Key result
SGLT2 inhibitors linked to ~25% lower real-world mortality in HFrEF, outpacing randomized trials.
Why the study?
Randomized trials established the efficacy of SGLT2 inhibitors in HFrEF, motivating an assessment of whether their effectiveness in routine practice is concordant with trial efficacy.
Does SGLT2 inhibitor therapy reduce all-cause mortality and heart failure hospitalization in real-world routine practice concordantly with randomized trial efficacy in adults with HFrEF (LVEF ≤40%)?
Meta-Analysis (n=110,827)
Yes
Does SGLT2 inhibitor therapy reduce all-cause mortality and heart failure hospitalization in real-world routine practice concordantly with randomized trial efficacy in adults with HFrEF (LVEF ≤40%)?
Hazard Ratio: 0.75 (95% CI 0.71–0.79)
Real-world observational mortality benefits of SGLT2 inhibitors in HFrEF are directionally concordant with but exaggerated relative to RCTs due to residual confounding from background therapy, while real-world hospitalization estimates diverge due to ascertainment differences, confirming that RCT estimates remain the most reliable guide for causal benefit.
Trial estimates remain the best guide to SGLT2 inhibitor benefit in HFrEF; real-world data confirm direction but likely overestimate effects due to confounding.
Randomized trials established the efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors in heart failure with reduced ejection fraction (HFrEF).We assessed whether their effectiveness in routine practice is concordant with trial efficacy, appraising and pooling each evidence stream separately.PubMed/MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.govwere searched from January 1, 2015 to July 2026 for randomized trials and comparative observational studies of SGLT2 inhibitors vs. placebo or nonuse in adults with left ventricular ejection fraction ≤40% reporting mortality or heart failure hospitalization.Risk of bias was assessed with the Cochrane Risk of Bias 2 and the Newcastle-Ottawa Scale.Adjusted all-cause mortality was pooled by random-effects meta-analysis with the Hartung-Knapp adjustment; other outcomes were synthesized narratively.Trial and observational estimates were never combined, and certainty was graded with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria.Eleven studies were included (two trials and nine observational).For all-cause mortality, the pooled observational HR (0.75, 95% CI 0.71-0.79;I² = 0%) indicated a larger apparent benefit than the pooled trial estimate (HR 0.87, 0.77-0.98).In one registry, the association attenuated to borderline nonsignificance after adjustment for background therapy.For heart failure hospitalization, a consistent trial benefit (HR 0.69, 0.62-0.78)contrasted with attenuated or null real-world estimates (HR 0.84-1.03).Realworld mortality associations with SGLT2 inhibitors in HFrEF are directionally concordant with trial efficacy, but their larger magnitude most plausibly reflects residual confounding, including co-prescription of other guideline-directed therapy.Real-world hospitalization estimates diverged from trials, likely reflecting outcome ascertainment.With very low-certainty observational evidence, the trial estimate remains the best guide to causal benefit.
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Hassanien et al. (2026) conducted a meta-analysis in Heart failure with reduced ejection fraction (HFrEF) (n=110,827). Sodium-glucose cotransporter 2 (SGLT2) inhibitors vs. Placebo (randomized trials) or nonuse/noninitiation (observational studies) was evaluated on All-cause mortality (pooled observational studies) (HR 0.75, 95% CI 0.71-0.79). SGLT2 inhibitors in HFrEF showed a larger apparent all-cause mortality reduction in real-world studies (HR 0.75, 95% CI 0.71-0.79) than in randomized trials (HR 0.87, 95% CI 0.77-0.98).
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