Related Experiment Videos
Efficacy and Safety of SGLT2 Inhibitors and Sotagliflozin in Heart Failure: A Systematic Review and Meta-Analysis of
Vicky Muller Ferreira1, Victor Ayres Muller2
1Cardiology, Independent Researcher, Rio de Janeiro, BRA.
Abstract:
Sodium-glucose cotransporter-2 (SGLT2) inhibitors have become a cornerstone of heart failure (HF) therapy, yet the totality of randomized evidence - including smaller trials beyond the landmark cardiovascular (CV) outcome studies - has not been comprehensively synthesized. We searched PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform (ICTRP) from inception to March 2026 for randomized controlled trials (RCTs) comparing any SGLT2 inhibitor or the dual sodium-glucose cotransporter-1/2 (SGLT1/SGLT2) inhibitor sotagliflozin with placebo or standard care in adults with HF. Random-effects Mantel-Haenszel risk ratios (RRs) with Hartung-Knapp-Sidik-Jonkman (HKSJ) confidence intervals (CIs) were used. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. The protocol was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD420251167908). Of 6,239 records identified, 114 studies met inclusion criteria and 59 RCTs (29,692 participants) were included in the quantitative synthesis. SGLT2 inhibitors reduced all-cause mortality (ACM; RR 0.90, 95% CI 0.83-0.98; p = 0.016; 26 trials; low certainty), although trim-and-fill adjustment for publication bias attenuated the finding (adjusted RR 0.92, 95% CI 0.84-1.00). HF hospitalization (HFH) was reduced (RR 0.74, 95% CI 0.69-0.79; 15 trials; moderate certainty), as were CV death (RR 0.86, 95% CI 0.76-0.98; seven trials; moderate certainty), the composite of CV death and HFH (RR 0.80, 95% CI 0.75-0.85; eight trials; high certainty), and serious adverse events (RR 0.94, 95% CI 0.90-0.99; 20 trials; high certainty). Genital infections were significantly increased (RR 3.75, 95% CI 1.72-8.19); no significant increases were observed for diabetic ketoacidosis (DKA), acute kidney injury (AKI), urinary tract infection (UTI), or hypotension. Subgroup analyses showed a greater ACM benefit in HF with reduced ejection fraction (HFrEF) than in HF with preserved ejection fraction (HFpEF) (interaction p = 0.039). Results were directionally consistent across 13 sensitivity scenarios and five alternative statistical models. SGLT2 inhibitors reduce HFH, CV death, the composite endpoint, and serious adverse events with moderate-to-high certainty; the all-cause mortality reduction is of low certainty and sensitive to publication bias.
Insights
Sodium-glucose cotransporter-2 (SGLT2) inhibitors significantly reduce heart failure hospitalizations and cardiovascular death. While all-cause mortality benefits are less certain, SGLT2 inhibitors improve overall safety outcomes in heart failure patients.
Area of Science:
- Cardiology
- Pharmacology
- Clinical Trials
Background:
- Sodium-glucose cotransporter-2 (SGLT2) inhibitors are established heart failure (HF) treatments.
- Previous evidence synthesis has not comprehensively included all randomized trials.
Purpose of the Study:
- To synthesize the totality of randomized evidence on SGLT2 inhibitors in adult HF patients.
- To assess the efficacy and safety of SGLT2 inhibitors across various HF outcomes.
Main Methods:
- Systematic search of multiple databases (PubMed, CENTRAL, ClinicalTrials.gov, ICTRP) up to March 2026.
- Inclusion of 59 randomized controlled trials (RCTs) with 29,692 participants.
- Meta-analysis using random-effects models and assessment of evidence certainty with GRADE.
Main Results:
- SGLT2 inhibitors significantly reduced HF hospitalization (moderate certainty), CV death (moderate certainty), and a composite of CV death/HFH (high certainty).
- All-cause mortality reduction was observed (low certainty) but sensitive to publication bias.
- Serious adverse events were reduced (high certainty), while genital infections increased; no significant increases in DKA, AKI, UTI, or hypotension were noted.
Conclusions:
- SGLT2 inhibitors demonstrate significant benefits in reducing HF hospitalizations, CV death, and composite outcomes with moderate-to-high certainty.
- The benefit for all-cause mortality is of low certainty and potentially influenced by publication bias.
- SGLT2 inhibitors appear to improve overall safety, despite an increased risk of genital infections.
Related Concept Videos
01:23Dipeptidyl Peptidase 4 Inhibitors
01:26Oral Hypoglycemic Agents: Biguanides and Glitazones
01:26Heart Failure Drugs: Inhibitors of Renin-Angiotensin System
01:27Glucose Transporters
Facilitated diffusion-glucose transporters (GLUTs) are encoded by the solute-linked carrier (SLC) family 2, subfamily A gene family, or SLC2A. The 14 GLUT protein members are distributed into three classes:
01:19Oral Hypoglycemic Agents: α-Glucosidase Inhibitors
Acarbose and miglitol are typically...
01:24Glucagon-like Receptor Agonists
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by the...