Diabetes Mellitus 101 for Medical Professionals An Aggressive Pathophysiologic Approach to Cardiometabolic Therapy for Type 2 Diabetes: Part 8 Stan Schwartz MD,FACP Clinical Associate Professor of Medicine, U of Pa. Cardiometabolic Institute Penn-Presbyterian Hospital,, UPHS 1

Ranolazine (15mg/kg) Plasma Insulin (% of baseline) Vehicle EFFECT OF RANOLAZINE ON PLASMA INSULIN RESPONSE DURING AN IVGTT IN NORMAL RATS Dhalla et al, unpubl data (on file, CVT Pharm) 1800 Ranolazine (15mg/kg) 1200 Plasma Insulin (% of baseline) 600 Vehicle 10 20 30 Time (min)

EFFECT OF RANOLAZINE AND GLYBURIDE ON PLASMA GLUCOSE AND INSULIN CONCENTRATIONS IN NORMAL RATS: eg: GLUCOSE DEPENDENT INSULIN RELEASE Dhalla et al, unpubl data (on file, CVT Pharm) GLYBURIDE RANOLAZINE GLYBURIDE RANOLAZINE 30 60 90 120 1 2 3 Glucose (mg/dl) Plasma Insulin (mg/dl) 30 30 30 30 TIME (min) Normal glycemia- no insulin release- eg: GLUCOSE DEPENDENT INSULIN RELEASE

Insulin Release (% of control) GLUCOSE DEPENDENCE OF THE EFFECT OF RANOLAZINE ONINSULIN SECRETION FROM HUMAN PANCREATIC ISLETS Dhalla et al, unpubl data (on file, CVT Pharm) P<0.05 400 300 Insulin Release (% of control) 200 100 RAN CON CON RAN Glucose-3mM Glucose-20mM

Insulin Release (% of control) CONCENTRATION DEPENDENT EFFECT OF RANOLAZINE ON INSULIN SECRETION FROM HUMAN PANCREATIC ISLETS Dhalla et al, unpubl data (on file, CVT Pharm) P<0.01 450 P<0.05 300 Insulin Release (% of control) 150 RAN 0 M RAN 100 M RAN 5 M RAN 0 M Glucose-3mM Glucose-25mM

MECHANISM OF ACTION OF RANOLAZINE TO STIMULATE INSULIN SECRETION Ranolazine inhibits late sodium current, resulting in decreased calcium overload in myocytes The effect of inhibition of the sodium current on insulin secretion in pancreatic beta cells is unknown

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

Ranolazine may be a preferred Anti-anginal in Patients With Diabetes Beta-blockers increase blood sugar, decrease recognition of hypoglycemia, and increase risk of claudication, increase risk overt DM in non-diabetics- only have secondary outcome studies- decreases pulse/ bp Calcium channel blockers can increase edema in those patients- who may have obesity-related venous insufficiency and may be on other meds that have edema risk (eg: TZD)- no outcome studies- decreases BP 3. Nitrates prevent use of ED agents (high risk of ED in this population) – no outcome studies- decreases BP 4. ? Additive reduction in ACS with tzd/ ranolazine

Use of Ranolazine in Patients With Diabetes- ‘Issue of Silent Ischemia’ 1. Real ‘Silent Ischemia’ -- in sense of neuropathy-related absence of chest discomfort 2. But ‘false’ ‘Silent Ischemia’-- in sense of they are likely to have: a. symptomatic anginal ‘equivalents’ b. progressive reduction in exercise capability, and patient then limits activity to avoid symptoms 3. BOTH

ULTIMATELY,WITH MORE DATA, could see Use of Ranolazine in a large number of Patients With Diabetes who have - (with better supporting data) Symtomatic Ischemia ‘Silent Ischemia’ ECHOS with decreased EF, diastolic dysfunction- edema with pio- Hx CHF History or risk for a.fib Cardio-protection peri-op

Practical problem in increasing Ranolazine’s use Overcome prior QT / arrhythmia worry Overcome their impression of ‘less effective’ given previous use as last line agent where it worked ~50% of time How to get cardiologist to use as first line for ischemia, esp. in dm- teach its glycemic benefit Get more data to use in other situations mentioned How to get primary/ endo’s comfortable in prescribing cardiac med without ‘offending cardiologists’

RANOLAZINE CAN BE USED IN PATIENTS WITH CAD AND DIABETES . Ranolazine affects Na+ channel function in cardiomyocytes, and is likely to do the same in beta-cells Ranolazine is approved for treatment of ischemic anginal-equivalents 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. 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) No Clinically relevant changes in blood pressure or heart rate Timmis AD, et al. Eur Heart J 2006;27:42-48