Beginning the Journey with Type 2 Diabetes James W. Reed, M.D., MACP, FACE Professor of Medicine, Associate Chair of Medicine Chief of Endocrinology & Metabolism Chief of Medicine Service at Grady for MSM

Global Projections for the Diabetes Epidemic: 1995-2010 26.5 32.9 24% 14.2 17.5 23% 9.4 14.1 50% 84.5 132.3 57% 1.0 1.3 33% 15.6 22.5 44% World 2000 = 151 million 2010 = 221 million Increase 46%

Diabetes in the United States >30% of individuals aged >60 y have diabetes mellitus or impaired fasting glucose 23.6 million have diabetes Millions of these people are unaware they have diabetes >1.3 million Americans develop diabetes yearly, >2,800 daily Harris et al. Diabetes Care. 1998;21:518. 2002 update.

Costs of Diabetes (US) 1 in every 7 health care dollars spent 10-15% of Medicare population has diabetes, but 25% of Medicare budget is spent on diabetes Estimated total costs attributable to diabetes (direct and indirect) ~ $174 billion (2007) Ranks #1 in direct health care costs of any disease category ~ $174 billion (2007) Ranks #2 in total health care costs (direct and indirect, diabetes and other) ~ $262 billion (2007) Slide 5: Costs of Diabetes (US) Diabetes is responsible for significant healthcare costs in the United States: 1 in every 7 healthcare dollars is spent on patients with diabetes. Although only 10-15% of the Medicare population has diabetes, as much as 25% of the Medicare budget is devoted to diabetes care. The total direct and indirect costs attributable to diabetes in 1997 were estimated to be $98 billion. Diabetes ranks as #1 in direct health care costs, a number estimated to be $91.1 billion in 1995. Diabetes ranks as #2 in total healthcare costs, a number estimated to be $137.7 billion in 1995. Songer TJ, Ettaro L. Studies on the cost of diabetes. Centers for Disease Control. Atlanta, GA. 1998. Centers for Disease Control and Prevention. Chronic diseases and conditions. Online edition. Atlanta, GA. 2000. American Heart Association. Heart and stroke statistical update. Dallas, TX. 1999. American Diabetes Association. Diabetes Facts and Figures. March 2000. Online Edition. Songer TJ, Ettaro L. Studies on the cost of diabetes. Centers for Disease Control. Atlanta, GA. 1998. Centers for Disease Control and Prevention. Chronic diseases and conditions. Online edition. Atlanta, GA. 2000. American Heart Association. Heart and stroke statistical update. Dallas, TX. 1999. American Diabetes Association. Diabetes Facts and Figures. March 2000. Online edition.

Diabetes: The Burden of Disease In 2007, diabetes-related economic losses were estimated to be: $174 billion direct health care costs 13.9 million hospital days 30.3 million office visits 120 million work-loss days 88 million disability days Diabetes Facts and Figures, American Diabetes Association, 2000.

Etiology of Type 2 Diabetes: Insulin Resistance and Diminished Insulin Secretion Genes Lifestyle and diet Insulin Resistance Normal -cell function Abnormal -cell function This diagram shows the contributions of insulin resistance and insulin deficiency to the expression of type 2 diabetes. The syndrome of insulin resistance develops over time in individuals who are genetically predisposed. Dietary and lifestyle factors such as obesity or a sedentary existence can also contribute to insulin resistance. Evidence of insulin resistance is found by examining the in vivo effectiveness of exogenous insulin in stimulating glucose uptake in peripheral tissues and glucose output by the liver. Larger amounts of insulin required to maintain glucose homeostasis indicate greater degrees of insulin resistance.1 When pancreatic -cell function is normal, insulin output increases to compensate for insulin resistance in such tissues as the liver, skeletal muscle, and adipose tissue, and the patient’s glucose tolerance remains within the normal range. However, if -cell function is abnormal or deteriorates, the amounts of insulin secreted by the pancreas are insufficient to compensate for insulin resistance, resulting in hyper-glycemia. Reference 1. Felig P et al. In: Endocrinology and Metabolism. 3rd ed. McGraw-Hill Inc; 1995. Compensatory Hyperinsulinemia Relative insulin deficiency Hyperglycemia Normoglycemia Type 2 diabetes

Insulin Resistance: Inherited and Acquired Influences Overeating Overweight Inactivity Aging Medications Illness Hyperglycemia/ glucose toxicity Elevated FFAs Rare Mutations Insulin receptor Glucose transporter Signaling proteins Common Forms Largely unidentified INSULIN RESISTANCE

