Type 2 Diabetes: Disease State Overview AF2086R0

Suggestions for Slide Deck Use The following unbranded slides are provided as a disease state library and may be used as background information at the beginning of any promotional program These slides should always supplement the affirmative deck unless the program is scheduled to be "disease state only"

Diabetes Disease State Overview Diabetes: epidemiology/pathophysiology – Prevalence and burden of diabetes – Core defects of type 2 diabetes – Complications and costs associated with type 2 diabetes – Predicting and preventing type 2 diabetes Treatment goals and strategies – Improving glycemic control – Reducing diabetes-related complications – Treating the whole patient

Every Day in the United States Approximately… *Patients ages ≥20 years. Centers for Disease Control. National Diabetes Fact Sheet. Accessed March 5, people lose their eyesight because of diabetes 66 people lose their eyesight because of diabetes 128 people begin treatment for end-stage renal disease (ESRD) 128 people begin treatment for end-stage renal disease (ESRD) 640 people die from diabetes and its complications 640 people die from diabetes and its complications 195 lower-limb amputations are performed because of diabetes 195 lower-limb amputations are performed because of diabetes More than 4000 new cases* of diabetes will be diagnosed today More than 4000 new cases* of diabetes will be diagnosed today

≈23.5 Million (10.7%) Americans 20 Years or Older Have Diabetes (Diagnosed or Undiagnosed)* *Data is from 2003–2006, projected to year NIDDK. National Diabetes Statistics Available at: Accessed February 11, Age group –3940–5960+ Percentage

*Data is from 2004–2006, projected to year NIDDK. National Diabetes Statistics. November Available at: Accessed February 11, Age group 20–3940–5960+ Number Adults Diagnosed with Diabetes in the United States* 1.6 million new cases of diabetes were diagnosed in people aged 20 years or older in 2007 Total economic costs of diabetes estimated to be $174 billion (2007) 281, , ,000

Age-adjusted Total Prevalence of Diabetes in the United States by Race/Ethnicity (Age ≥20) Non-Hispanic Whites Hispanic/Latino Americans Non-Hispanic Blacks American Indians/Alaska Natives Percentage NIDDK. National Diabetes Statistics. November Available at: Accessed February 11, Asian Americans 8

Economic Consequences of Diabetes Total Annual Cost in 2002: $132 Billion Disability and early mortality $40 billion Diabetes and diabetes supplies $23 billion Chronic complications $25 billion $44 billion General medical conditions Indirect costs* = $40 billionDirect costs † = $92 billion Stolar MW et al. JMCP. 2008;14:S1–S19. *Indirect costs include lost productivity, disability, and premature mortality. † Direct costs include: hospital inpatient care, nursing home care, physician office visits, total home healthcare costs, costs associated with hospice care, and diabetes supplies.

Annual Medical Expenditures and Length of Time with Diabetes Duration of Diabetes (Years) Cost in 2005 (dollars) Diagnosis of diabetes at age 50 Diagnosis of diabetes at age 65 Adapted from Trogdon JG et al. Diabetes Care. 2008;31:2307–2311. Annual cost increases with length of time with diabetes

Pathophysiology of Type 2 Diabetes Type 2 diabetes results from a progressive insulin secretory defect on the background of insulin resistance 1 Key pathophysiologic mechanisms leading to hyperglycemia in type 2 diabetes – Insulin resistance 2,3 – Beta-cell dysfunction 3 1. American Diabetes Association. Diabetes Care. 2009;32:S13–S DeFronzo RA. Med Clin North Am. 2004;88:787– Kahn SE. J Clin Endocrinol Metab. 2001;86:4047–4058.

