Early Intervention to Prevent and Treat Type 2 Diabetes

Transcription

1 endocrinology Board Review Manual Statement of Editorial Purpose The Hospital Physician Endocrinology Board Review Manual is a study guide for fellows and practicing physicians preparing for board examinations in endocrinology. Each manual reviews a topic essential to the current practice of endocrinology. PUBLISHING STAFF PRESIDENT, Group PUBLISHER Bruce M. White editorial director Debra Dreger assistant EDITOr Farrawh Charles executive vice president Barbara T. White executive director of operations Jean M. Gaul PRODUCTION Director Suzanne S. Banish PRODUCTION assistant Nadja V. Frist ADVERTISING/PROJECT director Patricia Payne Castle sales & marketing manager Deborah D. Chavis NOTE FROM THE PUBLISHER: This publication has been developed without involvement of or review by the American Board of Internal Medicine. Early Intervention to Prevent and Treat Type 2 Diabetes Editor: Stephen A. Brietzke, MD, FACP, FACE Associate Professor of Clinical Medicine, Division of Endocrinology, Department of Medicine, University of Columbia Missouri, Columbia, MO Contributors: Shilpa H. Jain, MD Fellow in Endocrinology, Department of Endocrinology, Brigham and Women s Hospital/Harvard Medical School, Boston, MA Annaswamy Raji, MD, MMSc Assistant Professor of Medicine, Department of Endocrinology, Brigham and Women s Hospital/Harvard Medical School, Boston, MA Table of Contents Introduction Case 1: A Patient with Prediabetes Case 2: A Patient with Newly Diagnosed Type 2 Diabetes Conclusion References Cover Illustration by Christine Armstrong Copyright 2008, Turner White Communications, Inc., Strafford Avenue, Suite 220, Wayne, PA ,. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of Turner White Communications. The preparation and distribution of this publication are supported by sponsorship subject to written agreements that stipulate and ensure the editorial independence of Turner White Communications. Turner White Communications retains full control over the design and production of all published materials, including selection of topics and preparation of editorial content. The authors are solely responsible for substantive content. Statements expressed reflect the views of the authors and not necessarily the opinions or policies of Turner White Communications. Turner White Communications accepts no responsibility for statements made by authors and will not be liable for any errors of omission or inaccuracies. Information contained within this publication should not be used as a substitute for clinical judgment. Endocrinology Volume 7, Part 2

2 Endocrinology Board Review Manual Early Intervention to Prevent and Treat Type 2 Diabetes Shilpa H. Jain, MD, and Annaswamy Raji, MD, MMSc INTRODUCTION Diabetes mellitus is a global epidemic and a growing public health problem. The worldwide prevalence of diabetes is projected to increase from an estimated 171 million (2.8%) in 2002 to 366 million (4.4%) in The proportion of the U.S. population affected by diabetes is even greater. Based on data from the National Health and Nutrition Examination Survey (NHANES), 9.3% of those aged 20 years or older (19.3 million, 2002 U.S. population) had diagnosed or undiagnosed diabetes, and an additional 20.6% had impaired fasting glucose (IFG). 2 Diabetes was the sixth leading cause of death in the United States in The complications of the disease including heart disease, hypertension, stroke, blindness, renal disease, and peripheral neuropathy contribute significantly to the morbidity and mortality associated with diabetes. The risk of death is roughly double in people with versus without diabetes. 3 The economic impact of diabetes also is enormous, with total (direct and indirect) costs estimated at $132 billion in In response to the clinical and economic burden of the diabetes epidemic, national guidelines call for strategies to prevent diabetes whenever possible and to intervene aggressively with treatment for those who develop the disease. This manual uses 2 case examples to examine the rationale for early, aggressive action on behalf of patients at risk for diabetes and its complications. Although this manual refers to prevention of diabetes, it is important to acknowledge that diabetes prevention trials have shown that most interventions delay rather than prevent diabetes or reverse its pathophysiology. CASE 1: A PATIENT WITH PREDIABETES CASE PRESENTATION A 45-year-old Hispanic woman is referred by her family physician to an endocrinologist for evaluation of prediabetes. The referral was prompted by a recent set of blood tests that revealed a fasting blood glucose level of 95 mg/dl. The patient has a history of gestational diabetes, and both her parents have type 2 diabetes. Since the delivery of her last child, the patient has been unable to lose weight. Her primary care physician had recommended decreasing the carbohydrate content in her meals and increasing her physical activity. However, she has been unsuccessful in making significant changes over the past year. Because of the family s tight budget, rice and beans are the staple diet. Also, after working a full day at her desk job, doing household chores, and taking care of her children, the patient cannot find time for exercise. On the weekends, she tries to walk in her neighborhood. Currently, she