Cardiovascular Disease US Leading Cause of Death (1998) 800 700 600 500 Deaths (thousands) 400 300 200 Despite advances in therapy including increasing use of antiplatelets, lipid-lowering therapy, calcium channel blockers, and beta-blockers, heart disease remains the leading cause of death in the United States. In 1998, of the more than 724,000 deaths attributed to this cause, more than 460,000 were caused by coronary heart disease. Stroke was the third leading cause of death in this year, resulting in more than 158,000 deaths. Stroke is the leading cause of disability. Morbidity & Mortality: 2000 Chart Book on Cardiovascular, Lung, and Blood Diseases. NHLBI. May 2000 (National Center for Health Statistics. Preliminary data for 1998. National Vital Statistics Report. Vol. 47, no. 25. Hyattsville, MD. 1999). 100 Heart disease Cancer Stroke COPD Morbidity & Mortality: 2000 Chart Book on Cardiovascular, Lung, and Blood Diseases. NHLBI. May 2000.

Prevalence of Diabetic Tissue Damage at Diagnosis of Type 2 Diabetes Prevalence Dagogo-Jack et al. Arch Int Med. 1997;157:1802-1817.

UKPDS: Complications at Diagnosis Tissue Damage Prevalence (%)* Retinopathy (>1 microaneurysm) 21 Abnormal ECG 18 Other macrovascular complication 9 Absent foot pulses (2) and/or ischemic feet 14 Impaired reflexes and/or decreased vibration sense 7 50% of patients had some form of diabetic complication at time of diagnosis. *Some patients had more than 1 complication at diagnosis. Adapted from UKPDS. Diabetologia. 1991;34:877-890.

Duration of follow-up (y) Duration of follow-up (y) Framingham Study and Joslin Patients Diabetes Is a CV Risk Factor Men Women 60 60 50 50 2x 40 40 4-5x Mortality rate per 1,000 Mortality rate per 1,000 30 30 20 20 10 10 0-3 4-7 8-11 12-15 16-19 20-23 0-3 4-7 8-11 12-15 16-19 20-23 Duration of follow-up (y) Duration of follow-up (y) Diabetes No Diabetes Krolewski AS et al. Am J Med. 1991;90(suppl 2A):56S-61S.

Methods for Diagnosing Diabetes FPG 126 mg/dL (after 8-h fast, confirmed) Casual plasma glucose 200 mg/dL with classic diabetes symptoms (confirmed): increased urination increased thirst unexplained weight loss OGTT value of  200 mg/dL in the 2-h sample Don’t use for diagnosis, but still suggestive: Fingerstick glucose A1c ADA. Diabetes Care. 2003;26:S5-S20.

Clinical Identification of the Metabolic Syndrome National Cholesterol Education Program Clinical Identification of the Metabolic Syndrome RISK FACTOR DEFINING MEASURES Abdominal obesity Waist circumference: Men >40 in (>102 cm) Women >35 in (>88 cm) Triglycerides ³150 mg/dL HDL-C Men <40 mg/dL HDL-C Women <50 mg/dL Blood pressure ³130/³85 mm Hg Fasting glucose ³110 mg/dL Slide 53: Current Treatment Paradigm The current treatment paradigm for type 2 diabetes consists of a stepwise approach with diet followed by a single oral agent, a second oral agent, and eventually insulin. Data from NHANES III indicate that the majority of patients with type 2 diabetes are poorly controlled by this approach. Failure of monotherapy results from the progressive nature of the disease and because a single drug does not address the defects in insulin secretion, hepatic glucose production, and peripheral insulin resistance that characterize type 2 diabetes. Furthermore, by waiting for failure before changing therapy, glucose toxicity may develop before the therapy is adjusted and impair the treatment response. Harris MI, Eastman RC, Cowie CC, et al. Racial and ethnic differences in glycemic control of adults with type 2 diabetes. Diabetes Care. 1999;22:403-408. Harris MI, Flegal KM, Cowie CC, et al. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The Third National Health and Nutrition Examination Survey, 1988-1994. Diabetes Care. 1998;21:518-524. ³3 Risk factors comprise the metabolic syndrome. ICD-9 Code 277.7 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001. 285:2486-2497.

