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The Link Between

The Link Between. Diabetes and Atherosclerosis. Overview and Clinical Considerations Highlighting Results of the Diabetes Sub-Study of the Heart Protection Study. Problems and Challenges in Managing Type 2 Diabetes Mellitus.

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The Link Between

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  1. The Link Between Diabetes and Atherosclerosis Overview and Clinical ConsiderationsHighlighting Results of the Diabetes Sub-Study of the Heart Protection Study

  2. Problems and Challenges in Managing Type 2 Diabetes Mellitus • The Problem Atherosclerosis is a prominent but underappreciated complication associated with diabetes mellitus • The ChallengeTherapies to reduce CHD risk are effective. Our challenge is to routinely apply the available therapies to adult patients with diabetes mellitus, in conjunction with appropriate glucose control CHD = coronary heart disease Adapted from Folsum AR et al Diabetes Care 1997;20:935-942; American Diabetes Association DiabetesCare 2002;25(suppl 1):S33-S49.

  3. Type 2 Diabetes Prevalence Is Projected to Reach 300 Million by 2025 • About 155 million adults worldwide diagnosed with diabetes in 2000 • 83 million women and 72 million men • Between 1995 and 2025, the prevalence of diabetes in adults will increase by 35% and the number of people with diabetes will increase by 122% EUROPE 2000: 30.8M 2025: 38.5M ASIA 2000: 71.8M 2025: 165.7M JAPAN 2000: 6.9M 2025: 8.5M USA 2000: 15M 2025: 21.9M AFRICA 2000: 9.2M 2025: 21.5M AMERICAS (Ex-US) 2000: 20M 2025: 42M OCEANIA 2000: 0.8M 2025: 1.5M Adapted from King H et al Diabetes Care 1998;21:1414-1431.

  4. Atherosclerosis Is Common in Newly Diagnosed Diabetes Mellitus • CVDs are common causes of morbidity and mortality in people with diabetes • >50% of patients with newly diagnosed type 2 diabetes show evidence of CVD • Atherosclerosis is a major cause of death among patients with diabetes mellitus • 75% from coronary atherosclerosis • 25% from cerebral or peripheral vascular disease • >75% of hospitalizations for individuals with diabetes are for atherosclerotic disease CVD = cardiovascular disease Adapted from Amos AF et al Diabet Med 1997;14:S7-S85; Hill Golden S Adv Stud Med 2002;2:364-370; Haffner SM et al N Engl J Med 1998;339:229-234; Sprafka JM et al Diabetes Care 1991;14:537-543.

  5. 67% Two-Thirds of People with Diabetes Die of CVD • Among people with diabetes, macrovascular complications, including CHD, stroke, and peripheral vascular disease, are the leading causes of morbidity and mortality Causes of mortality in people with diabetes CHD, stroke, and peripheral vascular disease Other Adapted from Alexander CM, Antonello S Pract Diabet 2002;21:21-28.

  6. Mortality Following First MI in People with and without Diabetes • Many patients with diabetes will not survive their first MI With diabetes Without diabetes 50 44%* 37%* 40 33% 30 Mortality rate (%) 20% 20 10 n=437 n=2699 n=183 n=743 0 Men Women 1 Year, hospitalized and nonhospitalized Time post-first MI MI = myocardial infarction *p<0.001 Adapted from Miettinen H et al Diabetes Care 1998;21:69-75.

  7. People with Diabetes Have MI Risk Levels Comparable to People with Prior MI 25 20% 19% 20 15 Incidence of fatal or nonfatal MI (%) 10 5 0 Diabetes (no prior MI) (n=890) Prior MI (no diabetes) (n=69) Patient type • Patients with diabetes without previous MI have as high of a risk of MI as nondiabetic patients with previous MI • These data provide a rationale for treating cardiovascular risk factors in diabetic patients as aggressively as in nondiabetic patients with prior MI Adapted from Haffner SM et al N Engl J Med 1998;339:229-234.

  8. People with Diabetes Have Increased Cardiovascular Risk Factors Risk factor Type 1 Type 2 Dyslipidemia Small, dense LDL +++ Increased apoB + ++ Low HDL +/– ++ Hypertriglyceridemia ++ ++ Hypertension + ++ Hyperinsulinemia/insulin resistance + ++ Central obesity – ++ Family history of atherosclerosis – + Cigarette smoking – – + = moderately increased compared with nondiabetic population; ++ = markedly increased compared with nondiabetic population;– = no increase compared with nondiabetic population; LDL = low-density lipoprotein; apoB = apolipoprotein B; HDL = high-density lipoprotein Adapted from Chait A, Bierman EL. In: Joslin's Diabetes Mellitus. 13th ed. Philadelphia: Lea & Febiger, 1994:648-664.

