# Comparative efficacy and safety of different SGLT2 inhibitor-based combination strategies in HFrEF: a systematic review and network meta-analysis

## TL;DR

This study compares different drug combinations for heart failure, finding that some SGLT2 inhibitor-based therapies may be more effective and safer than others.

## Contribution

A Bayesian network meta-analysis comparing six HFrEF treatment regimens, revealing distinct efficacy and safety profiles.

## Key findings

- Sotagliflozin-based therapy ranked highest for reducing cardiovascular death and hospitalization.
- ARNI-based triple therapy increased hypotension risk, while SGLT2 inhibitors protected against renal events.
- Dapagliflozin and ARNI-based therapies were comparable for reducing all-cause mortality.

## Abstract

The optimal combination therapy for heart failure with reduced ejection fraction (HFrEF) involving sodium-glucose transporter 2 inhibitors (SGLT2i), angiotensin receptor–neprilysin inhibitors (ARNI), and conventional triple therapy remains uncertain due to the lack of direct comparative evidence.

We conducted a Bayesian network meta-analysis of randomized controlled trials (RCTs) comparing six treatment regimens. Primary outcome was the composite of cardiovascular death and hospitalization. Secondary outcomes included all-cause mortality, Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, 6-minute walk distance (6MWD), N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and adverse events (hypotension, hyperkalemia, renal events). All analyses were performed under a Bayesian statistical framework, and the relative efficacy and safety of the six regimens were ranked using surface under the cumulative ranking curve (SUCRA) probabilities.

A total of 22 studies (21 RCTs) involving 24,499 patients were included. For the primary composite outcome, Sotagliflozin-based quadruple therapy ranked first (SUCRA: 90.8%; OR: 0.49, 95%CI: 0.16 to 1.47). Dapagliflozin+triple therapy (SUCRA: 76.8%; OR: 0.83, 95%CI: 0.69 to 0.98) and ARNI+BB+MRA (SUCRA: 76.6%; OR: 0.83, 95%CI: 0.75 to 0.92) demonstrated significant reductions in all-cause mortality. ARNI-based triple therapy was associated with a significantly increased risk of hypotension (OR: 1.67, 95%CI: 1.48 to 1.90), whereas Dapagliflozin and Empagliflozin showed protective effects against renal adverse events. No regimen significantly increased hyperkalemia risk. Additionally, a statistically significant interaction was observed between treatment effects and baseline diabetes burden for the primary outcome (p = 0.003).

This network meta-analysis demonstrates that while all quadruple therapy regimens improve outcomes in HFrEF, important distinctions exist. Sotagliflozin-based therapy may offer advantages in preventing hospitalizations, whereas Dapagliflozin and ARNI are comparable for mortality reduction. The safety profiles differ significantly, particularly regarding hypotension risk with ARNI and renal protection with SGLT2i. The choice of regimen should be individualized based on patient priorities, comorbidities, and safety tolerability profiles.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251112344

, identifier CRD420251112344.

Network meta-analysis of six therapeutic regimens in HFrEF: main results and clinical implications. Graphic summary of NMA on pharmacotherapies for HFrEF, highlighting key findings and clinical implications. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; BB, beta-blocker; CV, cardiovascular; Dapa, Dapagliflozin; Empa, Empagliflozin; LVEF, left ventricular ejection fraction; MRA, mineral receptor antagonist; NMA, network meta-analysis; Sota, Sotagliflozin; SUCRA, surface under the cumulative ranking curve.Flowchart illustrating a study on heart conditions and treatments. A heart icon indicates left ventricular ejection fraction (LVEF) under 40%. Arrow points to NMA involving six drug combinations, 22 studies, and 24,499 patients using a Bayesian model. Two treatment comparisons: ARNI+BB+MRA showing 6MWD SUCRA 81.76% and NT-proBNP SUCRA 86.95% with hypotension risk OR 1.67; SGLT2i+ACEi/ARB+BB+MRA affecting diabetes severity, showing significance with P = 0.003. Clinical implications include guidelines, personalized medicine, and references for clinicians. Dapa, Empa, and Sota drugs reduce mortality, dual protection, and cardiovascular death with respective outcomes.

Network meta-analysis of six therapeutic regimens in HFrEF: main results and clinical implications. Graphic summary of NMA on pharmacotherapies for HFrEF, highlighting key findings and clinical implications. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; BB, beta-blocker; CV, cardiovascular; Dapa, Dapagliflozin; Empa, Empagliflozin; LVEF, left ventricular ejection fraction; MRA, mineral receptor antagonist; NMA, network meta-analysis; Sota, Sotagliflozin; SUCRA, surface under the cumulative ranking curve.