Sotagliflozin May Steal the Spotlight in Heart Failure, but Questions Remain

Heart failure is a clinical syndrome of structural damage and functional impairment of cardiac tissue, leading to decreased ability of the ventricles to circulate blood throughout the body. The disease is categorized by symptom severity using assessment tools such as the New York Heart Association (NYHA) functional classification. The American College of Cardiology Foundation/American Heart Association (ACC/AHA) provides additional staging information in the development of heart failure.

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Heart failure affects an estimated 64 million people worldwide with the AHA estimating that 6.2 million of those are in the United States.¹ Among those who are diagnosed, the primary goals of treatment involve symptom management, slowing or reversing deterioration of myocardial function, and reducing mortality.² Thus far, mainstays of treatment have included beta blockers, renin-angiotensin system inhibitors, diuretics, mineralocorticoid receptor antagonists, and, more recently, sodium-glucose cotransporter (SGLT)2 inhibitors. One of the newest FDA-approved agents for heart failure is sotagliflozin (Inpefa; Lexicon), a dual SGLT2 and SGLT1 inhibitor.

Table.³ Sotagliflozin Quick Facts

Although newly approved, there is some debate regarding the benefits and populations in which sotagliflozin will be the most effective. It has been approved by the FDA in 2 primary patient populations including heart failure patients and type 2 diabetes patients with chronic kidney disease and additional cardiovascular risk factors. However, the 2 primary trials evaluating sotagliflozin only included patients with type 2 diabetes, so the effects in patients without diabetes, despite the approval, are still unclear.⁴

Another aspect of the debate is the role of SGLT1 inhibition in sotagliflozin’s clinical effects. The concentration of the medication is not expected to be high enough to inhibit SGLT1 in the renal tubules but may play a role in the myocardium. SGLT1 is upregulated in heart failure, which can lead to ventricular hypertrophy and dysfunction, but the clinical effects of myocardial SGLT1 inhibition are not fully elucidated.⁴

Despite these lingering questions, the 2 primary trials evaluating sotagliflozin, SOLOIST-WHF and SCORED, have promising results. The SOLOIST-WHF trial found a reduction in the composite of cardiovascular death and hospitalization in patients with type 2 diabetes who were hospitalized for worsening heart failure.⁵ The SCORED trial evaluated patients with type 2 diabetes, chronic kidney disease, and additional cardiovascular risk factors and found a reduction in the composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, as well as a reduction in the composite of cardiovascular death and hospitalization for heart failure.⁶ Both trials found diarrhea to be the most commonly occurring adverse event, though statistical significance was not noted.

Going forward, sotagliflozin may be a good alternative to SGLT2 inhibitors for heart failure patients, particularly those with type 2 diabetes. Hopefully more data will be discovered regarding SGLT1 inhibitors on the reduction of myocardial infarction and stroke that has been lacking in SGLT2 inhibitors.

References

1. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1789. Epub 2018 Nov 8.

2. Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circ. 2022;145:e895-e1032. doi:10.1161/CIR.0000000000001063

3. Sotagliflozin [package insert]. Lexicon Pharmaceuticals, Inc., The Woodlands, TX, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1a46614e-05f6-421a-b6f4-d6f8760d643a

4. Packer M. Dual SGLT1 and SGLT2 inhibitor sotagliflozin achieves FDA approval: landmark or landmine? Nat Cardiovasc Res 2, 705–707 (2023)

5. Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, Lewis JB, Riddle MC, Voors AA, Metra M, Lund LH, Komajda M, Testani JM, Wilcox CS, Ponikowski P, Lopes RD, Verma S, Lapuerta P, Pitt B; SOLOIST-WHF Trial Investigators. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. N Engl J Med. 2021 Jan 14;384(2):117-128.

6. Bhatt DL, Szarek M, Pitt B, Cannon CP, Leiter LA, McGuire DK, Lewis JB, Riddle MC, Inzucchi SE, Kosiborod MN, Cherney DZI, Dwyer JP, Scirica BM, Bailey CJ, Díaz R, Ray KK, Udell JA, Lopes RD, Lapuerta P, Steg PG; SCORED Investigators. Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease. N Engl J Med. 2021 Jan 14;384(2):129-139.