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Clinical Imperatives When Treating Patients with Diabetes

Clinical Imperatives When Treating Patients with Diabetes. ≥200 – 140 to 199 (ADA) >140 to <200 (AACE). Diabetes, IFG, IGT: Diagnostic criteria. Plasma glucose (mg/dL). Fasting. 2-hr postload*. Casual. ≥126 100 to 125 (ADA) >110 to <126 (AACE) –. Diabetes

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Clinical Imperatives When Treating Patients with Diabetes

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  1. Clinical Imperatives When Treating Patients with Diabetes

  2. ≥200 – 140 to 199 (ADA) >140 to <200 (AACE) Diabetes, IFG, IGT: Diagnostic criteria Plasma glucose (mg/dL) Fasting 2-hr postload* Casual ≥126 100 to 125 (ADA) >110 to <126 (AACE) – Diabetes Impaired fasting glucose (IFG) Impaired glucose tolerance (IGT) ≥200 – – *Following equivalent of 75 g anhydrous glucose in water ADA. Diabetes Care. 2006;29(suppl 1):S43-8.AACE. Endocr Pract. 2003;9:240-52.

  3. AHA/ACC/ADA: Multiple risk reduction in diabetes • ASA: Age >40 yr or with other risk factors, all with CV disease history • ACE inhibitor: Age >55 yr with another CV risk factor Pearson T et al. Circulation 2002.Grundy SM et al. Circulation 2004.ADA. Diabetes Care 2006.

  4. AACE: Managing diabetes Intensive glycemic control Intensive management of comorbid conditions* • A1C ≤6.5% • Glucose (mg/dL) • Preprandial ≤110 • Postprandial ≤140 • Lipid modifying • BP lowering • ASA for prevention of vascular events American Association of Clinical Endocrinologists Lifestyle intervention • Optimal nutrition • Physical activity • Smoking cessation • Weight control *Dyslipidemia, hypertension, early renal disease AACE. Endocr Pract. 2002;8(suppl 1):40-65.

  5. AHA/ACC secondary prevention guidelines:Diabetes management A1C goal <7% • Initiate lifestyle and pharmacotherapy to achieve near-normal A1C (IB) • Begin vigorous modification of other risk factors (eg, physical activity, weight management, BP control, cholesterol management) (IB) • Coordinate diabetic care with patient’s primary care physician or endocrinologist (IC) Smith SC et al. Circulation. 2006;113:2363-72.

  6. DPP: Benefit of diet/exercise or metformin on diabetes prevention in at-risk patients N = 3234 with IFG/IGT without diabetes 40 Placebo P 30 Metformin < 0.001 31% Cumulative incidence of diabetes (%) 20 Lifestyle 58% < 0.001 10 0 0 1.0 2.0 3.0 4.0 Years DPP Research Group. N Engl J Med. 2002;346:393-403.

  7. DPP: Benefit of diet/exercise or metformin on diabetes by race/ethnicity N = 3234 with IFG/IGT and without diabetes African American n = 645 American Indian n =171 White n = 1768 Hispanic n = 508 Asian n =142 0 -20 Reduction in new-onset diabetes(%) -40 -60 -80 Lifestyle vs metformin Lifestyle vs placebo Metformin vs placebo DPP Research Group. N Engl J Med. 2002;346:393-403.

  8. 3-Week diet + exercise yield favorable metabolic changes N = 31 overweight/obese men; weight 8.4 lbs μU/mL Baseline Follow-up *P < 0.01 †P < 0.05 Roberts CK. et al. J Appl Physiol. 2006;100:1657-65.

  9. 3-Week diet + exercise reduce proatherogenic factors N = 31 overweight/obese men; weight 8.4 lbs † * † pg/mL mg/L * † 8-iso-PGF2α Baseline Follow-up MPO = myeloperoxidase; 8-iso-PGF2α = 8-isoprostaglandin F2α sICAM-1 = soluble intracellular adhesion molecule 1 *P < 0.05; †P < 0.01 Roberts CK. et al. J Appl Physiol. 2006;100:1657-65.

