Click Here & Upgrade Expanded Features PDF Unlimited Pages Documents Complete Cardiovascular Risk in Type 2 Diabetes: New Therapeutic Approaches Barry J. Goldstein, MD, PhD Professor of Medicine, Biochemistry, and Molecular Pharmacology Jefferson Medical College of Thomas Jefferson University Thomas Jefferson University Hospital Philadelphia, Pennsylvania Cardiovascular Risk in the Spectrum of Type 2 Diabetes • Association of type 2 diabetes with CVD • Opportunities for intervention – Provide aggressive and early treatment – Manage glucose along with CV risk factors • Newer agents may prove useful – Exenatide (GLP-1 agonist) – Dual PPAR α/γ agonists (in development) Type 2 diabetes increases the risk of CVD ~ 70-80% of diabetes-related deaths are due to CVD § Any CVD event § Stroke Claudication § † † Cardiac failure § † CHD ‡ Males with diabetes ‡ MI § Females with diabetes Angina pectoris Sudden death * N/A † Coronary mortality † 1 2 3 4 5 6 Age-adjusted risk ratio (relative to non-diabetic individuals) *P < 0.1; † P < 0.05; ‡ P < 0.01; § P < 0.001 Adapted from Kannel WB, et al . Am Heart J 1990; 120:672–676. 1
Click Here & Upgrade Expanded Features PDF Unlimited Pages Documents Complete Metabolic Syndrome: A Network of Atherogenic Factors Type 2 Diabetes and Glycem ic Disorders Atherosclerosis Insulin Dyslipidem ia Resistance - Low HDL - Small, dense LDL ↑ FFA Visceral - Hypertriglyceridem ia Obesity ↑ Cytokines Hypertension Endothelial dysfunction ↓ Adiponectin / inflammation I mpaired thrombolysis - ↑ PAI-1 Goldstein BJ et al. Am J Car diol. 2002 Causes of Hyperglycemia in Type 2 Diabetes 92% of patients with T2DM have insulin resistance Increased glucose Insufficient glucose production disposal ↑ Glucose X Liver Muscle Pancreas Impaired insulin secretion Multiple Factors Affect Function in Predisposed β -Cells Type 2 diabetes Hyperglycemia (glucose toxicity) Insulin Resistance Visceral Obesity Protein Glycation β -cell Oxidative stress “Lipotoxicity” (elevated FFA, TG) Reaven Physiol Rev. 1995;75:473; Unger Ann Rev Med 2002;53:319. 2
Click Here & Upgrade Expanded Features PDF Unlimited Pages Documents Complete Diabetes Mellitus Impairs Endothelial Function 3000 2500 Lean W hole body 2000 Obese glucose uptake 1500 ( µm ol/ m 2 / min) NIDDM 1000 500 0 10 100 1000 10 000 100 000 Serum I nsulin ( pm ol/ m L) 5.0 Lean 4.5 4.0 Leg blood flow Obese 3.5 ( dL/ m in) NIDDM 3.0 2.5 2.0 10 100 1000 10 000 100 000 Serum I nsulin ( pm ol/ L) Laakso M et al. Diabetes. 1992; 41 : 1076–1083. Endothelial Dysfunction and Vascular Disease Normal Endothelium Abnormal Endothelium HTN Diabetes AII LDL Smoking ↑ TG ↓ HDL Dysfunction Barrier to LDL Vascular Tone Lipid Vasoconstriction Retention Retard Inhibit SMC ↑ Platelet/ Platelet and SMC Migration and Leukocyte Leukocyte Migration and Proliferation Adhesion Adhesion Proliferation After Vogel RA. Am J Med. 1999;107:479-487. Modifying disease progression through treatment Obesity IGT Diabetes (Uncontrolled) Prediabetes Type 2 diabetes What should treatment Macrovascular complications Microvascular complications aim to do? Postprandial Plasma glucose 126 (mg/dl) Fasting Insulin resistance Insulin level Relative 100 function Diabetes duration (years) –20 –10 0 10 20 30 Adapted from Bergenstal RM, et al. Diabetes mellitus, carbohydrate metabolism and lipid disorders. In Endocrinology . 4th ed. 2001. 3
Click Here & Upgrade Expanded Features PDF Unlimited Pages Documents Complete A Continuum of Glycemia and CV Risk? Evidence for No Glycemic Threshold � No A1C threshold is apparent � Finnish study by Kuusisto et al � UKPDS epidemiologic analysis � EPIC-Norfolk Study � Impaired glucose tolerance (IGT) and postprandial hyperglycemia are CV risk factors � Funagata Diabetes Study � Honolulu Heart Program � DECODE Study � Rancho Bernardo Study 10 FPG and 2-h PG Predict Mortality in Persons Not Known to Have Type 2 Diabetes DECODE Study FPG Categories 2-h PG Categories All subjects, n= 25,000 Subjects with FPG < 110, n= 20,500 Adjusted Hazard Ratios 2.0 1.9 2 2 1.7 1.6 1.2 1.0 1.0 1 1 0 0 < 110 110–125 126–139 > 140 < 140 140–200 > 200 2-h PG (mg/ dL) FPG (mg/ dL) FPG= fasting plasma glucose. DECODE Study Group. Lancet . 