Cardiovascular Challenges in Diabetes Part I Mechanism Moderator

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 A 1 C – 33 mg/d. L 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/valsartan 1 vs enalapril 2 for heart failure • Compared glycemic control in the diabetic subpopulation (n=3, 778) • Reductions in hemoglobin A 1 C 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 1. Neprilysin inhibitor/angiotension receptor blocker 2. 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 A 1 C (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? 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?