Two Defects Contributing to Type 2 Diabetes 1. Buchanan TA. Clin Ther. 2003;25(suppl 2):B32–B Kahn SE. J Clin Endocrinol Metab. 2001;86:4047–4058. Type 2 Diabetes Beta-cell Insulinresistance Beta-cell dysfunction Muscle tissueAdipose tissue Obesity (visceral) 1 Pancreas Obesity (visceral) 2 Liver

Natural Progression of Insulin Resistance in Patients with Type 2 Diabetes 1,2 Normal glycemia Insulin resistance rises, leading to beta cells working overtime to secrete more insulin Beta cells are unable to produce the insulin needed to compensate for the increased level of insulin resistance, causing glucose levels to rise, leading to type 2 diabetes* *Type 2 diabetes is diagnosed when FPG is ≥126 mg/dL. 3 Adapted from International Diabetes Center, Minneapolis, MN. 1 Insulin resistance Insulin production & secretion/ Beta-cell function Fasting plasma glucose 1. Bergenstal RM et al. Endocrinology. 4th ed. Philadelphia, PA: WB Saunders Company;2001:821– Ramlo-Halsted BA, Edelman SV. Clin Diab. 2000;18:80– American Diabetes Association. Diabetes Care. 2008;31(suppl1):S12–S54.

Diabetic Retinopathy Leading cause of blindness in adults Diabetic Nephropathy Major cause of kidney failure Cardiovascular Disease Stroke Diabetic Neuropathy Major cause of lower extremity amputations CV Disease & Stroke account for ~65% of deaths in T2D patients Type 2 Diabetes Associated with Serious Complications CV = cardiovascular. National Institute of Diabetes and Digestive and Kidney Diseases. National Diabetes Statistics fact sheet: general information and national estimates on diabetes in the United States, Bethesda, MD: U.S. Department of Health and Human Services, National Institute of Health, 2005.

Prevalence of Multiple Complications Among People with Type 2 Diabetes American Association of Clinical Endocrinologists. State of Diabetes Complications in America Report. Available at: Accessed March 5, 2009.

*In NHANES, “chronic kidney disease" refers to people with microalbuminuria (albumin:creatinine ratio >30 µg/mg). † In the NHANES analysis, "foot problems" includes foot/toe amputations, foot lesions, and numbness in the feet. ‡ "Eye damage" includes a positive response by NHANES participants to the question, "Have you been told diabetes has affected your eyes/had retinopathy?" Retinopathy is damage to the eye's retina. In NHANES, people without diagnosed diabetes were not asked this question, therefore, prevalence information for nondiabetics is not available. CHD = coronary heart disease; CHF = congestive heart failure. Prevalence of Macrovascular and Microvascular Complications of Diabetes MacrovascularMicrovascular American Association of Clinical Endocrinologists. State of Diabetes Complications in America Report. Available at: Accessed March 9, * † ‡

Prevalence of Diabetic Retinopathy *95% CI: 38.8%–41.7% † 95% CI: 7.4%–9.1% ‡ Diabetic retinopathy defined as a retinal vascular disorder characterized by signs of retinal ischemia and/or signs of increased retinal vascular permeability. Retinopathy severity level ≥14 retinopathy and/or macular edema. § Vision threatening retinopathy defined as severe retinopathy and/or diabetic macular edema. Retinopathy severity level ≥50 and/or macular edema. Kempen JH et al. Arch Ophthalmol. 2004;122:552– % † 40.3%* ‡ § Prevalence of retinopathy in diabetics age ≥40 years (%)

Number of Cases with ESRD Due to Diabetic Nephropathy Is Increasing in the United States Number of cases (thousands) Year Diabetes is the leading cause of ESRD ESRD = end-stage renal disease. CDC. Morbidity and Mortality Weekly Report. 2005;54(43)1097–1100.

