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Diabetes Mellitus 101 for Cardiologists (and Alike): 2015

Diabetes Mellitus 101 for Cardiologists (and Alike): 2015. An Aggressive Pathophysiologic Approach to Therapy of Type 2 Diabetes in Cardiometabolic Patients: Looking at Diabetes Medications with a Cardiologists Eye. Part 5. Stan Schwartz MD,FACP Affiliate, Main Line Health System

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Diabetes Mellitus 101 for Cardiologists (and Alike): 2015

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  1. Diabetes Mellitus 101 for Cardiologists (and Alike): 2015 An Aggressive Pathophysiologic Approach to Therapy of Type 2 Diabetes in Cardiometabolic Patients: Looking at Diabetes Medications with a Cardiologists Eye Part 5 Stan Schwartz MD,FACP Affiliate, Main Line Health System Emeritus, Clinical Associate Professor of Medicine, U of Pa. 6105472000

  2. Treatment of Type 2 Diabetes:Pathophysiology

  3. Natural History of Type 2 Diabetes Age 0-15 15-40+ 15-50+ 25-70+ Envir.+ Other Disease Genes Macrovascular Complications Obesity (visceral) Poor Diet Inactivity IR phenotypeAtherosclerosisobesityhypertensionHDL,TG, HYPERINSULINEMIA Endothelial dysfunctionPCO,ED Disability Insulin Resistance MICVAAmp pp>7.8 DEATH IGT Type II DM  Beta Cell Secretion BlindnessAmputationCRF EyeNerveKidney Risk of Dev. Complications ETOHBPSmoking Disability Microvascular Complications

  4. Prevention Age 0-15 15-40+ 15-50+ 25-70+ Envir.+ Other Disease Genes Macrovascular Complications Disability Obesity(visceral) Poor Diet Inactivity IR PhenotypeAtherosclerosisObesityHypertensionHDL,TG, HYPERINSULINEMIA Endothelial DysfunctionPCO,ED Insulin Resistance MICVAAmp pp>7.8 DEATH IGT Type 2 DM  -Cell Secretion BlindnessAmputationCRF EyeNerveKidney ETOHBPSmoking Risk of Complications Disability Microvascular Complications

  5. 70 62% Finnish 58% 58% 60 55% Da Qing – Diet + Exercise 50 42% 41% DPP-Lifestyle 40 Diabetes Mellitus Reduction (%) 31% DPP-Metformin 30 25% STOP-NIDDM 20 TRIPOD XENDOS 10 DREAM 0 Diabetes Prevention Clinical Trials Is it Possible to Delay the Onset of Type 2 DM? 55% PIOPOD FINNISH=Tuomilehto J, et al. N Engl J Med 2001; 344: 1343-50 DA QING=Pan XR, et al. Diabetes Care. 1997; 20: 537-44 DPP=Diabetes Prevention Program. Nathan DM, et al. N Engl J Med 2002; 346:393-403 STOP-NIDDM=Study TO Prevent Non-Insulin-Dependent Diabetes Mellitus. Chiasson JL, et al. Lancet 2002; 359:2072–77 TRIPOD=Troglitazone in the Prevention of Diabetes. Buchanan T, et al. Diabetes 2002; 51(9): 2796-2803 XENDOS=XEnical in the Prevention of Diabetes in Obese Subjects. Torgerson JS, et al. Diabetes Care 2004; 27 (1): 155-61 DREAM=Diabetes Reduction Assessment with Ramipril & Rosiglitazone Medication. Gerstein H, et al. Lancet 2006; 368:1096-1105

  6. Diabetes Prevention Program Main Study - Results And if Achieve Normal Glucose Tolerance, Reduce Risk Future DM to only 3%/year Metf.-30% reduction 50% reduction DeFronzo pilot- 3 drugs get 60% of pre-diabetes to normal

  7. ACT NOWStudy Results: Time to Occurrence of Diabetes (Kaplan-Meier analysis) 0.30 Placebo 6.8% per year HR = 0.19 (95%, CI) = 0.09, 0.39 P<0.00001 0.25 0.20 Cumulative Hazard 0.15 0.10 1.5% per year Pioglitazone 0.05 0 0 10 20 30 40 50 NNT = 3.5 patients with IGT for 1 year to prevent the development of 1 case of T2DM Months DeFronzo RA. ADA Scientific Sessions, Late-Breaking Clinical Studies, June 9, 2008.

