MANAGING THE PRE-DIABETIC PATIENT

Managing the PreDiabetic Patient CAPA 2012 2 Key Questions MANAGING THE PRE-DIABETIC PATIENT Ingrid Lopes, DO 1. What is pre-diabetes and is it a disease? 2. What is the metabolic key? 3. When and how should we screen our patients? 4. How shall we intervene? ADA Evidence Grading System for Clinical Recommendations Level of Evidence A B C E Description Clear or supportive evidence from adequately powered well-conducted, generalizable, randomized controlled trials Compelling nonexperimental evidence Supportive evidence from well-conducted cohort studies or case-control study Supportive evidence from poorly controlled or uncontrolled studies Conflicting evidence with the weight of evidence supporting the recommendation Expert consensus or clinical experience The Challenge An estimated 79 million U.S. adults have pre-diabetes, according to 2011 estimates, which represents over 1/3 rd of the adult population. But only 7% of those with prediabetes are aware of their condition. The estimate in 2008 was 57 million with pre-diabetes. Diabetes currently affects 8.3% of the U.S. population, or 25.8 million people. An estimated 7 million are undiagnosed. ADA. Diabetes Care 2012;35(suppl 1):S12. Table 1. http://www.cdc.gov/media/releases/2011/p0126_diabetes.html 1

Managing the PreDiabetic Patient CAPA 2012 5 Managing the PreDiabetic Patient CAPA 2012 6 A 40-year-old South Asian man... WHAT IS PRE-DIABETES & IS IT A DISEASE? A 40-year-old South Asian man presents for a routine visit. He has no 1 st -degree relatives with T2DM. He works at a desk in front of a computer most of the day and exercises by riding a stationary bike for 20-30 minutes once a week. Today his BMI is 24 kg/m2 and blood pressure is 129/84 mmhg. Physical exam is within normal limits. Should he be screened for pre-diabetes? Is there any evidence that he has hyperinsulinemia or insulin resistance placing him at increased risk for cardiovascular disease and T2DM and the corresponding microvascular complications? Prediabetes: IFG, IGT, Increased A1C Categories of increased risk for diabetes (prediabetes) * FPG 100 125 mg/dl (5.6 6.9 mmol/l): IFG OR 2-h plasma glucose in the 75-g OGTT 140 199 mg/dl (7.8 11.0 mmol/l): IGT OR A1C 5.7 6.4% *For all three tests, risk is continuous, extending below the lower limit of a range and becoming disproportionately greater at higher ends of the range. Fasting plasma glucose level Managing the PreDiabetic Patient CAPA 2012 8 Diagnostic Categories < 140 mg/dl 2-hour (75 g) OGTT result 140 199 mg/dl (impaired glucose tolerance or IGT) > 200 mg/dl < 100 mg/dl Normal Pre-Diabetes DM 100 125 mg/dl (impaired fasting glucose or IFG) Pre-Diabetes Pre-Diabetes DM > 126 mg/dl DM DM DM HbA 1c level < 5.7% 5.7 6.4% > 6.5% Normal Pre-Diabetes DM ADA. I. Classification and Diagnosis. Diabetes Care 2012;35(suppl 1):S13. Table 3. Adapted from Goldman s Cecil Medicine, 24 th ed., 2011, chapter 237 2

