Cardiovascular Challenges in Diabetes

Part I Mechanism Moderator: James L. Januzzi, MD Panelists: Javed Butler, MD, MPH Christopher P. Cannon, MD

Slide 1. Cardiovascular Effects GLP-1 receptor agonists (eg, liraglutide) Improved vascular outcomes SGLT-2 inhibitors (eg, empagliflozin) Improved HF, improved unexplained deaths; improved cardiac deaths DPP-4 inhibitors Break even effects Sulfonylurea therapies Increase CV risk

Slide 2. Primary Activation of Fibroblast and Reactive Fibrosis Is it oxidative stress or inflammation that intiates fibrotic process? Diffused fibrosis/myocardial interstitial fibrosis is harmful even where myocytes are intact Diastolic dysfunction Stiffness of ventricle Dysfunction of myocyte

Slide 3. Inflammation/Fibrosis How Do Newer Therapies Work? Reduction in collagen, results in reduction of fibrosis Reduction in fibrosis results in reverse remodeling with a reduction in inflammation Can improve left ventricular ejection fraction (low EF seen in patients with diabetes) and relaxation (decreasing risk for HF)

Part II Diabetes and Heart Failure Moderator: James L. Januzzi, MD Panelists: Javed Butler, MD, MPH Christopher P. Cannon, MD

Slide 4. Diabetes and Heart Failure A Reciprocal Relationship Diabetes increases the risk for heart failure Diabetic heart failure patients are at greater risk of adverse outcomes, including recurring hospitalization and death This interaction can potentially be modified to improve outcomes

Slide 5. GLP-1 Receptor Agonists and Cardiometabolic Benefits Liraglutide FIGHT Trial ~60% of study patients had diabetes Cardiometabolic effects despite lack of heart failure benefit 4 lb weight loss in patients with reduced ejection fraction heart failure Modest 0.5% reduction in hemoglobin A1C 33 mg/dL drop in triglycerides Did not cause hypoglycemia

Slide 6. Weight and Heart Failure The Obesity Paradox Weight loss in overweight patients is beneficial for general vascular health The role of weight in heart failure is unclear In very obese patients, bariatric surgery results in a reduction of heart failure rates However, higher body mass index is actually associated with a better outcome in heart failure Should a slightly overweight heart failure patient lose weight?

Slide 7. Effect of a Heart Failure Drug on Diabetes The PARADIGM Study Sacubitril/valsartan1 vs enalapril2 for heart failure Compared glycemic control in the diabetic subpopulation (n=3,778) Reductions in hemoglobin A1C in both arms, but better control with valsartan/sacubitril than with enalapril Reduction in new initiation of other antihyperglycemic agents by ~23%; decrease in insulin by 29% HDL increased, triglycerides decreased, weight decreased Neprilysin inhibitor/angiotension receptor blocker Angiotensinconverting enzyme inhibitor

Part III Management Moderator: James L. Januzzi, MD Panelists: Mikhail Kosiborod, MD Laurence Sperling, MD

Slide 8. Aggressive Glucose Control and Cardiovascular Benefit Dramatically greater reductions hemoglobin A1C (as much as 1.5%) have not improved cardiovascular death and heart failure Some diabetic drugs (eg, thiazolidinediones) actually increase risk

Slide 9. SGLT-2 Inhibitors and Cardiovascular Benefit EMPA-REG Trial Empagliflozin in >7,000 diabetic patients with cardiovascular risk 35% reduction in cardiovascular death Significant reduction in hospitalized heart failure Significant reduction in composite outcome of the two endpoints

Slide 10. Mechanism of Action in Cardiovascular Benefit SGLT-2 Inhibitors Inhibition of SGLT-2 glucose cotransport may result in sodium loss/natriuresis This leads to reduction in plasma volume Reduced plasma volume may mediate increased hematocrit Increased hematocrit is the leading variable in cardiac benefit in EMPA-REG

Slide 11. Is Benefit of Empagliflozin-Specific or a Class Effect Slide 11. Is Benefit of Empagliflozin-Specific or a Class Effect? CVD-REAL Study SGLT-2 inhibitors vs other diabetes drugs Propensity match: 150,000 patients per arm Improved outcomes with SGLT-2 inhibitors as a class ~40% reduction in hospitalization for heart failure ~50% relative risk reduction in mortality from all causes Results unchanged with removal of diabetic drugs that increase risk of hospitalization for heart failure Results consistent across different SGLT-2 inhibitors

Slide 12. Mechanism of Action in Cardiovascular Benefit GLP-1 Receptor Agonists The benefit of GLP-1 receptor agonists appear a little bit later than seen with SGLT-2 inhibitors Possible pleiotropic effects of GLP-1 receptor agonists?