GLP-1RA versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: An updated meta-analysis of randomized controlled trials.

Duhan S, Kurpad KP, Keisham B, Shtembari J, Brener A, Kanakadandi UB, Garg A, Adoni NA, Mehta SS

International journal of cardiology5 Jul 2025Cited by 5 (Europe PMC)

PMID40623630DOI10.1016/j.ijcard.2025.133604PepBankPUB-40623630

Publisher page PubMedAsk about this study

Summary

IntroductionCurrently, limited guideline-directed medical therapies are available for heart failure (HF) with preserved and mildly reduced ejection fraction (EF). Both are associated with an increased risk of hospitalization and death, especially in overweight, obese, or diabetic individuals.MethodsWe searched Cochrane, Embase, and MEDLINE from inception to November 2024. Trials with HF patients randomized for GLP-1RA (glucagon-like peptide-1 receptor agonists) and reported adverse cardiovascular and mortality outcomes were included. Statistical analysis was performed using Cochrane Review Manager 5.4.1.Results4474 patients with HF (preserved and mildly reduced EF) were included in the study. 2278 (50.91 %) received a GLP-1RA [either semaglutide (1914, 84 %) or Tirzepatide (364, 16 %)], and 2196 (49.01 %) received a placebo. GLP-1RA reduced the composite event of cardiovascular mortality and worsening HF exacerbation [139 vs. 194, RR: 0.64 (95 % CI: 0.45-0.92)]. However, on subgroup analysis, there was no significant difference in cardiovascular (CV) deaths [67 vs. 71, RR 0.89 (95 % CI: 0.65-1.24)]. The HF exacerbations were significantly reduced in the GLP-1RA group [83 vs. 138, RR 0.59 (95 % CI: 0.45-0.76)]. Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) was favorable for GLP-1RA [Std Mean Difference (SMD): 7.38 (95 % CI: 5.51-9.26)], reflected by an increase in 6-min walk distance in GLP-1RA groups [SMD: 17.69 (95 % CI: 11.87-23.34)] and contributed by a decrease in body weight in GLP-1RA groups [SMD -9.56 (95 % CI -12.74 to -6.39)].ConclusionGLP-1RA reduce HF exacerbations and can play a role in reducing hospitalizations, improving patient's functional status, and significantly impacting the global healthcare burden of HF. However, the current data does not indicate any overall mortality benefit.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study12

No result from this study comes from a test of the peptide.

Studies that did not test the peptide alone12

In this study, the peptide was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking the peptide.