Aggressive Control of Diabetes: Goals of Treatment NORMAL GOAL AMERICAN DIABETES ASSOCIATION HbA1C (%) < 6 < 7 Preprandial plasma glucose (mg/dL) <110 90-130 Peak postprandial plasma glucose (mg/dL) <140 < 180 AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS (AACE) HbA1C (%) < 6  6.5 Preprandial plasma glucose (mg/dL) <110 <110 2-hour postprandial glucose <140 <140 Target goals for levels of glycemic control have been established by the ADA, the European Diabetes Policy Group (EDPG), and the American Association of Clinical Endocrinologists (AACE). The ADA recommends a goal of 90-130 mg/dL for preprandial glucose and <7% for HbA1C. The EDPG recommends a goal of <110 mg/dL for preprandial glucose and 6.5% for HbA1C. The AACE recommends a goal of 110 mg/dL for preprandial glucose and 6.5% for HbA1C. Based on the results from epidemiologic studies, CV risk and overall mortality are decreased in individuals with lower values of HbA1C with no evidence of threshold. Based on these data, the new guidelines advocate more aggressive glycemic control. American Diabetes Association Clinical Practice Recommendations 2001. Diabetes Care. 2001;24(suppl 1):S1-S133. European Diabetes Policy Group. A desktop guide to type 2 diabetes mellitus. Diabet Med. 1999;16:716-730. American College of Endocrinology Consensus Conference on Guidelines for Glycemic Control White Paper. Washington, DC: AACE, August 2001. Available at: http://www.aace.com/pub/press/releases/diabetesconsensuswhitepaper.php. HbA1c is “gold standard” measure of diabetes control over previous 2-3 months American Diabetes Association. Diabetes Care. 2003;26(suppl 1):S33-S50; American College of Endocrinology Consensus Conference on Guidelines for Glycemic Control. August 2001, Washington, DC.

Lower A1C Reduces Incidence of Complications DCCT 9  7% 63% 54% 60% 41%* Kumamoto 9  7% 69% 70% – UKPDS 8  7% 17-21% 24-33% – 16%* A1C Retinopathy Nephropathy Neuropathy Macrovascular disease Three independent studies: DCCT (type 1), Kumamoto (type 2-lean), UKPDS (type 2-typical) showed significant benefits of similar magnitude by decreasing HbA1c. In the DCCT, when all major cardiovascular and peripheral vascular events were combined, intensive therapy reduced the risk of cardiovascular disease by 41%, although this reduction was not statistically significant. The relative youth of the patient cohort made the detection of a difference between treatments unlikely. The 16% reduced risk incidence of coronary heart disease in the UKPDS had a P value of 0.052, not quite statistically significant. *Not statistically significant. Diabetes Control and Complications Trial (DCCT) Research Group. N Engl J Med. 1993;329:977-986. Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28:103-117. UK Prospective Diabetes Study Group (UKPDS) 33. Lancet. 1998;352:837-853.

DECODE Trial: Relative Risk of Death* Shown by Blood Glucose Level *All causes, adjusted for age, sex, study center 2.4 2.0 Relative Risk of Death* 1.6 1.2 > 199 1.0 140-198 < 110 110-125 126- 139 2-h Postprandial Glucose (mg/dL) >140 < 140 Fasting Plasma Glucose (mg/dL) Adapted from Decode Study Group. Lancet. 1999;354:617-621.

Postprandial Glucose Is a Better Predictor of Myocardial Infarction and Death Glycemic Control (Blood Glucose Level, mg/dL) Good Borderline Poor P Value Fasting 80–109 110–139 >140 — MI per 1,000 123 147 183 NS Death per 1,000 164 220 203 NS Postprandial 80–144 145–179 >180 — MI per 1,000 120 165 209 <.05 Death per 1,000 167 199 262 <.05 Hanefeld and colleagues showed that postprandial hyperglycemia is a better predictor of myocardial infarction and death than fasting glucose in patients with type 2 diabetes. These data show the risk of myocardial infarction or death, based on fasting or postprandial blood glucose as the predictor, segregated across good, borderline, and poor control. While the postprandial values provided statistically significant prognostic information, the fasting levels did not. Hanefeld M et al. Diabetologia. 1996;39:1577-1583.

Effects of Risk Factors on CVD Mortality in Type 2 Diabetes - MRFIT 140 120 100 80 60 40 20 Nondiabetic Diabetic CVD death rate* per 10,000 person-years None One Two Three Number of risk factors *Age adjusted Adapted from Stamler J et al. Diabetes Care. 1993;16:434-444.

Atherosclerosis Timeline Foam cells Fatty streak Intermediate lesion Complicated lesion/rupture Fibrous plaque Atheroma Endothelial dysfunction Atherosclerosis timeline Content points: • The pathological effects of atherosclerosis occur over decades. A subtle injury to the endothelium initiates the atherosclerotic process.3 Injury of the vascular wall and endothelium underlie many stages in atherosclerosis progression from onset through formation of advanced lesions and clinical events.4 • Foam cells infiltrate the vessel and progress to formation of a fatty streak. Small pools of extracellular lipid form within the smooth muscle cell layers, disrupting the intimal lining of the vessel. The formation of atheroma and fibrous plaque, a pearly white area within the artery, disturbs the arterial wall. • The atheroma, or plaque, is composed of lipid, cell debris, smooth muscle cells and collagen (or calcium, in older persons). This type of advanced lesion can be found beginning in the fourth decade of life. Once the plaque becomes fibrous, the danger of rupture increases. • The clinically important complication of atheroma usually involves thrombosis. Most coronary thromboses result from rupture of the protective fibrous cap, which permits contact between the blood and the highly thrombogenic material in the lipid core of the lesion. • Stenoses seldom cause acute MI. Indeed, sizable atheromas may remain silent for decades or produce stable angina due to increased demand. From First Decade From Third Decade From Fourth Decade Thrombosis Hematoma Smooth Muscle & Collagen Growth Mainly by Lipid Accumulation Adapted from Pepine CJ. Am J Cardiol. 1998;82(suppl 10A):23S-27S.

