vildagliptin cohort* (n = 5,621) Treatments

Comparator cohort* (n = 5,071) No. of patients (%)

Treatments

No. of patients (%)

TZDs-vildagliptin

131 (2.3)

SUs-TZDs

253 (5.0)

SUs-vildagliptin

1,252 (22.3)

Metformin-TZDs

482 (9.5)

Metformin-vildagliptin

4,176 (74.4)

Metformin-SUs

3,946 (77.8)

Glinides-vildagliptin

10 (0.2)

Metformin-insulin

0 (0)

AGI-vildagliptin

47 (0.8)

Glinides-TZDs

3 (0.1)

Glinides-SUs

30 (0.6)

Glinides-metformin

38 (0.7)

AGIs-TZDs

10 (0.2)

AGIs-SUs

83 (1.6)

AGIs-metformin

223 (4.4)

AGIs-glinides

3 (0.1)

AGI = α-glucosidase inhibitor; ITT = Intention-to-treat; SU = Sulfonylurea; TZD = Thiazolidinedione.

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Asian Journal of Diabetology, Vol. 16, No. 4, October-December 2013

ORIGINAL STUDY

Vildagliptin as add-on or vildagliptin/metformin (fixed-dose)* Monotherapy failure Comparator dual therapy OADs**

Month

0

1

2

3

4

5

6

7

8

9

10

11

12

BL Demography

HbA1C

HbA1C

HbA1C

Weight

Weight

Weight

T2DM Meds

T2DM Meds

T2DM Meds

AEs, SAEs

Required

AEs, SAEs Optional

Required

Data Collection Opportunities

Figure 1. Study design. *Vildagliptin cohort: T2DM patients newly initiating vildagliptin as add-on, or newly initiating vildagliptin-metformin (fixed-dose) from nonvildagliptin monotherapy. **Comparator OAD cohort: T2DM patients newly initiating dual therapy with antidiabetic therapies other than vildagliptin (defined as SU, metformin, TZDs, metiglinides, a-glucosidase inhibitors as add-on dual therapy) except as add-on to vildagliptin, other DPP-4 inhibitors or GLP-1 mimetics/analogs.

AEs = Adverse events; AGI = a-glucosidase inhibitor; BL = Baseline; DPP-4 = Dipeptidyl peptidase-4; GLP-1 = Glucagon-like peptide-1; OAD = Oral antidiabetic drugs; SAEs = Serious AEs; SU = Sulfonylurea; T2DM = Type 2 diabetes mellitus; TZD = Thiazolidinedione.

values of age, BMI, HbA1C and duration of T2DM at baseline were 51.8 years, 26.6 kg/m2, 8.6% and 4.3 years, respectively. Despite the fact that this was a nonrandomized study, the baseline characteristics were comparable across the groups (Table 2).

At study entry, most patients were receiving metformin monotherapy. Table 3 reports index therapies in the ITT population for both cohorts. The percentage of patients achieving the primary efficacy endpoint was 68.5% in the vildagliptin cohort compared with 56.8% in the comparator cohort (Fig. 2A), with an unadjusted OR of 1.65 (95% CI: 1.53, 1.79; p < 0.0001) in favor of vildagliptin. For the secondary efficacy endpoint, the numbers were 25.7% patients in the vildagliptin cohort compared with 14.6% patients in the comparator cohort (Fig. 2A), resulting in an unadjusted OR of 2.03 (95% CI: 1.83, 2.25; p < 0.0001) in favor of vildagliptin.

After 12 months of treatment, vildagliptin resulted in a numerically greater adjusted mean change in HbA1C than the comparator cohort with a mean treatment difference of 0.3% in favor of vildagliptin (Fig. 2B).

Overall, 234 patients (4.2%) in the vildagliptin cohort and 248 patients (4.9%) in the comparator cohort reported adverse events (AEs). Three cases of

serious AEs (SAEs), namely myocardial infarction, foot abscess and uncontrolled hyperglycemia, were reported in the vildagliptin cohort versus none in the comparator cohort. However, none of the SAEs were suspected to be treatment-related. The patient who experienced myocardial infarction died during the study; he reported a medical history of hypertension, renal impairment, transient ischemic attack, diabetic retinopathy, dyslipidemia and hyperlipidemia. The death was not suspected to be due to the study drug.

A total of 19 patients (0.3%) reported hypoglycemia in the vildagliptin cohort versus 66 patients (1.3%) in the comparator cohort. Most of the hypoglycemic events in the comparator group were reported by patients who were receiving a metformin and SU combination (54 patients, 1.1%).

DISCUSSION Real-world studies are valuable for a country like India, which has a population with high prevalence of T2DM patients with poor glycemic control.4 Various studies have reported that Indian patients with T2DM have higher mean HbA1C11,12 than the recommended treatment goal,5,13 indicating poor glycemic control

Asian Journal of Diabetology, Vol. 16, No.4, October-December 2013

19

ORIGINAL STUDY

A Patients achieved study endpoints (%)

80 70 60

Vildagliptin

68.5

Comparator

56.8

50 40 30

25.7

20

14.6

10

0 B

Primary efficacy endpoint

Secondary efficacy endpoint

0.0

Change in HbA1C from baseline (%)

−0.2 −0.4 −0.6 −0.8 −1.0 −1.1

−1.2 −1.4

−1.4

−1.6

Figure 2. (A) Primary and secondary efficacy endpoints (PP population); (B) Change in HbA1C after 12 months of treatment (ITT population).