  10. Beyond lifestyle: Aggressive medical therapy in diabetes StatinsFibric acid derivatives Dyslipidemia Atherosclerosis ACE inhibitorsARBs β-blockersCCBsDiuretics Hypertension MetforminTZDsSulfonylureasNonsulfonylureasSecretagogues Insulin Hyperglycemia Insulin resistance Platelet activationand aggregation ASAClopidogrelTiclopidine Adapted from Beckman JA et al. JAMA. 2002;287:2570-81.

  11. Steno-2 supports aggressive multifactorial intervention in type 2 diabetes • Objective: Target-driven, long-term, intensified intervention aimed at multiple risk factors compared with conventional therapy • N = 160 patients with type 2 diabetes and microalbuminuria • Intensive treatment targets • BP <130/80 mm Hg • A1C <6.5% • Total-C <175 mg/dL • Triglycerides <150 mg/dL Gæde P et al. N Engl J Med. 2003;348:383-93.

  12. Steno-2: Multifactorial intervention on CV outcomes 53% RRR†P = 0.01 N = 160 with type 2 diabetes and microalbuminuria 60 50 Conventional Primary composite outcome* (%) 40 30 20 Intensive 10 0 0 12 24 36 48 60 72 84 96 Follow-up (months) *CV death, MI, stroke, CABG/PCI, amputation, PAD surgery †Adjusted for duration of diabetes, age, sex, smoking, CV disease Gæde P et al.N Engl J Med. 2003;348:383-93.

  13. Steno-2: Better risk factor control with intensive therapy Conventional therapy (n = 80) Intensive therapy (n = 80) 170 350 P < 0.001 P < 0.001 160 300 150 250 SBP(mm Hg) Total-C(mg/dL) 140 200 130 150 120 100 110 50 0 0 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 350 11 P = 0.015 P < 0.001 300 10 250 9 TG (mg/dL) AlC(%) 200 8 150 7 100 6 50 5 0 0 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 Follow-up (years) Follow-up (years) Gæde P et al. N Engl J Med. 2003;348:383-93.

  14. Steno-2: Effects of multifactorial intervention on microvascular and neuropathic outcomes Variable RR P Intensive better Conventionalbetter 0.39 Nephropathy 0.003 Reductions in the risk of microvascular complications were maintained at 8 years Retinopathy 0.42 0.02 Autonomicneuropathy 0.37 0.002 Peripheralneuropathy 1.09 0.66 0.0 0.5 1.0 1.5 2.0 2.5 Relative risk Gæde P et al. N Engl J Med. 2003;348:383-93.

  15. Benefits of aggressive LDL-C lowering in diabetes Primary event rate (%) Aggressive lipid-lowering better Aggressive lipid-lowering worse Difference in LDL-C(mg/dL) Treatment Control P TNT Diabetes, CHD ASCOT-LLA Diabetes, HTN CARDS Diabetes, no CVD HPS All diabetes Diabetes, no CVD 13.8 9.2 5.8 9.4 9.3 17.9 11.9 9.0 12.6 13.5 0.026 0.036 0.001 <0.0001 0.0003 22* 35† 46† 39† 39† 0.75 0.77 0.63 0.73 0.67 0.5 0.7 0.9 1 1.7 Relative risk *Atorvastatin 10 vs 80 mg/day †Statin vs placebo Shepherd J et al. Diabetes Care 2006. Sever PS et al. Diabetes Care 2005. HPS Collaborative Group. Lancet 2003. Colhoun HM et al. Lancet 2004.

  16. HPS: Statin beneficial irrespective of baseline lipid level and diabetes status Heart Protection Study Event rate (%) Simvastatin n = 10,269 Placebo n = 10,267 Statin better Placebo better LDL-C <116 mg/dL With diabetes 15.7 20.9 No diabetes 18.8 22.9 LDL-C ≥116 mg/dL With diabetes 23.3 27.9 No diabetes 20.0 26.2 24% reductionP < 0.0001 All patients 19.8 25.2 0.4 0.6 0.8 1.0 1.2 1.4 Event rate ratio HPS Collaborative Group. Lancet. 2003;361:2005-16.