takes no medication and does not drink alcohol or smoke. The patient is obese, with a body mass index (BMI) of 36 kg/m 2. She has central adiposity. Blood pressure is 125/80 mm Hg, and heart rate is 72 bpm. Acanthosis nigricans is noted at the back of the neck and in the axilla. Cardiovascular examination is normal. The remainder of the physical examination is unremarkable. An oral glucose tolerance test (OGTT) and fasting lipid profile are ordered and reveal the following: Fasting glucose, 98 mg/dl (normal, mg/dl) Glucose at 2 hours, 160 mg/dl (normal, < 140 mg/dl) Total cholesterol, 194 mg/dl (normal, mg/dl) Low-density lipoprotein (LDL) cholesterol, 120 mg/dl (normal, mg/dl) High-density lipoprotein (HDL) cholesterol, 38 mg/dl (normal, mg/dl) Triglycerides, 180 mg/dl (normal, mg/dl) Do these findings warrant concern? Is aggressive intervention indicated? This patient is at high risk for developing type 2 diabetes. She meets criteria for the diagnosis of impaired glucose tolerance (IGT), which indicates a state of declining pancreatic beta cell function. In addition, she has Hospital Physician Board Review Manual

3 several risk factors for type 2 diabetes. Without aggressive intervention, progression to diabetes is inevitable. A comprehensive assessment of diabetes risk factors, education about preventing diabetes and its complications, and interventions targeting the underlying mechanisms of glucose dysregulation are indicated for this patient. Although beyond the scope of this discussion, the patient s high lipid levels should also be addressed. In assessing risk for developing type 2 diabetes, it is important to investigate all possible risk factors to best gauge the level of risk in an individual patient. The case patient, for example, had diabetes while she was pregnant and has a strong family history of diabetes, in addition to being obese and physically inactive. Patients at such high risk require the most aggressive approach to preventing the onset of diabetes. For example, although the case patient has been unsuccessful in making lifestyle changes, the goal of patient education would be to emphasize the importance of making these changes and to encourage the patient to find even small ways to incorporate these changes into her life. RATIONALE FOR EARLY INTERVENTION TO PREVENT DIABETES For individuals born in the United States in 2000, the estimated lifetime risk of developing diabetes is 33% for men and 39% for women. 5 Current estimates indicate that type 2 diabetes accounts for 90% to 95% of all diagnosed cases of diabetes. 3 Identifying at-risk individuals prior to the onset of disease and targeting risk factors that promote insulin resistance are integral to the prevention of type 2 diabetes. Easily recognizable risk factors include obesity, sedentary lifestyle, 1 or more first-degree relatives with type 2 diabetes, non-caucasian ethnicity, and medical conditions associated with insulin resistance (ie, gestational diabetes, polycystic ovary syndrome). 6 When insulin resistance is accompanied by failure of pancreatic beta cells to hypersecrete insulin, compensation for insulin resistance falters and blood glucose rises, heralding the onset of IGT and, ultimately, diabetes. IGT is defined as a plasma glucose level between 140 and 199 mg/dl 2 hours after a 75-g glucose challenge (OGTT). IFG is defined as a fasting plasma glucose level between 100 and 125 mg/dl. The majority of patients with IFG and/or IGT develop type 2 diabetes Therefore, individuals with IGT and IFG are now considered to have prediabetes. Inflammatory markers such as C-reactive protein and interleukin-6 may identify patients at especially high risk for both diabetes and cardiovascular disease. 13,14 Multiple epidemiologic studies have shown that IFG and especially IGT predict increased risk for cardiovascular disease. 15,16 IFG and IGT are associated with different pathophysiology. In IFG, the liver is the major site of insulin resistance; in IGT, skeletal muscle is the major site of insulin resistance. 17 Both IFG and IGT have reduced first-phase insulin secretion in response to a meal, but in IGT there may also be a decreased late-phase insulin response. IGT and IFG can exist independently. Therefore, it is important to check plasma glucose levels as well as do an OGTT to rule out the possibility of prediabetes in high-risk individuals. Can lifestyle interventions lower the risk of type 2 diabetes? BENEFITS OF WEIGHT LOSS AND EXERCISE The rising prevalence of obesity and sedentary lifestyle has helped to fuel the diabetes epidemic. Unlike race or genetic predisposition, obesity and physical inactivity are major risk factors for type 2 diabetes that can be modified. Indeed, interventions that promote weight loss and increase physical activity have proved to be the most effective strategies for preventing type 2 diabetes. In the Finnish Diabetes Prevention Study, 522 overweight participants with IGT were randomized to an intervention of individualized diet and exercise counseling or to usual care. 8 The goals for the intervention group were a reduction in weight of at least 5%, a decrease in fat intake to less than 30% of total calories, a decrease in saturated fat intake to less than 10% of total calories, an increase in fiber intake to at least 15 g per 1000 kcal, and a daily dose of at least 30 minutes of moderately intense physical activity. After 4 years, there was a 58% risk reduction in diabetes in the intervention group compared with the usual care group. Study participants who did not develop diabetes were followed for an additional 3 years. 