CV Risk in Patients with Diabetes and No Prior MI Is Similar to Risk in Nondiabetics with Prior MI Schramm TK et al. Circulation. 2008; 117:1945– year incidence (%) CV = cardiovascular. For CV death, the hazard ratio was 2.42 in men with diabetes only and 2.44 in men with a prior MI only ( P= 0.60). Results for women were 2.45 and 2.62, respectively ( P< 0.001). MenWomen A population study of 3.3 million people

Annual National Cost of Type 2 Diabetes and Related Complications* *Cost estimates in this report were adjusted for inflation to reflect 2006 costs. American Association of Clinical Endocrinologists. State of Diabetes Complications in America Report. Available at: Accessed March 5, Cost in billions

Individual Costs by Complication* Annual Healthcare Costs *Cost estimates in this report were adjusted for inflation to reflect 2006 costs. American Association of Clinical Endocrinologists. State of Diabetes Complications in America Report. Available at: Accessed March 5, $ 1785 $ 4687 $ 6062 $ 7806 $ 7932 $ 9002 $ 14,150 $$$$$$$$$ $ 153 $ 480 $ 224 $ 448 $ 510 $ 439 $ ,00012,00014,00016,000 Heart attack Chronic kidney disease CHF Stroke CHD Foot problems Eye damage Total expenditures Out-of-pocket costs

Algorithm to Estimate Type 2 Diabetes Risk ItemPoints Fasting glucose level 100–126 mg/dL, yes/no10 Body mass index (BMI) 25.0–29.9, yes/no2 BMI ≥30.0, yes/no5 High-density lipoprotein cholesterol (HDL-C) level <40 mg/dL in men or <50 mg/dL in women, yes/no 5 Parental history of diabetes mellitus, yes/no3 Triglyceride level ≥150 mg/dL, yes/no3 Blood pressure ≥130/85 mmHg or receiving treatment, yes/no2 According to a study in a middle-aged white population, total points ≥25 corresponds to >35% 8-year risk of type 2 diabetes. Wilson PW et al. Arch Intern Med. 2007;167:1068–1074.

Preventing Development of Type 2 Diabetes Screening for prediabetes and asymptomatic type 2 diabetes should be considered in adults who are overweight or obese (BMI ≥25 kg/m 2 ) and have additional risk factors In those without risk factors, testing should begin at age 45 years If results are normal, testing should be repeated at least every 3 years Counseling on lifestyle modification is recommended for patients with impaired fasting glucose or impaired glucose tolerance – Weight-loss goal of 5%–10% of initial body weight – Physical activity with moderate intensity for 150 minutes per week American Diabetes Association. Diabetes Care. 2009;32(suppl 1):S13–S61.

Summary of Diabetes: Epidemiology/Pathophysiology Diabetes and diabetes-related complications (eg, heart disease, kidney disease, blindness, amputations) are highly prevalent 1 The pathophysiology of diabetes involves the development of insulin resistance and beta-cell dysfunction 2 Diabetes is strongly correlated with a number of microvascular risk factors and diseases, and is a contributor to macrovascular disease and mortality 1 Routine clinical measures may be used to identify patients at risk of developing type 2 diabetes who may benefit from lifestyle counseling 3 1. NIDDK. National Diabetes Statistics. November Available at: Accessed February 11, Kahn SE. J Clin Endocrinol Metab. 2001;86:4047– American Diabetes Association. Diabetes Care. 2009;32(suppl 1):S13–S61.

Diabetes Disease State Overview Diabetes: epidemiology/pathophysiology – Prevalence and burden of diabetes – Core defects of type 2 diabetes – Complications and cost associated with type 2 diabetes – Predicting and preventing type 2 diabetes Treatment goals and strategies – Improving glycemic control – Reducing diabetes-related complications – Treating the whole patient

Criteria for the Diagnosis of Diabetes Mellitus: ADA Standards of Medical Care, 2009 FPG  126 mg/dL (7.0 mmol/L) – Fasting is defined as no caloric intake for at least 8 hours OR Symptoms of hyperglycemia plus casual plasma glucose concentration  200 mg/dL (11.1 mmol/L) – Casual is defined as any time of day without regard to time since last meal – The classic symptoms of hyperglycemia include polyuria, polydipsia, and unexplained weight loss OR 2-h plasma glucose  200 mg/dL (11.1 mmol/L) during an OGTT – The test should be performed as described by WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water ADA = American Diabetes Association; OGTT = oral glucose tolerance test, WHO = World Health Organization. American Diabetes Association. Diabetes Care. 2009;32:S13–S61.

