Congestive Heart Failure: The Complication that Gets No Respect Richard J. Katz, MD Saturday, February 18, :30 a.m. 10:15 a.m.

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1 Congestive Heart Failure: The Complication that Gets No Respect Richard J. Katz, MD Saturday, February 18, :30 a.m. 10:15 a.m. The prevalence of the combination of diabetes and both systolic and diastolic heart failure is increasing independent of coronary associated artery disease. Patients with heart failure and diabetes have higher rates of hospitalizations and worse outcomes compared to heart failure patients without diabetes. Patients with diabetes and heart failure have several pathophysiologic abnormalities that may contribute to progressive cardiac dysfunction. In the past decade new data has expanded our understanding of the importance of glucose control and the impact classes of old and new diabetic medications on the risk of heart failure complications. References: 1. Bell et al. Etiologies of heart failure in patients with diabetes. Diabetes Care 2003;26: Dei Cas A et al. Concomitant diabetes mellitus and heart failure. Current Problems in Cardiology 2015;4: Zinman B et al. Empagliflozon, Cardiovascular outcomes in type 2 diabetes. NEJM 2015;373: Margulies KB et al. Effects of Liraglutide on Clinical Stability Among Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial. JAMA, 2016 Aug 2; Vol. 316 (5), pp Marso SP et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. NEJM 2016;375:

2 Congestive Heart Failure: The Complication that Gets No Respect Richard J Katz, MD George Washington University Six year CHF Incidence per 1000 person years by Age Group Nichols et al. Diabetes Care, Aug2004, Vol. 27 Issue 8, p Horwich et a.l JACC 2010 Heart Failure Progression

3 Diabetes and HFPEF DM No DM Paulus WJ et al. JACC 2012;62: Lindman BR et al. JACC 2014;64 (6):541 9 Effect of More vs Less Intensive Control of Glucose on Heart Failure Ray KK et al. Lancet 2009;373:1765

4 Mortality with Metformin in Patients with Heart Failure and Diabetes Rosiglitazone Pioglitazone Risk of Heart Failure with TZD Use Lago RM et al. Lancet 2007;320:1129 Product Labeled Heart Failure Cautions for Diabetes Medications

5 ORIGIN Trial: Secondary Outcomes ORIGIN Trial Investigators NEJM 2012:367: TECOS: Time to First Hospitalization for Heart Failure McGuire DK et al. JAMA Cardiology 2016;1:126 35

6 Cardiac Myocyte Substrate Utilization in Heart Failure Lixisenatide in Patients with Type 2 Diabetes and ACS: Heart Failure Hospitalization % 5 Nonischemic conditions: cardiac myocytes use fatty acids (FFA) and glucose to generate ATP via oxidative phosphorylation. Fatty acids are the predominant substrate under normal conditions. Heart failure: altered gene expression genes reduces FFA uptake and metabolism (solid red arrows) and cardiac myocyte insulin resistance reduces glucose uptake via the transporters GLUT1 and GLUT4 (dotted red arrows) impairing uptake and utilization of both substrates for ATP generation via oxidative phosphorylation. Either naturally occurring glucagon like peptide 1 (GLP 1) or degradation resistant GLP 1 agonists reduce insulin resistance and increase cardiac myocyte glucose uptake via signaling through the GLP 1R receptor that induces phosphorylation (activation) of AMP activated protein kinase (AMPK), (green arrows). Pfeffer M et al. NEJM 2015;373: Months Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes: Hospitalization for Heart Failure Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes Marso SP et al. NEJM 2016;375:31 22 Margulies KB et al. JAMA 2016;316:500 8

7 Sodium glucose co transporter 2 (SGLT2) Inhibitors: Metabolic and Hemodynamic Mechanisms Abdul Ghahani et al. Diabetes Care 2016;39: EMPA REG OUTCOME: Hospitalization for Heart Failure Zinman B et al. NEJM2015;373: SUMMARY