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

Mean Change in CIMT- Pioglitazone stopped progression 0.020 Glimepiride Pioglitazone 0.015 0.012 0.010 LS Mean Change From Baseline Posterior Wall CIMT (mm) 0.005 0.000 -0.001 -0.005 -0.010 Baseline CIMT Least squares (LS) mean (standard error) Glimepiride (n=186) 0.779 (0.0085) mm Pioglitazone (n=175) 0.771 (0.0085) mm Treatment group difference (final visit) -0.013 (95% CI: -0.024, -0.002) P=0.017

Primary Endpoint: Change in Percent Atheroma Volume (%) 0.9 P < 0.001 Glimepiride (n=181) 0.7 Pioglitazone (n=179) 0.73 0.5 Change in PAV (%) 0.3 P = 0.002 0.1 Slides from this deck are to be used only to respond to the specific unsolicited question posed. These slides are intended as a library from which only the individual slides needed to respond to the question posed are used. This slide shows the results for the primary efficacy parameter, the change in percent atheroma volume measured by intravascular ultrasound. The glimepiride group (shown in blue) had highly significant progression, 0.73%, p<.001, compared with baseline. Pioglitazone-treated patients had a reduction of -0.16%, which was statistically unchanged from baseline. The between groups p value was 0.002. These data demonstrate that, after 18 months of treatment, patients assigned to glimepiride had unequivocal progression of coronary atherosclerosis, whereas pioglitazone-treated patients had no progression of coronary atherosclerosis. To our knowledge, this is the first study in which a diabetes therapy has been shown to slow or prevent progression of coronary atherosclerosis. -0.16 -0.1 P = 0.44 -0.3 Presented at: American College of Cardiology March 29-April 1, 2008; Chicago, IL

Cardiac death, MI, coronary revasc, ACS (%) PROactive in the Context of Other Landmark Clinical Trials in Diabetic Patients HPS CARE 30 Placebo 40 Placebo CHD death, MI, revasc (%) 22% RRR P < 0.0001 25% RRR P = 0.05 30 Vascular events (%) 20 20 10 Simvastatin Pravastatin 10 1 2 3 4 5 6 1 2 3 4 5 Years Years Lancet. 2003;361. Circulation. 1998;98. MICRO-HOPE PROactive PROactive vs landmark clinical trials: Comparative benefit in patients with diabetes 25 Cardiac death, MI, coronary revasc, ACS (%) 20 Placebo 25% RRR P = 0.0004 Placebo The cardioprotective benefits demonstrated with pioglitazone in PROactive by study end (3 years) were similar to the benefits observed in subgroups of patients with diabetes at the end of other landmark clinical trials. Comparing the benefits of year 3 in each trial, observed benefits are greater in PROactive. Separation of the curves occurred prior to 1 year in PROactive, earlier than either CARE or HPS. CV risk reduction at study end (active vs placebo groups): HPS (Heart Protection Study): At a mean 4.8 year follow-up, simvastatin 40 mg daily reduced CV death, MI, stroke, or revascularization by 22% in 5963 participants with diabetes. CARE (Cholesterol and Recurrent Events): At a median 5 year follow-up, pravastatin 40 mg/day reduced CHD death or MI 20% in 586 patients with a previous MI. MICRO-HOPE (MIcroalbuminuria, Cardiovascular, and Renal Outcomes-Heart Outcomes Prevention Evaluation): After 4.5 years, ramipril 10 mg once daily reduced CV death, MI, and stroke by 25% in 3577 high-risk patients with diabetes. PROactive: In the subgroup of patients with prior MI, at the 3 year follow-up, pioglitazone 15–45 mg/day reduced cardiac death, nonfatal MI, coronary revascularization, and ACS by 19%. A longer follow-up would be expected to further improve these benefits. Slide citations: HPS: Collins R et al. Lancet. 2003;361:2005-2016. CARE: Goldberg RB et al. Circulation. 1998;98:2513-2519. MICRO-HOPE: HOPE Study Investigators. Lancet. 2000;355:253-259. PROactive: Erdmann E et al. www.proactive-results.com. 20 16% RRR P = 0.034 15 MI, stroke, CV death (%) 15 10 10 Ramipril Pioglitazone 5 5 1 2 3 4 5 1 2 3 Years Years 4 Lancet. 2000;355. Lancet. 2005;366. 4

Stroke Reduction: Proactive vs SPARCL

Sent home after CHF episode: TZD patients do no worse than Metformin patients; And Do BEST if sent home on BOTH

AFTER AMI; Patients sent home on TZD =Mortality vs. metformin And if on both, do better!!

Synthesis- Edema / CHF Fluid retention- Several mechanisms may underlie the development of peripheral oedema. 1. TZDs exhibit some properties of L-type calcium channel antagonism like calcium- channel blockers,  2. increase expression of vascular endothelial growth factor (VEGF),  3. improvement in insulin sensitivity associated a. actions on sodium reabsorption at the level of the kidney, b. augmenting insulin-mediated vasodilatation. 4.renal effect PPARγ-Induced Stimulation of Amiloride-Sensitive Sodium Current in Renal Collecting Duct Principal Cells is Serum and Insulin Dependent (DOI:10.1159/000358636) Not Cardiac issue Increase CHF likely due to salt retention in patients with Diastolic Dysfunction

Implications for Therapy Treat Central Mechanisms IR Treat Peripheral IR- fat, liver, muscle Treat Inflammation Treat Biome