Recommendations for Early Pharmacologic Treatment from AACE and ADA To reduce the risk of serious disease-related complications, 1,2 AACE recommends – Target A1C goal of ≤6.5% 2 – Earlier intervention with appropriate therapies and persistent titration to achieve goal 2 ADA recommends 3 – Target A1C goal of <7% “for most patients” – Achieving and maintaining glycemic goals and changing interventions when therapeutic goals are not being met AACE = American Association of Clinical Endocrinologists. 1. Stratton IM et al. BMJ. 2000;321:405– AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. Endocr Pract. 2007;13(suppl 1):4– American Diabetes Association. Diabetes Care. 2009;32:S13–S61.

United Kingdom Prospective Diabetes Study (UKPDS) Conventional Monotherapies Unable to Maintain Glycemic Control Over Time Median A1C (%) Time from randomization (years) FPG = fasting plasma glucose; MET = metformin. *Conventional therapy defined as dietary advice given at 3-month intervals where FPG was targeted at best levels feasible in clinical practice. If FPG exceeded 270 mg/dL, patients were re-randomized to receive nonintensive MET, chlorpropamide, glibenclamide, or insulin. If FPG exceeded 270 mg/dL again, those on SU would have MET added. If FPG exceeded 270 mg/dL after this, insulin was substituted. Adapted from UK Prospective Diabetes Study (UKPDS 34) Group. Lancet. 1998;352:854–865.

Patients reaching glycemic target Glycemic Targets Are Not Being Achieved Worldwide DICE = Diabetes in Canada Evaluation; NHANES = National Health and Nutrition Examination Surveys; RECAP-DM = Real-life Effectiveness and Care Patterns of Diabetes Management. 1. Harris SB et al. Diabetes Res Clin Pract. 2005;70:90– Ong et al. Ann Epidemol. 2008;18:222– Guisasola et al. Diabetes Obes Metab. 2008;10:8–15. UNITED STATES (NHANES) 2 HbA1c <7% 57% 43% EUROPE (RECAP-DM) 3 HbA1c <6.5% 74% CANADA (DICE) 1 HbA1c <7% 51% 49% 26% Patients not reaching glycemic target

Length of time between first monotherapy (A1C >8.0%) and switch/addition in therapy* *May include uptitration. Based on a prospective, population-based study using retrospective observational data. Brown JB et al. Diabetes Care. 2004;27:1535–1540. Months MET Only SU Only Patients Remain on Monotherapy >2 Years After First A1C >8.0%*

Risk of CV Events or Death Increased with HbA1c Level (EPIC-Norfolk) Age-adjusted relative risk (95% CI) Khaw KT et al. Ann Intern Med 2004; 141:413–420. Men CHD eventsCVD eventsAll-cause mortality CHD eventsCVD eventsAll-cause mortality Women 5–5.4% 5.5–5.9%  7% 6.5–6.9%6.0–6.4%HbA1c level: P  for linear trend across HbA1c categories for all endpoints. CHD = coronary heart disease; CI = confidence interval; CVD = cardiovascular disease; EPIC-Norfolk = European prospective investigation into cancer in Norfolk

Multifactorial Approach: Strategies for Reducing Diabetic Complications—Treating the Whole Patient Strategies for reducing microvascular complications – Routine screening for diabetes – Optimized glycemic control – Optimized BP control Strategies for reducing macrovascular complications – Optimized glycemic control – Treatment of hypertension and other established cardiovascular risk factors in diabetic and possibly prediabetic subjects* – Lipid control* – Antiplatelet therapy* *For appropriate patient population based on treatment guidelines. American Diabetes Association. Diabetes Care. 2008;31(suppl 1):S12–S54.

