Sotagliflozin Findings Suggest Benefit for Hard-to-Treat HF Population

A pair of trials involving sotagliflozin—a unique diabetes drug with a rocky history at FDA—suggest it offers benefits for patients who have heart failure with preserved ejection fraction (HFpEF), marking the first time investigators have shown this in a prospective trial.

Results from SOLOIST-WHF¹ and SCORED², presented this evening at the American Heart Association Scientific Sessions, also found that the dual inhibitor resulted in fewer cardiovascular (CV) events and can offer glycemic control even for patients with lower levels of renal function. This latter finding offers some irony, since the topline results from smaller trials in chronic kidney disease (CKD) led to the breakup between drug sponsor Lexicon Pharmaceuticals and Sanofi, its marketing partner.

According to the lead investigator, Deepak L. Bhatt, MD, of Harvard Medical School, the findings suggest that sotagliflozin could be an option for patients with significant comorbidities; if given to those hospitalized for heart failure, sotagliflozin could keep them from being readmitted—a priority in managed care. The findings were simultaneously published in the New England Journal of Medicine.

The results come more than a year after Sanofi cut ties with Lexicon following disagreements over how to interpret early findings from the SOTA-CKD3 and SOTA-CKD4 studies, which evaluated its effectiveness in patients with moderate and advanced renal decline. FDA had also twice rejected the drug’s proposed use as an add-on to insulin in type 1 diabetes (T1D).

Loss of funding during the COVID-19 pandemic forced an early end to the pair of phase 3 trials released today. While cautious about interpreting the HFpEF signal, Bhatt said he believes it should indicate good news from other trials studying sodium glucose co-transporter 2 (SGLT2) inhibitors in this hard-to-treat condition. Right now, there are no approved treatments for HFpEF, although FDA has accepted a new drug application from Novartis to evaluate sacubitril/valsartan (Entresto) for this use.

The road from here is complicated for sotagliflozin. When the trials had to end early, Bhatt and co-authors had to revamp end points and skip some planned analyses, which they acknowledge as limitations. But the data are strong enough, Bhatt said, to warrant another look from FDA.

There are distinct groups of patients who would benefit from the dual inhibitor mechanism of sotagliflozin, he said. “One particular niche could be patients with severe kidney disease.”

A Unique Mechanism of Action

Sotagliflozin is a dual inhibitor, meaning it targets proteins in both the gut and the renal system—sodium glucose co-transporters 1 and 2—that affect how the body retains or processes blood glucose. SGLT2 inhibitors, which reached the market in 2013, were designed to manage type 2 diabetes (T2D) by targeting the SGLT2 protein in the kidney, blocking its ability to retain up to 90% of filtered glucose. CV outcomes trials required by FDA revealed unexpected benefits in heart failure and preservation of kidney function, setting off a race for more studies to gain approvals in these conditions.

Unlike current rivals in the SGLT2 class, sotagliflozin also targets the SGLT1 protein, which affects the absorption of glucose in the gastrointestinal tract. The drug was approved for T2D (marketed as Zynquista) but also sought approval to stabilize the glycemic variability that affects the 1.25 million US patients with T1D. This use is approved in Europe. But FDA balked, citing concerns about diabetic ketoacidosis.

Results for SOLOIST-WHF. This trial randomly assigned 1222 patients with T2D who were recently hospitalized for worsening heart failure to receive either sotagliflozin or placebo. The primary end point was the total number of deaths from CV causes and hospitalizations and urgent visits for heart failure, including first and subsequent events. Patients were followed for a median of 9.0 months, with 48.8% getting their first dose of the study drug or placebo before discharge and 51.2% receiving it within 2 days. Results showed:

• The rate of primary end point events in the trial (events per 100 patient years) was 51.0 in the sotagliflozin group and 76.3 in the placebo group for a hazard ratio (HR) of 0.67; 95% CI, 0.52-0.85, P = .0009.
• The death rate from any cause was 13.5 in the sotagliflozin group and 16.3 in the placebo group (HR, 0.82; 95% CI, 0.59-1.14)
• More patients with sotagliflozin had diarrhea (6.1% vs 3.4%) and more had severe hypoglycemia (1.5% vs 0.3%), but the percentages of hypotension were similar (6.0% sotagliflozin vs 4.6% placebo).
• The percentage of patients with acute kidney injury was similar (4.1% for sotagliflozin vs 4.4% for placebo).

