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 7 Stan Schwartz MD,FACP Affiliate, Main Line Health System Emeritus, Clinical Associate Professor of Medicine, U of Pa. 6105472000 1

The Adipocytokine Syndrome: A New Model for Insulin Resistance and ß-Cell Dysfunction Atherothrombosis Liver Artery CRP, PAI-1 FFA, TNFa, IL-6 Angiotensinogen, PAI-1 FFA, TNFa Obesity IR Diabetes ASVD Adiponectin Adiponectin FFA Visceral fat cells Resistin, TNFa Leptin Sns FFA, TNFa, Leptin Muscle Brain Pancreas 2 2

Overweight and Obesity Increase the Risk of CV Disease Mortality 0.6 3.0 2.6 2.2 1.8 1.4 1.0 Men Women Relative Risk of Cardiovascular Disease Mortality These data are from the Cancer Prevention Study II, a prospective study of mortality in more than 1 million men and women in the United States. The risk of cardiovascular death was lowest at a BMI between 23.5 and 24.9 kg/m2 and was used as the reference BMI category. The mortality curves represent a continuum that begins to increase at a BMI of 26.5 kg/m2 in men and 25 kg/m2 in women. The risk of death from all causes was lowest at a BMI between 23.5 and 24.9 kg/m2 in men and 22.0 and 23.4 kg/m2 in women. A BMI between 23.5 and 24.9 kg/m2 was used as the reference BMI category for calculating relative risk. The mortality curves represent a continuum that begins to increase significantly at a BMI of 26.4 kg/m2 in men and 25 kg/m2 in women. Normal weight Overweight Obese >18 25 30 >40 BMI, kg/m2 Data are from 1 million men and women (average age, 57 years) followed for 16 years who never smoked and had no history of disease at enrollment. Calle EE, et al. N Engl J Med. 1999;341:1097-1105. Calle EE, Thun MJ, Petrelli JM, Rodriguez C, Heath CW. Body-mass index and mortality in a prospective cohort of US adults. N Engl J Med. 1999;341:1097-1105.

Weight Loss Reduces Cardiometabolic Risk Factors in Patients With Type 2 Diabetes Intensified Lifestyle Intervention, 8.6% Weight Loss Diabetes Support and Education, 0.7% Weight Loss 4 * -0.2 3 Δ A1C (%) -0.4 Δ HDL Cholesterol (mg/dL) 2 -0.6 1 * -0.8 Systolic Diastolic -10 -2.5 Δ Triglycerides (mg/dL) Δ Blood Pressure (mm Hg) * -20 -5.0 -30 * -7.5 * -40 Randomized, controlled trial; n = 5145; Patients with type 2 diabetes, age >18 y; Mean ± SE Intensified lifestyle intervention (n = 2496) vs diabetes support and education (n = 2463) therapy; *P<0.001 between groups Look AHEAD Research Group. Diabetes Care. 2007;30:1374-1383 4

and Insulin Resistance Pleotrophic Effects of PIOGLITAZONE: Modifying The Adipocytokine Syndrome: A Model Relating Obesity, Insulin Resistance and ß-Cell Dysfunction and ASCVD Reduce Atherosclerotic Risk Factors Liver: ↓Insulin resistance ↓Atherothrombosis ↓CRP, PAI-1 ↓ FFA, TNFa, IL-6 Angiotensinogen, PAI-1 et al ↓FFA, TNFa ↑Adiponectin ↑Adiponectin Improves peripheral Insulin Resistance in PIOGLITAZONE ↓ FFA resistin, TNFa Muscle ↓Size /# Visceral Fat Cells and Insulin Resistance ↓FFA, TNFa, Brain: Improve Satiety Decrease Hyperinsulinemia PANCREAS:Improve beta cell function

Effect of Pioglitazone on Abdominal Fat Distribution Visceral Fat, Decreased Baseline After PIO SC Fat, Increased Miyazaki Y, Matsuda M, DeFronzo RA. Diabetes Care. 2002;25:517-23.

Presrvation of B-Cell functionLeads to DURABILITY OF GLYCEMIC CONTROL WITH Pioglitazone 1 Hanefeld (n=250) Chicago (n=232) Charbonnel (n=317) PERISCOPE (n=178) Rosenstock (n=115) RECORD (n=301) Tan (n=249) PIO Change in HbA1c (%) PIO ROSI PIO -1 PIO PIO -2 1 2 3 4 5 6 TIME (years) 8

Metformin Advantages Improves insulin resistance in liver High initial response rate Effective, 2% HbA1c (1% with extended-release metformin) No initial weight gain or modest weight loss (UKPDS) Advantageous lipid profile No hypoglycemia when used alone or with TZD, incretins Potential to delay or prevent DM and progression, but secondary failure is = SU Decreases MIs (39% UKPDS obese subgroup,retrospective analysis) Decreases AGEs, improved endothelial dysfunction Cheap 10 10

Don’t order metformin as admit to hospital Disadvantages GI side effects on initiation Hold after radiologic studies using intravascular iodinated contrast media until Cr stable Risk of lactic acidosis: Don’t use if… Cr >1.4 female, >1.5 male Cr Clearance <70 (age >70), blood levels increase Cr Clearance <40, lactic acidosis cases seen Impaired hepatic function (CHF not a contr-indication any more) Don’t order metformin as admit to hospital 11 11

TZD TZD MECHANISM OF ACTION Effect of Meds on Fat Topography Direct PPAR effect on vascular cells to decrease endothelial dysfunction and inflammation IR, TG, FFA Insulin, BP, Inflam. En Dys. IR, TG, FFA Insulin, BP Inflam. En Dys. TZD Intra-muscular fat Subcutaneous fat Intra-abdominal fat The clinical significance of fat re-distribution from ectopic sites such as the abdominal viscera, liver, muscle and even from the circulation to the subcutaneous fat depot during thiazolidinedione therapy is highlighted by the occurrence of simultaneous changes in insulin resistance. Intra-hepatic fat 12 12