Managing the PreDiabetic Patient CAPA 2012 10 What is Type 2 Diabetes? Relationship of diabetes-specific complication and glucose tolerance. This figure shows the incidence of retinopathy in Pima Indians as a function of the fasting plasma glucose (FPG), the 2-h plasma glucose after a 75-g oral glucose challenge (2-h PG), or the A1C. Note that the incidence of retinopathy greatly increases at a fasting plasma glucose >116 mg/dl, or a 2-h plasma glucose of 185 mg/dl, or an A1C > 6.5%. (Blood glucose values are shown in mg/dl; to convert to mmol/l, divide value by 18.) (Copyright 2002, American Diabetes Association. From Diabetes Care 25(Suppl 1): S5 S20, 2002.) Harrison s Principles of Internal Medicine, 18 th ed., 2012, chapter 344 Although the primary defect is controversial, most studies support the view that insulin resistance precedes an insulin secretory defect but that diabetes develops only when insulin secretion becomes inadequate. The evidence: Insulin resistance, as demonstrated by reduced glucose utilization in skeletal muscle, is present in many nondiabetic, first-degree relatives of individuals with type 2 DM. As insulin resistance develops, pancreatic -cells respond, resulting in hyperinsulinemia, promoting an anabolic state. Over time, -cell exhaustion ensues, resulting in hypoinsulinemia and worsening hyperglycemia. Glucose and fat metabolism are in disarray, promoting vascular damage, including atherosclerosis, nephropathy and retinopathy. Harrison s Principles of Internal Medicine, 18 th ed., 2012, chapter 344 Managing the PreDiabetic Patient CAPA 2012 11 Managing the PreDiabetic Patient CAPA 2012 12 What is Pre-Diabetes? Prediabetes (IFG and/or IGT) should be viewed as a stage in the natural history of disordered glucose metabolism rather than as a distinctive clinical entity representing an interim condition and as a risk factor presaging (1) the development of diabetes and (2) an increase in cardiovascular and possibly microvascular complications. Interesting statistics: ~ 70% of those with prediabetes will progress to diabetes, at a rate of 5-10% per year Cardiovascular risk increases with increasing FPG and/or increasing HbA1c in a nondiabetic population Findings consistent with diabetic retinopathy have been demonstrated in 7.9% of a population with IGT Buysschaert M. Bergman M. Definition of Prediabetes. Med Clin N Am. 2011;95:289-297. What is Metabolic Syndrome? The National Cholesterol Education Program s Adult Treatment Panel III report (ATP III) defines this as a cluster of 6 interrelated components that lead to increased risk of cardiovascular disease and type 2 diabetes. The 6 components: Abdominal obesity Atherogenic dyslipidemia Raised blood pressure Insulin resistance +/- glucose intolerance Proinflammatory state Prothrombotic state If insulin resistance, whether primary or secondary to obesity, is in the chain of causation of metabolic syndrome, it would be an attractive target. Certainly, weight reduction and increased physical activity will reduce insulin resistance. Grundy et.al. Definition of Metabolic Syndrome. Circulation. 2004;109:433-438. 3

Connecting insulin resistance and cardiovascular disease A COMMON METABOLIC SOIL Goldman s Cecil Medicine, 24 th ed., 2011, chapter 237 Metabolic pathways underlying Pre-Diabetes and Metabolic Syndrome Release of adipokines promotes inflammation and a prothrombotic state. FFAs induce insulin resistance in muscle, impair beta-cell function through lipotoxicity, increase hepatic glucose output, and promote dyslipidemia. Grundy. Pre-Diabetes, Metabolic Syndrome., and Cardiovascular Risk. JACC 2012;59:635-43. Prevalence of Metabolic Syndrome in Different Categories of Pre-Diabetes in a European Population In those with both IFG and IGT, approximately three-fourths had metabolic syndrome. [NFG = normal fasting] Grundy. Pre-Diabetes, Metabolic Syndrome., and Cardiovascular Risk. JACC 2012;59:635-43. 4

Managing the PreDiabetic Patient CAPA 2012 17 Managing the PreDiabetic Patient CAPA 2012 18 Pre-Diabetes as a clinical syndrome Let s summarize: Pre-diabetes is a strong risk factor for type 2 diabetes, as well as for CVD, retinopathy and nephropathy. The macro- and microvascular damage accrues throughout the continuum. Insulin resistance is the piece that links pre-diabetes with metabolic syndrome and type 2 diabetes and contributes to the disordered glucose and fat metabolism seen in all three. Likely pathogenesis of pre-diabetes: ingestion of a high-glycemic diet over time, resulting in relative hyperglycemia and hyperinsulinemia (i.e., an anabolic state), causing steady weight gain, the development of insulin resistance, higher levels of insulin and glucose, eventually leading to -cell burn-out. IFG and IGT distinguish pre-diabetes. There can be metabolic syndrome without IFG or IGT, and there can be pre-diabetes without metabolic syndrome (there is even a small number with type 2 DM without metabolic syndrome!), but for most patients there is a common end-point. Pre-Diabetes as a clinical syndrome Of all the current public health epidemics (e.g., obesity, type 2 diabetes, etc), surely insulin resistance is at the top. Perhaps thinking of pre-diabetes as the clinical phenotype of insulin resistance helps to refocus our thinking and actions. Once we can agree on a reasonable course of action to identify those with pre-diabetes, then we can plan to screen them for hypertension and dyslipidemia, and prescribe an evidence-based, best-practice approach that offers the hope of reversing their insulin resistance and restoring normoglycemia. Managing the PreDiabetic Patient CAPA 2012 19 Managing the PreDiabetic Patient CAPA 2012 20 Is there a pre-diabetic phenotype? Definition: The phenotype of an organism is the class to which that organism belongs as determined by the description of the physical and behavioral characteristics of the organism, for example, its size and shape, its metabolic activities and its pattern of movement. Are all pre-diabetic phenotypes obese? Most of our current understanding of the pathophysiology and genetics [of type 2 DM] is based on studies of individuals of European descent. It is becoming increasing apparent that DM in other ethnic groups (Asian, African, and Latin American) has a different, but yet undefined, pathophysiology. In these groups, DM that is ketosis-prone (often obese) or ketosis-resistant (often lean) is commonly seen. Harrison s Principles of Internal Medicine, 18 th ed., 2012, chapter 344 5