01HumanNot a test of Semaglutide aloneSystematic reviewEfficacy outcome
In adults with heart failure with mildly reduced or preserved ejection fraction, pooled GLP-1 receptor agonists (semaglutide and tirzepatide) reduced the composite of cardiovascular death and worsening heart failure versus placebo.
In plain wordsIn adults with heart failure, pooled GLP-1 drugs (mostly semaglutide) lowered the combined risk of heart death or worse heart failure compared with placebo.
Peptide
Semaglutide
Outcome
DecreaseComposite of cardiovascular mortality and worsening HF
Study
n: not reported in source
Comparator
Placebo
Outcome group
Cardiovascular events · Cardiovascular
Measurements
Risk ratio
0.64 RR
composite event
Source sentences
Summary
GLP-1RA reduced the composite event of cardiovascular mortality and worsening HF exacerbation [139 vs. 194, RR: 0.64 (95 % CI: 0.45-0.92)].
2 context sentences(design, population, supporting numbers)
Summary · context
Trials with HF patients randomized for GLP-1RA (glucagon-like peptide-1 receptor agonists) and reported adverse cardiovascular and mortality outcomes were included.
Summary · context
2278 (50.91 %) received a GLP-1RA [either semaglutide (1914, 84 %) or Tirzepatide (364, 16 %)], and 2196 (49.01 %) received a placebo.
In this study, Semaglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Semaglutide.
Show in the study text Report a problemFND-4062363001
02HumanNot a test of Tirzepatide aloneSystematic reviewEfficacy outcome
In adults with heart failure with mildly reduced or preserved ejection fraction, pooled GLP-1 receptor agonists (semaglutide and tirzepatide) reduced the composite of cardiovascular death and worsening heart failure versus placebo.
In plain wordsIn adults with heart failure, pooled GLP-1 drugs (mostly semaglutide) lowered the combined risk of heart death or worse heart failure compared with placebo.
Peptide
Tirzepatide
Outcome
DecreaseComposite of cardiovascular mortality and worsening HF
Study
n: not reported in source
Comparator
Placebo
Outcome group
Cardiovascular events · Cardiovascular
Measurements
Risk ratio
0.64 RR
composite event
Source sentences
Summary
GLP-1RA reduced the composite event of cardiovascular mortality and worsening HF exacerbation [139 vs. 194, RR: 0.64 (95 % CI: 0.45-0.92)].
2 context sentences(design, population, supporting numbers)
Summary · context
Trials with HF patients randomized for GLP-1RA (glucagon-like peptide-1 receptor agonists) and reported adverse cardiovascular and mortality outcomes were included.
Summary · context
2278 (50.91 %) received a GLP-1RA [either semaglutide (1914, 84 %) or Tirzepatide (364, 16 %)], and 2196 (49.01 %) received a placebo.
In this study, Tirzepatide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Tirzepatide.
Show in the study text Report a problemFND-4062363002
03HumanNot a test of Semaglutide aloneSystematic reviewEfficacy outcome
In adults with heart failure with mildly reduced or preserved ejection fraction, pooled GLP-1 receptor agonists (semaglutide and tirzepatide) did not significantly change cardiovascular deaths versus placebo.
In plain wordsIn adults with heart failure, pooled GLP-1 drugs did not significantly change deaths from heart causes compared with placebo.
Peptide
Semaglutide
Outcome
No significant changeCardiovascular deaths
Study
n: not reported in source
Comparator
Placebo
Outcome group
Mortality · Cardiovascular
Measurements
Risk ratio
0.89 RR
cardiovascular deaths
Source sentences
Summary
However, on subgroup analysis, there was no significant difference in cardiovascular (CV) deaths [67 vs. 71, RR 0.89 (95 % CI: 0.65-1.24)].
2 context sentences(design, population, supporting numbers)
Summary · context
Trials with HF patients randomized for GLP-1RA (glucagon-like peptide-1 receptor agonists) and reported adverse cardiovascular and mortality outcomes were included.
Summary · context
2278 (50.91 %) received a GLP-1RA [either semaglutide (1914, 84 %) or Tirzepatide (364, 16 %)], and 2196 (49.01 %) received a placebo.
In this study, Semaglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Semaglutide.
Show in the study text Report a problemFND-4062363003
04HumanNot a test of Tirzepatide aloneSystematic reviewEfficacy outcome
In adults with heart failure with mildly reduced or preserved ejection fraction, pooled GLP-1 receptor agonists (semaglutide and tirzepatide) did not significantly change cardiovascular deaths versus placebo.
In plain wordsIn adults with heart failure, pooled GLP-1 drugs did not significantly change deaths from heart causes compared with placebo.
Peptide
Tirzepatide
Outcome
No significant changeCardiovascular deaths
Study
n: not reported in source
Comparator
Placebo
Outcome group
Mortality · Cardiovascular
Measurements
Risk ratio
0.89 RR
cardiovascular deaths
Source sentences
Summary
However, on subgroup analysis, there was no significant difference in cardiovascular (CV) deaths [67 vs. 71, RR 0.89 (95 % CI: 0.65-1.24)].
2 context sentences(design, population, supporting numbers)
Summary · context
Trials with HF patients randomized for GLP-1RA (glucagon-like peptide-1 receptor agonists) and reported adverse cardiovascular and mortality outcomes were included.
Summary · context
2278 (50.91 %) received a GLP-1RA [either semaglutide (1914, 84 %) or Tirzepatide (364, 16 %)], and 2196 (49.01 %) received a placebo.
