Cardio Diabetes Master Class Asian chapter January 28

Cardio Diabetes Master Class Asian chapter January 28 -30 2011, Shanghai Presentation topic (Pre) diabetes & sustained glycemic control: How and what is the time to act? Slide lecture prepared and held by: Dr Stanley S Schwartz, MD University of Pennsylvania Philadelphia, USA PHYSICIANS’ ACADEMY FOR CARDIOVASCULAR EDUCATION

Natural History of Type 2 Diabetes Age 0 -15 Genes Insulin Resistance 15 -40+ 15 -50+ 25 -70+ Envir. + Other Disease Macrovascular Complications Obesity (visceral) Poor Diet Inactivity IR phenotype Atherosclerosis obesity hypertension HDL, TG, HYPERINSULINEMIA Endothelial dysfunction PCO, ED FBS>5. 5, ppg>7. 8 IGT/IFG Beta Cell Secretion ETOH Risk of Dev. Complications BP Smoking Eye Nerve Kidney Disability MI CVA Amp Type II DM Blindness Amputation CRF Disability Microvascular Complications DEATH

Type 2 Diabetes: Two Principal Defects; Overview Genes Insulin resistancelipotoxicity -cell dysfunction/ Failure; dec. mass ± Environment peripheral hepatic Abn. First phase ± Environment 1 st & 2 nd IFG Glucose Toxicity IGT Type 2 diabetes Glucose Toxicity DM will NOT occur if B-cells not genetically predisposed Reaven GM. Physiol Rev. 1995; 75: 473 -486 Reaven GM. Diabetes/Metabol Rev. 1993; 9(Suppl 1): 5 S-12 S; Polonsky KS. Exp Clin Endocrinol Diabetes. 1999; 107 Suppl 4: S 124 -S 127.

Genes that Cause or are Associated with Diabetes Insulin Secretion Neonatal KCNJ 11/Kir 6. 2 ABCC 8/Sur 1 Insulin MODY HNF-1α, 1β, 4 α Glucokinase PDX 1/IPF 1 Neurod 1/Beta 2 KLF 11 CEL Mitochondrial diabetes Type 2 CDKAL 1 TCF 7 L 2 HHEX/IDE SLC 30 A 8/ZNT 8 WFS 1 NOTCH 2 -ADAM 30 Insulin action Insulin receptor PPARG PHENOTYPEObesity eg: age of FTO presentation, MCR 4 IFG/ IGT/Both/ Unknown severity IGFBP 2 CDKN 2 A/B KIF 11 JAZF 1 CDC 123 -CAMK 1 D TSPAN 8 -LGR 5 THADA ADAMTS 9 NOTCH-ADAM 30 depends on number of which kind of genes a person inherits – GENOTYPE Modified from Mc. Carthy, NEJM 363: 24, 2339.

Size and Time of Meal Determine Postprandial Duration Time of Meal 8: 00 AM 1: 00 PM 6: 00 PM 5 4 Time (h) for glucose to return 3 to premeal value 4. 7 4. 1 2. 4 1. 9 2 2. 4 4. 1 2. 1 1. 7 1. 3 1 0 Small meal (12. 5%) Medium meal (25%) Large meal (50%) Meal Size (% total daily calories) Service J. Diabetologia. 1983; 25: 316.

Mechanism of Glucotoxicity and Lipotoxicity The Glucosamine Hypothesis Glucose FFA Glucose Other pathways FFA Increased glucosamine Impaired insulin secretion from -cell Other pathways Insulin resistance in muscle and fat FFA=free fatty acid Hawkins M et al. J Clin Invest. 1997; 99: 2173 -2182; Rossetti L. Endocrinology. 2000; 141: 1922 -1925

Insulin Secretion Increases With Decreasing Insulin Action and Vice Versa Non-Progressors 400 AIR (µU/m. L) Insulin Secretion 500 300 NGT 200 IGT 100 Progressors DIA 0 0 NGT NGT 1 2 3 4 5 Insulin Resistance M-low (mg/kg EMBS per minute) Changes in AIR relative to changes in M-low in 11 Pima Indian subjects in whom glucose tolerance deteriorated from normal (NGT) to impaired (IGT) to diabetic (DIA) (progressors), and in 23 subjects who retained NGT (nonprogressors). The lines represent the prediction line and the lower and upper limits of the 95% confidence interval of the regression between AIR and M-low as derived from a reference population of 277 Pima Indians with NGT.