1999; 3 54: 617-621. ADA, AACE and IDF glycemic goals Biochemical index IDF 4 ADA 1,2 AACE 3 (Global) < 6.5 < 6.5 HbA 1c (%) < 7 mmol/l mg/dl mmol/l mg/dl mmol/l mg/dl Fasting/preprandial 5.0–7.2 < 110 < 6.0 90–130 < 110 < 6.0 plasma glucose Postprandial < 180 < 10.0 < 140 < 7.8 NA NA plasma glucose Bedtime plasma 110–150 NA NA NA 6.0–8.3 NA glucose 1 American Diabetes Association. Diabetes Care 2004; 27:S15–S35. 2 American Diabetes Association. Diabetes Care 2002; 25:S35–S49. 3 American Association of Clinical Endocrinologists. Endocrine Pract 2002; 8 (Suppl. 1):40–82. 4 http://www.idf.org/webdata/docs/IDF%20GGT2D.pdf. 4
Click Here & Upgrade Expanded Features PDF Unlimited Pages Documents Complete Majority of type 2 diabetes patients in US and EU have inadequate glycemic control US 1 EU 2 100 100 80 80 69% Subjects (%) Subjects (%) 64% 60 60 36% 40 40 31% 20 20 0 0 ≥ 7% < 7% ≤ 6.5% > 6.5% HbA 1c (%) HbA 1c (%) 1 Koro CE, et al . Diabetes Care 2004; 27:17–20. 2 Liebl A. Diabetologia 2002; 45:S23–S28. Patients remain on monotherapy > 1 year after first HbA 1c > 8.0%* Mean time between first HbA 1c > 8.0% and switch/addition in therapy (months)* 25 20.5 months 20 14.5 months 15 10 5 0 Metformin only Sulfonylurea only n = 513 n = 3,394 *May include uptitration Brown JB, et al . Diabetes Care 2004; 27:1535–1540. Conservative management of glycemia: traditional stepwise approach OAD OAD + Diet and OAD* monotherapy OAD OAD + multiple daily exercise monotherapy uptitration combination basal insulin insulin injections 10 HbA 1c (%) 9 8 HbA 1c = 7% 7 HbA 1c = 6.5% 6 Duration of diabetes Adapted from Campbell IW. Br J Cardiol 2000; 7:625–631. *OAD = oral antidiabetic 5
Click Here & Upgrade Expanded Features PDF Unlimited Pages Documents Complete Proactive management of glycemia: early combination approach Diet and exercise OAD monotherapy 10 OAD OADs combinations uptitration HbA 1c (%) OAD 9 OAD + multiple daily + basal insulin insulin injections 8 HbA 1c = 7% 7 HbA 1c = 6.5% 6 Duration of diabetes *OAD = oral antidiabetic Del Prato S, et al. Int J Clin Pract 2000; 7:625–631. Major Oral Therapy Options for Type 2 Diabetes Rosiglitazone Pioglitazone Metformin ↑ Glucose X Liver Muscle Pancreas Insulin GLP-1 agonists secretagogue (Exendin) (sulfonylureas) The atherosclerotic process Dyslipidemia and plaque rupture � LDL-C and thrombosis monocyte adhesion (MMP-9, PAI-1) and migration endothelial dysfunction plaque and inflammation formation LDL oxidation foam cell macrophage smooth muscle cell formation differentiation and proliferation and inflammation migration Modified from Plutzky J, et al . J Diabetes Complications 2002; 16:401–405. 6
Click Here & Upgrade Expanded Features PDF Unlimited Pages Documents Complete Metformin Advantages Disadvantages • Unique mechanism of action • GI side effects in up to 50% • High initial response rate • Not tolerated in up to 4% • “Insulin-sparing” with rare hypoglycemia • Risk of lactic acidosis • Long record of safety • Contraindicated in patients with impaired • Limited weight gain renal function and • Decreased macrovascular congestive heart failure complications with monotherapy as observed in UKPDS DeFronzo. Ann Intern Med. 1999;131:281-303. Inzucchi. JAMA. 2002;287:360-372. UKPDS Intensive Therapy Risk Decrease: Benefit of Metform in P = 0.002 P = 0.017 P = 0.011 P = 0.01 32% 42% 36% 39% Decrease Any diabetes- Diabetes- All-cause MI related related mortality end point mortality American Diabetes Association. Diabetes Care . 1999;22(suppl 1):S27-S31. UKPDS Group. Lancet . 1998;352:854-865. Effect of Metformin on Cardiovascular Risk Factors Meta-analysis of 32 studies involving a total of 2452 patients Hgb A1c -0.80% decrease P<0.00001 Blood pressure N.S. HDL-C N.S. Triglycerides 10 mg/dL decrease P=0.03 Total Chol 7.7 mg/dL decrease P=0.0002 LDL-C 8.4 mg/dL decrease P=0.00001 Wulffele et al., Br J Clin Pharmacol 2002 May 7
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