(A) Percentage of patients achieving study endpoints in PP population; unadjusted odds ratios (95% CI): 1.65 (1.53, 1.79) for primary endpoint and 2.03 (1.83, 2.25) for secondary endpoint; both p <0.0001. (B) Mean HbA1C change (± standard error) from baseline to study endpoint in ITT population using an ANCOVA model.

among Indians. In addition, our post hoc analyses indicated that patients enrolled in India had a numerically higher baseline HbA1C (8.6% ± 1.1%) than that reported for the overall population in the EDGE study (8.2% ± 1.3%).10 These post hoc analyses demonstrated that vildagliptin in combination with another OAD provides better glycemic control than any other two-agent OAD combination. After 12 months of treatment, the vildagliptin cohort exhibited a greater proportion of patients (unadjusted OR 1.65 [95% CI: 1.53, 1.79]) achieving the primary efficacy endpoint (reduction in HbA1C >0.3% without peripheral edema, hypoglycemic event, discontinuation due to a gastrointestinal event or weight gain ≥5%) and the secondary efficacy endpoint

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Asian Journal of Diabetology, Vol. 16, No. 4, October-December 2013

of HbA1C< 7% without hypoglycemia and weight gain ≥3% from a baseline HbA1C of ≥7% (unadjusted OR 2.03 [95% CI: 1.83, 2.25]) versus all other two-agent OAD combinations. The results for this secondary efficacy endpoint confirm results from other studies, which consistently showed better responder rates with vildagliptin versus comparators, although such comparisons have limitations.14,15 The reduction in HbA1C was numerically greater with vildagliptin combinations versus other two-agent OAD combinations, as in the overall EDGE study population.10 However, the vildagliptin cohort in the Indian population showed a numerically greater reduction (1.4%) when compared with the vildagliptin cohort in the overall EDGE study population (1.2%).10 This larger reduction in HbA1C in Indian patients may be partly explained by the higher baseline HbA1C in the Indian patients.

The vildagliptin cohort showed a good safety and tolerability profile without any clinically relevant trends, which further corroborates the good safety profile of vildagliptin.16,17 The study revealed that fewer patients in the vildagliptin cohort reported hypoglycemia than in the comparator cohort; the majority of patients reporting hypoglycemia were using a metformin and SU combination. This is consistent with results from a previously reported large pooled analysis of safety data, which showed that vildagliptin, as monotherapy or in combination with metformin, thiazolidinedione or an SU, is associated with significantly fewer hypoglycemic events than comparators.17 There were some limitations to our study. Because physicians were required to select any drug-based on their clinical judgment, the open study design resulted in a possible imbalance favoring the vildagliptin arm in the overall EDGE study population, although this did not seem to be the case in the Indian patients. Moreover, the patients were recruited both in specialty and routine care centers, which may have had an impact on the overall results because of poor quality and missing data that needed to be excluded from the effectiveness analyses. In addition, unlike in randomized controlled trials, reporting of AEs was based on a voluntary reporting scheme, which might have led to unnoticed or under-reported events.

CONCLUSION These post hoc analyses of the EDGE study confirmed that vildagliptin in combination with another OAD showed better overall clinical benefit versus any

ORIGINAL STUDY other two-agent OAD combination, as measured by a composite endpoint assessing effectiveness (HbA1C reduction) and tolerability (peripheral edema, gastrointestinal events, hypoglycemia and weight gain) in Indian patients with T2DM in a real-world setting.

Contributors All authors had full access to all data, and take responsibility for the integrity of the data and accuracy of analyses. SKW and GB were involved with study design, data collection and data interpretation. SS was involved in data interpretation and drafting of the manuscript. AG was involved with data interpretation. All authors actively participated in the preparation of the manuscript and provided critical review at each step.

Acknowledgments This study was funded by Novartis Pharma AG. The authors acknowledge Arvind Semwal (M. Pharm., Ph.D.), Novartis Healthcare Private Limited, Hyderabad, India, for providing writing assistance and editorial support towards the development of the manuscript.

Conflicts of Interest SKW does not have any conflict of interest regarding the financial aids/disclosures nor is he on a company board as a paid member. GB is an employee of Novartis Pharma AG, and AG and SS are employees of Novartis Healthcare Private Limited.

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12. Moses CR, Seshiah V, Sahay BK, Kumar A, Asirvatham AJ, Balaji V, et al. Baseline results indicate poor glycemic control and delay in initiation and optimization of insulin therapy: results from the improving management practices and clinical outcomes in type 2 diabetes study.

Indian J Endocrinol Metab 2012;16(Suppl 2):S432-3.

13. I ndian Council of Medical Research. Guidelines for Management of Type 2 Diabetes. 2005. Available at: http:// icmr.nic.in/guidelines_diabetes/guide_diabetes.htm 14. Bader G, Geransar P, Schweizer A. Vildagliptin more effectively achieves a composite endpoint of HbA1C < 7.0% without hypoglycaemia and weight gain compared with glimepiride after 2 years of treatment. Diabetes Res Clin Pract 2013;100(3):e78-81.

15. Ahrén B, Foley JE, Bosi E. Clinical evidence and mechanistic basis for vildagliptin’s action when added to metformin. Diabetes Obes Metab 2011;13(3):193-203.

16. Ligueros-Saylan M, Foley JE, Schweizer A, Couturier A, Kothny W. An assessment of adverse effects of vildagliptin versus comparators on the liver, the pancreas, the immune system, the skin and in patients with impaired renal function from a large pooled database of Phase II and III clinical trials. Diabetes Obes Metab 2010;12(6):495-509.

17. S chweizer A, Dejager S, Foley JE, Kothny W. Assessing the general safety and tolerability of vildagliptin: value of pooled analyses from a large safety database versus evaluation of individual studies. Vasc Health Risk Manag 2011;7:49-57.

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Asian Journal of Diabetology, Vol. 16, No.4, October-December 2013

21

CLINICAL STUDY

Prevalence and Pattern of Dyslipidemia among Type 2 Diabetic Patients at a Rural-Based Hospital in Gujarat, India.

HETAL PANDYA*, JD LAKHANI**, J DADHANIAâ&#x20AC; , A TRIVEDIâ&#x20AC;

ABSTRACT Only proper control of diabetes has shown statistically significant difference (p < 0.001) on the prevalence and severity of dyslipidemia, consolidate the fact that the proper treatment and strict control of diabetes is the most imported step in the prevention and treatment of complications of diabetes.

