Diabetes Mellitus 101 for Medical Professionals An Aggressive Pathophysiologic Approach to Cardiometabolic Therapy for Type 2 Diabetes: Stan Schwartz MD,FACP Clinical Associate Professor of Medicine, U of Pa. Cardiometabolic Institute Penn-Presbyterian Hospital, UPHS Part 7

RANOLAZINE INCREASED EXERCISE TREADMILL TEST PERFORMANCE IN CARISA Tolerance to Ranexa did not develop after 12 weeks of therapy and rebound angina (measured by exercise duration), was not observed Exercise Duration Chaitman BR, et al. JAMA. 2004;291: *p ≤ 0.05 Angina Onset 1-mm ST Depression Time (seconds)  =26.0 s*  =21.1 s  =24.1 * Placebo + bkgd therapy Ranexa (1000 mg bid) bkgd therapy

RANOLAZINE REDUCED ANGINA FREQUENCY AND NITROGLYCERIN USE (CARISA) AT 12 WEEKS 36%; p < Number of Angina Attacks/Week* Nitroglycerin Doses/Week † *Mean number of angina attacks/week at baseline: placebo = 4.6, Ranexa = 4.5 †Mean nitroglycerin doses/week at baseline: placebo 4.0 = Ranexa = 3.7 Placebo %; p < RanolazinePlacebo Ranolazine Chaitman BR, et al. JAMA. 2004;291:

Favors Ranolazine Favors Placebo Cardiovascular death MI End Point Hazard Ratio (95% CI) HR 1.00 P Value Ranolazine HAD NO ADVERSE EFFECT ON CVD DEATH OR MI AND SIGNIFICANTLY REDUCED RECURRENT ISCHEMIA AND WORSENING ANGINA MERLIN TIMI-36 Recurrent ischemia Worsening angina

Baseline Peak HR = 142 bpm After RAN (3-4 wks) Peak HR = 140 bpm Off Treatment (~ 5 mo) Peak HR = 140 bpm Reversible Perfusion defect size 25% 10% 21% Effects of Ranolazine on Stress MPI (Polar Maps) RestExercise Venkataraman, Iskandrian et al, ICNC9 Abstract (2009).

Risk for SCD in Patients With or Without Nonsustained VT* *VT ≥ 8 beats and ≥ 100 bpm Scirica BM, et al. J Am Coll Cardiol. 2009;53 (Suppl 1): A121 (Modified). MERLIN TIMI-36 Sudden Cardiac Death Days After Randomization 0% 2% 4% 6% 8% 10% No. At Risk VT ≥ 8 Beats No VT ≥ 8 Beats Placebo VT No VT RR (95% CI): 3.03 (1.64, 5.56); p < Ranolazine VT No VT RR (95% CI): 1.28 (0.40, 4.10); p = 0.68 Sudden Cardiac Death Days After Randomization 0% 2% 4% 6% 8% 10% No. At Risk VT ≥ 8 Beats No VT ≥ 8 Beats

No Adverse Clinical Outcomes Due to QTc Prolongation  In the overall patient population  No increase in all-cause mortality, CV death, or SCD  Decrease in arrhythmia on Holter including 37% relative risk reduction in VT ≥ 8 beats (p < 0.001)  In patients at high risk for arrhythmia (QTc > 450 msec, or EF < 40%)  Decrease (p < 0.005) in the incidence of VT ≥ 8 beats  Decrease (NS) in the incidence of SCD  Ranolazine does not increase risk of CV death or SCD among patients with prolonged QTc at baseline Patients at high risk for arrhythmia were allowed to be enrolled QTc > 450 msec n = 1233 QTc > 500 msec n = 147 EF < 40% n = 882 MERLIN TIMI-36 Data on file. CV Therapeutics, Inc.

Ranexa ® (ranolazine extended-release tablets) PI Data on file. CV Therapeutics, Inc. Placebo (n = 3189) Ranexa (n = 3162) p Value* Number of patients with Holter data Incidence of clinically significant arrhythmias, n (%) 87%80%< Any VT  100 bpm  3 beats 61%52% New-onset atrial fibrillation2.4%1.7% Any bradycardic episode Supraventricular tachycardia 47% 55% 40% 45% *Cochran-Mantel-Haenszel general association (CMH) test stratifying by the intention for early invasive management. No Proarrhythmic Effect Observed During 7-Day Holter Monitoring The reductions in arrhythmias seen with Ranexa did not lead to reductions in mortality, arrhythmia hospitalization, or arrhythmia symptoms. MERLIN TIMI-36

EFFECT OF RANOLAZINE (12 months) ON CV OUTCOMES STRATIFIED BY DIABETES MELLITUS Recurrent IschemiaCV Death or MI HR 1.09 P = 0.46 HR 0.92 P = 0.43 HR 0.75 P = HR 0.95 P = 0.50 Morrow DA, AHA 2007, Orlando, FL Percent (%) Percent (%) No Diabetes PLACRAN PLACRAN PLACRAN PLACRAN Diabetes No Diabetes Diabetes

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

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

Glycemic Benefit of Ranolazine Proportional to Baseline HgA1c

EFFECT OF RANOLAZINE ON HbA1c AND NEW-ONSET DIABETES MELLITUS IN MERLIN TIMI-36 ; Reduced development of New IFG 41% 32% % P=0.003 New Onset Diabetes Mellitus* *Among 644 patients without evidence of dysglycemia at entry (no history of diabetes, FPG <100 mg/dL, HbA1c <6%); †1-year cumulative incidence; data on file, CVT New Impaired Fasting Glucose >110 mg/dL or HbA1c ≥6%* † n=325n=339 Placebo Ranolazine HR=0.68 Change in HbA1c (%) % 7.3% 8% P=0.32 HR=0.92 Placebo Ranolazine

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.

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