1. 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. 6105472000 An Aggressive Pathophysiologic Approach to Therapy of Type 2 Diabetes in Cardiometabolic Patients: Looking at Diabetes Medications with a Cardiologists Eye Part 15

2. ● 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 MECHANISM OF ACTION OF RANOLAZINE TO STIMULATE INSULIN SECRETION

3. 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

4. Ranolazine may be a preferred Anti- anginal in Patients With Diabetes 1.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 2.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

5. 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

6. ULTIMATELY,WITH MORE DATA, could see Use of Ranolazine in a large number of Patients With Diabetes who have - (with better supporting data) 1.Symtomatic Ischemia 2.‘Silent Ischemia’ 3.ECHOS with decreased EF, diastolic dysfunction- edema with pio- 4.Hx CHF 5.History or risk for a.fib 6.Cardio-protection peri-op

7. Practical problem in increasing Ranolazine’s use 1.Overcome prior QT / arrhythmia worry 2.Overcome their impression of ‘less effective’ given previous use as last line agent where it worked ~50% of time 3.How to get cardiologist to use as first line for ischemia, esp. in dm- teach its glycemic benefit 4.Get more data to use in other situations mentioned 5.How to get primary/ endo’s comfortable in prescribing cardiac med without ‘offending cardiologists’

8. Therapy for Type II Diabetes

9. American Diabetes Association. Clinical Practice Recommendations. Diabetes Care. 2004,27:S15-S35 The American Association of Clinical Endocrinologists. Medical Guidelines for the Management of Diabetes Mellitus. Endocr Pract. 2002; 8(Suppl. 1): 40-82 A1C (%) Normal: 4-6% Fasting/Preprandial (mg/dL) (plasma equivalent) Postprandial (mg/dL) (2-hour) ACE <6.5 <110 <140 ADA <7.0 90-130 <180* * Peak Goals for individual patients may vary. Aim for the Lowest A1C Possible without Hypoglycemia. Targets for Glycemic Control

10. Relative Contribution of FBG and PPG Varies With A1C Range Adapted from Monnier L, et al. Diabetes Care. 2003;26:881-885. Thus, to get to glycemic goals, one must control PPG as well as FBS. (incretins, alpha-glucosidase inhibitors, TZDs, glinides, fast-insulin analogues) Inc PPG increases Micro- and macro- vascular disease

11. Non-Insulin Therapy for Type II Diabetes

12. Non-Insulin Therapy for Hyperglycemia in Type 2 Diabetes, Treating Defronzo’s Octet: Match Patient Characteristics to Drug Characteristics 5. Gut CHO Absorption: Incretin, Pramlintide, Glucosidase inh. Peripheral glucose uptake -- - 1.Pancreatic insulin Secretion: Incretin, ranolazine 2.Pancreatic glucagon Secretion- Incretin HYPERGLYCEMIA 6.Fat- TZD, metformin 7.Brain- TZD,INCRETIN, bromocryptine 8.Kidney- SGLT2 3. Muscle- TZD, Incretin 4.Liver Hepatic glucose production: Metformin, incretin De