18 Without receiving any further counseling on lifestyle modifications, a 43% reduction in relative risk of diabetes was maintained over the 3-year period (for a total of 7 years) in the intervention group. The Diabetes Prevention Program demonstrated that lifestyle changes were superior to pharmacotherapy with metformin in reducing the risk of developing type 2 diabetes. 9 More than 3000 ethnically diverse patients with IGT or IFG were randomized to an intensive program of lifestyle modification, standard lifestyle recommendations plus metformin 850 mg twice daily, or standard lifestyle recommendations plus placebo. The goals for the intensive lifestyle modification group were 7% weight loss and 150 minutes of physical activity per week. Patients in the intensive lifestyle modification group lost significantly more weight and participated in more physical activity as compared with both the metformin and placebo groups Endocrinology Volume 7, Part 2

4 Change in physical activity, MET-hr/wk Change in weight, kg A B Medication adherence, % C Metformin Metformin Placebo Placebo Placebo Lifestyle Metformin Lifestyle Time, yr Figure 1. Changes in body weight (A) and leisure physical activity (B) and adherence to medication regimen (C) in the Diabetes Prevention Program, according to study group. Each data point represents the mean value for all participants examined at that time. The number of participants decreased over time because of the variable length of time that persons were in the study. For example, data on weight were available for 3085 persons at 0.5 year, 3064 at 1 year, 2887 at 2 years, and 1510 at 3 years. Changes in weight and leisure physical activity over time differed significantly among the treatment groups (P < for each comparison). MET = metabolic equivalents. (Adapted with permission from Knowler WC, Barrett- Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. Diabetes Prevention Program Research Group. N Engl J Med 2002;346:396. Copyright 2002 Massachusetts Medical Society. All rights reserved.) (Figure 1). After an average follow-up of 2.8 years, intensive lifestyle changes decreased the incidence of diabetes by 58% and decreased fasting blood glucose by 63%, as compared with placebo. Lifestyle modifications were also more cost-effective than metformin. From a societal perspective, compared with metformin, intensive lifestyle interventions cost $10,000 less to prevent 1 case of diabetes and $47,600 less for each quality-adjusted life-year. 19 In these clinical trials, recommendations for specific lifestyle interventions were accompanied by regular, time-intensive counseling personalized for each patient. Through individualized coaching on how to improve their diet and increase their physical activity, patients were able to lose weight. As these trials demonstrated, even modest reduction in weight significantly reduces the incidence of type 2 diabetes. 8,9 Ideal body weight does not need to be attained to prevent diabetes. Furthermore, physical activity, even without weight loss, can reduce insulin resistance, as exercise increases insulin-mediated glucose uptake and promotes glycogen synthesis. 20 Given that nonpharmacologic interventions are highly effective, is there a rationale for considering pharmacologic measures to prevent diabetes? Like the case patient, many patients seen in clinical practice attempt lifestyle changes but have difficulty achieving and maintaining the goals of these interventions. Adopting and adhering to a healthy diet and a regimen of regular physical activity can be challenging for many patients. The degree of individualized diet and exercise counseling achieved in clinical trials has not yet proven feasible in routine clinical care settings. Not surprisingly, the results of lifestyle intervention trials have not been replicated in clinical practice. Although no medication has proven to be as effective or as well tolerated as lifestyle interventions, pharmacologic treatments may be an option for delaying the onset of type 2 diabetes. The U.S. Food and Drug Administration has not approved the use of any medication for this purpose, but clinical trials have suggested that a few pharmacologic interventions may help to reduce the risk of type 2 diabetes. Regardless of whether or not a medication is tried, it is important to continue to emphasize the importance of lifestyle changes and to encourage efforts to lose weight and increase physical activity. What pharmacologic agents have been evaluated for reducing the risk of type 2 diabetes? INSULIN-SENSITIZING AGENTS Metformin In the Diabetes Prevention Program, metformin 850 mg twice daily reduced the incidence of diabetes (7.8 cases/100 person-years versus 11 cases/100 personyears in the placebo group, or 31%), although not as significantly as the intensive dietary and exercise counseling intervention (4.8 cases/100 person-years, or 58% compared with placebo; Figure 2). 9 Subgroup analysis revealed that metformin was most effective in young (age < 60 years) and obese (BMI 35 kg/m 2 ) patients with fasting plasma glucose levels of 110 to 125 mg/dl. Metformin decreased fasting blood glucose by 48% (compared with 63% for the intensive lifestyle group). In treating IGT, metformin was not nearly as effective as lifestyle interventions. Metformin was associated with a significantly higher rate of gastrointestinal (GI) symptoms, but there Hospital Physician Board Review Manual

