Comparative Effects of Pharmacological Treatment on Heart Failure with Mildly Reduced or Preserved Ejection Fraction: A Systematic Review and Network Meta-analysis of Randomized Controlled Trials
- Design
- Meta-analysis · Hard outcome
- Match to healthy normal-weight adults aged 55–75
- Different populationINDIRECT: all included trials enrolled patients with heart failure with mildly reduced or preserved ejection fraction, with no BMI or diabetes data reported.
- Could weight loss explain it?
- PossiblyNo weight, body mass index or HbA1c data are reported for the pooled trials, and nothing separates a drug effect from weight or metabolic change. The primary efficacy comparisons were null for cardiovascular death and all-cause mortality, but one GLP-1 result was not: heart failure hospitalisation was lower with semaglutide than with exenatide, so there is a result whose mediation can be asked about.
- Study tier
- Study tier 2MODERATE: a random-effects network meta-analysis that pools 20 randomized trials with hard outcomes, rated down because none of the trials provided head-to-head comparisons and the authors themselves grade the reported comparisons as low or very low certainty in places.
- Assessment
- Version 3 · Checked against the source by AI · Nov 6, 2026
Study facts come from the paper. Population match, weight-loss explanation and study tier are our judgments, made against the reference group of healthy normal-weight adults aged 55–75.
A systematic review and network meta-analysis pooled 20 randomized placebo-controlled trials, covering 10 drugs across 35 publications, in people with heart failure with mildly reduced or preserved ejection fraction. No drug differed from another in cardiovascular death, all-cause mortality or serious adverse events. Heart failure hospitalisation was lower with semaglutide (risk ratio 0.43, 95% CI 0.20-0.91), dapagliflozin (0.57) and empagliflozin (0.54) than with exenatide, while adverse events were more frequent with tirzepatide than empagliflozin (1.17, 1.04-1.32) and, by class, with GLP-1 drugs than SGLT-2 inhibitors (0.87, 0.78-0.96). None of the comparisons came from head-to-head trials, so all are indirect.
01Findings
What the study reported
- Drugs
- Semaglutide, Exenatide, Tirzepatide
- Comparator
- placebo in the included trials; the network also yielded indirect drug-versus-drug and class-versus-class comparisons
- Primary outcome
- cardiovascular death, hospitalization for heart failure and all-cause mortality (efficacy); adverse events and serious adverse events (safety)
- Effect
- No significant differences among the individual drugs for CV death, all-cause mortality or serious adverse events; versus exenatide, HF hospitalization was lower with semaglutide (RR 0.43, 95% CI 0.20-0.91), dapagliflozin (0.57, 0.36-0.91) and empagliflozin (0.54, 0.34-0.86); versus empagliflozin, tirzepatide had a higher risk of adverse events (1.17, 1.04-1.32); by class, SGLT-2I had a lower risk of adverse events than GLP-1RA (0.87, 0.78-0.96), with no class differences in efficacy
- 95% confidence interval
- 95% CI 0.20-0.91 (semaglutide versus exenatide, HF hospitalization)
- Follow-up
- Not stated
- Adverse events
- No significant differences in serious adverse events among the individual drugs; tirzepatide had a higher risk of adverse events than empagliflozin (RR 1.17, 95% CI 1.04-1.32), and SGLT-2I a lower risk than GLP-1RA as classes (RR 0.87, 95% CI 0.78-0.96)
- Limitations
- None of the 20 trials provided head-to-head comparisons, so every drug-versus-drug estimate is indirect and the authors grade the certainty of these comparisons from moderate down to very low; no pooled sample size, follow-up or event counts are reported.
Who was studied
- Obesity status
- not reported in abstract
- Diabetes status
- not reported in abstract
- Cvd status
- heart failure with mildly reduced or preserved ejection fraction required
- Ckd status
- not reported in abstract
- Baseline condition
- heart failure with mildly reduced or preserved ejection fraction
- Inclusion exclusion
- randomized controlled trials comparing a non-steroidal mineralocorticoid receptor antagonist, soluble guanylate cyclase stimulator, SGLT-2 inhibitor or GLP-1 receptor agonist with placebo in patients with HFmrEF/HFpEF
Study quality details
- Study design
- Meta-analysis
- Sample size
- not extracted
- Randomization
- yes
- Blinding
- not stated
- Comparator
- placebo in the included trials; the network also yielded indirect drug-versus-drug and class-versus-class comparisons
- Follow up duration
- not stated
- Outcome type
- hard
- Replication
- not assessed
- Consistency with other evidence
- not assessed
- Population applicability
- INDIRECT
- Statistical precision
- risk ratios with 95% confidence intervals from a frequentist random-effects network meta-analysis of 20 randomized trials, none of them head-to-head; no pooled sample size, follow-up or event counts reported
- Risk of bias
- not assessed
- Peer review status
- yes
02Funding
Funding and conflicts
- Funding
- the National Natural Science Foundation of China; the Natural Science Foundation of Guangdong Province of China; the Science Foundation of Guangdong Second Provincial General Hospital; the Young Top Talent Project in the Special Support Plan for Training High-level Talents in Guangdong
- Industry funded
- No
- Manufacturer
- not stated in source
- Sponsor role
- not reported in abstract
- Author conflicts
- The named authors declare no potential conflicts of interest relevant to the manuscript.