Managing the PreDiabetic Patient CAPA 2012 21 Managing the PreDiabetic Patient CAPA 2012 22 Which one is the lean pre-diabetic? A 40-year-old South Asian man... A 40-year-old South Asian man presents for a routine visit. He has no 1 st -degree relatives with T2DM. He works at a desk in front of a computer most of the day and exercises by riding a stationary bike for 20-30 minutes once a week. Today his BMI is 24 kg/m2 and blood pressure is 129/84 mmhg. Physical exam is within normal limits. His waist circumference is 95 cm. Random (non-fasting) blood glucose today by fingerstick is 140 mg/dl. Has your assessment of his risk changed? WHO (1998-99) Metabolic Syndrome Insulin resistance, defined as either: Type 2 diabetes Impaired fasting glucose Impaired glucose tolerance Plus any 2 of the following: Hypertension > 140/90 mm Hg Triglycerides > 150 mg/dl or HDL-C < 35 mg/dl in men, < 39 mg/dl in women BMI > 30 kg/m2 and/or waist-hip ratio > 0.9 in men, 0.85 in women Microalbuminuria Managing the PreDiabetic Patient CAPA 2012 23 Comparison of the original WHO, NCEP ATPIII, and AACE definitions NCEP ATPIII (2001, 2005) Metabolic Syndrome At least 3 of the following 5 criteria: Waist circumference: Men > 40 inches Women > 35 inches Triglycerides > 150 mg/dl HDL-C Men < 40 mg/dl Women < 50 mg/dl or HDL-lowering medication Fasting glucose > 100 mg/dl Hypertension > 130/85 mm Hg or taking anti- HTN medication AACE (2003) Insulin Resistance Syndrome 2-hour GTT > 140 mg/dl Fasting glucose between 110 and 126 mg/dl BMI > 25 kg/m2 Triglycerides > 150 mg/dl HDL-C Men < 40 mg/dl Women < 50 mg/dl Hypertension > 130/85 mm Hg Other related factors: Family history of T2DM, HTN or CVD Polycystic ovarian syndrome Sedentary lifestyle High-risk ethnicity Fatty liver disease Acanthosis nigricans (Pediatric modifications of risk variable thresholds) Managing the PreDiabetic Patient CAPA 2012 24 Harmonized Definition of Metabolic Syndrome (AHA & IDF, 2009) Abdominal obesity Hypertriglyceridemia Reduced HDL-C Elevated blood pressure Hyperglycemia Risk Factor Measure and threshold for diagnosis (3 out of 5 qualifies as metabolic synd.) Waist circumference (see next slide) Serum triglycerides > 150 mg/dl (1.7 mmol/l), or Drug treatment for elevated triglycerides Serum HDL-C <40 mg/dl (1.0 mmol/l) for men <50 mg/dl (1.3 mmol/l) for women, or Drug treatment for reduced HDL-C Systolic and diastolic blood pressure 130 mmhg systolic 85 mmhg diastolic, or Drug treatment for known hypertension Fasting glucose (mg/dl) > 100 mg/dl, or Drug treatment for hyperglycemia Blaha M. Tota-Maharaj R. Metabolic Syndrome: from risk factors to management. (2012-06-04). SEEd Medical Publishers. Kindle Edition. 6

