Management of cad in diabetes

Management of CAD in Diabetes the cardiovascular equivalent is challenging.The slides take you from the epidemiology,ADD,and CV benefit and how to manage CAD

1. Management of CAD in Diabetes

2. Leading cause of death in both type1 and type2 diabetes mellitus. CV disease equivalent ( mortality in diabetics same as those with previous MI). The risk increases with duration of diabetes. Overall worse prognosis. 2 ᵒ prevention of CV events is not synonymous with cardio protection in diabetes. Efficacy of cardio protection of anti-diabetic drugs is essential. ( CVOT trials needed for FDA approval ). Benjamin EJ, Blaha MJ, Chiuve SE, et al. Circulation 2017;135:e146-603 . Saydah SH, Eberhardt MS, Loria CM, Brancati FL. Am J Epidemiol 2002;156:714-9 . Schramm TK,Gislason GH,Kober L,et al. Circulation 2008;117:195-54. Berry C,Tardif JC,Bourassa MG. JACC 2007;49:643-56. GoAS,Mozaffarian D, Roger VL, et al. Circulation 2014;129:e28-292. Donahoe SM, Stewart GC,Mc Cabe CH,et al. JAMA 2007;298:765-75 Cardiovascular Disease (CVD) in Diabetes

3. Management of CAD in diabetes Issues 1. Lifestyle and diet – how different are they ? 2. How intensive the glucose levels to be controlled? 3. Statins and risk of diabetes – are they safe ? 4. How cardioprotective are the antidiabetics? 5. Risk of stent thrombosis? 6. Which to prefer CABG or PCI in multivessel disease ?

4. Glycemic control –How aggressive ? Trial Evidence Trial Name No. of patients Standard Arm HBA1C Intensive Arm HBA1C Events ACCORD >10,000 Target of 7-8% Median 7.5% Target of < 6% Median 6.4 % 22% increase in mortality in intensive strategy. ADVANCE 11,140 7.0% 6.3% Reduction in composite outcome of both micro and macro complications by 10% ( major was reduction in nephropathy ) No observed reduction when considered for macrovascular complications separately . VADT 1791 7.5% < 6.0 % No significant difference over a 5.6 year followup period on outcome of MI, stroke,CV death,revascularization . 1).ACCORD - Action to Control Cardiovascular Risk in Diabetes,NEJM 2008;358:2560-72. 2).ADVANCE- Action in Diabetes and Vascular Disease :A Preterax and Diamicron Modified Release Controlled Evaluation. NEJM 2008;358:2560-72. 3).VADT Veterans Affairs Diabetes Trial. NEJM 2009;360:129-39.

5. Hypoglycemia effect Independent risk of mortality. 5-17% in ICCU. Decreases myocardial blood flow reserve and increases infarct size. No additional benefit from lowering blood glucose levels below range of 140-180 mg/dl Insulin infusion therapy to aim blood glucose levels in the same range.

6. Newer Antidiabetic drugs

7. Antidiabetic Drug Safety Most oral diabetic medications reduce HbA1c levels by a similar amount,by approx. 1 absolute percentage point . Are all Cardioprotective ? NO It is disappointing, that neither intensive glycemic control nor the use of specific diabetes medications is associated with any suggestion of cardiovascular benefit. HbA1c – not a valid surrogate for assessing either the CV risks or benefits of diabetes therapy .. 2008 – pre and post approval for all new antidiabetic drugs to rule out excess CV risk. (CVOT trials) Bennett WL,Maruthur NM et al.Ann Intern Med 2011;154:602-13 Hiatt WR,Kaul S et al.NEJM 2013;369:1285-7.

8. Therapuetic Classes Effect on CVD risk factors Other Direct and Indirect Effects on Heart Biguanides (Metformin) ↓ in macrovascular end points Improved Lipid profile - Sulfonylureas Weight gain Hypoglycemia Impaired Ischemic preconditioning Prandial glucose regulators ( Meglinitides ) Weight gain Hypoglycemia Thiazolidinediones / Glitazones Increased LDL levels Reduced restenosis after coronary stenting Heart failure Excess ischemic CV risk with rosiglitazone Alpha glucosidase inhibitors Reduce inflammatory markers Possible ↓ in risk of CV event - DPP4 inhibitors( Gliptins ) - Heart failure Amylin analogues Weight loss Incretin mimetics Weight loss Insulin Weight gain Hypoglycemia