Keywords: Dyslipidemia atherogenic lipid profile, elevated triglycerides, HDL cholesterol, LDL cholesterol, obesity, metabolic syndrome, diabetes

I

t is currently estimated that diabetes prevalence by 2030 will include 439 million adults worldwide.1 South East Asian countries bear the highest burden of diabetes, including India which may have up to 33 million cases.2 Coronary artery disease (CAD) accounts for the primary cause of death in almost all patients with diabetes. Despite major advances in primary and secondary prevention of CAD in the past 50 years, patients with diabetes still are relatively at an increased risk of CAD as compared to those without diabetes.3

Even as the causes of increased cardiovascular risk in type 2 diabetes are multifactorial, an atherogenic lipid profile characterized by elevated triglycerides and low levels of high-density lipoprotein (HDL) cholesterol are few major modifiable factors contributing progressively in cardiovascular risk.4,5 Although three recent clinical trials of cholesterol lowering have shown that lowering low-density lipoprotein (LDL) cholesterol in diabetic

*Associate Professor **Professor and Head â&#x20AC; Junior Resident Dept. of Medicine SBKS Medical Institute and Research Centre, Vadodara, Gujarat Address for correspondence Dr Hetal Pandya Associate Professor Dept. of Medicine SBKS Medical Institute and Research Centre Vadodara, Gujarat E-mail: drhetalpandya@gmail.com

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Asian Journal of Diabetology, Vol. 16, No. 4, October-December 2013

persons does reduce the incidence of CAD6-8 the relative importance of LDL cholesterol, compared with the characteristic dyslipidemia, in determining CAD risk in diabetic individuals is still a subject of debate. A question of particular importance is the relative role of various lipoprotein abnormalities in determining CAD risk in diabetic individuals in context to the ethnicity and region where they live.

India has diverse lifestyle pattern and ethnic variations, thus epidemiological profile of diabetes mellitus may be different in different geographical areas. Gujarat is considered as one of the rich and developed state of India. A diet rich in oil and sugar content has pushed Gujarat to the forefront of contributors of diabetic patients in India. Ethnic Gujarati people are presumed to have high prevalence of CAD risk factorsobesity, metabolic syndrome, diabetes, hypertension, dyslipidemia because of traditional Gujarati food and less physically active lifestyle. In our previous study on Diabesity in Gujarati population, even rural underdeveloped areas of Gujarat had shown an increasing trend of lifestyle disorders like diabetes and obesity.9 Another study had also shown increasing prevalence of another lifestyle disorder-hypertension and obesity in Gujarati population.10 Though the burden of diabetes and dyslipidemia in India is mainly contributed by urban population, the increasing trend of diabetes and even dyslipidemia is observed in rural population too, because of urbanization and changing lifestyle and food habits. There are very

CLINICAL STUDY few data available for prevalence of dyslipidemia and diabetes from Indian continent, which are mainly from South Indian urban population and few from North Indian urban population.11-14 We were unable to find studies on prevalence and pattern of dyslipidemia in diabetic Gujarati population. The present study aims to bridge the gap by studying prevalence, pattern and severity of dyslipidemia in diabetic patients especially in rural areas of Gujarat.

their blood pressure is ≥130/85. ADA criteria for treatment of diabetes (HbA1C < 7% or fasting/preprandial plasma glucose <130 mg/dl and postprandial plasma glucose <180 mg/dl for two consecutive visits) were used to divide the patients in controlled and uncontrolled groups.16 All the observations were tabulated and results were expressed as percentage and mean SD (standard deviation).

RESULTS

MATERIAL AND METHODS A prospective cross-sectional study was planned to analyze the pattern of dyslipidemia in diabetic patients attending the Diabetes Clinic and Outpatient Department of Dhiraj General Hospital attached with SBKS Medical Institute and Research Centre over a period of six months (July 2010 to December 2010).

The study population included already diagnosed on treatment diabetic patients and newly diagnosed diabetes mellitus (DM) patients. The patients who already had history of CAD or cerebrovascular accident (CVA) or were diagnosed as having CAD or CVA on enrolment and patients already taking lipid-lowering drugs were excluded from the study. Diabetic patients having other chronic systemic or metabolic disorder were not included in the study.

Detailed history and clinical examination of all the enrolled patients was done. Anthropometric measurements (weight, height, waist circumference [WC] and hip circumference) were taken using standard methods. Fasting blood sample was collected for serum lipid profile investigation after 10 hours overnight fast serum cholesterol, serum triglyceride, serum HDL, serum LDL, serum VLDL levels were measured using calibrated ERBACHEM 5 Plus, semi-automated machine. Cut-off normal values for individual lipid levels were taken as per the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel III).15 The term mixed dyslipidemia is used when two or more individual lipid levels were abnormal.

The patients were categorized in different subgroups such as male/female, urban/rural, controlled/ uncontrolled, obese/nonobese, hypertensive/nonhypertensive for subgroup analysis of diabetic dyslipidemia. All diabetic patients were categorized as urban if living in place with >1 lac population, obese or nonobese using body mass index (BMI) criteria of ≥23 proposed for South-Asian population (IDF-modified ATP III criteria)15 and as hypertensive if

Out of 171 diabetic patients enrolled in the study, 100 were male and 71 were female patients. The mean age of study population was 54.8 ± 10.12 (male: 54.7 ± 10.65 and female: 54.9 ± 9.42). The mean duration from the first diagnosis of diabetes for the study patients was 5.1 ± 4.64 years. Only 9.9% of patients had DM since >10 years and 23.4% were diagnosed as diabetics in last two years only. Around, 33.9% were diabetics since 2 to 5 years and 32.7% were diabetics since 5 to 10 years. Further, 43.9% (n = 75) of patients were from urban area and 56.1% (n = 96) were from the rural area.

The mean BMI of study population was 25.6 ± 5.81 (male: 24.5 ± 4.71 and female: 27.2 ± 6.81). Also, 68.4% (n = 117) of all diabetic patients participated in study were found to be obese by modified ATP III criteria of BMI ≥23 for South-Asian population. Only 19.3% of study patients were well-controlled. Only 24% (n = 41) were hypertensive and 26.3% (n = 45) were smokers, all were males (Table 1).

Individual serum lipid results were as follows. Mean serum cholesterol level was 188.9 ± 43.70, mean serum triglyceride was 174.6 ± 69.44, mean serum HDL was 46.2 ± 17.08, mean serum LDL was 105.9 ± 34.06 and mean serum VLDL level was 33.4 ± 11.08 (Table 2).

82.5% (141)

17.5% (30) Patients without dyslipidemia

Patients with dyslipidemia

Figure 1. Percentage distribution of dyslipidemia in diabetic patients.