Stratton IM et al. BMJ. 2000;321:405–412. Improved Glycemic Control Has Been Shown to Help Reduce the Risk of Complications According to the United Kingdom Prospective Diabetes Study (UKPDS) 35, every 1% decrease in A1C resulted in: Decrease in risk of any diabetes-related endpoint ( P <0.0001) 21% Decrease in risk of microvascular complications ( P <0.0001) 37%

UKPDS: Long-Term Intensive Glucose Control in Type 2 Diabetes Multicenter, randomized study with 10-year follow-up 1 – One of the longest and largest type 2 diabetes trials ever conducted 2 – 4209 patients newly diagnosed with type 2 diabetes 1 Study Design – After a 3-month run-in period, patients with FPG >108 mg/dL but <270 mg/dL were randomized to receive either intensive therapy (SU or insulin or, if more than 120% of ideal body weight, MET) or conventional therapy (diet only) 1 Primary study objective – To determine whether long-term improved glycemic control was able to sustain risk reductions in microvascular complications, and if intensive therapy had a long-term effect on macrovascular outcomes 1 Primary outcome – Prespecified aggregate clinical outcomes were any diabetes-related endpoint, diabetes-related death, death from any cause, myocardial infarction, stroke, peripheral vascular disease, and microvascular disease 1 FPG = fasting plasma glucose. 1. Holman et al. N Engl J Med. 2008;359:1577– Lawton J et al. Br J Gen Pract. 2003;53:394–398.

Sustained Intensive Glycemic Control Can Reduce Diabetes-Related Complications Long-term intensive glycemic control is associated with a significantly decreased risk of MI or death from any cause, in addition to known risk reductions in microvascular disease Any diabetes-related endpoint ( P = 0.04 for SU-insulin; P = 0.01 for MET) Microvascular disease ( P = for SU-insulin; P = 0.31 for MET) Myocardial infarction ( P = 0.01 for SU-insulin; P = for MET) Death from any cause ( P = for SU-insulin; P = for MET) SU- insulin MET SU- insulin MET SU- insulin MET SU- insulin MET -21% -24% -15% -13% -16% -33% -27% -9% Holman et al. N Engl J Med. 2008;359:1577–1589. Risk Reductions for Intensive-Therapy Regimens at 10-Year Follow-up

Treating the Whole Patient: Statin Therapy in Patients with Diabetes Reduced CV Risk (CARDS) Relative CV Risk Reduction 37% (95% CI: –52 to –17) Years Atorvastatin Placebo Placebo 127 CV events* Atorvastatin 83 CV events* Cumulative hazard (%) P = *CV events included stroke. CARDS = Collaborative Atorvastatin Diabetes Study. Colhoun HM et al. Lancet. 2004;364:685–696.

Treating the Whole Patient: Patients Reaching Intensive Treatment Goals at 7.8 Years* (Steno-2) Intensive therapy (n = 80) † Conventional therapy (n = 80) ‡ A1C <6.5% Patients (%) Cholesterol <175 mg/dL Triglycerides <150 mg/dL Systolic BP <130 mmHg Diastolic BP <80 mmHg P = 0.06 P <0.001 P = 0.19 P = P = *Mean. † Intensive treatment included stepwise implementation of behavior modification and pharmacologic therapy that targeted hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, along with secondary prevention of cardiovascular disease with aspirin. ‡ Conventional treatment was based on the Danish Medical Association guidelines. Gæde et al. N Engl J Med. 2003;348:383–393.

Treating the Whole Patient: Intensive Therapy Reduced Composite Macrovascular Endpoints (Steno-2) Primary composite endpoint* (%) Intensive therapy Conventional therapy HR † = 0.47 (95% CI, ) 53% Months of Follow-up *Composite endpoint of death from cardiovascular causes, nonfatal myocardial infarction, coronary-artery bypass grafting, percutaneous coronary intervention, nonfatal stroke, amputation, or surgery for peripheral atherosclerotic artery disease, P =0.007; † Unadjusted HR. CI = confidence interval; HR = hazard ratio. Gæde et al. N Engl J Med. 2003;348:383–393.

