Diabetes Mellitus 101 for Cardiologists (and Alike): 2015 Stan Schwartz MD,FACP Affiliate, Main Line Health System Emeritus, Clinical Associate Professor of Medicine, U of Pa An Aggressive Pathophysiologic Approach to Therapy of Type 2 Diabetes in Cardiometabolic Patients: Looking at Diabetes Medications with a Cardiologists Eye Part 14

Glycemic Benefit of Ranolazine Proportional to Baseline HgA1c

INFLUENCE OF FASTING GLUCOSE AT BASELINE ON THE EFFECT OF RANOLAZINE TO LOWER GLYCEMIC VARIABLES IN ALL PATIENTS AT 4 MONTHS- Implies glucose-dependent Insulin Release. Chisholm, Dhalla, Karwatowska-Prokopczuk and Belardinelli (2008). CVT unpublished MERLIN data Change in FPG as a function of baseline FPG < Baseline FPG (mg/dl) (n) Change from baseline in fasting glucose (mg/dl)

PATIENTS WITH DIABETES WERE MORE LIKELY TO ACHIEVE HbA1c < 7% WITH RANEXA VS PLACEBO CARISA MERLIN TIMI-36 Timmis AD, et al. Eur Heart J. 2006;27: Baseline 12 Weeks 38% Percent With HbA1c < 7% Placebo (n = 37) Ranexa (n = 47) 43% 26% 55%* Placebo (n = 770) Ranexa (n = 707) Baseline 4 Months 44% 49% 43% 59% † *p = vs placebo † p < vs placebo.

Safety of Ranexa in Patients With Diabetes HR 95% CI p Value* Recurrent ischemia Overall cohort vs placebo – Patients with diabetes vs placebo – * Patients with diabetes vs without diabetes – Death, any cause – CV death or MI – * New or worsening heart failure – † Sudden cardiac death – *p for interaction = † p for interaction = Morrow DA, et al. Circulation. 2009;119: NOTE: Data Not Included in New Label MERLIN TIMI-36

Recurrent Ischemia in Patients with Diabetes Mellitus RANOLAZINE (N=1104) Results PLACEBO (N=1116) Days after Randomization Recurrent Ischemia (%) Hazard Ratio 0.75 (95% CI 0.61 to 0.93) P = % 15.1% Morrow DA et al. Circulation 2009; epub

OTHER GLYCOMETABOLIC PARAMETERS IN PATIENTS WITH DIABETES MELLITUS Body weight (kg) LDL (mmol/L) Trig (mmol/L) HDL (mmol/L) Hypoglycemia (%) 33 MEDIAN CHANGE FROM BASELINE PLACEBO N=1117 RANOLAZINE N=1098 Morrow DA, AHA 2007, Orlando, FL

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

SUMMARY ● Ranolazine significantly and dose- dependently reduces HbA1c. ● The magnitude of HbA1c lowering by ranolazine is correlated with the levels of HbA1c and FPG at baseline. ● There was no increase in the incidence of hypoglcyemia in ranolazine-treated patients

EFFECT OF RANOLAZINE ON PLASMA INSULIN RESPONSE DURING AN IVGTT IN NORMAL RATS Ranolazine (15mg/kg) Vehicle Plasma Insulin (% of baseline) Time (min) Dhalla et al, unpubl data (on file, CVT Pharm)

EFFECT OF RANOLAZINE AND GLYBURIDE ON PLASMA GLUCOSE AND INSULIN CONCENTRATIONS IN NORMAL RATS: eg: GLUCOSE DEPENDENT INSULIN RELEASE GLYBURIDE RANOLAZINE Glucose (mg/dl) Plasma Insulin (mg/dl) GLYBURIDERANOLAZINE TIME (min) Dhalla et al, unpubl data (on file, CVT Pharm) Normal glycemia- no insulin release- eg: GLUCOSE DEPENDENT INSULIN RELEASE

GLUCOSE DEPENDENCE OF THE EFFECT OF RANOLAZINE ONINSULIN SECRETION FROM HUMAN PANCREATIC ISLETS Insulin Release (% of control) Glucose-3mMGlucose-20mM P< Dhalla et al, unpubl data (on file, CVT Pharm) RAN CON

CONCENTRATION DEPENDENT EFFECT OF RANOLAZINE ON INSULIN SECRETION FROM HUMAN PANCREATIC ISLETS Insulin Release (% of control) Dhalla et al, unpubl data (on file, CVT Pharm) Glucose-3mM Glucose-25mM P<0.05 P<0.01 RAN 0  M RAN 0  M RAN 100  M RAN 5  M