UKPDS: Metformin Study Results in Overweight Patients Conventional A1C = 7.4% A1C = 8.0% Risk* P value Risk* P value 32% .0023 7% NS Any diabetes-related end point 42% .017 20% NS Diabetes-related deaths 39% .01 21% NS Myocardial infarction 41% NS 14% NS Stroke Microvascular disease 29% NS 16% NS *Compared with conventional therapy. . UKPDS Group. Lancet. 1998;352:854-865.

Thiazolidinediones in Diabetes Therapy Mechanism of action reverses underlying etiology TZDs improve insulin sensitivity Glucose control achieved without hypoglycemia TZD monotherapy or metformin combination (no increase in insulin) Possible secondary benefits include: Preservation of pancreatic b-cell function May help reduce progression of disease Protective cardiovascular effects Improve dyslipidemia( ↑HDL,↓TG, ↓LDL density) ↓Renal microalbumin excretion ↓VSMC proliferation and migration in arterial wall Enhance thrombolytic mechanisms

MICRO-HOPE: Primary Outcomes Nonfatal MI Total mortality Stroke CV Death -5 -10 % -15 -20 -25 22%‡ 24%† -30 33%§ -35 *P<.0001 ‡P<.01 §P<.0074 †P<.004 -40 37%* The Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Lancet. 2000;355:253-259.

HOPE and MICRO-HOPE: Event Reductions for Primary End Points and Total Mortality 25% Total mortality 16% 33% Stroke 32% 22% MI 20% 37% CV death 26% 5 10 15 20 25 30 35 40 Percent Diabetic Overall The HOPE Study Investigators. Lancet. 2000;355:253-259.

The Deadly Quartet Insulin Resistance Type 2 Diabetes Hypercoagulability Insulin Resistance Dyslipidemia Hypertension

Recognizing the Insulin-Resistant Patient Insulin resistance is associated with: Abdominal obesity Glucose intolerance First-degree relative with type 2 diabetes Absent nocturnal drop in BP Salt sensitivity History of gestational diabetes Dyslipidemia Hypertension Increased PAI-1/ Platelets Acanthosis nigricans

Nutrition Therapy, Exercise, Lifestyle Changes decrease fat content and total calories decrease saturated fat decrease salt for hypertension healthy diet weight reduction in obese patients Exercise increase energy expenditure with moderate-intensity exercise Lifestyle changes to reduce cardiovascular risk factors (eg, smoking cessation) Training in self-management and SMBG ©1997 PPS

Sulfonylureas: Mechanism of Action 1 Intestine: glucose absorption 2 Muscle and adipose tissue: glucose uptake Insulin resistance Blood glucose 4 Liver: hepatic glucose output Insulin resistance 3 Pancreas: insulin secretion Sulfonylureas insulin secretion DeFronzo RA. Diabetes. 1988;37:667-687. Lebovitz HE. In Joslin's Diabetes Mellitus. 1994:508-529. ©1997 PPS

Meglitinides: Mechanism of Action 1 Intestine: glucose absorption 2 Muscle and adipose tissue: glucose uptake Insulin resistance Blood glucose 4 Liver: hepatic glucose output Insulin resistance 3 Pancreas: insulin secretion Meglitinides Insulin secretion Wolffenbuttel BHR. Eur J Clin Pharmacol. 1993;45:113-116. ©1998 PPS

Metformin: Mechanism of Action 1 Intestine: glucose absorption 2 Muscle and adipose tissue: glucose uptake Metformin glucose utilization Insulin resistance Blood glucose 4 Liver: hepatic glucose output Metformin HGO Insulin resistance 3 Pancreas: insulin secretion ©1997 PPS DeFronzo RA et al. J Clin Endocrinol Metab. 1991;73:1294-1301.

a-Glucosidase Inhibitors: Mechanism of Action 1 Intestine: glucose absorption Acarbose glucose absorption secondary to digestion of carbohydrate 2 Muscle and adipose tissue: glucose uptake Insulin resistance Blood glucose 4 Liver: hepatic glucose output Insulin resistance 3 Pancreas: insulin secretion Amatruda JM. In: Diabetes Mellitus. 1996. ©1997 PPS