In this study, Tirzepatide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Tirzepatide.
Show in the study text Report a problemFND-4062363004
05HumanNot a test of Semaglutide aloneSystematic reviewEfficacy outcome
In adults with heart failure with mildly reduced or preserved ejection fraction, pooled GLP-1 receptor agonists (semaglutide and tirzepatide) reduced heart failure exacerbations versus placebo.
In plain wordsIn adults with heart failure, pooled GLP-1 drugs (mostly semaglutide) reduced heart failure flare-ups compared with placebo.
Peptide
Semaglutide
Outcome
DecreaseHeart failure exacerbations
Study
n: not reported in source
Comparator
Placebo
Outcome group
Cardiovascular events · Cardiovascular
Measurements
Risk ratio
0.59 RR
HF exacerbations
Source sentences
Summary
The HF exacerbations were significantly reduced in the GLP-1RA group [83 vs. 138, RR 0.59 (95 % CI: 0.45-0.76)].
2 context sentences(design, population, supporting numbers)
Summary · context
Trials with HF patients randomized for GLP-1RA (glucagon-like peptide-1 receptor agonists) and reported adverse cardiovascular and mortality outcomes were included.
Summary · context
2278 (50.91 %) received a GLP-1RA [either semaglutide (1914, 84 %) or Tirzepatide (364, 16 %)], and 2196 (49.01 %) received a placebo.
In this study, Semaglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Semaglutide.
Show in the study text Report a problemFND-4062363005
06HumanNot a test of Tirzepatide aloneSystematic reviewEfficacy outcome
In adults with heart failure with mildly reduced or preserved ejection fraction, pooled GLP-1 receptor agonists (semaglutide and tirzepatide) reduced heart failure exacerbations versus placebo.
In plain wordsIn adults with heart failure, pooled GLP-1 drugs (mostly semaglutide) reduced heart failure flare-ups compared with placebo.
Peptide
Tirzepatide
Outcome
DecreaseHeart failure exacerbations
Study
n: not reported in source
Comparator
Placebo
Outcome group
Cardiovascular events · Cardiovascular
Measurements
Risk ratio
0.59 RR
HF exacerbations
Source sentences
Summary
The HF exacerbations were significantly reduced in the GLP-1RA group [83 vs. 138, RR 0.59 (95 % CI: 0.45-0.76)].
2 context sentences(design, population, supporting numbers)
Summary · context
Trials with HF patients randomized for GLP-1RA (glucagon-like peptide-1 receptor agonists) and reported adverse cardiovascular and mortality outcomes were included.
Summary · context
2278 (50.91 %) received a GLP-1RA [either semaglutide (1914, 84 %) or Tirzepatide (364, 16 %)], and 2196 (49.01 %) received a placebo.
In this study, Tirzepatide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Tirzepatide.
Show in the study text Report a problemFND-4062363006
07HumanNot a test of Semaglutide aloneSystematic reviewEfficacy outcome
In adults with heart failure with mildly reduced or preserved ejection fraction, pooled GLP-1 receptor agonists (semaglutide and tirzepatide) improved the KCCQ clinical summary score versus placebo.
In plain wordsIn adults with heart failure, pooled GLP-1 drugs gave better symptom scores than placebo.
Peptide
Semaglutide
Outcome
IncreaseKCCQ clinical summary score
Study
n: not reported in source
Comparator
Placebo
Outcome group
Heart function · Cardiovascular
Measurements
Std mean difference
7.38 SMD
KCCQ-CSS
Source sentences
Summary
Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) was favorable for GLP-1RA [Std Mean Difference (SMD): 7.38 (95 % CI: 5.51-9.26)]
2 context sentences(design, population, supporting numbers)
Summary · context
Trials with HF patients randomized for GLP-1RA (glucagon-like peptide-1 receptor agonists) and reported adverse cardiovascular and mortality outcomes were included.
Summary · context
2278 (50.91 %) received a GLP-1RA [either semaglutide (1914, 84 %) or Tirzepatide (364, 16 %)], and 2196 (49.01 %) received a placebo.
In this study, Semaglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Semaglutide.
Show in the study text Report a problemFND-4062363007
08HumanNot a test of Tirzepatide aloneSystematic reviewEfficacy outcome
In adults with heart failure with mildly reduced or preserved ejection fraction, pooled GLP-1 receptor agonists (semaglutide and tirzepatide) improved the KCCQ clinical summary score versus placebo.
In plain wordsIn adults with heart failure, pooled GLP-1 drugs gave better symptom scores than placebo.
Peptide
Tirzepatide
Outcome
IncreaseKCCQ clinical summary score
Study
n: not reported in source
Comparator
Placebo
Outcome group
Heart function · Cardiovascular
Measurements
Std mean difference
7.38 SMD
KCCQ-CSS
Source sentences
Summary
Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) was favorable for GLP-1RA [Std Mean Difference (SMD): 7.38 (95 % CI: 5.51-9.26)]
2 context sentences(design, population, supporting numbers)
Summary · context
Trials with HF patients randomized for GLP-1RA (glucagon-like peptide-1 receptor agonists) and reported adverse cardiovascular and mortality outcomes were included.
Summary · context
2278 (50.91 %) received a GLP-1RA [either semaglutide (1914, 84 %) or Tirzepatide (364, 16 %)], and 2196 (49.01 %) received a placebo.
In this study, Tirzepatide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Tirzepatide.
Show in the study text Report a problemFND-4062363008
09HumanNot a test of Semaglutide aloneSystematic reviewEfficacy outcome