  17. ASCOT-LLA: Atorvastatin reduces CV events in patients with diabetes and hypertension N = 2532, baseline LDL-C 128 mg/dL 14.0 Placebo 23% Risk reduction P = 0.036 12.0 10.0 8.0 % 6.0 Atorvastatin 10 mg 4.0 2.0 HR = 0.77 (0.61–0.98) 0 Years 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Number at risk 1258 1231 1209 1191 1171 1065 699 370 Placebo 1274 1237 1219 1200 1175 1058 714 375 Atorvastatin Nonfatal MI, CV mortality, UA, stable angina, arrhythmias, stroke, TIA, PAD, retinal vascular thrombosis, revascularization Sever PS et al. Diabetes Care. 2005;28:1151-7.

  18. MICRO-HOPE, PERSUADE: ACEI reduces CV events in diabetes MICRO-HOPE (n = 3577) CV death/MI/stroke PERSUADE (n = 1502) CV death/MI/cardiac arrest 25 25 Placebo Placebo 25% RRR P = 0.0004 19% RRR P = 0.13 20 20 Primary outcome (%) 15 15 Ramipril 10 mg Perindopril 8 mg 10 10 5 5 0 0 0 1 2 3 4 5 0 1 2 3 4 5 Follow-up (years) Follow-up (years) HOPE Study Investigators. Lancet. 2000;355:253-9. Daly CA et al. Eur Heart J. 2005;26:1369-78.

  19. TZD + statin: Favorable effects on inflammatory markers and adiponectin ROSI 4 mg ROSI 4 mg + ATORVA 10 mg N = 30 with DM2 and hyperlipidemia treated with rosiglitazone; add-on atorvastatin after 3 months; follow-up 6 months * * † Change from baseline (%) * * * † * Adiponectin † *P < 0.05 vs baseline; †P < 0.05 vs ROSI monotherapy Chu C-S et al. Am J Cardiol. 2006;97:646-50.

  20. Principal mechanisms of action for oral diabetic agents α-Glucosidase inhibitors Thiazolidinediones Muscle and adipose tissue: ↓insulin resistance ↑glucose uptake Intestine: ↓glucose absorption Biguanides Blood glucose Liver: ↓hepatic glucose output ↑glucose uptake Pancreas: ↑insulin secretion Sulfonylureas and repaglinide Adapted from Krentz AJ, Bailey CJ. Drugs. 2005;65:385-411.

  21. Oral antihyperglycemic agents Trujillo J. Formulary. 2006;41:130-41. Luna B, Feinglos MN. Am Fam Physician. 2001;63:1747-56.

  22. Beyond glucose lowering: Effects of antidiabetic agents NA = data not available *Sulfonylureas and meglitinides AGI = alpha glucosidase inhibitor  = no change Adapted from Granberry MC, Fonseca VA.Am J Cardiovasc Drugs. 2005;5:201-9.

  23. TZD vs sulfonylurea: Glycemic control over time N = 203 patients with type 2 diabetes A1C Fasting plasma glucose 250 10.0 9.5 9.0 % mg/dL 200 8.5 8.0 7.5 0 0 -8 -4 0 4 8 12 16 28 40 52 Treatment week ROSI 8 mg/d GLYB Baseline Week 8 Week 52 GLYB = glyburide St. John Sutton M et al. Diabetes Care. 2002;25:2058-64.

  24. TZD + sulfonylurea efficacy in type 2 diabetes 160 † * 80 0 * -20 N = 102; changes after 16 weeks HOMA-IR Intact proinsulin CRP Adiponectin‡ %Change * * † † GLIM GLIM+ ROSI 4 mg GLIM + ROSI 8 mg *P < 0.05 vs baseline †P < 0.005 vs baseline ‡Adjusted for BMI changes GLIM = glimepiride 3 mg; ROSI = rosiglitazone Pfützner A et al. Metabol Clin Exp. 2006;55:20-5.

