1. 1 Diabetes Mellitus Evidence and Guidelines Andrew P. DeFilippis, Ty J. Gluckman, James Mudd, Catherine Campbell, & Roger S. Blumenthal

2. 2 AGE=Advanced glycation end products, CRP=C-reactive protein, CHD=Coronary heart disease HDL=High- density lipoprotein, HTN=Hypertension, IL-6=Interleukin-6, LDL=Low-density lipoprotein, PAI-1=Plasminogen activator inhibitor-1, SAA=Serum amyloid A protein, TF=Tissue factor, TG=Triglycerides, tPA=Tissue plasminogen activator Subclinical Atherosclerosis Atherosclerotic Clinical Events Hyperglycemia  AGE  Oxidative stress Inflammation  IL-6  CRP  SAA Infection  Defense mechanisms  Pathogen burden Insulin Resistance HTN Endothelial dysfunction Dyslipidemia  LDL  TG  HDL Thrombosis  PAI-1  TF  tPA Disease Progression Biondi-Zoccai GGL et al. JACC 2003;41:1071-1077 Mechanisms by which Diabetes Mellitus leads to CHD

3. 3 Consists of a constellation of major risk factors, life- habit risk factors, and emerging risk factors Over-represented among populations with CVD Often occurs in individuals with a distinctive body-type including an increased abdominal circumference The Metabolic Syndrome

4. 4 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497 Risk FactorDefining Level Waist circumference (abdominal obesity)>40 in (>102 cm) in men >35 in (>88 cm) in women Triglyceride level>150 mg/dl HDL-C level<40 mg/dl in men <50 mg/dl in women Blood pressure>130/>85 mmHg Fasting glucose>100 mg/dl ATP III Definition of the Metabolic Syndrome Defined by the presence of >3 risk factors HDL-C=High-density lipoprotein cholesterol

5. 5 40–49 Ford ES et al. JAMA 2002;287:356-359 Prevalence, % 20–70+ Age, yrs 20–29 30–39 50–59 60–69  70 National Health and Nutrition Examination Survey (NHANES) Metabolic Syndrome: Prevalence in U.S. Adults Men Women

6. 6 CHD Prevalence No MS/No DM 54% MS/No DM 29% DM/No MS 2% DM/MS 15% 8.7% 13.9% 7.5% 19.2% Metabolic Syndrome: CHD Prevalence* National Health and Nutrition Examination Survey (NHANES) % of Population = Alexander CM et al. Diabetes 2003;52:1210-1214 *Among individual >50 years CHD=Coronary heart disease, DM=Diabetes mellitus, MS=Metabolic syndrome

7. 7 0 1 2 3 4 CVD * CHD † 012345 Mortality hazard ratio Number of Metabolic Syndrome Criteria * Adjusted for age, sex, race or ethnicity, education, smoking status, non–HDL-C level, recreational and non-recreational activity, white blood cell count, alcohol use, prevalent heart disease, and stroke † Similar adjustments except for prevalent stroke Ford ES et al. Atherosclerosis 2004;173:309-314 Metabolic Syndrome: Risk of Death CHD=Coronary heart disease, CVD=Cardiovascular disease Risk is Proportional to the Number of ATP III Criteria

8. 8 Tuomilehto J et al. NEJM 2001;344:1343-1350 Intervention Control 11% 23% % with Diabetes Mellitus Metabolic Syndrome: Risk of Developing DM Finnish Diabetes Prevention Study † Defined as a glucose >140 mg/dl 2 hours after an oral glucose challenge 522 overweight (mean BMI=31 kg/m 2 ) patients with impaired fasting glucose † randomized to intervention ‡ or usual care for 3 years Lifestyle modification reduces the risk of developing DM ‡ Aimed at reducing weight (>5%), total intake of fat ( 15 g/1000 cal); and physical activity (moderate at least 30 min/day)

9. 9 Metabolic Syndrome: Risk of Developing DM Diabetes Prevention Program (DPP) Knowler WC et al. NEJM 2002;346:393-403 *Includes 7% weight loss and at least 150 minutes of physical activity per week Placebo Metformin Lifestyle modification Incidence of DM (%) 0 20 30 10 40 0 0 1423 Years 3,234 patients with elevated fasting and post-load glucose levels randomized to placebo, metformin (850 mg bid), or lifestyle modification* for 3 years Lifestyle modification reduces the risk of developing DM