Asian Journal of Diabetology, Vol. 16, No. 4, October-December 2013

23

CLINICAL STUDY Table 1. Patient Characteristics and Prevalence of Dyslipidemia Characteristic

No. of patients (n = 171, [%])

Dyslipidemia (n [%])

P value

26 (15.2%)

22 (84.6%)

< 0.5

89 (52%)

72 (80.9%)

56 (32.8%)

47 (83.9%)

Male

100 (58.5%)

85 (85%)

Female

71 (41.5%)

56 (78.9%)

Urban

75 (43.9%)

61 (81.3%)

Rural

96 (56.1%)

80 (83.3%)

Controlled

33 (19.3%)

20 (60.6%)

Uncontrolled

138 (80.7%)

121 (87.7%)

Obese (BMI ≥23)

117 (68.4%)

99 (84.6%)

Nonobese (BMI <23)

54 (31.6%)

42 (77.8%)

Nonhypertensive (<130/85)

130 (76%)

106 (81.5%)

Hypertensive (≥130/85)

41 (24%)

35 (85.4%)

Age (years) <45 46-60 >60 Sex < 0.5

Locality < 0.5

Control of DM < 0.001

Obesity < 0.5

Hypertension < 0.5

Smoking Smoker

45 (26.3%)

40 (88.9%)

Nonsmoker

126 (73.7%)

101 (80.2%)

< 0.5

Duration of DM <2 years

40 (23.4%)

33 (82.5%)

2-5 years

58 (33.9%)

45 (77.6%)

5-10 years

56 (32.7%)

48 (85.7%)

>10 years

17 (9.9%)

15 (88.2%)

< 0.5

Table 2. Serum Lipid Levels of Diabetic Patients Serum lipid

Mean ± SD

Abnormal value

Deranged lipid level n (%)

S. cholesterol

188.9 ± 43.70

>200 mg/dl

62 (36.3%)

S. triglyceride

174.6 ± 69.44

>150 mg/dl

96 (56.1%)

S. HDL

46.2 ± 17.08

<40 mg/dl

61 (35.7%)

S. LDL

105.9 ± 34.06

>100 mg/dl

98 (57.3%)

S. VLDL

33.4 ± 11.08

>32 mg/dl

85 (49.7%)

Out of 171 DM patients, 36.3% (n = 62) patients were having high serum cholesterol level, while almost similar number. of patients, 35.7% (n = 61) had low serum HDL levels. About 56.1% (n = 96) had high serum triglyceride level, while almost similar numbers of patients, 57.3% (n = 98) also had serum LDL levels

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Asian Journal of Diabetology, Vol. 16, No. 4, October-December 2013

above normal range. About 49.7% (n = 85) also showed high serum VLDL levels about (Table 2 and Fig. 1).

DISCUSSION Patients with DM have a 2 to 4 fold increased risk of cardiovascular, peripheral vascular and cerebrovascular

CLINICAL STUDY

Deranged lipid level %

Serum lipid

S. VLDL

49.70%

S. LDL

57.30%

S. HDL

35.70%

S. triglyceride

56.10% 36.30%

S. cholesterol 0.00%

10.00% S. cholesterol

20.00%

30.00%

40.00%

S. triglyceride

S. HDL

50.00% S. LDL

60.00%

70.00% S.VLDL

Figure 2. Prevalence of individual lipid abnormalities in diabetics.

disease, which are the leading causes of morbidity and mortality in this population. Many Western epidemiological studies have shown an association between diabetic dyslipidemia, which is characterized by hypertriglyceridemia; low levels of HDL cholesterol; postprandial lipemia and small, dense LDL cholesterol particles and the occurrence of cardiovascular disease.17-19 The analysis of data from our study provides an opportunity to examine dyslipidemia a major CAD risk factor in population-based sample of well-characterized type 2 diabetic individuals. The present study shows very high prevalence of dyslipidemia (82.5%) in ethnic Gujarati diabetic population which recommend the use of terminology “diabetes lipidus” for them (Fig. 2).

Diabetic dyslipidemia is not only prevalent in urban Gujarat (81.3%) as assumed by lavish lifestyle of fat and sugar rich food and lesser physical work but it is also increasingly witnessed in rural remote areas in similar proportion (83.3%), which is a worrisome scenario.

More so, both males and females had deranged lipid levels in almost similar numbers (M: 85% and F: 78.9%).

So “diabetic dyslipidemia”/”diabetes lipidus” might become a synonym for diabetes in Gujarati population as a whole with its serious impact on rapidly rising prevalence of CAD in Gujarati’s.

Another interesting finding observed was that diabetic patients having well-controlled blood sugar level had less prevalence of dyslipidemia. On enrolment most of the diabetic patients had uncontrolled status (80.7%).

About 87.7% of these patients also had dyslipidemia, while only 60.6% of controlled or well-treated diabetes group had dyslipidemia (p < 0.001) (Fig. 3). This finding

26

Asian Journal of Diabetology, Vol. 16, No. 4, October-December 2013

consolidates the theory that strict control of diabetes itself is very necessary for favorable lipid profile.

The analysis of individual lipid levels shows that the mean levels of all lipids were in abnormal range except serum HDL level (Table 2), which is surprising as it is quite low in many studies on diabetic patients.

There has been a recent focus on the characteristic dyslipidemia of type 2 diabetes, which includes elevated triglycerides, low HDL cholesterol and a preponderance of small dense LDL particles. These characteristics were highly prevalent in diabetic participants in this cohort.

Hypertriglyceridemia (56.1%) and high serum LDL level (57.3%) were noted in large number of patients in our study has been observed in almost all studies done in diabetic patients but the prevalence of these abnormalities is quite high in Gujarati diabetic population in comparison to low serum HDL levels (35.7%) which is considered as one of the major component of diabetes dyslipidemia.

Hypercholesterolemia (36.3%) and high level of serum VLDL (49.7%) were also found in large number of patients (Table 2).

In our study, most of the diabetic patients had mixed dyslipidemia, that is more than one lipid abnormality.

The most common mixed abnormality detected was hypertriglyceridemia and high LDL level (39.1%), which is different from our western counterparts showing hypertriglyceridemia and low serum HDL as major abnormality. The serum LDL levels were not found to be very high in most of these studies as they had used a more relaxed cut-off point of ≥130 for serum LDL.4,5 Individually also these two abnormalities (hypertriglyceridemia and high LDL

CLINICAL STUDY

70 60 50 40 30 20 10 0

80 60 40 20 0 Controlled (n = 33)

S. Cholesterol

S. Triglyceride

Uncontrolled (n = 138) S. HDL

<45

S. LDL S. VLDL

Figure 3. Prevalence of dyslipidemia in patients with controlled and uncontrolled diabetes.

Cholesterol

80

60

60

40

40

20

20 <23 Cholesterol

0

>23 Triglyceride

HDL

LDL

VLDL

Triglyceride

>60 HDL

LDL

VLDL

Figure 4. Age-specific prevalence of different lipid levels.