- Independent replication
- unknown
Funding is shown on every study and never used to score it.
04Source
The source, as retrieved
Abstract
[BACKGROUND] The comparative efficacy and safety of the new drugs (including sodium-glucose cotransporter-2 inhibitors [SGLT-2Is], glucagon-like peptide-1 receptor agonists [GLP-1RAs], non-steroidal mineralocorticoid receptor antagonists [nsMRAs], and soluble guanylate cyclase stimulators [sGCs]) for heart failure with mildly reduced or preserved (HFmrEF/HFpEF) ejection fraction remains largely unclear. We conducted a systematic review and network meta-analysis to evaluate their comparative effects on HFmrEF/HFpEF, aiming to provide evidence-based guidance for treatment selection. [METHODS] MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials were comprehensively searched. We included randomized controlled trials that compared nsMRA, sGC, SGLT-2I, and GLP-1RA with placebo for patients with HFmrEF/HFpEF. Primary efficacy outcomes were cardiovascular (CV) death, hospitalization for heart failure (HF hospitalization), and all-cause mortality, while primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs). The main analysis was conducted to compare the effects on HFmrEF/HFpEF between individual drugs. A frequentist network meta-analysis with random-effects models was used to calculate risk ratios (RRs) for dichotomous outcomes and standardized mean differences (SMDs) for continuous outcomes. [RESULTS] A total of 20 randomized controlled trials (RCTs, including 10 drugs from 35 publications) were included for analyses, but none provided head-to-head direct comparisons. No significant differences among all the individual drugs were found in risks of CV death or all-cause mortality. Compared with exenatide, low or moderate certainty evidence showed that dapagliflozin (RR 0.57, 95% CI 0.36-0.91), empagliflozin (RR 0.54, 95% CI 0.34-0.86), and semaglutide (RR 0.43, 95% CI 0.20-0.91) were related to decreased risk of HF hospitalization. No significant differences in the risk of SAEs were found among the individual drugs. Compared with empagliflozin, very low certainty evidence showed that tirzepatide (RR 1.17, 95% CI 1.04-1.32) was related to increased risk of AEs. When comparing the four drug classes (nsMRA, sGC, SGLT-2I, and GLP-1RA), no significant differences in efficacy outcomes were found, while SGLT-2I (RR 0.87, 95% CI 0.78-0.96) was associated with a decreased risk of AEs compared with GLP-1RA. [CONCLUSIONS] No significant differences among the individual SGLT-2I, GLP-1RA, nsMRA, and sGC drugs were found in risks of CV death, all-cause mortality or SAEs in patients with HFmrEF/HFpEF. Further evidence is needed to support these comparative effects and update guidance on medication choice for HFmrEF/HFpEF. [REGISTRATION] PROSPERO identifier number CRD420251143542.
Where this record came from
| Source | Retrieved | Identifier |
|---|---|---|
| pubmed | Nov 1, 2026 | 42955666 first ingestion |
| pubmed | Nov 1, 2026 | 42955666 duplicate matched on doi |
| pubmed | Nov 1, 2026 | 42955666 duplicate matched on doi |
| owner-review | Nov 6, 2026 | reviewed_by set to Carrie Schluter (2026-11-05) on the owner's own confirmation. The assessment is unchanged and still the auto-classifier's, so its extracted values stay withheld under the 2026-10-18 decision. |
| funding-repair | Nov 6, 2026 | funding_source: 'not reported in abstract' -> 'the National Natural Science Foundation of China'; industry_funded: 'unclear' -> 'no'. IN-067: funding_source, industry_funded and manufacturer re-derived from PubMed's grants metadata, which PASS-SPEC did not admit as a source until v1.3, so the review had replaced a named funder with a placeholder. Judgments, population, effects, prose and conflicts fields are unchanged. Owner decision IN-067 option 1, 2026-11-06. |
| pubmed | Nov 8, 2026 | 42955666 duplicate matched on doi |
| pubmed | Nov 8, 2026 | 42955666 duplicate matched on doi |
| pubmed | Nov 8, 2026 | 42955666 duplicate matched on doi |