Treating the Whole Patient: a 5.5-Year * Follow-up (Steno-2) Intensive Therapy Sustains Cardiovascular Benefits Cumulative Incidence of Any Cardiovascular Event † (%) Intensive therapy Conventional therapy Years of Follow-up *Mean. † Secondary composite endpoint of cardiovascular events, including death from cardiovascular causes, nonfatal stroke, nonfatal myocardial infarction, coronary-artery bypass grafting, percutaneous coronary intervention, revascularization for peripheral atherosclerotic artery disease, and amputation. Gæde et al. N Engl J Med. 2008;358:580– HR 0.41 (95% CI, 0.25 to 0.67; P <0.001) 59%

*High risk patients are those with acute coronary syndromes or previous cardiovascular events. AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; ADA = American Diabetes Association; EASD = European Association for the Study of Diabetes; HDL = high-density lipoprotein; LDL = low-density lipoprotein. 1. ADA Standards of Medical Care in Diabetes – Diabetes Care. 2009;32:S13–S American Association of Clinical Endocrinologists. Endocrine Practice. 2007;13(suppl 1):3–68. Management of Type 2 Diabetes Type 2 diabetes requires a multifactorial approach for the management of glucose levels, blood pressure, and lipids to reduce complications 1 Recommendations for type 2 diabetes: Lifestyle Modification Hypertension Dyslipidemia: LDL Dyslipidemia: HDL HbA1c Goal Combination therapy within 3 mo if not at HbA1c goal ADA/EASD 1 Target <130/80 mmHg Target LDL <100 mg/dL (<70 mg/dL for high- risk patients * ) Target HDL >40 mg/dL in men, >50 mg/dL in women <7% ACE/AACE 2 Target <130/80 mmHg Target LDL <100 mg/dL (<70 mg/dL for high- risk patients * ) Target HDL >40 mg/dL in men, >50 mg/dL in women ≤6.5%

Summary of Treatment Goals and Strategies Glycemic control is fundamental to the management of diabetes 1 The UKPDS demonstrated significant risk reductions in microvascular complications in type 2 diabetes with more intensive glycemic control. The benefit of A1C–lowering to reduce CVD in type 2 diabetes is supported by UKPDS data 2 There is a need to treat the whole patient, including management of hyperglycemia, CV risk factors and other comorbidities. This is key in reducing diabetes-related complications 3 1. AACE. Endocr Pract. 2007;13(suppl 1):4– Stratton IM et al. BMJ. 2000;321:405– American Diabetes Association. Diabetes Care. 2008;31(suppl 1):S12–S54.

Conclusions: Management of Type 2 Diabetes Diabetes is a major clinical problem – Pathophysiology involves insulin resistance and beta-cell dysfunction 1 Diabetes is correlated with increased risk of microvascular and macrovascular diseases and events – Microvascular complications are predominately driven by hyperglycemia 2,3 – Macrovascular complications are multifactorial and complex 4 1. Kahn SE. J Clin Endocrinol Metab. 2001;86:4047– AACE. Endocr Pract. 2007;13(suppl 1):4– Stratton IM et al. BMJ. 2000;321:405– American Diabetes Association. Diabetes Care. 2008;31(suppl 1):S12–S54.

Conclusions: Management of Type 2 Diabetes (cont) A1C reduction has been shown to reduce the risk of microvascular complications and may contribute to risk reduction of macrovascular endpoints 1 Early intervention is needed to get A1C to goal (diet and exercise should always be recommended) 2 It is challenging to maintain A1C control over time with traditional monotherapies 3 AACE and ADA * guidelines recommends use of combination therapy to achieve and sustain glycemic goals 2,4 *ADA guidelines recommend that a second medication should be added within 3 months if patients are not at goal. 1. Stratton IM et al. BMJ. 2000;321:405–412; 2. American Diabetes Association. Diabetes Care. 2008;31(suppl 1):S12–S54; 3. UKPDS. Lancet. 1998;352:854–865; 4. AACE. Endocr Pract. 2007;13(suppl 1):4–68.