80

0

45-60

non-HT Cholesterol

Triglyceride

HT HDL

LDL

VLDL

Figure 5. Obesity- specific prevalence of different lipid levels.

Figure 6. Hypertension-specific prevalence of different lipid levels.

level) are considered as major CAD risk factors, so both together can be considered as very critical CAD risk factors in diabetic patients and need very prompt management for the prevention of CAD.

older group (83.9%), which is a very dangerous trend correlating with higher rate of CAD in younger Indian population with statistically insignificant difference (p < 0.5) (Table 1). Hypertriglyceridemia and high LDL levels were observed in all age groups (Fig. 4). Obesity (BMI â&#x2030;Ľ23 as per IDF, modified ATP III criteria for SouthAsian population) better termed as â&#x20AC;&#x2DC;Diabesityâ&#x20AC;&#x2122; is seen in 68.4% of diabetic patients, which is similar to our previous study on prevalence of diabesity in Gujarati population (Fig. 5).9 A very high rate of dyslipidemia (84.6%) was observed in patients with diabesity which suggests that obesity, diabetes and dyslipidemia all major CAD risk factors go hand in hand in Gujarati population. As observed in all other subgroups, hypertriglyceridemia and high LDL levels were also noted in diabesity group. But, more surprisingly even nonobese diabetic patients also had high prevalence of dyslipidemia (75.9%) with similar pattern as obese patients without any statistically significant difference (p < 0.5).

The other types of mixed dyslipidemia observed in our study were: (1) hypercholesterolemia with high LDL level and (2) hypertriglyceridemia with hypercholesterolemia.

All lipid levels were found to be deranged in 10.5% of the diabetic patients, suggesting very high rate of severe form of dyslipidemia in diabetic patients.

So, we suggest not to concentrate on any specific lipid level in Indian diabetic patients but to analyze the complete lipid profile as a whole and to start intensive therapy for the same as early as possible.

We had also done subgroup analysis for dyslipidemia in these patients according to nonmodifiable and modifiable confounding factors that might affect dyslipidemia. Young diabetic patients (<45 years of age) had similar prevalence of dyslipidemia (84.6%) as

Asian Journal of Diabetology, Vol. 16, No. 4, October-December 2013

27

CLINICAL STUDY Table 3. Age, Obesity, HT, Urban/Rural, Specific Prevalence of Dyslipidemia Among Diabetic Males and Females Abnormal lipid level

M/F

Female Total S. triglyceride Male (>150 mg/dl) Female Total

HT

BMI â&#x2030;Ľ 23 (n = 117)

<130/85 (n = 126)

â&#x2030;Ľ 130/85 (n = 41)

8

19

11

6

31

12

26

31

7

3

10

11

3

24

8

16

19

5

11 (42.3%) 29 (32.6%) 22 (39.3%) 9 (27.3%)

55 (39.9%) 20 (37.1%) 42 (35.9%) 50 (39.7%) 12 (29.3%)

13

27

14

11

51

13

41

44

10

6

24

12

6

33

10

32

32

10

19 (50%) 51 (57.3%) 26 (46.4%) 17 (51.5%) 84 (61.6%) 23 (42.6%) 73 (62.4%) 76 (60.3%) 20 (48.8%) 8

19

12

7

29

13

26

28

11

Female

4

9

9

3

20

5

17

12

10

Total

Female Total Male Female Total

12 (46.2%) 28 (31.5%) 21 (37.5%) 10 (30.3%) 49 (35.5%) 18 (33.3%) 43 (36.8%) 40 (31.7%) 21 (51.2%) 10

30

16

9

53

18

38

45

11

4

23

15

6

24

11

31

29

13

14 (53.8%) 53 (59.6%) 31 (55.4%) 15 (45.5%) 77 (55.8%) 29 (53.7%) 69 (59%) 74 (58.7%) 24 (58.5%) 12

26

12

9

44

10

24

41

9

6

18

11

5

26

11

40

26

9

18 (69.2%) 44 (49.4%) 23 (41.1%) 14 (42.4%) 70 (50.7%) 21 (38.9%) 64 (54.7%) 67 (53.2%) 18 (43.9%)

In diabetic hypertensive subgroup of patients, 82.9% of patients had deranged lipid levels, while nonhypertensive DM group also showed similar trend (81.5%) with similar type of dyslipidemia (Fig. 6).

Similarly, urbanized lifestyle was found to have little impact on prevalence and pattern of dyslipidemia in diabetic patients. Both urban and rural diabetic population showed almost 82% prevalence of dyslipidemia. Other confounding factors like smoking and duration of diabetes also failed to show any statistically significant difference (p < 0.5) on prevalence and type of dyslipidemia in diabetic patients. So from the subgroup analysis, it can be interpreted that diabetes itself is responsible for very high rate dyslipidemia as well as for particular pattern of dyslipidemia by mechanism of insulin resistance. Age, duration of diabetes, obesity, hypertension like confounding factors were not able to influence the prevalence and pattern of diabetic dyslipidemia in our study. Only proper control of diabetes has shown statistically significant difference (p < 0.001) on prevalence and severity of dyslipidemia, consolidating the fact that the proper treatment and strict control of diabetes is the most important step in prevention and treatment of complications of diabetes.

28

Obesity

Male

Male S. LDL (>100 mg/dl)

S. VLDL (>32 mg/dl)

Control of DM

<45 years 45-60 years > 60 years Controlled Uncontrolled BMI <23 (n = 26) (n = 89) (n = 56) (n = 33) (n = 138) (n = 54)

S. cholesterol Male (>150 mg/dl)

S. HDL (<40 mg/dl)

Age group

Asian Journal of Diabetology, Vol. 16, No. 4, October-December 2013

As shown in our study, dyslipidemia in diabetes, very critical CAD risk factor has a high prevalence in Gujarati population, but surprisingly only very few diabetic patients (14.3%) were investigated for their lipid profile in past. For this reason, we strongly recommend detailed lipid profile to be done for each and every diabetic patient at the time of diagnosis and regularly on follow-up.

