Clinical Overview: Sotagliflozin (Inpefa) for Heart Failure

The FDA approved sotagliflozin (Inpefa) in May 2023 for the purpose of lowering the risk of cardiovascular death and heart failure in adult patients with heart failure, type 2 diabetes mellitus, chronic kidney disease, and additional cardiovascular risk factors.¹ Sotagliflozin is an orally administered dual SGLT1/2 inhibitor that achieves its pharmacological effects by decelerating glucose absorption in the gastrointestinal tract and enhancing glucose excretion in the urine.²

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Sodium-glucose co-transporter types 1 and 2 (SGLT1 and SGLT2) play crucial roles in glucose transport within the body. SGLT1 is primarily responsible for facilitating glucose absorption in the gastrointestinal tract, whereas SGLT2 is the primary transporter involved in reabsorbing glucose in the glomerulus.²

Sotagliflozin is an inhibitor of both SGLT1 and SGLT2. Inhibiting SGLT1 leads to a delay in glucose absorption and a reduction in postprandial hyperglycemia. Meanwhile, inhibiting SGLT2 decreases the renal reabsorption of filtered glucose, resulting in increased urinary glucose excretion.²

SOLOIST-WHF was a phase 3 clinical trial conducted under double-blind, randomized, and placebo-controlled conditions. Among patients with diabetes and recent exacerbation of heart failure, sotagliflozin therapy, whether initiated prior to or shortly after discharge, led to a notable reduction in the overall count of cardiovascular-related deaths, as well as hospitalizations and urgent visits for heart failure compared with placebo.³

A total of 1222 patients were randomly assigned, with 608 assigned to the sotagliflozin group and 614 to the placebo group. They were followed for a median duration of 9.0 months. The initial dose of sotagliflozin or placebo was administered to 48.8% of patients before discharge and a median of 2 days after discharge for the remaining 51.2%.³

Among these patients, 600 primary endpoint events occurred, with 245 in the sotagliflozin group and 355 in the placebo group. The rate of primary endpoint events, measured as the number of events per 100 patient-years, was lower in the sotagliflozin group compared to the placebo group (51.0 vs. 76.3). The hazard ratio was 0.67 with a 95% confidence interval [CI] of 0.52 to 0.85, and the result was statistically significant (P<0.001).³

The rate of cardiovascular-related deaths was 10.6 in the sotagliflozin group and 12.5 in the placebo group, with a hazard ratio of 0.84 and a 95% CI of 0.58 to 1.22. The rate of all-cause mortality was 13.5 in the sotagliflozin group and 16.3 in the placebo group, with a hazard ratio of 0.82 and a 95% CI of 0.59 to 1.14.³

Notably, sotagliflozin was associated with a higher incidence of diarrhea compared to the placebo (6.1% vs. 3.4%), as well as a higher occurrence of severe hypoglycemia (1.5% vs. 0.3%). The percentage of patients experiencing hypotension and acute kidney injury was similar between the sotagliflozin cohort and the placebo cohort (6.0% and 4.6% for hypotension, 4.1% and 4.4% for acute kidney injury, respectively).³

Even with the compelling evidence from the SOLOIST-WHF trial supporting the safety and efficacy of sotagliflozin in this economically significant clinical context, some experts believe that the drug may encounter a challenging journey as it competes for a share of the market against 2 well-established, yet significantly underutilized, SGLT2 inhibitors: dapagliflozin (Farxiga) and empagliflozin (Jardiance).⁴

On the contrary, some experts anticipate a distinctive role for sotagliflozin, particularly due to additional aspects of the drug's performance in trials that they believe provide it with a competitive advantage. This advantage includes evidence showing that sotagliflozin, within the SGLT2 inhibitor class, reduces the incidence of strokes and myocardial infarctions. Moreover, there is evidence of its apparent ability to reduce HbA1c levels in patients with type 2 diabetes and an estimated glomerular filtration rate below 30 mL/min/1.73m².⁴

In the SCORED trial among individuals with diabetes and chronic kidney disease, with or without albuminuria, sotagliflozin was linked to a reduced risk of the combined outcome of cardiovascular-related deaths, hospitalizations due to heart failure, and urgent visits for heart failure by 26% when compared to a placebo.⁵

The data from SOLOIST-WHF and SCORED seem to be at least as promising as the data concerning another SGLT2 inhibitors in the context of heart failure. However, what sets them apart are the rates of myocardial infarction (MI) and stroke observed in the SCORED trial.⁴

Per US label, the suggested dosage is 200 mg of sotagliflozin to be taken once daily before the initial meal of the day. If further glycemic control is required and the patient can tolerate sotagliflozin at 200 mg, the dosage may be escalated to 400 mg taken once daily after 2 weeks of therapy.

Warnings for therapy include risk of diabetic ketoacidosis for type 1 diabetes mellitus and other ketoacidosis, volume depletion, urosepsis and pyelonephritis, hypoglycemia with concomitant use with insulin and insulin secretagogue, necrotizing fasciitis of the perineum and genital mycotic infections.⁶

References

1. FDA Update: Sotagliflozin Approved For Broad HF Treatment. American College of Cardiology. https://www.acc.org/Latest-in-Cardiology/Articles/2023/06/05/18/34/FDA-Update-Sotagliflozin-Approved-For-Broad. Accessed on October 19, 2023.
2. Lapuerta P, Zambrowicz B, Strumph P, et al. Development of sotagliflozin, a dual sodium-dependent glucose transporter 1/2 inhibitor. Diab Vasc Dis Res. 2015 Mar;12(2):101-10. doi: 10.1177/1479164114563304.
3. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. N Engl J Med 2021; 384:117-128 doi: 10.1056/NEJMoa2030183
4. FDA Approves New Drug, Sotagliflozin, for Heart Failure. Medscape. https://www.medscape.com/viewarticle/992518. Accessed on October 19, 2023.
5. Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease. N Engl J Med 2021; 384:129-139
   DOI: 10.1056/NEJMoa2030186
6. Inpefa (sotagliflozin). [prescribing information]. The Woodlands, TX: Lexicon Pharmaceuticals, Inc.; May 2023.