In adults with heart failure with mildly reduced or preserved ejection fraction, pooled GLP-1 receptor agonists (semaglutide and tirzepatide) increased 6-minute walk distance versus placebo.
In plain wordsIn adults with heart failure, pooled GLP-1 drugs increased walking distance in 6 minutes compared with placebo.
Peptide
Semaglutide
Outcome
Increase6-minute walk distance
Study
n: not reported in source
Comparator
Placebo
Outcome group
Exercise and physical function · Cardiovascular
Measurements
Std mean difference
17.69 SMD
6-min walk distance
Source sentences
Summary
reflected by an increase in 6-min walk distance in GLP-1RA groups [SMD: 17.69 (95 % CI: 11.87-23.34)]
2 context sentences(design, population, supporting numbers)
Summary · context
Trials with HF patients randomized for GLP-1RA (glucagon-like peptide-1 receptor agonists) and reported adverse cardiovascular and mortality outcomes were included.
Summary · context
2278 (50.91 %) received a GLP-1RA [either semaglutide (1914, 84 %) or Tirzepatide (364, 16 %)], and 2196 (49.01 %) received a placebo.
In this study, Semaglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Semaglutide.
Show in the study text Report a problemFND-4062363009
10HumanNot a test of Tirzepatide aloneSystematic reviewEfficacy outcome
In adults with heart failure with mildly reduced or preserved ejection fraction, pooled GLP-1 receptor agonists (semaglutide and tirzepatide) increased 6-minute walk distance versus placebo.
In plain wordsIn adults with heart failure, pooled GLP-1 drugs increased walking distance in 6 minutes compared with placebo.
Peptide
Tirzepatide
Outcome
Increase6-minute walk distance
Study
n: not reported in source
Comparator
Placebo
Outcome group
Exercise and physical function · Cardiovascular
Measurements
Std mean difference
17.69 SMD
6-min walk distance
Source sentences
Summary
reflected by an increase in 6-min walk distance in GLP-1RA groups [SMD: 17.69 (95 % CI: 11.87-23.34)]
2 context sentences(design, population, supporting numbers)
Summary · context
Trials with HF patients randomized for GLP-1RA (glucagon-like peptide-1 receptor agonists) and reported adverse cardiovascular and mortality outcomes were included.
Summary · context
2278 (50.91 %) received a GLP-1RA [either semaglutide (1914, 84 %) or Tirzepatide (364, 16 %)], and 2196 (49.01 %) received a placebo.
In this study, Tirzepatide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Tirzepatide.
Show in the study text Report a problemFND-4062363010
11HumanNot a test of Semaglutide aloneSystematic reviewEfficacy outcome
In adults with heart failure with mildly reduced or preserved ejection fraction, pooled GLP-1 receptor agonists (semaglutide and tirzepatide) decreased body weight versus placebo.
In plain wordsIn adults with heart failure, pooled GLP-1 drugs lowered body weight compared with placebo.
Peptide
Semaglutide
Outcome
DecreaseBody weight
Study
n: not reported in source
Comparator
Placebo
Outcome group
Body weight · Metabolic and weight
Measurements
Std mean difference
−9.56 SMD
body weight
Source sentences
Summary
contributed by a decrease in body weight in GLP-1RA groups [SMD -9.56 (95 % CI -12.74 to -6.39)]
2 context sentences(design, population, supporting numbers)
Summary · context
Trials with HF patients randomized for GLP-1RA (glucagon-like peptide-1 receptor agonists) and reported adverse cardiovascular and mortality outcomes were included.
Summary · context
2278 (50.91 %) received a GLP-1RA [either semaglutide (1914, 84 %) or Tirzepatide (364, 16 %)], and 2196 (49.01 %) received a placebo.
In this study, Semaglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Semaglutide.
Show in the study text Report a problemFND-4062363011
12HumanNot a test of Tirzepatide aloneSystematic reviewEfficacy outcome
In adults with heart failure with mildly reduced or preserved ejection fraction, pooled GLP-1 receptor agonists (semaglutide and tirzepatide) decreased body weight versus placebo.
In plain wordsIn adults with heart failure, pooled GLP-1 drugs lowered body weight compared with placebo.
Peptide
Tirzepatide
Outcome
DecreaseBody weight
Study
n: not reported in source
Comparator
Placebo
Outcome group
Body weight · Metabolic and weight
Measurements
Std mean difference
−9.56 SMD
body weight
Source sentences
Summary
contributed by a decrease in body weight in GLP-1RA groups [SMD -9.56 (95 % CI -12.74 to -6.39)]
2 context sentences(design, population, supporting numbers)
Summary · context
Trials with HF patients randomized for GLP-1RA (glucagon-like peptide-1 receptor agonists) and reported adverse cardiovascular and mortality outcomes were included.
Summary · context
2278 (50.91 %) received a GLP-1RA [either semaglutide (1914, 84 %) or Tirzepatide (364, 16 %)], and 2196 (49.01 %) received a placebo.
In this study, Tirzepatide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Tirzepatide.
Show in the study text Report a problemFND-4062363012

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 3Current
11 Oct 2026, 00:04 UTC
Study results updated
Version 2
9 Oct 2026, 03:07 UTC
Study data updated · source update from Europe PMC
Version 1
9 Oct 2026, 03:06 UTC
First added · source update from Europe PMC

GLP-1RA versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: An updated meta-analysis of randomized controlled trials.

Summary

Results from this study12

Studies that did not test the peptide alone12

Version history

Subjects

Publication types

MeSH terms

Keywords