SAM: Insulin Secretion/Insulin Resistance Index During OGTT- Progressive loss of Beta-cell Function Whether Lean or Obese Adapted from Gastaldelli A, et al. Diabetologia. 2004; 47: 31 -39.

Clinical Consequences of Abnormal First- phase Secretion and Elevated Post-Prandial Sugars • PPG increases – Variability – Microvasular disease and adverse pregnancy outcomes – ASVD risk factors – adverse CV outcomes • Treating elevated PPG leads to – Reduce Microvasular disease and Pregnancy Outcomes – Reduce CV Markers and Outcomes – Prevent Diabetes

Clinical Consequences of Abnormal First- phase Secretion and Elevated Post-Prandial Sugars • PPG increases – Variability – Microvasular disease and adverse pregnancy outcomes – ASVD risk factors – adverse CV outcomes • Treating elevated PPG leads to – Reduce Pregnancy Outcomes – Reduce CV Markers and Outcomes – Prevent Diabetes

Prevalence of Retinopathy vs Duration of Type 2 Diabetes Patients 80 Time of diagnosis with retinopath 60 Wisconsin population Apparent y (%) 40 onset prior to 20 diagnosis Australian population DM= 0 Prediabetes 2 15 10 Years -10 -6. 5 -4. 2 0 Harris MI et al. Diabetes Care. 1992; 15: 815 -819 5

Abnormal PPG associated with Macrosomia Infant Birth Weight Percentil e Mean Nonfasting Glu cose 180 160 >97 140 90– 96 120 75– 89 100 50– 74 80 25– 49 60 10– 24 3– 9 40 <3 20 0 1 st Trimester 2 nd Trimester 3 rd trimesterr Macrosomia associated with increased C-section rate, infant morbidity Jovanovic-Peterson et al. Am J Obstet Gynecol 1991; 164: 103.

Clinical Consequences of Abnormal First- phase Secretion and Elevated Post-Prandial Sugars • PPG increases – Variability – Microvasular disease and adverse pregnancy outcomes – ASVD risk factors – adverse CV outcomes • Treating elevated PPG leads to – Reduce Pregnancy Outcomes – Reduce CV Markers and Outcomes – Prevent Diabetes

Clinical Consequences of Abnormal First- phase Secretion and Elevated Post-Prandial Sugars • PPG increases – Variability – Microvasular disease and adverse pregnancy outcomes – ASVD risk factors – adverse CV outcomes • Treating elevated PPG leads to – Reduce Pregnancy Outcomes – Reduce CV Markers and Outcomes – Prevent Diabetes

Clinical Consequences of Abnormal First- phase Secretion and Elevated Post-Prandial Sugars • PPG increases – Variability – Microvasular disease and adverse pregnancy outcomes – ASVD risk factors – adverse CV outcomes • Treating elevated PPG leads to – Reduced Microvasular disease and Pregnancy Outcomes – Reduce CV Markers and Outcomes – Prevent Diabetes

Reduction of Retinopathy in Patients with IGT in Da Qing Study Gong et al Diabetologia 54 : 300, 2011

Effectiveness of Postprandial Monitoring and Treatment Reduces Adverse Outcomes 45 40 35 30 No Care 25 Preprandial 20 15 10 Postprandial * † ‡ 5 †P=. 04 0 Large for Gestational Age hypoglycemia *P=. 05 Cesarean Section Neonatal ‡P=. 01 De. Veciana et al. N Engl J Med 1995; 26: 774.

Clinical Consequences of Abnormal First- phase Secretion and Elevated Post-Prandial Sugars • PPG increases – Variability – Microvasular disease and adverse pregnancy outcomes – ASVD risk factors – adverse CV outcomes • Treating elevated PPG leads to – Reduce Pregnancy Outcomes – Reduce CV Markers and Outcomes – Prevent Diabetes

Early Treatment, Even in Overt Diabetes, Decreases Micro and Macro Vascular RISK &DCCT

Clinical Consequences of Abnormal First- phase Secretion and Elevated Post-Prandial Sugars • PPG increases – Variability – Microvasular disease and adverse pregnancy outcomes – ASVD risk factors – adverse CV outcomes • Treating elevated PPG leads to – Reduce Pregnancy Outcomes – Reduce CV Markers and Outcomes – Delay or Prevent Diabetes preserve beta-cell function and alter the natural history of type 2 Diabetes?

