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Liraglutide Use in Heart Failure Patients

Cardioprotective effects of the drug are focus of research.

The incidence of heart failure in patients with type 2 diabetes is increasing. Ensuring proper glycemic control has been shown to prevent cardiovascular complications. However,  in order to obtain the desired glycemic goals, certain medications have to be employed. Newer antidiabetic medications provide great benefits for lowering blood sugar and providing a significant reduction in hemoglobin A1c. Additionally, newer findings suggest that GLP-1 analogues provide cardiovascular protection in diabetes patients. Treatment with these agents has shown to have direct effects on cardiac function and structure. Some evidence suggests a vasodilatory effect through nitric oxide mediators. Other benefits seen include: reduction in inflammation, improved exercise capacity, and improved LV ejection fraction (LVEF). However, these findings haven’t been replicated in high-risk patients with early stages of cardiac dysfunction. In the LEADER trial conducted by Steven Marso and colleagues, it was found that patients with type 2 diabetes had nonsignificant lower rates of non-fatal myocardial infarction, stroke, and hospitalizations for heart failure when treated with liraglutide. This outlines the potential role of these agents in patients with diabetes and cardiovascular disease.

Recently, the FIGHT trial studied the clinical stability of liraglutide in patients hospitalized for acute heart failure. In this multicenter, double-blind, placebo-controlled randomized trial, patients who had heart failure and a reduced left ventricular ejection fraction (LVEF) were randomized to 1:1 ratio to receive either liraglutide or placebo subcutaneous injections. Only those patients with a hospitalization history (within 14 days) and on oral diuretic therapy with 40 mg of furosemide or an equivalent were eligible for participation. Patients with or without type 2 diabetes were also included in the study. After the exclusion and inclusion criteria, 300 patients were part of the study; 154 in the intervention group and 146 on the placebo group.  Primary end-points of the study included the following: re-hospitalization for heart failure, time-averaged proportional change in proBNP, and death. Secondary end-points included other cardiac events, changes in cardiac function and structure, changes in the 6-minute walk distances, and changes in the KCCQ clinical summary score.

After the study concluded, those patients receiving the up-titration regimen of liraglutide (0.6-1.2-1.8 mg/day every 14 days) for 180 days did not achieve any significant difference in the primary end-point when compared to placebo (P=0.31). Similar findings were seen in the secondary end-points. However, researchers looked into weight effects of liraglutide and saw significant differences at 30 days (−1.7 kg intergroup difference; 95% CI, −2.9 to −0.5 kg]; P = .004) and 90 days (intergroup change -1.9kg; 95% CI, -3.4-0.4kg; P=0.01); no significant changes at 180 days (P=0.09). Furthermore, 178 patients had diabetes in the study with no significant differences seen in the primary and secondary end-points. However, it was suggested there was a higher risk of heart failure events in this patient population and greater in magnitude when compared to the overall study subjects. Hyperglycemia was reported less frequently in the liraglutide group (10%) than in the placebo group (18%); only 1% of the study subjects experienced hypoglycemia. However, inadequate statistical power was not able to establish rates of side effects between both study groups.

In conclusion, the use of liraglutide did not provide any stability benefits for the incidence of re-hospitalization following an acute heart failure episode. Therefore, liraglutide does not show any improvement in heart failure status despite highlighted benefits in previous studies. Authors believe that glucose-dependent insulin secretion seen with GLP-1 analogues may have deleterious results in patients with diabetes and heart failure. One limitation of this study is the inability to detect differences in clinical events due to lack of power. Additionally, the patient population studied in this clinical trial was based on referrals within the NHLBI Heart Failure Network and does not provide sufficient representation for those patients with advanced heart failure outside of these centers. The pathway through which GLP-1 analogues provide cardioprotective effects needs to be further evaluated in order to establish a relationship between their use and cardiovascular health outcomes.

Practice Pearls:

  • Liraglutide does not provide any additional benefits in the risk of re-hospitalization due to acute heart failure.
  • The cardioprotective benefits of liraglutide and other GLP-1 analogues do not provide clinical stability after an acute heart failure.
  • Patients with heart failure and diabetes warrant close monitoring due to an increased risk of HF exacerbations.

 

Researched and prepared by Pablo A. Marrero-Núñez – USF College of Pharmacy Student Delegate – Doctor of Pharmacy Candidate 2017, reviewed by Dave Joffe, BSPharm, CDE

 

References:

Htike, Z. Z., T. Yates, E. M. Brady, D. Webb, L. J. Gray, D. Swarbrick, G. P. Mccann, K. Khunti, and M. J. Davies. “Rationale and Design of the Randomised Controlled Trial to Assess the Impact of Liraglutide on Cardiac Function and Structure in Young Adults with Type 2 Diabetes (the LYDIA Study).” Cardiovasc Diabetol Cardiovascular Diabetology 15.1 (2016): n. pag. Web.

Margulies, Kenneth B., Adrian F. Hernandez, Margaret M. Redfield, Michael M. Givertz, Guilherme H. Oliveira, Robert Cole, Douglas L. Mann, David J. Whellan, Michael S. Kiernan, G. Michael Felker, Steven E. Mcnulty, Kevin J. Anstrom, Monica R. Shah, Eugene Braunwald, and Thomas P. Cappola. “Effects of Liraglutide on Clinical Stability Among Patients With Advanced Heart Failure and Reduced Ejection Fraction.” Jama 316.5 (2016): 500. Web.

Marso, Steven P., Gilbert H. Daniels, Kirstine Brown-Frandsen, Peter Kristensen, Johannes F.e. Mann, Michael A. Nauck, Steven E. Nissen, Stuart Pocock, Neil R. Poulter, Lasse S. Ravn, William M. Steinberg, Mette Stockner, Bernard Zinman, Richard M. Bergenstal, and John B. Buse. “Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes.” New England Journal of Medicine N Engl J Med 375.4 (2016): 311-22. Web.