Managing the PreDiabetic Patient CAPA 2012 25 Race/ethnic thresholds for abdominal obesity in the Harmonized definition. Caucasian Population Asian (including Japanese) Threshold for abdominal obesity Men > 94 cm (increased risk) > 102 cm (still higher risk) Women > 80 cm (increased risk) > 88 cm (still higher risk) > 90 cm > 80 cm Chinese > 85 cm > 80 cm Managing the PreDiabetic Patient CAPA 2012 26 Obtaining a waist measurement Middle East, Mediterranean > 94 cm > 80 cm Sub-Saharan African > 94 cm > 80 cm Ethnic Central & South American > 90 cm > 80 cm Blaha M. Tota-Maharaj R. Metabolic Syndrome: from risk factors to management. (2012-06-04). SEEd Medical Publishers. Kindle Edition. Recommendations: Testing for Diabetes in Asymptomatic Patients WHEN AND HOW SHOULD WE BEGIN TO SCREEN OUR PATIENTS? Consider testing overweight/obese adults (BMI 25 kg/m 2 ) with one or more additional risk factors In those without risk factors, begin testing at age 45 years (B) If tests are normal Repeat testing at least at 3-year intervals (E) Use A1C, FPG, or 2-h 75-g OGTT (B) In those with increased risk for future diabetes Identify and, if appropriate, treat other CVD risk factors (B) ADA. II. Testing in Asymptomatic Patients. Diabetes Care 2012;35(suppl 1):S13. 7

Criteria for Testing for Diabetes in Asymptomatic Adult Individuals (1) 1. Testing should be considered in all adults who are overweight (BMI 25 kg/m 2 *) and who have one or more additional risk factors: Physical inactivity First-degree relative with diabetes High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander) Women who delivered a baby weighing >9 lb or were diagnosed with GDM Hypertension ( 140/90 mmhg or on therapy for hypertension) HDL cholesterol level <35 mg/dl (0.90 mmol/l) and/or a triglyceride level >250 mg/dl (2.82 mmol/l) Women with polycystic ovarian syndrome (PCOS) A1C 5.7%, IGT, or IFG on previous testing Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans) History of CVD Criteria for Testing for Diabetes in Asymptomatic Adult Individuals (2) 2. In the absence of criteria (risk factors on previous slide), testing for diabetes should begin at age 45 years 3. If results are normal, testing should be repeated at least at 3-year intervals, with consideration of more frequent testing depending on initial results (e.g., those with prediabetes should be tested yearly), and risk status *At-risk BMI may be lower in some ethnic groups. ADA. Testing in Asymptomatic Patients. Diabetes Care 2012;35(suppl 1):S14. Table 4. ADA. Testing in Asymptomatic Patients. Diabetes Care 2012;35(suppl 1):S14. Table 4. Managing the PreDiabetic Patient CAPA 2012 32 The USPSTF s Recommendations Screening for T2DM in Adults The USPSTF recommends screening for type 2 diabetes in asymptomatic adults with sustained blood pressure (either treated or untreated) greater than 135/80 mm Hg. The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for type 2 diabetes in asymptomatic adults with blood pressure of 135/80 mm Hg or lower. Screening for HTN in Adults The USPSTF recommends screening for high blood pressure in adults aged 18 and older. Screening for lipid disorders in Adults The USPSTF strongly recommends screening men aged 35 and older for lipid disorders and women aged 45 and older for lipid disorders if they are at increased risk for coronary heart disease. The USPSTF makes no recommendation for or against routine screening for lipid disorders in men aged 20 to 35, or in women aged 20 and older who are not at increased risk for coronary heart disease. http://www.uspreventiveservicestaskforce.org/adultrec.htm REFRAMING THE QUESTION: WHEN SHOULD WE TEST FOR PRE-DIABETES? 8