  9. Greater Risk of Death with Diabetes and One Risk Factor than with No Diabetes and Three Risk Factors* 140 Diabetes No diabetes 120 100 Age-adjusted CVD death rate per 10,000 person-years 80 60 40 20 0 None One only Two only All three Risk factors *Serum cholesterol >200 mg/dl, smoking, systolic blood pressure >120 mmHg Adapted from Stamler J et al Diabetes Care 1993;16:434-444.

  10. Patients with Diabetes and Low Cholesterol Had Higher Risk of Cardiovascular Mortality than Those without Diabetes and High Cholesterol 160 DiabetesNo diabetes 140 120 Cardiovascular mortality per 10,000 person-years 100 80 60 40 20 0 <4.7 4.7–5.1 5.2–5.7 5.8–6.2 6.3–6.7 6.8–7.2 7.3 Total cholesterol (mmol/L) Adapted from Stamler J et al Diabetes Care 1993;16:434-444.

  11. “Normal” LDL-C Levels in People with Diabetes Can Be Misleading...Small, Dense LDL-C Particles Are More Atherogenic apoB LDL-C No diabetes Diabetes LDL particles LDL particles Small, dense LDL with more apoB “Normal” LDL-C level, however: “Normal” LDL-C level Number of LDL particles Concentration of apoB Higher Lower CHD risk Adapted from Austin MA, Edwards KL Curr Opin Lipidol 1996;7:167-171; Austin MA et al JAMA 1988;260:1917-1921; Sniderman AD et al Diabetes Care 2002;25:579-582.

  12. In People with Diabetes, Macrovascular Complications Are Two Times Greater than Microvascular Complications 25 20% 20 15 People with diabetes developing complications within 9 years of diagnosis (%) 9% 10 5 n=5102 n=5102 0 Macrovascular complications Microvascular complications Adapted from Turner R et al Ann Intern Med 1996;124:136-145.

  13. In UKPDS Intensive Glucose Control Significantly Reduced Microvascular Disease Rate* Conventional Intensive glucose glucose control control % Risk (n=2729) (n=1138) reduction p Macrovascular events MI 17.4 14.7 16 0.052 Stroke 5.0 5.6 –11 NS PVD 1.6 1.1 35 NS Diabetes-related death 11.5 10.4 10 NS All-cause mortality 18.9 17.9 6 NS Microvascular events 11.4 8.6 25 0.0099 All events** 46.0 40.9 12 0.029 NS = not significant; PVD = peripheral vascular disease*Per 1000 patient-years**Combined microvascular and macrovascular events Adapted from United Kingdom Prospective Diabetes Study Group (UKPDS) Lancet 1998;352:837-853.

  14. In UKPDS LDL-C Was the Strongest Predictor of CHD Risk in People with Diabetes % Increase in CHD risk LDL-C  of 1 mmol/L 57 HDL-C  of 0.1 mmol/L –15 Systolic blood pressure  of 10 mmHg 15 HbA1c level  of 1% 11 Smoking was also a major contributor to CHD risk These data support the need for reducing LDL-C to lower CHD riskin people with diabetes mellitus. Glucose control is also important in reducing the risk of microvascular complications. Adapted from Turner RC et al BMJ 1998;316:823-828.

  15. Lipid Guidelines for Patients with DiabetesAmerican Diabetes Association Guidelines Patients with diabetes need lipid-lowering therapy because effective management of blood glucose only modestly improves plasma levels of LDL-C or HDL-C. Dietary therapy Drug treatment Adults with diabetes LDL goal initiation level initiation level Without CHD <100 mg/dl 100 mg/dl 130 mg/dl With CHD <100 mg/dl 100 mg/dl 100 mg/dl “...people with type 2 diabetes typically have a preponderance of smaller, denser, LDL particles, which possibly increases atherogenicity….” Adapted from American Diabetes Association Diabetes Care 2002;25(suppl 1):S33-S49; American Diabetes Association Diabetes Care 2002;25(suppl 1):S74-S77.

  16. Lipid Guidelines for Patients with DiabetesEuropean Societies “…patients with diabetes, the [cholesterol] treatment goals should be lower….” • CHD risk increases with diabetes • LDL-C goal: <100 mg/dl (2.5 mmol/L) • For patients with diabetes or established CVD Adapted from De Backer G et al Eur Heart J 2003;24:1601-1610.