CONCLUSION Our study highlighted the very high prevalence of dyslipidemia associated with diabetes as one of the highest ranked risk factor for CAD in Indians, especially Gujarati population. One or another lipid level is found to be abnormal in most of the diabetic patients, suggesting that whole lipid profile must be done and evaluated at regular intervals in these patients. The present study also highlights the importance of strict control of diabetes in prevention and treatment of dyslipidemia associated with diabetes as dyslipidemia is more frequent in uncontrolled diabetic patients than controlled ones. It is of paramount importance to aim for the stricter goals and specific thresholds for

CLINICAL STUDY dyslipidemia in Indian diabetic patients to start early and prompt preventive measures to reverse the tide of the rising CAD epidemic in Asian Indians.

REFERENCES 1. Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 2010;87(1):4-14.

2. Health situation in the South East Asia Region 1998-2000.

WHO Regional office for South East Asia, New Delhi 2002.

3. American Heart Association. Heart Disease and Stroke Statistics-2008. Update Dallas, Texas: American Heart Association.

4. UK Prospective Diabetes Study 27: Plasma lipids and lipoproteins at diagnosis of NIDDM by age and sex.

Diabetes Care 1997;20(11):1683-7.

5. Cowie CC, Howard BV, Harris MI. Serum lipoproteins in African Americans and whites with non-insulindependent diabetes in the US population. Circulation 1994;90(3):1185-93.

6. Pyŏrälä K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival (4S). Diabetes Care 1997;20(4):614-20.

7. Sacks FM, Pfeffer AM, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and recurrent events trial investigators. N Engl J Med 1996;335(14):1001-9.

8. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279(20):1615-22.

9. Pandya H, Lakhani JD, Patel N. Obesity is becoming synonym for diabetes in rural areas of India also-an alarming situation. Int J Biol Med Res 2011;2(2):556-60.

10. Joshi A, Bhugra P, Lakhani J, Desai S. Body mass index and central obesity in Hypertensive patients. Guj Med Jr 2004;61(3):33-6.

11. Misra A, Pandey RM, Devi JR, Khanna N, Vikram NK, Sharma R. High prevalence of diabetes, obesity and dyslipidemia in urban slum population in northern India.

Int Obes Relat Metab Disord 2001;25:1722-9.

12. Mishra A, Khurana L. Obesity and metabolic syndrome in developing countries. J Clin Endocrinol Metab 2008;93: 59-30.

13. Ramachandran A, Snehalatha C, Satyavani K, Sivasankari S, Vijay V. Metabolic syndrome in urban Asian Indian adults - a population study using modified ATP III criteria.

Diab Res Clin Pract 2003;60(3):199-204.

14. Mohan V, Shanthirani S, Deepa R, Premalatha G, Sastry NG, Saroj R, Chennai Urban Population Study (CUPS No. 4). Intra-urban differences in the prevalence of the metabolic syndrome in southern India-the Chennai Urban Population Study (CUPS No. 4). Diabet Medi 2001;18(4):280-70.

15. Expert panel on detection, evaluation and treatment of high blood cholesterol in adults. Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA 2001;285(19):2486-97.

16. American Diabetes Association. Standards of medical care in diabetes-2007. Diabetes Care 2007;30(Suppl 1):S4-S41.

17. Campos H, Moye LA, Glasser SP, Stampfer MJ, Sacks FM. Low-density lipoprotein size, pravastatin treatment and coronary events. JAMA 2001;286(12):1468-74.

18. Sacks FM, Campos H. Clinical review 163: Cardiovascular endocrinology. Low-density lipoprotein size and cardiovascular disease: a reappraisal. J Clin Endocrinol Metab 2003;88(10):4525-32.

19. Jungner I, Sniderman AD, Furberg C, Aastveit AH, Holme I, Walldius G. Does low-density lipoprotein size add to atherogenic particle number in predicting the risk of fatal myocardial infarction? Am J Cardiol 2006;97(7):943-6.

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29

PRACTICE GUIDELINES

ADA Releases Revisions to Recommendations for Standards of Medical Care in Diabetes MARA LAMBERT

C

aring for patients with diabetes mellitus requires addressing many issues beyond glycemic control. To help physicians provide optimal care for these patients, the American Diabetes Association (ADA) releases annual revisions to its clinical practice recommendations for standards of medical care.

The recommendations include screening, diagnostic, and therapeutic actions that have been shown or are believed to have beneficial outcomes in patients with diabetes. Current criteria for the diagnosis of diabetes are listed in Table 1.

SUMMARY OF REVISIONS The 2011 revisions to the ADA recommendations include small changes related to new evidence released since the previous version. In addition, some sections have undergone major changes. “Detection and Diagnosis of Gestational Diabetes Mellitus” now includes the 75-g oral glucose tolerance test and new diagnostic criteria for gestational diabetes. The new criteria will significantly increase the prevalence of gestational diabetes, mostly because only one abnormal value is needed for a diagnosis instead of two.

These changes were made in response to worldwide increases in obesity and diabetes rates, and with the goal of improving outcomes for women and their infants. “Hypertension/Blood Pressure Control” reflects new evidence emphasizing the importance of setting individual blood pressure goals for each patient. “Nephropathy Screening and Treatment” now includes a table of suggested management options for complications in patients with advanced chronic kidney disease. The “Children and Adolescents” section no longer provides lower limits for A1C targets, and includes a discussion on appropriate individualization and safety. The recommendations specify that glycemic goals in children should be set after weighing the benefits of a lower A1C level against

Source: Adapted from Am Fam Physician. 2012;85(5):514-515.

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Asian Journal of Diabetology, Vol. 16, No. 4, October-December 2013

Table 1. Criteria for the Diagnosis of Diabetes Mellitus A1C ≥ 6.5 percent* Fasting plasma glucose ≥ 126 mg per dL (7.0 mmol per L)† or Two-hour plasma glucose ≥ 200 mg per dL (11.1 mmol per L) during oral glucose tolerance test‡ Random plasma glucose ≥ 200 mg per dL (in patients with classic symptoms of hyperglycemia or hyperglycemic crisis) Results should be confirmed with repeat testing in the absence of unequivocal hyperglycemia *Test should be performed in a laboratory using a method certified by the National Glycohemoglobin Standardization Program and standardized to the Diabetes Control and Complications Trial assay. †Fasting

is defined as no caloric intake for at least eight hours.

‡Test

should be performed as described by the World Health Organization, using a glucose load with the equivalent of 75 g of anhydrous glucose dissolved in water.

the risks of hypoglycemia. Finally, the “Strategies for Improving Patient Care” section reflects growing evidence that supports the effectiveness of restructuring systems of chronic care delivery. To improve care, the recommendations suggest implementing components of the Chronic Care Model and the Patient Centered Medical Home initiative.

