Insulin Secretagogues: Sulfonylureas and “Glinides” Safety and Efficacy -Decreases HbA1c approx 1–2%(sfu, repaglinide)(0.5-1.0%,neteglanide) -Adverse events: Wt gain, sulfa allergy (sfu,rare), -cell apoptosis (sfu) Main risk = hypoglycemia , inc ischemia risk(~50% less w/repaglinide,75% less with neteglanide) Increase Cancer vs Metformin Abnormal ischemia pre-conditioning SO WHY USE SOMETHING THAT DESTROYS BETA-CELLS - and you’ll need more expensive agents ANYWAY, in 3 years when SU stops working Davies MJ. Curr Med Res Opin. 2002;18(Suppl 1):s22-30. 1

CV Risk of SU and Insulin So benefit of both SU/Insulin in research studies –UKPDS, DCCT/EDIC But adverse risk in ‘real world’ use Pharmacoepidemiology and Drug Safety. 2008;(17):753-759.

Increased Mortality with SU Endo 2012, abstract Fits FDA criteria for market withdrawal DOI: 10.1177/1479164112465442 Diabetes and Vascular Disease Research published online 4 January 2013 Thomas Forst, Markolf Hanefeld, Stephan Jacob, Guido Moeser, Gero Schwenk, Andreas Pfützner and Axel Haupt review and meta-analysis of observational studies Acute coronary syndrome in patients with diabetes mellitus: perspectives of an interventional cardiologist. Sanon S, Patel R, Eshelbrenner C, Sanon VP, Alhaddad M, Oliveros R, Pham SV, Chilton R. Am J Cardiol. 2012 Nov 6;110(9 Suppl):13B-23B

Other Meds with ‘synergistic’ Glycemic and CV Benefit Alpha-glucosidase Inhibitors Acarbose – CV outcome benefit in pre-diabetes!! Colsevelam lipid benefit (Ranolazine) Decrease angina ( or equivalent) Decreases arrhythmia Improves diastolic dysfunction, thus-decreases edema of Pio-, Decreases HgA1c, FBS in glucose dependent fashion , no hypoglycemia

Glycemic Benefit of Ranolazine: Proportional to Baseline HgA1c

Safety of Ranexa in Patients With Diabetes MERLIN TIMI-36 Safety of Ranexa in Patients With Diabetes HR 95% CI p Value* Recurrent ischemia Overall cohort vs placebo 0.87 0.76–0.99 0.03 Patients with diabetes vs placebo 0.75 0.61–0.93 0.008* Patients with diabetes vs without diabetes 0.95 0.80–1.11 0.10 Death, any cause 0.98 0.70–1.36 0.91 CV death or MI 1.09 0.86–1.38 0.46* New or worsening heart failure 1.01 0.73–1.39 0.95† Sudden cardiac death 0.76 0.41–1.39 0.37 *p for interaction = 0.29. †p for interaction = 0.68. Morrow DA, et al. Circulation. 2009;119:2032-2039.

RANEXA CAN BE USED IN PATIENTS WITH CAD AND DIABETES Ranexa does not increase the incidence of hypoglycemia compared with placebo Ranexa does not increase the incidence of: Weight gain Cardiovascular adverse events Dyslipidemia (LDL, HDL, total cholesterol, and triglycerides) Clinically relevant changes in blood pressure or heart rate Timmis AD, et al. Eur Heart J 2006;27:42-48

Ranolazine may be VERY Beneficial in Patients With Diabetes 1. avoid hypoglycemic agents- use Metformin/Incretin/tzd//bromocryptine/ ranolazine for CV/ glucose 2. In patients with TZD edema, diastolic dysfunction benefit obviates Edema 3. Ranolazine / Incretins peri-op / peri-cath for cardio-protection 4. ?incretin/ranolazine similarities- heart/beta cell- ? no additional benefit, additive, supra-additive