  8. Alter the Natural History of Diabetes Age 0-15 15-40+ 15-50+ 25-70+ Envir.+ Other Disease Genes Macrovascular Complications Disability Obesity(visceral) Poor Diet Inactivity IR PhenotypeAtherosclerosisObesityHypertensionHDL,TG, HYPERINSULINEMIA Endothelial DysfunctionPCO,ED Insulin Resistance MICVAAmp pp>7.8 DEATH IGT Type 2 DM  -Cell Secretion BlindnessAmputationCRF EyeNerveKidney ETOHBPSmoking Risk of Complications Disability Microvascular Complications

  9. ADOPT: Treatment effect on primary outcome N = 4351 Hazard ratio (95% CI) Rosiglitazone vs metformin, 0.68 (0.55–0.85), P < 0.001 Rosiglitazone vs glyburide, 0.37 (0.30–0.45), P < 0.001 40 Glyburide 30 Cumulative incidence of mono-therapy failure*(%) Metformin 20 Rosiglitazone 10 0 0 1 2 3 4 5 Years *Time to FPG >180mg/dL Kahn SE et al. N Engl J Med. 2006;355:2427-43.

  10. Exenatide: Sustained A1cReductions Mean  A1c (%) Time (wk) 0 10 20 30 40 50 60 70 80 90 0.5 Baseline A1C 8.3% Placebo BID (N = 128) Exenatide 5 mcg BID (N = 128) Exenatide 10 mcg BID (N = 137) 0.0 8.3% 8.3% -0.5 -1.0 -1.5 -2.0 Open-Label Extension Placebo-Controlled Trials Kendall D, et al. American Diabetes Association Scientific Sessions. June 2005

  11. Natural History of Type 2 Diabetes-Insulin Resistance Age 0-15 15-40+ 15-50+ 25-70+ Envir.+ Other Disease Genes Macrovascular Complications Obesity Poor Diet Inactivity IR phenotypeAtherosclerosisobesityhypertensionHDL, TG Endothelial dysfunctionPCO Disability Insulin Resistance MICVAAmp DEATH IGT Type II DM  Beta Cell Secretion d.ec 1st phase Inc 2nd phase BlindnessAmputationCRF EyeNerveKidney Risk of Dev. Complications ETOHBPSmoking Disability Microvascular Complications

  12. Insulin- Resistance Peripheral Insulin Resistance- Induced Hyperinsulinemia has Adverse Downstream Effects Hyperinsulinemia Insulin Mitogenic pathway (MAPK) Metabolic pathway (PI3K) Proliferation, ENDOTHELIAL DYSFUCTION, INFLAMMATION Hyperglycemia Glucose transport Glykogen synthese

  13. Greater the Insulin Level, > CV Risk

  14. Multiple Causes of Insulin Resistance-Multiple Therapies Central IR Weight Reduction DM MEDS- SGLT-2 inh. GLP-1 RAs Appetite suppressants Bromocriptine-QR Biome IR OBESITYPeripheral IR Inflam- mation IR Anti- Inflam. Incretins Pro- Biotics, Pre-Biotics’ Antibiotics Pioglitazone Metformin

  15. Implications for Therapy • Understand and Treat Central Mechanisms IR • Understand and Treat Peripheral IR- fat, liver, muscle • Understand and Treat Inflammation • Understand and Treat Biome

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