  17. Lipid Guidelines for Patients with DiabetesNational Cholesterol Education Program (NCEP) Intensive CHD prevention strategy is warranted [for patients with diabetes], with LDL-C as a primary treatment target • Diabetes is a CHD risk equivalent • Diabetes confers same risk of CHD as does prior history of CHD • Patients with diabetes have unusually high death rates following MI Dietary therapy Drug treatmentAdults with diabetes LDL goal initiation level initiation level With or without CHD <100 mg/dl 100 mg/dl 130 mg/dl (100–129 mg/dl: drug optional) Adapted from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults JAMA 2001;285:2486-2497.

  18. Lipid Guidelines for Patients with Diabetes International Atherosclerosis Society “Patients with diabetes experience significant CVD risk reduction with control of other risk factors . . . including LDL-C.” • All patients should undergo therapeutic lifestyle changes Drug treatment Drug treatmentAdults with diabetes LDL goal recommended optional High risk* <100 mg/dl 100 mg/dl <100 mg/dl Multiple risk factors** <130 mg/dl 130 mg/dl <130 mg/dl *High-risk patients include those with established CHD (history of MI, stable or unstable angina, or coronary artery procedures), noncoronary forms of atherosclerotic disease, or multiple risk factors (10-year risk >20%). **Risk factors that modify LDL-C goals are smoking, hypertension, low HDL-C, and advanced age (men 45 years; women 55 years). Adapted from International Atherosclerosis Society. Harmonized clinical guidelines on prevention of atherosclerotic vascular disease. Available at: http://www.athero.org/download/guidelines.pdf.

  19. Heart Protection StudyDiabetes Sub-Study • Almost 6000 men and women, aged 40–80 years with diabetes mellitus • 1981 persons with history of CHD • 3982 persons with no history of CHD • People randomized to simvastatin 40 mg or placebo • Mean duration of follow-up—five years • Objective—to evaluate the long-term benefits of simvastatin and/or antioxidantsin people with diabetes withor without CHD regardless of cholesterol level • Primary endpoints—first major coronary events* and first major vascular events** • Statin not considered clearly indicated or contraindicated by patients’ primary physicians *Nonfatal MI or death from coronary disease **Major coronary events, stroke of any type, and coronary or noncoronary revascularizations Adapted from Heart Protection Study Collaborative Group Eur Heart J 1999;20:725-741; Heart Protection Study Collaborative Group Lancet 2002;360:7-22; Heart Protection Study Collaborative Group Lancet 2003;361:2005-2016.

  20. Impact of Simvastatin on LDL-CNine Out of 10 Patients with Diabetes Achieved Goal* 92% 91% 100 80 60 Patients (%) 40 20 n=3985** n=1978** 0 Without CHD With CHD • Results from the five-year Heart Protection Study (HPS) of almost 6000 patients with diabetes with or without CHD indicated that 92% of patients with diabetes, but without CHD, and 91% of patients with CHD who received simvastatin 40 mg achieved the European Guidelines LDL‑C treatment goal of <3 mmol/L (115 mg/dl)*** *By the four-month point in HPS **These populations differ from those reported in later HPS publications (3982 and 1981) because three patients were reclassified after the four-month point. The percentages of patients achieving LDL-C goal are not affected.***Based on random sampling of patients with diabetes Adapted from Armitage J, Collins R Heart 2000;84:357-360.

  21. Placebo Simvastatin Impact of Simvastatin on First Major Vascular EventsAll Patients and Patients with Diabetes 24% risk reduction(p<0.0001) 22% risk reduction(p<0.0001) 30 25.2 25.1 20.2 19.8 20 Patients with major vascular events by year 5 (%) 2585patients with events 749patients with events 2033 patients with events 601 patients with events 10 n=10,267 n=10,269 n=2985 n=2978 0 All patients* Patients with diabetes *Includes patients with CHD, occlusive disease of noncoronary arteries, diabetes, or treated hypertension Adapted from Heart Protection Study Collaborative Group Lancet 2002;360:7-22; Heart Protection Study Collaborative Group Lancet 2003;361:2005-2016.

  22. Placebo Simvastatin Impact of Simvastatin on First and Subsequent Major Vascular EventsAll Patients and Patients with Diabetes 85 events avoided per 1000 patients taking simvastatin 91 events avoided per 1000 patients taking simvastatin 371 360 400 286 269 300 Number of first and subsequent major vascular events per 1000 patients by year 5 2585patients with 3697 events 748patients with 1109events 200 2033 patients with 2763 events 601 patients with 852events 100 n=10,267 n=10,269 n=2985 n=2978 0 All patients* Patients with diabetes *Includes patients with CHD, occlusive disease of noncoronary arteries, diabetes, or treated hypertension Adapted from Heart Protection Study Collaborative Group Lancet 2003;361:2005-2016.