5 were no differences in rates of hospitalization or mortality compared with lifestyle intervention and placebo. 8 Acarbose In the STOP-NIDDM trial, approximately 1400 patients with IGT and IFG were randomized to acarbose 100 mg or placebo 3 times daily. 21 All patients were encouraged to maintain or lose weight with diet and regular exercise. Intention-to-treat analysis revealed that acarbose decreased the progression from prediabetes to diabetes by 25% over 3.3 years, even though 25% of patients in the acarbose group discontinued the medication due to GI side effects. Thirty-two percent of acarbose-treated patients developed diabetes compared with 42% of placebo-treated patients. Thiazolidinediones Use of thiazolidinediones (TZDs) for diabetes prevention has been studied in various populations In the TRIPOD (Troglitazone In Prevention Of Diabetes) trial, troglitazone decreased the risk of diabetes by approximately 50% in Hispanic women with a history of gestational diabetes. 22 However, troglitazone was associated with significant hepatotoxicity, which prompted its withdrawal from the market. Women in the TRIPOD study who had not developed diabetes were then recruited for the PIPOD (Pioglitazone In Prevention Of Diabetes) study, which demonstrated that treatment with pioglitazone 45 mg daily continued to prevent the development of diabetes. 23 In the DREAM (Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication) trial, more than 5000 overweight patients with IGT (plasma glucose, mg/dl) and/or IFG (plasma glucose, mg/dl) without cardiovascular disease were randomized to rosiglitazone (titrated to 8 mg daily), ramipril (to 15 mg daily), both, or placebo. 24,25 After a median of 3 years, rosiglitazone reduced the composite outcome of incident diabetes or death by 60% and increased the likelihood of regression to normal fasting glucose and glucose tolerance by 70% to 80% as compared with placebo. 24 Ramipril did not significantly reduce the risk of death or diabetes; however, it led to normoglycemia in a small number of patients. 25 The combination of rosiglitazone and ramipril had no apparent benefit. The effect of rosiglitazone on glucose metabolism demonstrated in the DREAM trial should be viewed cautiously. The median fasting plasma glucose level and median 2-hour post-glucose load level at study entry were close to normal glycemic targets. Furthermore, rosiglitazone was associated with a significantly higher prevalence of peripheral edema, a 2.2-kg greater body Cumulative incidence of diabetes, % Placebo Metformin Lifestyle Year Figure 2. Cumulative incidence of diabetes according to study group. At 3 years, the cumulative incidence of diabetes was 29% in the placebo group, 22% in the metformin group, and 14% in the intensive lifestyle intervention group. The cumulative incidence rates differed significantly among the 3 groups (P < for each comparison). (Adapted with permission from Knowler WC, Barrett- Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. Diabetes Prevention Program Research Group. N Engl J Med 2002;346:397. Copyright 2002 Massachusetts Medical Society. All rights reserved.) weight, and, importantly, an increased frequency of heart failure. 24 In addition, a recent meta-analysis of clinical trials involving rosiglitazone and an interim analysis of data from the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes) study raised concern of an increased risk for myocardial infarction (MI) and death from cardiovascular disease associated with rosiglitazone use. 26,27 Due to ongoing controversy and concern regarding use of rosiglitazone, caution should be used when prescribing the drug for individual patients. Summary The Table provides an indirect comparison of interventions to prevent type 2 diabetes (ie, lifestyle interventions, metformin, acarbose, and rosiglitazone). 24 Although rosiglitazone was the most effective in preventing type 2 diabetes, its significant safety concerns bar its use for prevention of a disease that has not yet developed, particularly when there are safer and less costly options available. 28 Use of acarbose is limited by poor patient adherence. Metformin was recommended by a panel of experts convened by the American Diabetes Association (ADA) in patients with IFG and/or IGT, if any of the following features applies: age younger than 60 years, BMI of 35 kg/m 2 or greater, family history of diabetes in first-degree relatives, high triglyceride level, Endocrinology Volume 7, Part 2