DETECTION AND DIAGNOSIS OF GESTATIONAL DIABETES At the first prenatal visit, patients with risk factors should be screened for undiagnosed type 2 diabetes using standard diagnostic criteria. Pregnant women who are not known to have diabetes should be screened for gestational diabetes at 24 to 28 weeks’ gestation with a 75-g oral glucose tolerance test. A diagnosis of gestational diabetes is made if any of the following levels of plasma glucose are exceeded: ≥ 92 mg per dL (5.1 mmol per L) when fasting, 180 mg per dL (10 mmol per L) at one hour, or 153 mg per dL (8.5 mmol per L) at two hours. At six to 12 weeks postpartum,

PRACTICE GUIDELINES women with gestational diabetes should be screened for persistent diabetes. In women with a history of gestational diabetes, lifelong screening for diabetes at least every three years is recommended.

TESTING FOR DIABETES IN ASYMPTOMATIC PATIENTS Physicians should consider testing for type 2 diabetes and assessing the risk of future diabetes in asymptomatic persons of any age who are overweight or obese (i.e., body mass index ≥ 25 kg per m2) and who have one or more additional risk factors for diabetes. In patients with no risk factors, testing should start at 45 years of age.

Appropriate tests include A1C measurement, fasting plasma glucose measurement, or a two-hour 75-g oral glucose tolerance test. Testing should be repeated every three years if results are normal. If patients are found to have an increased risk of future diabetes, physicians should identify and treat risk factors for cardiovascular disease.

PREVENTION/DELAY OF TYPE 2 DIABETES Patients with impaired glucose tolerance, impaired fasting glucose, or an A1C level of 5.7 to 6.4 percent should be referred to an ongoing support program.

Effective support programs should target weight loss of 7 percent of body weight and physical activity of at least 150 minutes of moderate activity (e.g., walking) per week. Because of the potential cost savings of prevention, support programs should be covered by third-party payers.

Follow-up counseling should be performed to improve the chance of successful prevention. Metformin therapy should be considered for the prevention of type 2 diabetes in persons at highest risk, including those with multiple risk factors, especially persons who demonstrate progression of hyperglycemia (e.g., A1C level ≥ 6 percent) despite lifestyle interventions.

Patients with prediabetes should be screened annually for diabetes.

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LIGHTER READING

My mother was dying of leukemia. My two older sisters, father and I had shared the last three weeks in the hospital room with her. In two years, she had gone from a strong matriarch to a helpless invalid.

For the last three days, she had been in a semiconscious state of moaning and lifelessness. She could no longer speak through her dry, swollen lips. Her eyes had the blank void of a moonless midnight. On the night of the third day, I knew what I must do. I must cease being the selfish, clinging son. I sped purposefully to the chapel. There I gave God permission to take my mother. I could no longer stand to see her suffer, so I prayed for the permanent healing that only death can bring.

I returned to the room with a peaceful heart for I knew by the next morning my mother would also be at peace.

I had the best night’s sleep in weeks. The next morning, as the sun broke through the window, I awoke. My first thoughts were, “It’s over”.

But then a noise, a stirring directed my attention from the window to the bed. A small movement made me realize that my mother was still alive. It was all I could do to keep from screaming aloud, “God, how can you do this to me? I became a selfless son, and gave you permission to end this, and you still kept her in her misery.” But before I could have exclaimed this, I was shocked to see that there was more than just a movement.

My mother rolled onto her side, and looked into the glare of the newly risen sun. Then, as the sun made sparkling starbursts in her eyes, she licked her parched lips, and said “Gee, it’s going to be a beautiful day today”. Needless to say this got our attention quickly.

Being the youngest, and fastest, I was first to her bedside. “Mom, it’s me, Jerry, do you recognize me”?

“Of course I do Jerry”, she replied.

We all took our turns talking to her. Other relatives came and were able to talk to her, as she answered not in her old voice, but rather in the voice of a child.

The doctor’s explanation was that the brain stem was being destroyed, accounting for the sudden change. It was a joyous day of laughing, and celebrating life with our family. That night we all went to sleep peacefully.

The next morning, we were awakened to the stirring of

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Asian Journal of Diabetology, Vol. 16, No. 4, October-December 2013

angel’s wings, and my mother was finally healed of her suffering. She had awakened to the Risen Son. The next few days were hectic with funeral plans. It was only after the funeral that I stopped to think of what had happened. If God had answered my prayer, in my time, in my way, my final memories of my mother would have been that of a helpless invalid, with void eyes, lying motionless in a deathbed. Instead, God answered my prayer in his time, in his omniscient way.

Now, my memories of my mother are of a day of laughing and rejoicing. Since that time I have had many rocky roads. Financial failure. A divorce. The loss of my father. But throughout it all, regardless of how stormy the night might be, I know that through God’s love, and perfect timing, I can awaken the next morning to a newly risen sun, or to the Risen Son, and say “Gee, it’s going to be a beautiful day today.”

—Ms Ritu Sinha

Mediocrity knows nothing higher than itself, but talent instantly recognizes genius.

— Sr Arthur Conan Doyle

MAKE SURE

During Medical Practice A 62-year-old diabetic with coronary artery disease, on treatment for the same, came for follow-up.

Oh My God! Why didn’t you put him on antioxidants?

©IJCP Academy

LEARNING PATIENCE WITH GOD

QUOTE

AN INSPIRATIONAL STORY

Lighter Side of Medicine

Make sure to add antioxidants to the prescription because of their free radical scavenging and other beneficial effects.

KK Aggarwal

The Asian Journal of

DIABETOLOGY Information for Authors

Manuscripts should be prepared in accordance with the ‘Uniform requirements for manuscripts submitted to biomedical journals’ compiled by the International Committee of Medical Journal Editors (Ann. Intern. Med. 1992;96: 766-767).

Indian Journal of Clinical Practice strongly disapproves of the submission of the same articles simultaneously to different journals for consideration as well as duplicate publication and will decline to accept fresh manuscripts submitted by authors who have done so.

The boxed checklist will help authors in preparing their manuscript according to our requirements. Improperly prepared manuscripts may be returned to the author without review. The checklist should accompany each manuscript.

Authors may provide on the checklist, the names and addresses of experts from Asia and from other parts of the World who, in the authors’ opinion, are best qualified to review the paper.