  23. Impact of Simvastatin on First Major Vascular EventsSignificant Risk Reduction Within 2 Years 1.4 1.2 1.0 Risk ratio(±95% CI) * 0.8 * 22% risk reduction(p<0.0001) 0.6 0.4 Year 2 Year 3 Year 4 Year 5+ Allfollow-up Year 1 *Risk reduction was less pronounced in years 4 and 5 because by study end, one-third of placebo-allocated patients were taking a statin and about one-sixth of patients randomized to simvastatin had stopped their statin therapy. The increased risk reduction in years 2 and 3 would have likely continued if the patients remained compliant. Adapted from Heart Protection Study Collaborative Group Lancet 2002;360:7-22; Heart Protection Study Collaborative Group. Available at: http://www.ctsu.ox.ac.uk/~hps/. Accessed November 4, 2003.

  24. Impact of Simvastatin in Patients with DiabetesMajor Coronary Events, Stroke, and Revascularization Placebo Simvastatin 27%risk reduction* 17%risk reduction*** 15 12.6 24%risk reduction** 10.4 9.4 10 8.7 Patients with event by year 5 (%) 6.5 5.0 5 n=2985 n=2978 n=2985 n=2978 n=2985 n=2978 0 Major coronary event Stroke Revascularization *p<0.0001; **p<0.01; ***p=0.02 Adapted from Heart Protection Study Collaborative Group Lancet 2003;361:2005-2016.

  25. Impact of Simvastatin in Patients with Diabetes and No Prior CVDMajor Vascular Events 33% risk reduction(p=0.0003) 15 13.5 9.3 10 Patients with major vascular events by year 5 (%) 5 n=1457 n=1455 0 Placebo Simvastatin Adapted from Heart Protection Study Collaborative Group Lancet 2003;361:2005-2016.

  26. Impact of Simvastatin in Patients with Diabetes With Low LDL-C 27% risk reduction (p=0.0007) Placebo Simvastatin 25 20.9 20 30% risk reduction (p=0.05) 15.7 15 Patients with major vascular events by year 5 (%) 11.1 10 8.0 5 n=1207 n=1219 n=668 n=675 0 Baseline LDL-C<3.0 mmol/L Baseline LDL-C<3.0 mmol/L without CVD Adapted from Heart Protection Study Collaborative Group Lancet 2003;361:2005-2016.

  27. Placebo Simvastatin Impact of Simvastatin in Patients with Diabetes With or without Optimal Glycemic Control 21% risk reduction (p=0.002) 21% risk reduction (p=0.002) 30 27.5 22.6 22.6 18.3 20 Patients with major vascular events by year 5 (%) 10 n=1355 n=1334 n=1595 n=1610 0 Suboptimal glycemic control (HbA1c7.0%) Optimal glycemic control (HbA1c <7.0%) Adapted from Heart Protection Study Collaborative Group Lancet 2003;361:2005-2016.

  28. Impact of Simvastatin in Patients with DiabetesWith or without Treated Hypertension or Obesity Regardless of treated hypertension Regardless of bodymass index Placebo Simvastatin 22% risk reduction* 17% risk reduction* 21% risk reduction* 22% risk reduction* 29.1 30 30 24.0 24.0 23.6 22.3 20.3 Patients with major vascular events by year 5 (%) 19.6 17.9 20 20 10 10 n=1783 n=1782 n=1202 n=1196 n=646 n=629 n=1123 n=1060 0 0 Without treatedhypertension With treated hypertension Lean Obese *p<0.05 Adapted from Heart Protection Study Collaborative Group Lancet 2003;361:2005-2016.

  29. Impact of Simvastatin in Patients with DiabetesBy Age and Gender Placebo Simvastatin Regardless of age Regardless of gender 21% risk reduction* 21% risk reduction* 40 40 31.6 24% risk reduction* 25% risk reduction* 27.8 30 30 25.9 22.8 Patients with major vascular events by year 5 (%) 20.1 18.6 20 20 15.7 14.2 10 10 n=1696 n=1675 n=1289 n=1303 n=2083 n=2064 n=902 n=914 0 0 Age <65 years Age 65 years Male Female *p<0.05 Adapted from Heart Protection Study Collaborative Group Lancet 2003;361:2005-2016.

  30. In Over 20,000 Patients in HPSSimvastatin 40 mg Had a Safety Profile Comparable to Placebo 100 10 8 5.1% Patients (%) 4.8% 6 4 2 0 Placebo(n=10,267) Simvastatin (n=10,269) Discontinuations due to any adverse event Adapted from Heart Protection Study Collaborative Group Lancet 2002;360:7-22.