6 Table. Interventions to Prevent Type 2 Diabetes Intervention Variable Lifestyle Metformin Acarbose Rosiglitazone Trial FDPS 8,18 DPP 9 DPP 9 STOP NIDDM 21 DREAM 24 Mean follow-up, yr Patient characteristics Mean age, yr Body mass index, kg/m Outcomes Weight change, kg* Relative reduction in occurrence of 58 (30 70) 58 (48 66) 31 (17 43) 25 (10 37) 62 (56 67) type 2 diabetes (95% CI), % Adverse events None Musculoskeletal symptoms GI symptoms GI symptoms Peripheral edema, weight gain, heart failure Persistence of effect Confirmed Pending Pending No Pending NOTE: Enrollment criteria for all trials included impaired fasting glucose, impaired glucose tolerance, or both. CI = confidence interval; DPP = Diabetes Prevention Program; DREAM = Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication; FDPS = Finnish Diabetes Prevention Study; GI = gastrointestinal; STOP NIDDM = Study to Prevent Non Insulin-Dependent Diabetes Mellitus. (Adapted with permission from Nathan DM, Berkwits M. Trials that matter: rosiglitazone, ramipril, and the prevention of type 2 diabetes [editorial]. Ann Intern Med 2007;146:462.) *All estimates are mean weight change relative to within-group baseline except for rosiglitazone, which is mean weight change relative to placebo. Reduction in hazard (1.0 hazard ratio); acarbose estimate adjusted for age, sex, and body mass index. Absolute percentage difference (drug placebo). low HDL cholesterol level, hypertension, or hemoglobin A 1c ( ) greater than 6%. 29 TREATMENT FOR OBESITY When lifestyle interventions are not effective in promoting weight loss, anti-obesity medications may be considered. Orlistat 30,31 and sibutramine 32,33 have been effective in achieving modest weight loss. Additionally, orlistat, when accompanied by lifestyle changes, resulted in a greater reduction in the incidence of type 2 diabetes over 4 years and produced greater weight loss than was observed in a control group in a clinically representative obese population. 30 New pharmacologic agents in development are focused on inhibition of nutrient absorption, enhancement of satiety, and alteration of metabolism or energy balance. 34 Bariatric surgery is an option for patients with a BMI of 40 kg/m 2 or greater who are without comorbidities or for patients with a BMI of 35 kg/m 2 or greater who have significant comorbidities (eg, hypertension, type 2 diabetes, dyslipidemia, sleep apnea). CASE CONCLUSION The endocrinologist informs the patient that, while she does not have diabetes, her blood sugar levels are high and likely to increase to the level of diabetes unless they do something to intervene. The physician recommends that they begin by making a serious effort at lifestyle changes, with the primary goal of a 10% weight loss over the next 6 months achieved by diet and increased physical activity. She emphasizes that even modest weight loss will decrease the patient s risk of developing diabetes. The physician helps the patient identify ways to incorporate 150 minutes of physical activity per week into her daily life. She also refers the patient to a nutritionist to help identify ways to decrease calories, reduce dietary fat, and increase fiber intake. Over the next 6 months, the patient makes an effort to change her diet and find time for exercise. She loses 8 lb (roughly a 4% decrease) but is unable to achieve her weight loss goal. The endocrinologist discusses the possibility of the patient starting metformin at 850 mg twice daily. She stresses that the patient s young age, obesity, family history of diabetes, and dyslipidemia make her a good candidate for metformin. The patient is unsure and promises to work harder to lose weight. At her next follow-up visit 3 months later, the patient is proud to report that she has engaged her entire family in a lifestyle makeover. She has lost another 9 lb and has begun walking 40 minutes every morning before work. The endocrinologist congratulates the patient on her achievements and encourages her to keep up the good work. She is returned to the care of her family physician for follow-up, with a plan for periodic visits with the endocrinologist as needed. Hospital Physician Board Review Manual

7 CASE 2: A PATIENT WITH NEWLY DIAGNOSED TYPE 2 DIABETES CASE PRESENTATION A 52-year-old African-American man is referred to an endocrinologist for evaluation of newly diagnosed type 2 diabetes. The patient has a history of hypertension, hyperlipidemia, and osteoarthritis. His medications include hydrochlorothiazide 25 mg daily, atorvastatin 20 mg daily, aspirin 81 mg daily, and acetaminophen as needed. The patient denies polyuria, polydipsia, chest pain, shortness of breath, or swelling of the lower extremities. His diet consists of fried chicken, hamburgers, and frequent snacking with potato chips. He does not exercise regularly due to his arthritis. With the new diagnosis of diabetes, he has recently stopped smoking, after a 30 pack-year history. He drinks alcohol occasionally. Both of his parents had type 2 diabetes, and his father was diagnosed with coronary artery disease at age 55 years. The patient is overweight with a BMI of 29 kg/m 2. Blood pressure is 130/80 mm Hg, and heart rate is 80 bpm. Capillary fingerstick glucose testing reveals a blood glucose level of 215 mg/dl. Mild acanthosis nigricans is noted on physical examination. There is no appreciable retinopathy and no thyromegaly. Cardiovascular examination reveals decreased distal pulses. Neurologic examination reveals absent Achilles reflex, but sensation to 10-g monofilament testing is intact. Foot examination is normal, with no ulcerations. Laboratory tests are ordered and reveal the following:, 8.2% Fasting plasma glucose, 190 mg/dl (normal, mg/dl) Urine microalbumin/creatinine ratio, 25 mg albumin/g creatinine (normal, 0 30 mg/g) Serum creatinine, 1.3 mg/dl (normal, mg/dl) Estimated glomerular filtration rate, 90 ml/min/1.73 m 2 Total cholesterol, 165 mg/dl (normal, mg/dl) LDL cholesterol, 95 mg/dl (normal, mg/dl) HDL cholesterol, 42 mg/dl (normal, mg/dl) Triglycerides, 140 mg/dl (normal, mg/dl) Total bilirubin, 1.0 mg/dl (normal, mg/dl) Alanine aminotransferase, 25 U/L (normal, U/L) Aspartate aminotransferase, 22 U/L (normal, U/L) Alkaline phosphatase, 110 U/L (normal, U/L) Thyroid-stimulating hormone, 2.3 miu/l (normal, miu/l) Is aggressive diabetes treatment indicated for this patient? What are the current recommended goals for treating adults with type 2 diabetes? RATIONALE FOR AGGRESSIVE TREATMENT OF TYPE 2 DIABETES Type 2 diabetes occurs when beta cells cannot secrete compensatory quantities of insulin sufficient to overcome peripheral insulin resistance. Prior to onset of diabetes, beta cells compensate for the insulin resistance by increasing insulin production. However, over time, beta cell function declines, insulin secretion is impaired, and hyperglycemia ensues. Once diabetes has developed, the goal is to prevent long-term complications, such as retinopathy, nephropathy, neuropathy, and atherosclerosis. Aggressive glucose-lowering has been shown to decrease microvascular complications of diabetes. In type 2 diabetes, the Kumamoto study was the first to examine the impact of glycemic control on diabetes-related complications. 35 The study enrolled 110 Japanese patients with type 2 diabetes and randomized patients to multiple daily insulin injections or conventional once- or twicedaily insulin injections. At 6 years, mean was 7.1% in the multiple insulin injection group and 9.4% in the conventional group. The lower with the multiple injection regimen was associated with a 69% risk reduction in worsening of retinopathy and a 70% risk reduction in the progression of nephropathy. This risk reduction in microvascular complications was similar to the results observed in the Diabetes Control and Complications Trial, which enrolled patients with type 1 diabetes. 36 The U.K. Prospective Diabetes Study (UKPDS) also demonstrated that aggressive glycemic control reduces microvascular complications in patients with type 2 diabetes. 37 Approximately 4000 patients with newly diagnosed type 2 diabetes were randomized to intensive glycemic control with a sulfonylurea or insulin or to conventional glycemic control with diet only. In the conventional group, if patients developed hyperglycemic symptoms or markedly elevated fasting plasma glucose, medications were added. At 10 years, median was significantly lower in the intensive treatment group compared with the conventional group (7.0% versus 7.9%, respectively). Improved glycemic control was associated with a 25% risk reduction in microvascular complications and a 6% Endocrinology Volume 7, Part 2

8 Adjusted incidence/1000 person-yr, % Myocardial infarction Microvascular endpoints peak postprandial capillary plasma glucose less than 180 mg/dl, blood pressure less than 130/80 mm Hg, LDL cholesterol less than 100 mg/dl, triglyceride level less than 150 mg/dl, and HDL cholesterol greater than 40 mg/dl. 6 CASE CONTINUED The patient expresses a preference to avoid taking any medications to control his diabetes, and he asks whether he can get good results from diet and exercise. He acknowledges his bad eating habits, but he feels that, if he can quit smoking, he can fix his diet. He also asks about exercise options that will not aggravate his arthritis. What is the role of lifestyle interventions in treating type 2 diabetes? What specific lifestyle interventions should be recommended for this patient? Updated mean, % Figure 3. Micro- and macrovascular complication rates reported in the U.K. Prospective Diabetes Study. Incidence rates and 95% confidence intervals for myocardial infarction and microvascular complications are shown by category of updated mean hemoglobin A 1c ( ) concentration at mean duration of diabetes of 10 years, adjusted for age, sex, and ethnic group. (Adapted from 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;321:407. Copyright 2000, with permission from BMJ Publishing Group.) reduction in all-cause mortality. There was no significant difference in macrovascular outcomes between the intensive treatment group and the conventional group. Further analysis of UKPDS data revealed a correlation between and risk of microvascular and macrovascular complications. 38 The incidence of microvascular disease and MI increased with level (Figure 3). Other studies have also noted an association between glycemic control and macrovascular disease. 39,40 To date, pharmacologic lowering of has not been shown to reduce the incidence of cardiovascular disease in type 2 diabetes. However, prospective trials studying the impact of aggressive glycemic control on cardiovascular disease in type 2 diabetes are underway. 41,42 GOALS OF TREATMENT The ADA recommends the following goals for treatment of adults with type 2 diabetes: less than 7.0%, preprandial capillary plasma glucose of 70 to 130 mg/dl, NONPHARMACOLOGIC TREATMENT In patients with type 2 diabetes, moderate weight loss of 5% of body weight has been associated with improved insulin sensitivity, a more favorable lipid profile, and reduction in blood pressure. 43 Nutritional interventions appear to have more of an impact on weight loss, whereas regular physical activity is important for weight maintenance. 44 Medical nutrition therapy has been shown to reduce by 1% to 2%. 