Clinical Heart and Vascular Center
SGLT2 Inhibition and ARNI in Heart Failure: Two ‘White Hot’ Topics
By Mark Drazner, M.D., M.Sc., Clinical Chief of Cardiology; Medical Director, LVAD/Cardiac Transplantation
At the AHA Scientific Sessions, I presented at the Trending Topics: Clinical Science Session focusing on heart failure and cardiomyopathies. The intent of this session was to summarize key findings presented at the AHA. I chose to focus on two major trending topics, which I described as “white hot” topics in cardiology. The first was the role of sodium-glucose cotransporter-2 (SGLT2) inhibition as a therapy for patients with heart failure, and the second was the role of angiotensin receptor-neprilysin inhibitor (ARNI) therapy in patients with heart failure who have a left ventricular ejection fraction (LVEF) >40%.
As most readers know, SGLT2 inhibitors, developed as therapy for diabetes, have been shown in clinical trials of patients with diabetes to reduce the risk of heart failure events. At the AHA, a prespecified subgroup analysis of the landmark DAPA-HF trial was presented. This subgroup analysis assessed whether dapagliflozin, a SGLT2 inhibitor, had efficacy in patients with established class II-IV heart failure with LVEF ≤40% even if they did not have diabetes. The primary outcome reported was a 27% reduction in the risk of CV death, heart failure hospitalization, or urgent heart failure visit in the subjects without diabetes. This benefit was driven largely by reduction in HF hospitalizations; indeed, there was no reduction in all-cause mortality. The investigators also showed that the benefits of dapagliflozin were not affected by baseline hemoglobin A1C tertiles among the non-diabetic subjects, and that dapagliflozin also led to improvements in quality of life as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). I concluded that if additional trials confirm these findings, we (the cardiology community) will need to own SGLT2 inhibitors as a therapy for heart failure rather than consider them a treatment for diabetes.
“The second interesting study was an analysis assessing whether ARNI therapy may be beneficial in subjects with LVEF >40%. If so, this would be a fundamental change in our approach to such patients, and thus, this analysis warrants close scrutiny.”
The second interesting study was an analysis assessing whether ARNI therapy may be beneficial in subjects with LVEF >40%. If so, this would be a fundamental change in our approach to such patients, and thus, this analysis warrants close scrutiny. The landmark PARADIGM-HF trial demonstrated large benefits of sacubitril-valsartan in those with heart failure with reduced ejection fraction (HFrEF). In contrast, in subjects with heart failure and LVEF ≥45% in PARAGON-HF, sacubitril-valsartan did not reduce a composite endpoint of heart failure hospitalization and cardiovascular death (p = 0.06). At the AHA, investigators presented data in which they combined these two trials and reported that sacubitril-valsartan appeared to convey benefit among subjects with an LVEF >40% (potentially as high as 55% or even higher). However, this study was also published simultaneously in Circulation, and in a supplemental analysis using a different methodology (categorizing patients by LVEF ≤40%, >40% to 50%, and >50%), this conclusion appeared less robust. I concluded that additional data are needed before I extend ARNI therapy to patients with heart failure who have an LVEF >40%.