10. 10 Metabolic Syndrome: Risk of Developing DM Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) Trial Gerstein HC et al. Lancet 2006;368:1096-1105 CVD=Cardiovascular disease, DM=Diabetes mellitus, IFG=Impaired fasting glucose, IGT=Impaired glucose tolerance 0.6 0.4 0.2 0.0 01234 Placebo Rosiglitazone Incident DM or Death Years 60% RRR, P<0.0001 5,269 patients with IFG and/or IGT, but without known CVD randomized to rosiglitazone (8 mg) or placebo for a median of 3 years Thiazolidinediones reduce the risk of developing DM

11. 11 Diabetes Mellitus: Lifetime Risk Narayan et al. JAMA 2003;290:1884-1890

12. 12 Mokdad AH et al. JAMA 2003;289:76-79 Diabetes Mellitus: Prevalence in U.S. Adults

13. 13 10 9 20 11 9 6 38 19 3* 30 Total CVDCHDCardiac failure Intermittent claudication CVA Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Disease. Ruderman N et al, eds. Oxford; 1992. P<0.001 for all values except *P<0.05 Risk ratio MenWomen 0 2 4 10 8 6 Age-adjusted Annual Rate/1000 Diabetes Mellitus: Risk of CVD Events CHD=Coronary heart disease, CVD=Cardiovascular disease Framingham Heart Study: 30 year follow-up

14. 14 Haffner SM et al. NEJM 1998;339:229–234 Patients with DM but no CHD experience a similar rate of MI as patients without DM but with CHD Events*/100 person-years Prior CHD 45 DM No DM No prior CHD 50 40 30 20 10 0 19 20 3.5 Diabetes Mellitus: Risk of Myocardial Infarction *Fatal or non-fatal MI CHD=Coronary heart disease, DM=Diabetes mellitus, MI=Myocardial infarction

15. 15 01 2 34 56 7 8 20 40 60 80 100 Nondiabetic subjects without prior MI Diabetic subjects without prior MI Nondiabetic subjects with prior MI Diabetic subjects with prior MI Years Survival (%) Diabetes Mellitus: Risk of Death Haffner SM et al. NEJM 1998;339:229–234 Patients with DM but no CHD experience a similar rate of death as patients without DM but with CHD CHD=Coronary heart disease, DM=Diabetes mellitus, MI=Myocardial infarction

16. 16 WOMEN MEN Sprafka JM et al. Diabetes Care 1991;14:537-543 100 80 60 40 0 Survival (%) Months Post-MI No diabetes n=228 n=1628 Months Post-MI 0204060 Diabetes 80 020406080 Diabetes No diabetes n=156 n=568 Survival post-MI in Diabetics and Non-diabetics Minnesota Heart Survey MI=Myocardial infarction

17. 17 % relative risk reduction P=0.03 P<0.01 P=0.05 P=0.02 UKPDS Group. Lancet 1998;352:837-853 A lower HbA 1c is associated with reduced vascular risk in diabetics Intensity of Glucose Control in DM in UKPDS DM=Diabetes mellitus, HbA 1C =Glycosylated hemoglobin

18. 18 * Death from CV causes, nonfatal MI, CABG, PCI, nonfatal stroke, amputation, or surgery for PAD Primary Endpoint* (%) Months of Follow-Up 20 1224364860728496 Intensity of Risk Factor Control in DM STENO-2 Study 40 60 0 Intensive Therapy † Conventional Therapy † Aggressive treatment of dyslipidemia, hyperglycemia, hypertension, microalbuminuria, and secondary prevention of CV disease Gaede P et al. NEJM 2003;348:383-393 CABG=Coronary artery bypass graft surgery, CV=Cardiovascular, DM=Diabetes mellitus MI=Myocardial infarction, PAD=Peripheral artery disease, PCI=Percutaneous coronary intervention 160 patients with type 2 DM randomized to targeted intensive multifactorial intervention † or conventional treatment of CV risk factors for 8 years Lifestyle modification reduces the risk of developing DM HR=0.47, P=0.008

19. 19 Goals Recommendations Diabetes Mellitus Guidelines Goal HbA1C <7% Intensive lifestyle modification to prevent the development of DM (especially in those with the metabolic syndrome) Aggressive management of CV risk factors Hypoglycemic Rx to achieve a normal to near normal fasting plasma glucose as defined by the HbA1C Weight reduction and exercise Oral hypoglycemic agents Insulin therapy Coordination of diabetic care with the patient’s primary physician and/or endocrinologist CV=Cardiovascular, DM=Diabetes mellitus, HbA1C=Glycosylated hemoglobin, Rx=Treatment