Is it Possible to Delay the Onset of Type 2 DM? 80% Diabetes Mellitus Reduction (%) 80 70 60 62% 58% 55% 50 42% 41% 40 DPP-Lifestyle DPP-Metformin 31% 30 Finnish-Diet+ Exercis Da Qing – Diet + Exercise 25% STOP-NIDDM 20 TRIPOD 10 XENDOS DREAM 0 Diabetes Prevention Clinical Trials PIOPOD Act. NOW 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

ACT NOW Study Results: Time to Occurrence of Diabetes (Kaplan-Meier analysis) Cumulative Hazard 0. 30 Placebo HR = 0. 19 (95%, CI) = 0. 09, 0. 39 P<0. 00001 0. 25 0. 20 6. 8% per year 80% reduction in progression to DM 0. 15 0. 10 Pioglitazone 0. 05 1. 5% per year 0 0 10 NNT = 3. 5 patients with IGT for 1 year to prevent the development of 1 case of T 2 DM 20 30 40 Months De. Fronzo RA. ADA Scientific Sessions, Late-Breaking Clinical Studies, June 9, 2008. 50

β cell-specific effects of (PPAR-γ ) agonists in type 2 diabetes mellitus

Incretins • Increases Insulin Secretion and decreases glucagon secretion in a Glucose-dependent manner • Thus low risk hypoglycemia vs Sus • Improves First-phase insulin release, inc. b-cell mass in rodents • GLP-1 receptor agonists (not DPP-4 inhibitors) also decrease appetite, and slows gastric emptying which usually results in weight loss

PHYSICIANS’ ACADEMY FOR CARDIOVASCULAR EDUCATION

And Reduce Variability Augers for Avoiding Step-Care Therapy; use Early Combination. Therapy

Relative Contribution of FBG and PPG Varies With A 1 C Range Inc PPG increases Microand macrovascular disease Can’t get to glycemic goals, UNLESS control PPG (incretins, alpha-glucosidase inhibitors, TZDs, glinides, fast-insulin analogues) Adapted from Monnier L, et al. Diabetes Care. 2003; 26: 881 -885.

Therapeutic Strategies for Improving B-cell function, treating Prediabetes, PPG, DM Central dec. Dopa ésym. tone, inc HGP, é PPG Fast-acting bromocryptine

The New ADA Guidelines for Type 2 Diabetes: AKA- David Nathan’s Regimen- DNR Revised Treatment Algorithm At diagnosis: Lifestyle + metformin STEP 1 Tier 1* Tier 2† Hb. A 1 C >7. 0% STEP 2 Add basal insulin STEP 3 Add sulfonylurea Add GLP-1 agonist Add pioglitazone ± SU Intensive insulin NOT Glyburide, chlorpropamide NOT Rosiglitazone Does Not Address Pathophysiology, Preservation B-cell function, PPG control

A Pathophysiologic Approach to Treating Diabetic Hyperglycemia-AACE Principles of the AACE Guidelines / A 1 C Goal less than or equal to 6. 5% 1. Minimize risk/severity of Hypoglycemia 5. Lifestyle Modification Essential and NO SMOKING 2. Minimize risk/severity of Weight gain 6. Combination frequently required; Complimentary mechanisms of action 3. Fast therapeutic changes (2 -3 months, earlier even better) 7. When using insulin, add an insulin-sensitizing agent if possible 4. Address fasting and postprandial glucose 8. Cost is important but, safety and efficacy trump cost Asymptomatic 6. 5% 7. 5% 9. 0 Hb. A 1 c Continuum – if not at goal, advance Rx 12% Symptomatic • Monotherapy • Metformin • Pioglitazone • GLP-1 agonist • DPP-4 Inhibitor • (or AGI) Dual Combination • Metformin • Pioglitazone • GLP-1 agonist • DPP-4 Inhibitor (or AGI / secretagogue / colesevelam) Triple Combination • Metformin • Pioglitazone • GLP-1 agonist • DPP-4 Inhibitor (or AGI / secretagogue / colesevelam) Insulin* • +/- Other agents *Insulin analogs Not NPH/regular If over 9. 0% or above and symptomatic If triple combo fails Diet and Exercise Therapeutic Choice Should Match The Drug With Patient Characteristics AGI = alpha glucosidase inhibitor Provided by Dr. Stanley S. Schwartz.