43 The ADA nutritional recommendations include reducing total calories, limiting fat to less than 30% of total calories with less than 7% of total calories from saturated fats (minimizing trans fats), reducing dietary cholesterol to less than 200 mg/day, assuring adequate fiber intake, and consuming at least 2 servings of fish per week. 45 Although low-carbohydrate diets can lead to significant short-term weight loss, 46,47 restriction of carbohydrates to less than 130 g/day is not recommended in patients with type 2 diabetes due to unknown long-term side effects. 45 Low-fat diets produce a similar amount of long-term weight loss as low-carbohydrate diets. 48 Carbohydrates are an important source of energy, fiber, vitamins, and minerals. Choosing carbohydrates with a lower glycemic index (eg, high-fiber fruits and vegetables) may improve glycemic control and lipid profiles. 49,50 Two meta-analyses showed that regular exercise can decrease by 0.6% to 0.7%, independent of weight loss. 51,52 Trials included in these meta-analyses were at least 8 weeks in duration and assessed exercise at different levels of intensity. Regular physical activity has also been associated with lower risk of cardiovascular disease in patients with diabetes. 53 The ADA recommends at Hospital Physician Board Review Manual

9 least 150 minutes per week of moderate activity and/or at least 90 minutes per week of vigorous aerobic exercise in order to help with weight maintenance, improve glycemic control, and prevent cardiovascular disease. 54 For the case patient, whose current is 8.2%, lifestyle interventions may be sufficient to reduce his to the recommended level (< 7%). This patient would benefit from meeting with a nutritionist to discuss how he can decrease total caloric intake and reduce the amount of fat in his diet. In addition, he should be encouraged to increase his physical activity in a variety of ways, not just through a formal exercise regimen. Lowintensity exercise (eg, walking) can lead to improved glycemic control. 55 Vigorous exercise and weight loss are not necessary to reduce. 51 If the case patient can incorporate these lifestyle interventions, he might achieve control of diabetes without pharmacotherapy. CASE CONTINUED The patient is advised to avoid fried foods, choose leaner meats including seafood, and eat vegetables and fruits for snacks instead of potato chips. In addition, he is started on a walking plan. He is encouraged to walk for 10 minutes, 3 times per week, and over the next 2 months to gradually increase his walking to 30 minutes, 5 times per week. Unfortunately, after 6 months, the patient stopped eating a low-fat diet and returned to his sedentary lifestyle. On a recent follow-up visit, his had increased from 8.2% to 8.5%. The patient is advised that he should begin medical treatment for his diabetes, and options for initiating therapy are discussed. The physician encourages the patient to redouble his efforts to make lifestyle changes, emphasizing that diet and exercise are just as important for helping to get his diabetes in control. She reminds him that he was successful in quitting smoking, so he should be confident that he can make other difficult changes to improve his health. What medications would be appropriate for initial therapy in this patient? How should therapy be escalated if glycemic control is not at goal on the initial regimen? PHARMACOLOGIC TREATMENT The natural history of type 2 diabetes is eventual beta cell failure. 56 Therefore, treatment of hyperglycemia often requires pharmacotherapy to compensate for loss of beta cell function. Medications should be selected to target both fasting and postprandial hyperglycemia. Other factors to consider are efficacy in reducing hyperglycemia and lowering the risk for cardiovascular disease, side effects, likelihood of compliance, and cost of the medication. Pharmacologic options for treating type 2 diabetes can be divided into 7 categories based on mechanism of action: suppressants of hepatic glucose production (eg, metformin), insulin secretagogues (eg, sulfonylureas, meglitinides), insulin-sensitizing agents (eg, TZDs), inhibitors of GI glucose absorption (eg, α-glucosidase inhibitors), incretins (eg, exenatide, sitagliptin), amylin agonists (eg, pramlintide), and insulin. Metformin decreases hepatic gluconeogenesis, reduces insulin resistance, and can favorably influence the lipid profile. 57,58 is generally reduced by up to 1.5%, and metformin does not cause hypoglycemia or weight gain. 8,59,60 Apart from GI side effects in some patients, metformin is typically well tolerated. Sulfonylureas and meglitinides lower glucose levels by stimulating insulin secretion. However, they differ in their binding sites on the sulfonylurea receptor. Sulfonylureas and meglitinides have been shown to decrease by 1.5%. 61,62 Both classes of medications can lead to an approximate 2-kg weight gain. The meglitinides have a shorter half-life and therefore should be given with each meal; however, the short half-life of meglitinides reduces the risk of hypoglycemia as compared with sulfonylureas. TZDs decrease insulin resistance at peripheral sites of insulin action, specifically muscle, liver, and fat. When used as monotherapy, TZDs can decrease by 0.8% to 1.6%. 63,64 Pioglitazone has also been shown to improve the lipid profile and may reduce cardiovascular outcomes. 