  25. PROactive: Reduced requirement for insulin use 25 Placebon = 362 (21%) 20 53% RRR HR 0.47 (0.39–0.56)*P < 0.0001 15 Patients(%) 10 Pioglitazonen = 183 (11%) 5 0 0 6 12 18 24 30 36 Follow-up (months) *Unadjusted Dormandy JA et al. Lancet. 2005;366:1279-89.

  26. Sulfonylurea + TZD or metformin: Comparison of lipid and renal effects N = 639 with poorly controlled DM2; change after 52 weeks † † Change(%) ‡ † * Metformin 850–2550 mg + sulfonylurea Pioglitazone 15–45 mg + sulfonylurea *P = 0.008, †P < 0.001, ‡P = NS Hanefeld M et al. Diabetes Care. 2004;27:141-7.

  27. TZDs and metformin reduce risk of MI Case-control study of first MI in patients with type 2 diabetes n Insulin-sensitizing drugs Sulfonylureamonotherapy P Patients Controls Monotherapy Metformin 38 87 0.01 TZD 7 19 0.03 Combination therapy TZD + sulfonylurea 7 18 0.04 Metformin + sulfonylurea 40 62 0.19 0 0.2 0.4 0.6 0.8 1.0 1.2 Odds ratio for MI (95% CI)* *Adjusted for age, sex, BMI, ACE inhibitor use, history of hypertension or hypercholesterolemia Sauer WH et al. Am J Cardiol. 2006; 97:651-4.

  28. Improving blood glucose control: Potential role of combination therapy Patients reaching A1C goal(%) ADA Goal <7% AACE Goal 6.5% Metformin 1 g/dayUptitrated to 2 g/day Rosiglitazone 8 mg/day +Metformin 1 g/day 7.9 277 8.0 296 Baseline A1C (%) = n = Adapted from Weissman P et al. Curr Med Res Opin. 2005;21:2029-2035.

  29. DPP-IV inhibitors • Potentially important in early DM2 to prevent deterioration of glucose metabolism • Decrease rate of GLP-1 degradation • Partially restore impaired insulin secretion • Protect -cells • Oral DPP-IV inhibitors in phase 3 development • Sitagliptin • Vildagliptin DPP-IV = dipeptidyl peptidase-IV GLP-1 = glucagon-like peptide-1 Smyth S, Heron A. Nat Med. 2005;12:75-80.

  30. DPP-IV inhibitors, GLP-1 analogs: New classes of antidiabetic agents GLP-1: An incretin hormone GLP-1 is released after meals Glucose-dependent insulin secretion from -cells Levels in type 2 diabetes (“incretin defect”) Rapidly inactivated by DPP-IV New antidiabetic agents: Dual actions GLP-1 analogs DPP-IV inhibitors Glucose-dependent insulin secretion Resistant to DPP-IV degradation GLP-1 degradation Glucose-dependent insulin secretion Mest H-J, Mentlein R. Diabetologia. 2005;48:616-20. Smyth S, Heron A. Nat Med. 2005;12:75-80.

  31. AMIGO trials: GLP-1 analog in type 2 diabetes AC 2993: Diabetes Management for Improving Glucose Outcomes; 30-week, placebo-controlled trials of exenatide sc added to oral hypoglycemic therapy 1Buse JB et al. Diabetes Care. 2004;27:2628-35.2DeFronzo RA et al. Diabetes Care. 2005;28:1092-100.3Kendall DM et al. Diabetes Care. 2005;28:1083-91.

  32. Managing diabetes as a CHD equivalent: ABCs of coronary prevention D Diet Don’t smoke Decrease diabetes risk E Exercise Adapted from Cohen JD. Lancet. 2001;357:972-3.

  33. Proatherogenic effects of insulin resistance Insulin resistance Hypertension Obesity Inflammation Hyperinsulinemia Diabetes Dyslipidemia Thrombosis Atherosclerosis

  34. Summary: Expanding risk factor control to enhance CV outcomes • Insulin resistance is an independent risk factor for atherosclerosis • Aggressive lifestyle modification and pharmacotherapy can decrease CV risk and prevent new-onset diabetes • TZDs target insulin resistance and appear to improve CV risk factors

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