A prespecified analysis of a large global trial of patients with symptomatic heart failure with mildly reduced and preserved ejection fraction “seals the deal” on the efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors to manage and improve their symptoms.
The prespecified analysis of the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trial included 5,795 patients with mildly reduced and preserved ejection fraction who completed the Kansas City Cardiomyopathy Questionnaire (KCCQ) after taking the SGLT2 inhibitor dapagliflozin or placebo. The results were published online in the Journal of the American College of Cardiology.
“We’ve known from studies prior to DELIVER that SGLT2 inhibitors have been shown to improve health status, patient symptoms and quality of life among those that are living with heart failure and mildly reduced [HFmrEF] and preserved [HFpEF] ejection fraction,” lead author Mikhail N. Kosiborod, MD, vice president for research at Saint Luke’s Health System, and codirector of the St. Luke’s Michael and Marly Haverty Cardiometabolic Center of Excellence at St. Luke’s Mid America Heart Institute, Kansas City, Mo., said in an interview. “But the picture was incomplete for a number of different reasons, partly because the previous studies were either relatively modest in size, geographically limited, or suggested potential attenuation of these benefits in patients with completely normal ejection fraction.”
Specifically, the study authors noted the EMPEROR-Preserved trial of the SGLT2 inhibitor empagliflozin showed improvement in health status vs. placebo across the range of EF except in those with normal EF of 65% or greater. The PRESERVED-HF trial of dapagliflozin demonstrated a more robust response than EMPEROR-Preserved or DELIVER, but PRESERVED-HF patients were recruited only in the United States and had more debilitating HF symptoms at baseline.
“Because of the results of the DELIVER trial and because of how large, extensive, and inclusive the trial was, it really seals the deal on the value of SGLT2 inhibitors in patients with heart failure,” said Dr. Kosiborod, who is also a professor of medicine at the University of Missouri–Kansas City.
The DELIVER analysis found that the effects of dapagliflozin on reducing cardiovascular death and worsening HF were greatest in patients who had the most debilitating symptoms at baseline, measured as KCCQ total symptom score (TSS) as 63 or less, the lowest of three tertiles used in the analysis. At baseline, these patients had the highest rates of CV death or worsening HF than those in the other two tertiles: KCCQ-TSS of 63-84, and greater than 84.
Compared with placebo, treated patients in the lowest KCCQ-TSS quartile had a 30% reduction in risk for the primary composite outcome, which consisted of time to first CV death or HF event (hazard ratio, 0.70; 95% confidence interval, 0.58-0.84; P < .001). In the second tertile, the relative risk reduction was 19% (HR, 0.81; 95% CI, 0.65-1.01; P < .006), and the highest quartile showed no significant difference between treatment and placebo (HR, 1.07; 95% CI, 0.83-1.37; P < .62).
“The most important take home message is that the SGLT2 inhibitor dapagliflozin significantly improved patient symptoms as measured by the Kansas City Cardiomyopathy Questionnaire symptom score,” Dr. Kosiborod said. “It improved those symptoms within 1 month and those benefits were sustained out to 8 months.”
DELIVER patients also showed improvement in all other key KCCQ domains across the board, he added. “In addition, dapagliflozin also improved the proportion of patients who had small, moderate, and large improvements in a responder analysis. So really, by every measure that we had, dapagliflozin had a significant beneficial effect.”
The DELIVER results taken collectively with the EMPEROR-Preserved and PRESERVED-HF trials cinch the deal for SGLT2 inhibitors, Dr. Kosiborod said. “They deliver on the triple goal of care in patients with heart failure. They reduce the risk of cardiovascular death and worsening heart failure and they improve patient symptoms, function and quality of life – and they accomplish that across the entire continuum of heart failure regardless of ejection fraction, regardless of whether patients are hospitalized or in an ambulatory setting, regardless of age or background therapies or other comorbidities.”
He added: “It’s a pretty historic development because we haven’t had that before.”
AstraZeneca funded the DELIVER trial. Dr. Kosiborod disclosed financial relationships with Alnylam, Amgen, Applied Therapeutics, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi, Pharmacosmos and Vifor Pharma.