Meta-analysis of sotagliflozin, a dual sodium-glucose-cotransporter 1/2 inhibitor, for heart failure in type 2 diabetes

Abstract

Sodium-glucose co-transporters (SGLTs) mediate sodium and glucose transport across cell membranes. SGLT2 inhibitors have a recognized place within heart failure (HF) guidelines. We evaluated the effect of sotagliflozin on HF and cardiovascular outcomes in participants with type 2 diabetes. Scopus, Medline, Embase and Central were searched from inception until 2 June 2023. Randomized controlled trials evaluating sotagliflozin in type 2 diabetes participants and reporting HF events were selected. Major adverse cardiovascular events (MACE) and systolic blood pressure were evaluated. The Cochrane risk of bias tool (RoB 2.0) was used. Pooled mean difference (MD), relative risk (RR), 95% confidence intervals and the number needed to treat (NNT) were estimated (PROSPERO: CRD42023432732). We selected nine studies (n = 15 320 participants: n = 8040 intervention and n = 7280 control). The median follow-up was 13.4 months (Q1 = 13, Q3 = 21). One study recruited participants with HF at baseline. After a follow-up of >52 weeks, sotagliflozin significantly reduced the risk of HF [n = 8 studies; RR = 0.66 (0.64, 0.69)], stroke [n = 6 studies; RR = 0.75 (0.58, 0.97)] and MACE [n = 8 studies; RR = 0.73 (0.66, 0.81)]. The NNT was 20 and 26 for HF and MACE, respectively. Sotagliflozin lowered systolic blood pressure [n = 7; MD = -2.38 mmHg (-2.79, -1.97)]. No dose-dependent effect was identified for HF [200 mg: RR = 0.38 (0.16, 0.89), 400 mg: RR = 0.57 (0.39, 0.85), P-value = 0.22]. The high risk of bias was a limitation of this review. Sotagliflozin reduced HF and cardiovascular events in type 2 diabetes participants. Research exploring its effects in HF and comparisons with SGLT2 inhibitors is warranted to determine if dual SGLT inhibition surpasses selective inhibition.

Keywords: heart failure; meta‐analysis; sodium‐glucose co‐transporter 1 (SGLT1); sodium‐glucose co‐transporter 2 (SGLT2); sotagliflozin; type 2 diabetes mellitus.

Figure 1

PRISMA flow chart illustrating the study selection process for inclusion in this review.

Figure 2

‘Traffic light’ plot of the domain‐level judgements for composite heart failure and bar plots of the distribution of risk‐of‐bias judgements within each bias domain.

Figure 3

Forest plot for the risk of composite cardiac failure events of sotagliflozin compared with placebo. CI, confidence interval; RR, relative risk.

Figure 4

Simplified diagrammatic illustration of the heart benefits related to SGLT1 inhibition by both direct and indirect pathways. Direct: SGLT1 inhibition may reduce the hyperglycaemia‐induced generation of reactive oxygen species (ROS) in myocardial cells, matrix metalloproteinases (MMP) in cardiac fibroblasts and toxic calcium accumulation in myocardial cells. Indirect: Antihypertensive, diuretic and natriuretic effects by increased renal glucose excretion and weight‐loss properties by an increase in glucagon‐like peptide‐1 (GLP‐1) and short‐chain fatty acids (SCFA). BP, blood pressure; SGLT, sodium‐glucose co‐transporter. Created by BioRender®.