Eugene Barrett M.D., Ph.D. University of Virginia 6/18/2007. Diagnosis and what is it Glucose Tolerance Categories FPG

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1 Diabetes Mellitus: Update 7 What is the unifying basis of this vascular disease? Eugene J. Barrett, MD, PhD Professor of Internal Medicine and Pediatrics Director, Diabetes Center and GCRC Health System Charlottesville, VA, U.S.A. 1 1 mg/dl 1 mg/dl Diagnosis and what is it Glucose Tolerance Categories FPG Diabetes Mellitus Impaired Fasting Glucose Normal 7. mmol/l 5.7 mmol/l mg/dl 14 mg/dl -Hour PG on OGTT Diabetes Mellitus Impaired Glucose Tolerance Normal Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;: mmol/l 7.8 mmol/l Prevalence of Diabetes among US women (CDC Virginia 5.- 7%, 1997) Background Retinopathy % Affected mg/dl mmol/L Fasting Plasma 4 Glucose Type 1 Type Etiologic Classification of Diabetes Mellitus Other specific types Gestational β-cell destruction with lack of insulin resistance with insulin deficiency Genetic defects in β-cell function, exocrine pancreas diseases, endocrinopathies, drug- or chemicalinduced, and other rare forms resistance with β-cell dysfunction Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;: Diabetes is a Common Disease : Estimated Prevalence of Diabetes in the US: 3 Adult Men and Women Percent of Population Harris, et al. Diabetes Care. 1998;1:518-54, with permission Age (y) Men Women 1

2 Percent of Population Estimated Prevalence of Diabetes in the US: Breakdown by Ethnicity Diagnosed Undiagnosed Prevalence of gestational diabetes in UK Non-Hispanic White African American Hispanic American Data from Harris, et al. Diabetes Care. 1998;1: Diabetes An expensive disease Retinopathy- Microvascular Disease Direct and indirect costs of diabetes estimated to be $1 Billion annually in the USA in Costs to most health systems is -3 fold greater annually for patients with diabetes % Affected mg/dl mmol/L Fasting Plasma 1 Glucose Framingham Heart Study 3-Year Follow-Up: CVD Events in Patients With Diabetes (Ages 35-4) Risk ratio 8 4 Men 3 38 Women Total CHD Cardiac Intermittent Stroke CVD failure claudication Age-adjusted annual rate/1, P<.1 for all values except *P<.5. Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Disease. Ruderman N et al, eds. Oxford; * Women, Diabetes, and CHD Diabetic women are at high risk for CHD Diabetes eliminates relative cardioprotective effect of being premenopausal risk of recurrent MI in diabetic women is three times that of nondiabetic women Age-adjusted mean time to recurrent MI or fatal CHD event is 5.1 yr for diabetic women vs 8.1 yr for nondiabetic women Kannel WB. Am Heart J. 1985;11: Abbott RD et al. JAMA. 1988;:

3 RR CVD 1. Exercise and CVD in women 1.7 Manson et al NEJM (1) 71, Adjusted for age and walking time P<.1 for trend Rare walking < mph -3 mph 3-4 mph >4 mph N= 1,89 1,9 3, Walking Pace (mph) among walkers.4 13 CHD in Diabetes Multiple risk factors present (Type ) Atherosclerosis pathologically similar in DM but more extensive and extends distally Higher prevalence at an earlier age in DM. Higher event rate and mortality post-mi CHF more common (especially in women) Ischemia more frequently silent Responses to invasive interventions are generally poorer in DM patients. 14 Multiple Risk Factors in DM and Resistance Syndrome Type 1 Fatal CVD Risk Hypertension is common High triglycerides and low HDL-cholesterol Proteinuria appears to be an identifying risk factor in DM1 and DM Inflammatory markers increased (hscrp, VCAM, PAI-1 others) Endothelial dysfunction is common in DM Autonomic neuropathy Diabetic cardiomyopathy 15 Endothelial Functions Arterial and capillary endothelial functions: Conduit vessels - Smooth, quiescent surface to avoid activation of clotting factors, chemokines, platelets, and adhesion factors Resistance vessels - Regulate systemic blood pressure NO, EDHF, endothelins, prostacyclins, etc. Pre-capillary arterioles - Regulate flow distribution within a tissue 17 Capillaries regulate nutrient exchange 18 3