9. Why do we need newer AntiDiabetic drugs?

10. The other effects of Anti Diabetic Drugs

11. Completed and ongoing CVOTs William T. Cefalu et al. Dia Care 2018;41:14-31

12. SGLT2 inhibitors CV benefits Adverse effects

13. Lancet Diabetes Endocrinol 2017;15:709-717 Parameter Hazard Ratio P value CV mortality due to heart failure 0.53 <0.0001 Major adverse CV events 0.78 <0.0001 Hospitalization due to HF 0.70 <0.0001 Severe hypoglycemia 0.75 0.001 Reduction of CV endpoints and risk of hypoglycemia among patients receiving SGLT2 inhibitors vs other glucose lowering drugs

14. EMPA –REG OUTCOME trial Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients CV effects of 10 or 25 mg of empagliflozin added to standard therapy Diabetic patients with known CVD Beneficial CV effects – hemodynamic rather than anti atherosclerotic mechanism of action (much earlier than other drugs). N Engl J Med 2015; 373:2117-2128

15. N Engl J Med 2015; 373:2117-2128 Outcome Placebo N = 2333 Empagliflozin N= 4687 HR 95% CI P value % Rate/1000 patient years % Rate /1000 patient years Death from CV cause,non fatal MI,non fatal stroke 12.1 43.9 10.5 37.4 0.86 0.04 superiority Death from any cause 8.3 28.6 5.7 19.4 0.68 (0.57-0.82) <0.001 Death from CV cause 5.9 20.2 3.8 12.4 0.62 <0.001 Hospitalization 4.1 14.5 2.7 9.4 0.65 (0.50 -0.85) 0.002 Non fatal stroke 2.6 9.1 3.2 11.2 1.24 (0.92 -1.67) 0.16

16. CANVAS trial CANAGliflozin cardioVascular Assessment Study Reduction in HF hospitalizations Superior to placebo in reducing the primary combined outcome of CV death, MI and stroke but did not improve individually. N Engl J Med 2017; 377:644-657

17. FDA APPROVAL FOR CV RISK REDUCTION OCTOBER 2018

18. Canagliflozin Canagliflozin

19. No hypolgycemia or weight gain EXAMINE - Algogliptin SAVOR TIMI 53 – Saxagliptin TECOS - Sitagliptin All three drugs were not found to increase adverse CV events, CV mortality, or all cause mortality Neither was there a signal of CV benefit. DPP4 INHIBITORS EXAMINE ;N Engl J Med 2013; 369:1327-1335.SAVOR TIMI 53 ; N Engl J Med 2013; 369:1317-1326.TECOS ; N Engl J Med 2015; 373:232-242

20. GLP1 agonists Injectable drugs Activate the GLP1 receptor Inhibit glucagon secretion Delay gastric emptying CV benefit – not a class effect

21. Statins and Diabetics Mechanism is not known. CARDS trial (Atorvastatin) – highest CV events The risk of DM is approximately 1 excess case per 1000 individuals treated with a moderate intensity statin for one year and approximately 3 excess cases per 1000 individuals treated with a high intensity statin for 1 year. Those who develop diabetes should continue statin therapy to reduce the risk of CVD events. Coulhon et al.Primary prevention of CVD with Atorvastatin in type 2 diabetes.Lancet 2004;365:685-96. Stone NJ, Robinson J, Lichtenstein AH, et al. Circulation 2013. http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a.short

22. Stent thrombosis (ST) Multifactorial Delayed healing and impaired endothelialization – a common feature of pathology in ST gets aggravated in diabetes, particularly insulin dependent diabetes. ACUITY trial – IDDM is a significant independent predictor of definite or probable ST occuring within 30 days. TRITON TIMI – 2:1 risk of stent thrombosis. HORIZONS AMI trial – risk of acute,subacute,late very late ST. ACUITY trial. Aoki et al. Circulation 2009;119:687-98. TRITON TIMI trial.Wiviott D et al. Circulation 2008;118:1626-36. HORIZONS AMI trial.Dangas GD et al.Circulation 2011;123:1745-56.

23. CABG vs PCI CABG > PCI – Incomplete revasculariation,progression of diffuse disease formation of new lesions in PCI patients. In BARI trial – CABG group 3 grafts vs PCI group 2 stents. Bilateral Internal thoracic grafts – increased sternal wound complications. Radial artery grafts are very prone to spasm in diabetics. Radial grafts have less patency than SVG grafts in diabetics. Choudhary BP, Antoniades C, Brading AF, et al. Diabetes mellitus as a predictor for radial artery vasoreactivity in patients undergoing coronary artery bypass grafting. J Am Coll Cardiol 2007;50: 1047–53

24. Take home message Diabetes is Cardiovascular Disease Equivalent. Aggressive sugar control is not advised in patients with CAD,due to the deleterious effects. Statins to be recommended in the usual doses , though the risk of diabetes is of remote possibility. SGLT2 inhibitors have cardiovascular risk reduction benefit among the newer antidiabetic drugs. Complete revascularization to be opted in a patient with diabetes and Multivessel disease.

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