  31. In Over 20,000 Patients in HPSSimvastatin 40 mg Comparable to Placebo Incidence of Muscle Pain Percentage of patients with muscle pain over the study duration Year1 2 3 4 5 6 Simvastatin 40 mg 5 6 6 6 6 7 Placebo 5 6 6 6 7 7 • The risk of myopathy* with simvastatin 40 mg was 0.01% above placebo on an annualized basis *Myopathy defined as muscle symptoms plus creatine kinase >10 times the upper limit of normal Adapted from Heart Protection Study Collaborative Group Lancet 2002;360:7-22.

  32. In Over 20,000 Patients in HPSImpact of Simvastatin 40 mg on Renal Function Placebo Simvastatin –2.2(p<0.05) –1.8(p<0.0001) 15 12.9 –1.7(p<0.001) 10.7 10 8.9 Increase in plasma creatinine concentration (µmmol/L) 7.4 7.1 5.7 5 n=7697 n=7999 n=2172 n=2291 n=5525 n=5708 0 All patients Patients withdiabetes Patients withoutdiabetes Adapted from Heart Protection Study Collaborative Group Lancet 2003;361:2005-2016.

  33. Lipid Lowering in Patients with DiabetesConclusions • Patients with diabetes have an alarming rate of CHD events, and many do not survive their first MI • LDL-C has been identified in UKPDS and by all major guidelines as a primary target for reducing CHD risk in patients with diabetes • In UKPDS, intensive glucose control significantly reduced microvascular events such as retinopathy; however, it produced a modest and nonsignificant reduction in macrovascular events, such as MI and stroke • Patients with diabetes need lipid-lowering therapy because effective management of blood glucose only modestly improves plasma levels of LDL-C or HDL-C; this improvement frequently does not meet levels recommended by guidelines Adapted from American Diabetes Association Diabetes Care 2002;25(suppl 1):S33-S49; Miettinen H et al Diabetes Care1998;21:69-75; Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults JAMA 2001;285:2486-2497; United Kingdom Prospective Diabetes Study Group Lancet 1998;352:837-853; American Diabetes Association Diabetes Care 2002;25(suppl 1):S74-S77; De Backer G et al Eur Heart J 2003;24:1601-1610.

  34. Heart Protection Study Major Medical Conclusions In almost 6000 patients with diabetes • Over 90% reached the European Guidelines LDL-C goal on simvastatin 40 mg* • Simvastatin significantly reduced the risk of • Major vascular events by 22% (p<0.0001) • Stroke by 24% (p=0.01) • Revascularization by 17% (p=0.02) • Benefits of simvastatin were evident regardless of CHD history, blood glucose control, baseline LDL-C, hypertension status, obesity, age, and gender • Simvastatin therapy was well tolerated and had a safety profile comparable to placebo *By the four-month point in HPS, based on random sampling of patients with diabetes Adapted from Heart Protection Study Collaborative Group Lancet 2002;360:7-22; Armitage J, Collins R Heart2000;84:357-360; Heart Protection Study Collaborative Group Lancet 2003;361:2005-2016.

  35. Heart Protection StudyMedical Implications • Based on the results of HPS, simvastatin 40 mg daily shouldbe considered routinely for patients with diabetes • Simvastatin 40 mg is the only statin proven in a wide range of patients with diabetes to • reduce the risk of major coronary events • reduce the risk of stroke • reduce the risk of both coronary and noncoronary revascularization • reduce the risk of developing peripheral macrovascular complications (including peripheral revascularization, limb amputations, and leg ulcers) Adapted from Heart Protection Study Collaborative Group Lancet 2003;361:2005-2016.

  36. Treatment Strategies for Patients with Diabetes Treatment goals for diabetes should include • Optimum glycemic control and elimination of hyperglycemia-related symptoms • Dietary and lifestyle changes • Exercise • Medication • Prevention of microvascular complications • Control of glycemia • Control of blood pressure • Monitoring and screening • Prevention of CHD, MI, and other macrovascular complications • Control dyslipidemia:  LDL-C,  HDL-C,  TG • Dietary and lifestyle changes and exercise • Drug therapy with statins Adapted from Powers AC. In Harrison’s Principles of Internal Medicine. 15th ed. New York: McGraw-Hill, 2001:2109-2137; American Diabetes Association Diabetes Care 2002;25(suppl 1):S74-S77.

  37. References Please refer to notes page.

  38. References(cont’d) Please refer to notes page.

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