1. Cardiovascular Challenges in Diabetes

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

3. 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

4. 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

5. 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)

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

7. 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

8. 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

9. 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?

10. 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

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

12. 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

13. 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

14. 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

15. 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

16. 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?