Sotagliflozin's HFpEF Benefit Confirmed by New Analyses

Will Pass

May 24, 2021

It's now official: The investigational sodium-glucose cotransporter (SGLT) 1/2 inhibitor sotagliflozin is the first agent clearly shown in a prespecified analysis of randomized trials to improve clinical outcomes in patients with heart failure with reduced ejection fraction (HFpEF).

Researchers who ran the SCORED and SOLOIST–WHF pivotal trials for sotagliflozin first made that claim in November 2020 when reporting top-line results from a prespecified meta-analysis of the two trials during the American Heart Association annual scientific sessions. A follow-up report during the annual scientific sessions of the American College of Cardiology fleshed out the evidence and firmed up their landmark conclusion.

The meta-analysis (Abstract 410-08) included 4,500 patients with type 2 diabetes and diagnosed heart failure at entry; its primary endpoint, which was the same in both trials, was the combined incidence of cardiovascular death and the total number of either hospitalization for heart failure or urgent outpatient visits for heart failure.

Compared with placebo, treatment with sotagliflozin for a median of about 15 months dropped this composite endpoint by a relative 33% among the 1,931 who began the study with a left ventricular ejection fraction (LVEF) of at least 50% (HFpEF), by a relative 22% in the 1,758 patients who entered with an LVEF of less than 40% (patients with heart failure with reduced ejection fraction), and by a relative 43% among the 811 patients who began with an LVEF of 40%-49% (patients with heart failure with mid-range ejection fraction). The relative risk reductions were significant for all three subgroups, Deepak L. Bhatt, MD, reported at the meeting.

Equally Effective "Across the Full Range of LVEFs"

Perhaps as notable and unprecedented was the further finding that the clinical benefits seen with treatment of patients with type 2 diabetes with sotagliflozin was consistent regardless of the ejection fraction they had at entry. Enrolled patients with baseline LVEFs in the range of 25% received a relative benefit from sotagliflozin treatment that was statistically no different from the benefit seen in patients who entered with an LVEF in the neighborhood of 45%, 65%, or at any other level across the LVEF spectrum, a finding that Bhatt called "remarkable" during a press briefing. "The results show the benefit of sotagliflozin across the full range of LVEFs."

"We are very excited in the heart failure world by the SGLT2 inhibitors; we've been impressed by their reduction in heart failure hospitalizations, but we wonder about the patients with HFpEF, where we haven't had a blockbuster drug to give," said Ileana L. Piña, MD, a heart failure specialist and medical officer with the Food and Drug Administration.

The new findings "look like they could pose a regulatory indication [for sotagliflozin] for patients with type 2 diabetes and heart failure across the entire spectrum of heart failure," said Christopher M. O'Connor, MD, a heart failure specialist and president of the Inova Heart & Vascular institute in Falls Church, Va., and designated discussant for Bhatt's report.

SCORED randomized 10,584 patients with type 2 diabetes and chronic kidney disease to treatment with sotagliflozin or placebo on top of guideline-directed medical therapy. During a median 16 months of treatment, the combined primary endpoint occurred at a rate of 5.6 events/100 patient years on sotagliflozin and 7.5 events/100 patient years in the controls, a significant 26% relative reduction with sotagliflozin (N Engl J Med. 2021 Jan 14;384[2]:129-39). Nearly a third of the enrolled patients had heart failure, with representation across the range of LVEF.

SOLOIST-WHF randomized 1,222 patients with type 2 diabetes who were recently hospitalized for worsening heart failure. During a median 9 months of follow-up, the primary endpoint occurred at a rate of 51 events/100 patient years in the sotagliflozin-treated patients and a rate of 76 events/100 patient years in the controls, a significant 33% relative reduction with sotagliflozin (N Engl J Med. 2021 Jan14;384[2]:117-28). Both trials stopped prematurely because of sponsorship issues.

In addition to the 4,500 patients with heart failure at entry in both trials, SCORED included a total of more than 6,700 without diagnosed heart failure at baseline, and in this subgroup treatment with sotagliflozin cut the incidence of the primary endpoint by a significant 27% compared with control patients.

A Significant On-Treatment Reduction in CV Death

Other new, notable findings from the meta-analysis included the observation that while treatment with sotagliflozin failed to produce a significant reduction in cardiovascular death, compared with placebo, in the intent-to-treat analysis of all patients and of those with heart failure at baseline (it produced nonsignificant point-estimate reductions of 11% compared with placebo for all patients, and of 23% for patients who began the study with heart failure), it did result in a significant 23% relative risk reduction when the researchers focused on patients while they remained adherent to their sotagliflozin regimen (the on-treatment analysis). This 23% relative reduction appeared among all enrolled patients, as well as in the subgroup that started with diagnosed heart failure.

"Given the totality of data from the SGLT2 inhibitors, I think this is a real finding," Bhatt said.

Additional analyses also showed that, among women, treatment with sotagliflozin was linked with significant relative reductions in the primary endpoint of roughly 30% compared with placebo among all patients, and also among those with heart failure at baseline. "HFpEF is a problem particularly in older women, and we showed that the benefit was consistent in men and women," Bhatt said.

He acknowledged that results are expected soon from two pivotal trials that are examining two different SGLT2 inhibitors, dapagliflozin and empagliflozin, in patients with HFpEF. "I think there will be a class effect for both SGLT2 inhibitors and sotagliflozin for reducing heart failure events in patients with HFpEF, and I predict that the dapagliflozin and empagliflozin trials will have positive results," Bhatt said.

Sotagliflozin differs from the SGLT2 inhibitors by also inhibiting SGLT1, an enzyme found in the gastrointestinal system that, when inhibited, results in increased glucose excretion from the gut and a cut in bloodstream levels of postprandial glucose levels. The Food and Drug Administration accepted data from SCORED and SOLOIST-WHF as part of the evidence the agency is now considering for granting a new drug approval to sotagliflozin.

SCORED and SOLOIST–WHF were initially sponsored by Sanofi, and later by Lexicon Pharmaceuticals. Bhatt's institution, Brigham and Women's Hospital, has received funding from Sanofi and Lexicon Pharmaceuticals. He has been a consultant to and received honoraria from K2P, Level Ex, and MJH Life Sciences; he has been an adviser to Cardax, Cereno Scientific, Myokardia, Novo Nordisk, Phase Bio, and PLx Pharma; and he has received research funding from numerous companies. Piña has no relevant disclosures. O'Connor has been a consultant to Arena, Bayer, Bristol-Myers Squibb, Merck, and Windtree, and he has an ownership interest in Biscardia.

American College of Cardiology (ACC) 2021 Scientific Session

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