Keeping SCORED: How Sotagliflozin May Be the Rising Star of SGLT Inhibitors

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce renal tubular absorption of glucose and provide cardiovascular (CV) benefits by increasing natriuresis, improving cardiac energy metabolism, and reducing proinflammatory states, cardiac remodeling, and ischemia/reperfusion (1). Empagliflozin has shown a reduction in all-cause and CV mortality and heart failure (HF) hospitalization rates in type-2 diabetes mellitus (T2DM) (2) and a reduction in CV mortality and HF hospitalization rates with reduced or preserved EF (3-4). Canagliflozin has shown renal protection, reduction in death from MI and stroke, and lower HF rates in T2DM and chronic kidney disease (CKD) (5). Dapagliflozin has shown lower rates of HF hospitalization and lower risk of worsening HF regardless of T2DM and in reduced EF, although the benefit in MACE reduction was unclear (6-7).

As opposed to SGLT2i, SGLT1i reduces gut absorption of glucose and galactose. They also reduce myocardial sodium and glucose levels, reactive oxygen species generation, and cardiac dysfunction post-infarction (1). In the SOLOIST-WHF trial, sotagliflozin (SGLT1/2i) demonstrated a 33% reduction in all-cause and CV mortality and HF hospitalizations compared to placebo (HR 0.67; 95% CI 0.52 to 0.85; P<0.001) with benefits in reduced and preserved ejection fraction (HR 0.72; 95% CI 0.56-0.94 and HR 0.48; CI 0.27-0.86, respectively) in patients with T2DM and worsening heart failure (8).

Dr. Deepak Bhatt, one of the lead investigators of SOLOIST-WHF, presented the SCORED trial at the American College of Cardiology Annual Scientific Session 2022. The SCORED trial studied sotagliflozin (400mg daily) vs. placebo in stable T2DM and CKD patients. In the primary end-point (CV death, HF hospitalization, and urgent visit for HF), there was a significant reduction in sotagliflozin compared to placebo within the first 3 months (11.3% vs. 14.4%, HR 0.74, 95% CI 0.63-0.88, p = 0.0004) (9). In the pooled SCORED and SOLOIST-WHF data, the primary end-point for sotagliflozin vs. placebo was 15.5 vs. 21.1 per 100 patient-years (p = 0.000002). Dr. Bhatt notes, “as with other SGLT2 inhibitor trials, SCORED demonstrated a significant reduction in heart failure events. However, it also found a significant reduction in MACE, including significant reductions in both total heart attacks and total strokes. This benefit on ischemic endpoints emerged early and was significant by approximately three months. The benefit was consistent in those with or without a history of known cardiovascular disease at baseline.”

With the results from SCORED, a lot of excitement surrounds the use of dual SGLTi for cardiovascular benefits compared to SGLT2i alone. However, future studies must be conducted to appreciate the benefits of dual SGLT inhibition in cardio-renal protection. Though, we’ll be keeping SCORED on our minds for now.

References:

1. Lopaschuk GD, Verma S. Mechanisms of Cardiovascular Benefits of Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: A State-of-the-Art Review. JACC Basic Transl Sci. 2020;5(6):632-644. Published 2020 Jun 22. doi:10.1016/j.jacbts.2020.02.004
2. Zinman B., Wanner C., Lachin J.M., for the EMPA-REG OUTCOME Investigators Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128.
3. Packer M, Anker SD, Butler J, et al. Effect of Empagliflozin on the Clinical Stability of Patients With Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial [published correction appears in Circulation. 2021 Jan 26;143(4):e30]. Circulation. 2021;143(4):326-336. doi:10.1161/CIRCULATIONAHA.120.051783
4. Packer M, Butler J, Zannad F, et al. Effect of Empagliflozin on Worsening Heart Failure Events in Patients With Heart Failure and Preserved Ejection Fraction: EMPEROR-Preserved Trial. Circulation. 2021;144(16):1284-1294. doi:10.1161/CIRCULATIONAHA.121.056824
5. Perkovic V., Jardine M.J., Neal B., for CREDENCE Trial Investigators Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295–2306.
6. Wiviott S.D., Raz I., Bonaca M.P., for the DECLARE-TIMI 58 Investigators Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380 380:347–357.
7. McMurray J.J.V., Solomon S.D., Inzucchi S.E., for the DAPA-HF Trial Committees and Investigators Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381 1995–200.
8. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. N Engl J Med. 2021;384(2):117-128. doi:10.1056/NEJMoa2030183
9. Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk – SCORED. Presented by Dr. Deepak L. Bhatt at the American College of Cardiology Annual Scientific Session (ACC 2022), Washington, DC, April 2, 2022.