Assessing for the pre-diabetic phenotype Does our patient express the pre-diabetic phenotype? Annual screening of all patients over age 18 years for: blood pressure BMI waist size Annual follow-up if all 3 values are WNL. If SBP > 130 and/or DBP > 80, BMI > 25, and/or increased waist size, then assess risk factors and offer lifestyle support (exercise, nutrition, weight). Assess the following risk factors: higher-risk ethnicity personal history of GDM, PCOS or CVD 1 st degree relative with type 2 DM acanthosis nigricans per physical exam age > 45 years sedentary lifestyle (e.g., sitting > 9 hours per day; exercising < 60 minutes per week) Annual screening of all patients over age 18 years for: blood pressure 129/84 BMI waist size > 90 cm Annual follow-up if all 3 values are WNL. If SBP > 130 and/or DBP > 80, BMI > 25, and/or increased waist size, then assess risk factors and offer lifestyle support (exercise, nutrition, weight). Assess the following risk factors: higher-risk ethnicity personal history of GDM, PCOS or CVD 1 st degree relative with type 2 DM acanthosis nigricans per physical exam age > 45 years sedentary lifestyle (e.g., sitting > 9 hours per day; exercising < 60 minutes per week) Testing for Pre-Diabetes Fasting plasma glucose 100 125 mg/dl HbA1c 5.7 6.4% Keep in mind that abnormal lipids do not define pre-diabetes Lipid Panel Managing the PreDiabetic Patient CAPA 2012 35 Serum triglycerides > 150 mg/dl HDL-C < 40 mg/dl (men) HDL-C < 50 mg/dl (women) Back to our patient Managing the PreDiabetic Patient CAPA 2012 36 Based on his diastolic BP of 84, waist size of 95 cm, South Asian ethnicity, and sedentary lifestyle, he seems to moderately express the pre-diabetes phenotype. Assessing fasting labs is a reasonable next step. His FPG is 100 mg/dl HbA1c is 6.6% Triglycerides are 150 mg/dl So he does have pre-diabetes and is likely in an early stage of this clinical syndrome. Our recommendations include weight loss and exercise, participating in a lifestyle education group for 16 sessions, and regular monitoring of his BP, BMI, waist size, & labs. 9

Recommendations: Prevention/Delay of Type 2 Diabetes HOW SHALL WE INTERVENE? Refer patients with IGT (A), IFG (E), or A1C 5.7 6.4% (E) to ongoing support program Targeting weight loss of 7% of body weight At least 150 min/week moderate physical activity Follow-up counseling important for success (B) Based on cost-effectiveness of diabetes prevention, thirdparty payers should cover such programs (E) Consider metformin for prevention of type 2 diabetes if IGT (A), IFG (E), or A1C 5.7 6.4% (E) Especially for those with BMI >35 kg/m 2, age <60 years, and women with prior GDM (A) In those with prediabetes, monitor for development of diabetes annually (E) ADA. IV. Prevention/Delay of Type 2 Diabetes. Diabetes Care 2012;35(suppl 1):S16. The DPP Intensive Lifestyle Intervention Model Goals Achieve and maintain a weight reduction of at least 7% of initial body weight through a healthy low-calorie, low-fat diet Engage in moderate intensity physical activity, such as brisk walking, for at least 150 minutes per week Method Design of a 16-lesson curriculum covering diet, exercise, and behavior modification Taught by case managers on a 1-to-1 basis during the first 24 weeks Approach was flexible, culturally sensitive and individualized Subsequent individual sessions (usually monthly) and group sessions with the case managers reinforced behavioral changes Can lifestyle changes be durable? A closer look at the Diabetes Prevention Program In the original study, 3,234 subjects with IGT plus IFG were randomized into 3 treatment arms: 1. Intensive lifestyle changes aimed at reducing body weight by 7% through low-fat diet and 150 minutes of weekly exercise; 2. Metformin 850 mg BID and standard lifestyle recommendations; 3. Placebo BID and standard lifestyle recommendations. Mean age was 51 years; mean BMI was 34; 68% were female; 45% self-identified as ethnic/racial minorities. The average follow-up was 2.8 years. The incidence of diabetes was 4.8, 7.8 & 11.0 cases per 100 person-years in the 3 treatment arms above, respectively. Intensive lifestyle intervention reduced the incidence by 58% and metformin by 31% as compared with placebo. Knowler WC, Barrett-Conner E, Fowler SE, et al., for the Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403. 10