Results for SCORED. This trial evaluated sotagliflozin’s ability to prevent CV events in patients with diabetes and CKD with or without albuminuria. This study randomized 10,584 to sotagliflozin or placebo, with a revised primary end point of the total number of deaths from CV disease, total hospitalizations for heart failure, and urgent visits for heart failure. Results include:

• The rate of primary end point events (events per 100 patient years) was 5.6 for sotagliflozin and 7.5 for placebo, for an HR of 0.74 (95% CI, 0.63-0.88), P = .0004).
• The rate of deaths from CV causes per 100 patient-years was 2.2 with sotagliflozin and 2.4 with placebo (HR, 0.90; 95% CI, 0.73 to 1.12; P = 0.35).
• Two original coprimary end points were reported: first occurrence of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke, with an HR of 0.84 (95% CI, 0.72 to 0.99); and first occurrence of death from CV causes or hospitalization for heart failure, with an HR of 0.77 (95% CI, 0.66 to 0.91).
• The total number of deaths from CV causes, hospitalizations for HF, nonfatal myocardial infarctions, and nonfatal strokes was 7.6 for sotagliflozin and 10.4 for placebo, for an HR of 0.72 (0.72 (0.63–0.83).

Bhatt showed data indicating the reduction in glycated hemoglobin (A1C) was twice as great as placebo across both moderate (eGFR ≥30 ml/min/1.73 m2) and severe eGFR <30 ml/min/1.73 m2) renal decline.

The first occurrence of a sustained decrease of ≥50% in the eGFR from baseline for ≥30 days, long-term dialysis, renal transplantation, or sustained eGFR of <15 ml/min/1.73 m2 for ≥30 days was 0.5 events per 100 patient years in sotagliflozin and 0.7 events for placebo, for an HR of 0.71 (0.46–1.08).

A Signal at Last in HFpEF

Bhatt said other evidence has suggested that SGLT2 inhibition could offer benefits in HFpEF, but until now investigators have not found a signal in a prospective trial. During Monday's evening session, he presented pooled data from the SOLOIST-WHF and SCORED trials, and found that the HR for 1758 patients with HFrEF was 0.78 (95% CI, 0.63–0.96, P = .02), and the HR for 739 patients with HFpEF was 0.63 (95% CI, 0.45-0.89, P= .009).

“For the first time we've actually demonstrated prospectively that an SGLT2 inhibitor with SGLT1 inhibition capability is something that is useful for heart failure with preserved ejection fraction,” he said, noting that there are 2 ongoing trials, DELIVER for dapagliflozin and EMPEROR-Preserved for empagliflozin, that are examining this question for SGLT2 inhibitors.

“I would predict based on the results of SOLOIST, and the combined SOLOIST/SCORED [results], for that those trials will also be positive,” Bhatt said in response to a question from The American Journal of Managed Care®.

Dapagliflozin received approval earlier this year to treat patients with heart failure with reduced ejection fraction (HFrEF), and results presented in August show empagliflozin (Jardiance) is effective in HFrEF.

References

1. Bhatt DL, Szarek M, Steg PG, et al. for the SOLOIST-WHF Trial Investigators. Sotagliflozin in patients with diabetes and recent worsening heart failure for the SOLOIST-WHF Trial. N Engl J Med. Published online November 16, 2020. doi: 10.1056/NEJMoa2030183

2. Bhatt DL, Szarek M, Pitt B, et al., for the SCORED Trial Investigators. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med. Published online November 16, 2020. doi: 10.1056/NEJMoa2030186