The latest drug shown to benefit patients with heart failure with reduced ejection fraction, the SGLT2 inhibitor empagliflozin, works just as well when added on top of a second major agent used to treat these patients, the renin-angiotensin system–inhibiting combination of sacubitril/valsartan, based on a post-hoc analysis of data from the EMPEROR-Reduced trial.
“When there are two very effective treatments, it’s common for people to ask: Which should I use?’ The goal of my presentation was to emphasize that the answer is both. We shouldn’t choose between neprilysin inhibition [sacubitril inhibits the enzyme neprilysin] and SGLT2 [sodium-glucose transporter 2] inhibition; we should use both,” said Milton Packer, MD at the virtual annual meeting of the Heart Failure Society of America.
EMPEROR-Reduced had the primary goal of testing the safety and efficacy of the SGLT2 inhibitor empagliflozin (Jardiance) in patients with heart failure with reduced ejection fraction (HFrEF). The results showed that adding this drug on top of standard treatments led to a 25% relative cut in the study’s primary efficacy endpoint, compared with placebo, and had this effect regardless of whether or not patients also had type 2 diabetes (N Engl J Med. 2020 Aug 29. doi: 10.1056/NEJMoa2022190).
Among the 3,730 patients enrolled in the trial, 727 (19%) were on sacubitril/valsartan (Entresto) at entry, which gave Dr. Packer the data to perform the analysis he reported. He presented the study’s three major endpoints as well as a quality of life analysis that compared the performance of empagliflozin in patients who were on sacubitril/valsartan at baseline with the other study patients, who were either on a different type of renin-angiotensin system (RAS) blocker (roughly 70% of study patients) or on no RAS inhibition (about 10% of patients).
The results showed no statistically significant indication of an interaction, suggesting that patients with sacubitril/valsartan on board had just as good response to empagliflozin as patients who were not on this combination. The landmark PARADIGM-HF trial proved several years ago that treatment of HFrEF patients with sacubitril/valsartan led to significantly better outcomes than did treatment with another form of RAS inhibition (N Engl J Med. 2014 Sep 11;371:993-1004).
For example, EMPEROR-Reduced’s primary endpoint, the combined rate of cardiovascular death or hospitalization for heart failure, fell by 36% relative to placebo in patients who received empagliflozin on top of sacubitril/valsartan, and by 23% relative to placebo among the remaining patients who received empagliflozin on top of a different type of RAS inhibitor drug or no RAS inhibition.
“Background treatment with sacubitril/valsartan did not diminish, and may have enhanced the efficacy of empagliflozin,” concluded Dr. Packer. Further analyses also showed that concurrent sacubitril/valsartan had no statistically significant impact on empagliflozin’s ability to reduce the rate of total heart failure hospitalizations, or to slow progressive loss of renal function, compared with placebo. The fourth efficacy analysis Dr. Packer presented showed that empagliflozin was also as effective for improving a quality-of-life measure in patients compared with placebo regardless of the type of RAS inhibition used. For all four outcomes, the point-estimate of empagliflozin’s benefit was higher when used along with sacubitril/valsartan.
Brian L. Claggett, PhD, a biostatistician at Brigham and Women’s Hospital and Harvard Medical School in Boston, designated discussant for the report, disagreed with Dr. Packer’s suggestion that the efficacy of empagliflozin may have been greater when administered against a background of sacubitril/valsartan. From a statistical perspective, there is no basis to suggest that patients did better when they were on both drugs, he cautioned. But Dr. Claggett acknowledged that the new analyses suggested that empagliflozin’s benefit wasn’t compromised by concurrent sacubitril/valsartan use. He also highlighted the value of more fully documenting the safety and efficacy of a new drug when used as part of “comprehensive therapy” with the established drugs that a patient may concurrently receive.
Dr. Packer also presented several measures of treatment safety that all showed similar rates of adverse effects between the empagliflozin and placebo recipients regardless of background RAS inhibition. A notable finding was that the incidence of hypokalemia was 5.9% in patients on empagliflozin and sacubitril/valsartan and 7.5% among patients on empagliflozin and a different type of RAS inhibition.
EMPEROR-Reduced was funded by Boehringer Ingelheim and Eli Lilly, the companies that market empagliflozin. Dr. Packer has received personal fees from Boehringer Ingelheim and Eli Lilly and from several other companies. Dr. Claggett has been a consultant to Amgen, AO Biome, Biogen, Corvia, Myokardia, and Novartis.