By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved the first dual sodium-glucose cotransporter 2 and 1 (SGLT2/1) inhibitor. Sotagliflozin is the fifth drug in the SGLT class, following canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin — all of which are predominately SGLT2 inhibitors. Available in Europe since 2019, sotagliflozin is distributed as Inpefa.
INDICATIONS
Sotagliflozin can be prescribed to lower the risk of cardiovascular (CV) death, hospitalization for heart failure, and urgent heart failure visits among adults living with heart failure or type 2 diabetes mellitus, chronic kidney disease, and other CV risk factors.1
DOSAGE
Start patients on 200 mg daily, then titrate to 400 mg as tolerated.1 For patients who have been diagnosed with decompensated heart failure, begin dosing when patients are hemodynamically stable. Sotagliflozin will be available as 200-mg and 400-mg tablets.
POTENTIAL ADVANTAGES
SGLT1 inhibition delays glucose absorption in the intestine (reducing postprandial glucose), accelerates secretion of glucagon-like peptide 1 (GLP-1), and slows glucose-dependent insulinotropic polypeptide (GIP) production.2,3 However, it remains to be established whether the presence of SGLT1 inhibition provides added, significant clinical advantage.
POTENTIAL DISADVANTAGES
Sotagliflozin inhibits SGLT2, resulting in significant excretion of glucose in urine. It shares the same warning and precautions as other SGLT2 inhibitors, such as diabetic ketoacidosis, volume depletion, urosepsis/pyelonephritis, necrotizing fasciitis of the perineum, and genital mycotic infection.1 Other adverse reactions include urinary tract infections and diarrhea.1 Diarrhea might be unique to sotagliflozin because of inhibition of SGLT1 expressed in the intestine.3
COMMENTS
The approval of sotagliflozin was based on two Phase III, randomized, double-blind, placebo-controlled trials (SOLOIST-WHF and SCORED).1,4,5 During SOLOIST-WHF, researchers randomized subjects with type 2 diabetes who were hospitalized for worsening heart failure with either reduced or preserved ejection fraction. During SCORED, investigators randomized subjects with type 2 diabetes and chronic kidney disease. In SOLOIST-WHF, the authors randomized 608 subjects to sotagliflozin and 614 to placebo. After a median follow-up of nine months, sotagliflozin reduced the composite primary endpoint (total occurrence of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit) by 33% (51 per 100 patient-years vs. 76; HR, 0.67; 95% CI, 0.52-0.85). Hospitalization and urgent visits for heart failure were significantly lower (36% reduction). Death from cardiovascular causes was not statistically different. Men, participants age 65 years and older, and those with estimated glomerular filtration rates less than 60 mL/min/1.73 m2 showed more benefit with sotagliflozin.
In the SCORED trial, the authors randomized 5,292 subjects to sotagliflozin and 5,292 to placebo. Sotagliflozin reduced the primary composite endpoint by 25% (5.6 per 100 patient-years vs. 7.5; HR, 0.75; 95% CI, 0.63-0.88) after a median follow-up of 16 months. Similarly, hospitalization rates and urgent visits for heart failure were significantly lower (33%); there was no significant difference in cardiovascular death rates. For one of the secondary endpoints (a combination of the total number of deaths from CV causes, nonfatal myocardial infarction, and nonfatal strokes), the authors reported a 23% reduction (HR, 0.77; 95% CI, 0.65-0.91).5
CLINICAL IMPLICATIONS
Since the approval of the first SGLT2 inhibitor (canagliflozin) in 2013 to treat type 2 diabetes, three others have been approved, some with broader indications (including patients with heart failure and chronic kidney disease).6 Sotagliflozin is the fifth drug in the SGLT inhibitor class to be approved and is the first with dual SGLT2/1 inhibition. The potential added clinical benefit remains to be established. Three investigators from SOLOLIST-WHF/SCORED postulated there might be added benefit of SGLT1 inhibition, citing the findings from SCORED that showed a 23% reduction in composite total death from CV causes, nonfatal myocardial infarction, and nonfatal strokes.3,5 The cost for a 30-day supply of sotagliflozin 200-mg is $598. The cost for 400-mg tablets was not available at the time of this review. The cost for empagliflozin, which carries a similar FDA indication (i.e., reducing the risk of CV death, hospitalization, and urgent visits for heart failure) is $593 per 30-day supply for both strengths (10 mg and 25 mg).
REFERENCES
1. Lexicon Pharmaceuticals, Inc. Inpefa prescribing information. May 2023.
2. Cefalo CMA, Cinti F, Moffa S, et al. Sotagliflozin, the first dual SGLT inhibitor: Current outlook and perspectives. Cardiovasc Diabetol 2019;18:20.
3. Pitt B, Bhatt DL, Metra M. Does SGLT1 inhibition add to the benefits of SGLT2 inhibition in the prevention and treatment of heart failure? Eur Heart J 2022;43:4754-4757.
4. 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.
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.
6. Padda IS, Mahtani AU, Parmar M. Sodium-glucose transport protein 2 (SGLT2) inhibitors. StatPearls. Last updated May 21, 2023.
Sotagliflozin tablets can be prescribed to lower the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits among adults living with heart failure or type 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors.
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