65,66 However, any potential cardiovascular benefit of TZDs has been questioned by the recent meta-analysis and interim findings from the RECORD study referred to earlier. 26,27 In the meta-analysis (of 42 randomized clinical trials), rosiglitazone was associated with a significant increase in the risk of MI and a nonsignificant increase in the risk of death from cardiovascular causes. 26 It is important to note that none of the clinical trials were designed to evaluate cardiovascular outcomes. In the RECORD trial, the primary outcome is hospitalization or death from cardiovascular causes. 27 The interim findings were not sufficient to evaluate the effect of rosiglitazone on the primary endpoint or on the risk of MI. However, rosiglitazone was associated with a significant increase in heart failure. In view of the ongoing controversy regarding use of these drugs, TZDs should be prescribed only after careful consideration of risks versus benefits in an individual patient. Finally, the use of TZDs may be further limited by their adverse effects of fluid retention and weight gain and their high cost. α-glucosidase inhibitors decrease postprandial hyperglycemia by slowing the rate of carbohydrate digestion. Endocrinology Volume 7, Part 2

10 Diagnosis Lifestyle intervention + metformin No 7% Yes* Add basal insulin (most effective) Add sulfonylurea (least expensive) Add TZD (no hypoglycemia) No 7% Yes* No 7% Yes* No 7% Yes* Intensify insulin Add TZD Add basal insulin Add sulfonylurea No 7% Yes* No 7% Yes* Add basal insulin or intensify insulin Intensive insulin + metformin ± TZD *Check every 3 months until less than 7% and then at least every 6 months. Although 3 oral agents can be used, initiation and intensification of insulin therapy is preferred based on effectiveness and expense. Figure 4. Algorithm for the management of patients with type 2 diabetes. = glycosylated hemoglobin; TZD = thiazolidinedione. (Adapted with permission from The American Diabetes Association. Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes [published erratum appears in Diabetes Care 2006;49:2816 8]. Diabetes Care 2006;29:1968. Copyright 2006 American Diabetes Association.) They can reduce by 0.5% to 0.8%, making them less effective than other antihyperglycemic agents. 71 In addition, GI adverse effects (eg, diarrhea, flatulence) associated with α-glucosidase inhibitors have caused a high rate of discontinuation. Incretins (ie, glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic peptide) are GI peptides that enhance glucose-mediated insulin release. Exenatide, (a GLP-1 analogue) can lower by 0.5% to 1.0% when used in combination with metformin, a sulfonylurea, or insulin It also has produced a 1.6- to 2.8-kg weight loss at 30 weeks when used in combination with a sulfonylurea or metformin, respectively. 72,73 Sitagliptin prevents the breakdown of GLP-1 by inhibiting the dipeptidyl peptidase 4 enzyme. Sitagliptin has been shown to reduce by 0.5% to 1.0% as a single agent or when combined with metformin. 75,76 Pramlintide decreases glucagon release and thereby decreases postprandial hyperglycemia. It has modest -lowering effects at 0.5% to 0.7%. 77 Side effects include nausea and weight loss. Insulin is the oldest and most effective medication for lowering. 78 When used correctly, insulin can lower any to goal. 79,80 The major side effects of insulin are weight gain and hypoglycemia. APPROACH TO THERAPY Selection of an antihyperglycemic agent should be individualized to each patient. For the case patient, metformin, sulfonylureas, and TZDs could potentially help decrease his current of 8.5% to less than 7%. Given the potential for weight loss, low cost, and tolerability of metformin, a popular approach is to start metformin as monotherapy. It is important to monitor every 3 months. If the patient s glycemic control is not at goal, adding a second agent would be appropriate. Every 1% increase in is associated with a 21% increased risk for any diabetes-related death, 14% increased risk of MI, and 37% increased risk for microvascular complications. 38 Therefore, acting aggressively to reduce is always appropriate. Figure 4 outlines an approach that can be used in making management decisions for patients with type 2 diabetes. 10 Hospital Physician Board Review Manual

11 CONCLUSION The keys to prevention of type 2 diabetes and its complications are early detection, aggressive glycemic control, regular exercise, and weight loss. Nonpharmacologic and pharmacologic approaches should be used to reach glycemic goals and to help promote weight reduction. Escalation of therapy to a multidrug regimen is often needed to prevent the microvascular and macrovascular complications of type 2 diabetes. REFERENCES 1. Wild S, Roglic G, Green A, et al. Global prevalence of diabetes: estimates for the year 2000 and projections for Diabetes Care 2004;27: Cowie CC, Rust KF, Byrd-Holt DD, et al. Prevalence of diabetes and impaired fasting glucose in adults in the U.S. population: National Health and Nutrition Examination Survey Diabetes Care 2006;29: Centers for Disease Control and Prevention. National Diabetes Fact Sheet. Available at Accessed 21 Aug Hogan P, Dall T, Nikolov P. Economic costs of diabetes in the US in American Diabetes Association. 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