Covering letter –

– –

The covering letter should explain if there is any deviation from the standard IMRAD format (Introduction, Methods, Results and Discussion) and should outline the importance of the paper.

Principal/Senior author must sign the covering letter indicating full responsibility for the paper submitted, preferably with signatures of all the authors.

Articles must be accompanied by a declaration by all authors stating that the article has not been published in any other Journal/Book. Authors should mentioned complete designation and departments, etc. on the manuscript.

Manuscript – Three complete sets of the manuscript should be submitted and preferably with a CD; typed double spaced throughout (including references, tables and legends to figures).

–

The manuscript should be arranged as follow: Covering letter, Checklist, Title page, Abstract, Keywords (for indexing, if required), Introduction, Methods, Results, Discussion, References, Tables, Legends to Figures and Figures.

–

All pages should be numbered consecutively beginning with the title page.

Note: Please keep a copy of your manuscript as we are not responsible for its loss in the mail. Manuscripts will not be returned to authors.

Title page Should contain the title, short title, names of all the authors (without degrees or diplomas), names and full location of the departments and institutions where the work was performed,

name of the corresponding authors, acknowledgment of financial support and abbreviations used.

– The title should be of no more than 80 characters and should represent the major theme of the manuscript.

A subtitle can be added if necessary.

– A short title of not more than 50 characters (including inter-word spaces) for use as a running head should be included.

– The name, telephone and fax numbers, e-mail and postal addresses of the author to whom communications are to be sent should be typed in the lower right corner of the title page.

– A list of abbreviations used in the paper should be included. In general, the use of abbreviations is discouraged unless they are essential for improving the readability of the text.

Summary – The summary of not more than 200 words. It must convey the essential features of the paper.

– It should not contain abbreviations, footnotes or references.

Introduction – The introduction should state why the study was carried out and what were its specific aims/objectives.

Methods – These should be described in sufficient detail to permit evaluation and duplication of the work by others.

– Ethical guidelines followed by the investigations should be described.

Statistics The following information should be given: – The statistical universe i.e., the population from which the sample for the study is selected.

– Method of selecting the sample (cases, subjects, etc. from the statistical universe).

– Method of allocating the subjects into different groups.

– Statistical methods used for presentation and analysis of data i.e., in terms of mean and standard deviation values or percentages and statistical tests such as Student’s ‘t’ test, Chi-square test and analysis of variance or non-parametric tests and multivariate techniques.

–

Confidence intervals for the measurements should be provided wherever appropriate.

Results – These should be concise and include only the tables and figures necessary to enhance the understanding of the text.

Asian Journal of Diabetology, Vol. 16, No.4, October-December 2013

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Discussion –

This should consist of a review of the literature and relate the major findings of the article to other publications on the subject. The particular relevance of the results to healthcare in India should be stressed, e.g., practicality and cost.

References These should conform to the Vancouver style. References should be numbered in the order in which they appear in the texts and these numbers should be inserted above the lines on each occasion the author is cited (Sinha12 confirmed other reports13,14...). References cited only in tables or in legends to figures should be numbered in the text of the particular table or illustration. Include among the references papers accepted but not yet published; designate the journal and add ‘in press’ (in parentheses). Information from manuscripts submitted but not yet accepted should be cited in the text as ‘unpublished observations’ (in parentheses).

At the end of the article the full list of references should include the names of all authors if there are fewer than seven or if there are more, the first six followed by et al., the full title of the journal article or book chapters; the title of journals abbreviated according to the style of the Index Medicus and the first and final page numbers of the article or chapter. The authors should check that the references are accurate. If they are not this may result in the rejection of an otherwise adequate contribution.

Examples of common forms of references are: Articles Paintal AS. Impulses in vagal afferent fibres from specific pulmonary deflation receptors. The response of those receptors to phenylguanide, potato S-hydroxytryptamine and their role in respiratory and cardiovascular reflexes.

Q. J. Expt. Physiol. 1955;40:89-111.

Books Stansfield AG. Lymph Node Biopsy Interpretation Churchill Livingstone, New York 1985.

Articles in Books Strong MS. Recurrent respiratory papillomatosis. In: Scott Brown’s Otolaryngology. Paediatric Otolaryngology Evans JNG (Ed.), Butterworths, London 1987;6:466-470.

Tables –

These should be typed double spaced on separate sheets with the table number (in Roman Arabic numerals) and title above the table and explanatory notes below the table.

Legends – These should be typed double spaces on a separate sheet and figure numbers (in Arabic numerals) corresponding with the order in which the figures are presented in the text.

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The legend must include enough information to permit interpretation of the figure without reference to the text.

Asian Journal of Diabetology, Vol. 16, No. 4, October-December 2013

Figures – Two complete sets of glossy prints of high quality should be submitted. The labelling must be clear and neat.

– All photomicrographs should indicate the magnification of the print.

– Special features should be indicated by arrows or letters which contrast with the background.

– The back of each illustration should bear the first author’s last name, figure number and an arrow indicating the top. This should be written lightly in pencil only. Please do not use a hard pencil, ball point or felt pen.

– Color illustrations will be accepted if they make a contribution to the understanding of the article.

–

Do not use clips/staples on photographs and artwork.

–

Illustrations must be drawn neatly by an artist and photographs must be sent on glossy paper. No captions should be written directly on the photographs or illustration. Legends to all photographs and illustrations should be typed on a separate sheet of paper. All illustrations and figures must be referred to in the text and abbreviated as “Fig.”.

Please complete the following checklist and attach to the manuscript: 1. Classification (e.g. original article, review, selected summary, etc..)_____________________________ 2. Total number of pages _______________________ 3. Number of tables ___________________________ 4. Number of figures __________________________ 5. Special requests ___________________________ 6.

Suggestions for reviewers (name and postal address) Indian 1.___________ Foreign 1.______________

2.___________ 2.______________

3.___________ 3.______________

4.___________ 4.______________ 7. All authors’ signatures_______________________ 8. Corresponding author’s name, current postal and e-mail address and telephone and fax numbers ___________________________________________ ___________________________________________ ___________________________________________

For Editorial Correspondence Dr K.K. Aggarwal Group Editor-in-Chief

Asian Journal of Diabetology

E-219, Greater Kailash, Part-1 New Delhi - 110 048 E-mail: editorial@ijcp.com, Website: www.ijcpgroup.com