Can lifestyle changes be durable? A closer look at the Diabetes Prevention Program The 10-year follow-up program included 2,665 participants from the original study. On the basis of the benefits from the intensive lifestyle intervention, all participants were offered group-implemented lifestyle intervention. The metformin and placebo subjects were unmasked and placebo discontinued. During the 10-year follow-up, the original lifestyle group partly regained weight lost during the first intervention. The modest weight loss with metformin was maintained. Diabetes incidence rates during the follow-up study were 5.9 per 100- person years for lifestyle, 4.9 for metformin, and 5.6 for placebo. But at 10 years, diabetes incidence was reduced by 34% in the lifestyle group and 18% in the metformin group compared to placebo. Additional Therapeutic Approaches Dyslipidemia Goals: LDL < 100 mg/dl; statin therapy is 1 st -line If CVD is present: LDL < 70 mg/dl and LDL + vldl < 100 mg/dl. Hypertension SBP < 130 and DBP < 85 mmhg; preferably SBP < 120 and DBP < 80. Opinion favors ACE-I and ARB (also CCB) as 1 st -line; betablockers and thiazides may increase conversion to T2DM (?). Prothrombotic factors The JPAD trial showed no benefit from aspirin to prevent CVD events in diabetes, and so cannot be recommended at this time in pre-diabetes. Knowler WC, Fowler SE, Hamman RF, et al., for the Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009;374:1677-86. Grundy. Pre-Diabetes, Metabolic Syndrome., and Cardiovascular Risk. JACC 2012;59:635-43. Ogawa, et al. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA. 2008 Nov 12;300(18):2134-41. Managing the PreDiabetic Patient CAPA 2012 43 Additional Therapeutic Approaches: Prescriptions for Weight Loss Managing the PreDiabetic Patient CAPA 2012 44 Successful loss of 5-10% of body weight in obese adults has been attributed to eating less fat, exercising more, joining a commercial weight loss program and/or using prescription weight loss medication. FDA-approved treatments have included: Dopaminergic agents (e.g., phentermine, phendimetrazine, diethylpropion) Pancreatic lipase inhibitor (e.g., orlistat) Off-label approaches: Antidepressant agents (e.g., bupropion HCl) Antiepileptics (e.g., topiramate, zonisamide) Antidiabetic agents Biguanides (e.g., metformin) GLP-1 receptor agonists (e.g., exenatide) Nicklas J. et al. Successful Weight Loss Among Obese U.D. Adults. Am J Prev Med. 2012 May;42(5):481-5. 11

Managing the PreDiabetic Patient CAPA 2012 45 Bariatric Surgery Consider bariatric surgery for adults with BMI >35 kg/m 2 and type 2 diabetes (Level of evidence B) After surgery, life-long lifestyle support and medical monitoring is necessary (Level of evidence B) Insufficient evidence to recommend surgery in patients with BMI <35 kg/m 2 outside of a research protocol (Level of evidence E) Well-designed, randomized controlled trials comparing optimal medical/lifestyle therapy needed to determine long-term benefits, costeffectiveness, risks (Level of evidence E) ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S27. Materials and Links National Diabetes Prevention Program http://www.cdc.gov/diabetes/prevention/index.htm Highly recommended! Source of A Change for Life video and complete, updated 16-week Diabetes Prevention Program curriculum, with training guides, handouts, and more, all free of charge. National Diabetes Information Clearinghouse: DPP http://diabetes.niddk.nih.gov/dm/pubs/preventionprogram/ Diabetes Prevention Program Manual of Operations http://www.bsc.gwu.edu/dpp/manuals.htmlvdoc The Group Lifestyle Balance Program at the University of Pittsburgh http://www.diabetesprevention.pitt.edu/grouplifestyleoverview.aspx Bibliography American Diabetes Association. Standards of Medical Care in Diabetes 2012. Diabetes Care 2012;35(Suppl 1):S11-S63. Blaha, Michael J. ; Tota-Maharaj, Rajesh (2012-06-04). Metabolic Syndrome. From Risk Factors to Management. SEEd Medical Publishers. Kindle Edition. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA: US Dept of Health & Human Services, Centers for Disease Control & Prevention, 2011. Fowler MJ. Microvascular and macrovascular complications of diabetes. Clin Diabetes 2008;26:77-82. Goldman s Cecil Medicine, 24 th ed., 2011, chapters 236 and 237. Grundy, SM. Pre-diabetes, metabolic syndrome, and cardiovascular Risk. J Am Coll Cardiol 2012;59:635-43. Harrison s Principles of Internal Medicine, 18 th ed., 2012, chapters 242 & 344. 12

Bibliography Knowler WC, Barrett-Conner E, Fowler SE, et al., for the Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403. Knowler WC, Fowler SE, Hamman RF, et al., for the Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009;374:1677-86. Mottillo S, Filion KB, Genest J, et al. The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol 2010;56:1113-32. Ogawa H, Nakayama M, Morimoto T, et al., for the JPAD trial investigators. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA 2008;18:2134-41. Young C. New considerations in metabolic syndrome and prediabetes. JAOA 2010;110(Suppl 3):S23-S25. 13