4 Endothelial Dysfunction in Diabetes Mellitus In Type DM, measurement of post-ach flow was decreased in 15/1 studies, and postischemic in 3/3 (~3 control and 3 type patients) In Type 1 DM measurement of post-ischemic conduit vessel was decreased in 5/8 studies ( ~5 control and 5 type 1 patients overall) 19 5 Year Event Rates - HPS - DM Known CAD No CAD -1 4S: Subgroup With IFG (FG mg/dl or.1-.9 mmol/l) Total mortality Coronary mortality Major coronary events Revascularizations Simvastatin 33.4% 13.8% - Placebo P 37.8% <.1 18.% <.1 Δ in events (%) P=.1-43 P= P=.5 1 Haffner SM et al. Diabetes. 1998;(suppl 1):A54. Abstract. CARDS - Treatment Effect on the Primary Endpoint Event Primary endpoint Placebo* Atorva* 17 (9.%) 83 (5.8%) Hazard Ratio Relative Risk (CI) -37% (-5, -17) p=.1 Acute coronary events 77 (5.5%) 51 (3.%) -3% (-55, -9) Coronary revascularisation Stroke 34 (.4%) 4 (1.7%) -31% (-59, +1) 39 (.8%) 1 (1.5%) -48% (-9, -11) * N (%) with an event Favors Atorvastatin Favors Placebo 3 4 4

5 ACE Inhibition in DM Hope Trial Ramipril Placebo (n=188) (n=179) P Combined MI Stroke CV Death UKPDS Blood Pressure Control blood pressure control reduced risk for any diabetes-related endpoint 4% p=.4 diabetes-related deaths 3% p=.19 stroke 44% p=.13 microvascular disease 37% p=.9 heart failure 5% p=.43 retinopathy progression 34% p=.38 deterioration of vision 47% p=.3 5 Diabetes Related Deaths (cumulative) 144 of 1148 patients (13%) % of patients with an event % 15% 1% 5% % Less tight BP control (n=39) Beta blocker (n=358) ACE inhibitor (n=4) Less tight vs Tight p=.19 ACE vs Beta blocker p= Years from randomisation 7 8 Glucose Control Study Summary UKPDS The intensive glucose control policy maintained a lower HbA 1c by mean.9 % over a median follow up of 1 years from diagnosis of type diabetes with reduction in risk of: 1% for any diabetes related endpoint p=.9 5% for microvascular endpoints p=.99 1% for myocardial infarction p=.5 4% for cataract extraction p=.4 1% for retinopathy at twelve years p=.15 33% for albuminuria at twelve years p=.54 9 Microvascular Summary Glycemic control can slow progression or reverse microalbuminuria ACEs and ARBs can lower BP and slow progression or reverse microalbuminuria ACEs and ARBs slow the decline in Scr in DM patients with albuminuria and delay or prevent ESRD 3 5

6 Summary Recommendations Summary Recommendations Education of patients so they know their ABCs (A1C, Blood Pressure, Cholesterol) Lifestyle issues Diet-Heart healthy diet (<7% sat. fat, < 3% total fat), with balanced whole grain carbs, fruits and vegetables. Exercise 3-4 min most days of the week Drug treatment ASA All over 4 y.o. unless contraindicated BP ACEs, ARBs slow the decline in Scr in DM patients with albuminuria and delay or prevent ESRD, diuretic, beta blockers Lipids LDL-C < 7 with known CVD, < 1 otherwise Glucose A1C <7 and as close to normal as can be safely achieved 31 3 Achieving Glucose Goal of A1C <7 and as close to normal as can be safely achieved Oral agents: Metformin Sulfonylureas Alphaglucosidase inhibitors Thiazolidinedion es DPP-IV inhibitors Inhaled insulin Injectable agents Short acting analogs Regular insulin Intermediate insulin (NPH) Long acting analogs Exanitide Diabetes a preventable disease Several trials of diabetes prevention have been conducted for type 1 diabetes using vaccine strategies. None have yet been successful For Type diabetes, multiple trials successfully demonstrated that both lifestyle changes and pharmacologic interventions can delay or prevent diabetes among individuals at high risk Pramlintide Study Da Qing F/U Yr Prevention of DM DM Control 8% Incidence Diet Exercise 44% Risk Reduction 31% Diabetes and Vascular Disease Vascular pathology is the underlying lesion of Diabetes ASCVD remains the major cause of mortality and morbidity in DM DPS 4 Yr 3% 11% 58% Microvascular disease is a leading cause of blindness and ESRD DPP 3 Yr 9% 14% 58% Aggressive Rx and introduction of preventive strategies (lipid, BP, ACE, ASA) is warranted in all DM patients 35 3