Open AccessSystematic Review The Efficacy of Glucagon-like Peptide-1 Based Therapies in Heart Failure Across the Spectrum of Left Ventricular Ejection Fraction: A Systematic Review and Meta-Analysis by Theodoros Christophides Theodoros Christophides Scilit Preprints.org Google Scholar Dr Theodoros Christophides studied with scholarship at University College London (UCL), achieving in [...] Read more 1,2,*, Gisella Figlioli Gisella Figlioli Scilit Preprints.org Google Scholar 3,4, Sotiris Christoforou Sotiris Christoforou Scilit Preprints.org Google Scholar 2, Kyriacos Ioannou Kyriacos Ioannou Scilit Preprints.org Google Scholar 2, Maria Kounnafi Maria Kounnafi Scilit Preprints.org Google Scholar 2, Daniele Piovani Daniele Piovani Scilit Preprints.org Google Scholar 3,4, Stefanos Bonovas Stefanos Bonovas Scilit Preprints.org Google Scholar 3,4 and Georgios Nikolopoulos Georgios Nikolopoulos Scilit Preprints.org Google Scholar 2,* 1 Department of Cardiology, Nicosia General Hospital, State Health Services Organisation, Paleos Dromos Lefkosias-Lemesou No. 215, 2029 Strovolos, Nicosia, Cyprus 2 Medical School, Shacolas Educational Centre for Clinical Medicine, University of Cyprus, Paleos Dromos Lefkosias-Lemesou No.215/6, 2029 Strovolos, Nicosia, Cyprus 3 Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy 4 IRCCS Humanitas Research Hospital, Via Alessandro Manzoni 56, 20089 Rozzano, Milan, Italy * Authors to whom correspondence should be addressed. J. Clin. Med. 2026, 15(12), 4450; https://doi.org/10.3390/jcm15124450 (registering DOI) Submission received: 4 May 2026 / Revised: 2 June 2026 / Accepted: 3 June 2026 / Published: 9 June 2026 Abstract Background/Objectives: Despite advances in heart failure (HF) pharmacotherapy, novel treatments are needed for its main subtypes: preserved (HFpEF), mildly reduced (HFmrEF), and reduced (HFrEF) ejection fraction. Glucagon-like peptide-1 (GLP-1) based therapies have shown cardioprotective effects. We conducted a systematic review and meta-analysis (Prospero Registration Number CRD42024606997) assessing the efficacy of GLP-1 based therapies (GLP-1 receptor agonists including tirzepatide) across the spectrum of left ventricular ejection fraction on cardiovascular (CV) outcomes. Methods: The PubMed, Embase, Scopus and trial registries were searched until December 2025 for randomised controlled trials (RCTs) involving adults with HF treated with GLP-1 based therapies. Outcomes included heart failure hospitalisations (HFH), CV, and all-cause mortality. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated using random-effects models. Subgroup analyses were performed by HF subtype, age, coronary artery disease (CAD) presence, and GLP-1 based therapeutic agent. Results: Fourteen RCTs (15,180 participants), at low risk of bias, were included. These agents significantly reduced HFH (RR: 0.84, 95% CI: 0.71–0.99), especially in HFpEF patients with stable CAD (RR: 0.61, 95% CI: 0.46–0.79). Limited data suggested benefits for exenatide in HFmrEF patients (RR: 0.67, 95% CI: 0.47–0.95). CV mortality was reduced in HFrEF patients 40% (RR: 0.67, 95% CI: 0.53–0.85; Cochran’s Q test, p = 0.27; I 2 = 21%) [ 15, 16, 17, 22, 23]. Results were neutral in patients with HFrEF and HFmrEF. There was insufficient data to draw valid inferences for patients presenting with acute coronary syndromes (ACS). A clear benefit was also observed in patients with HFpEF aged ≥65 years (RR: 0.54, 95% CI: 0.38–0.77; Cochran’s Q test, p = 0.57; I 2 = 0%) [ 15, 16, 23]. The data was insufficient to assess younger patients. Evidence from two studies suggested potential harm in those with HFrEF, but this was based on limited data (RR: 1.38, 95% CI: 1.03–1.85; Cochran’s Q test, p = 0.61; I 2 = 0%; Q b test of HF group differences, p = 0.01) [ 7, 22]. From pooled analyses of a limited number of studies, semaglutide demonstrated significant benefit in patients with HFpEF ( n = 2 studies; RR: 0.54, 95% CI: 0.30–0.98; Cochran’s Q test, p = 0.29; I 2 = 12%), and exenatide in those with HFmrEF ( n = 2 studies; RR: 0.67, 95% CI: 0.47–0.95; Cochran’s Q test, p = 0.30; I 2 = 5.9%) [ 16, 17, 22, 23]. Tirzepatide, a glucose-dependent insulinotropic polypeptide (GIP) analogue and a GLP-1 RA (dual action), was used in one study showing a benefit in patients with HFpEF (RR: 0.54, 95% CI: 0.34–0.85) [ 15]. In the context of sensitivity analysis, excluding this study, which employed a dual GIP analogue/GLP-1 RA, did not change the results for patients with HFpEF ( n = 3 studies; RR: 0.64, 95% CI: 0.46–0.90; Cochran’s Q test, p = 0.43; I 2 = 0%) [ 16, 22, 23]. No conclusive inferences could be made for HFrEF or other GLP-1 RAs owing to inadequate data. 3.5. Study Outcomes—Mortality (All-Cause and Cardiovascular) A pooled analysis ( Figure 3) of nine studies (ten RRs, as one study provided separate estimates for HF phenotypes) [ 24] demonstrated neutral effects on all-cause mortality (RR: 0.91, 95% CI: 0.81–1.02; Cochran’s Q test, p = 0.61; I 2 = 0%) [ 7, 15, 16, 17, 18, 19, 20, 22, 24]. The dataset included 10,498 participants (mean age 63.8 ± 2.6 years), of whom 67% were male, with a mean follow-up of 3.0 years. Results were consistent across subgroups stratified by LVEF (including further stratification by type of RCT, i.e., ITT and post-hoc subgroup analyses), age, CAD status, and use of the dual GIP analogue/GLP-1 RA tirzepatide. Excluding the study that provided data for calculating a risk ratio rather than reporting a HR did not change the results [ 16]. An analysis ( Figure 4) of eight studies (nine RRs as one study provided separate estimates for HF phenotypes) [ 24] demonstrated a borderline protective effect of GLP-1 RAs on CV mortality (RR: 0.84, 95% CI: 0.72–0.98; Cochran’s Q test, p = 0.62; I 2 = 0%) [ 14, 15, 16, 18, 19, 20, 22, 24]. This dataset included 9954 participants (mean age 64.0 ± 2.7 years), 65% male, with mean follow-up of 3.0 years. Estimates suggested a significant benefit in HFrEF (2 studies involving post-hoc analyses in patients 40%) in the majority of the available studies. The weight-reducing effects of GLP-1 based treatments remain a subject of ongoing debate, given their potential to influence HF outcomes. However, the relationship is complex and must be interpreted in the context of the “obesity paradox” seen in HFpEF and HFrEF patients [ 32]. Although obesity is a well-known risk factor for the development of HF, observational studies in patients with established HF have paradoxically shown an association between higher BMI and improved survival [ 32]. This phenomenon may reflect reverse causation, the limitations of BMI as a surrogate for body composition, or the potential protective role of a greater metabolic reserve, rather than a true protective effect of excess adiposity [ 33]. Importantly, unintentional weight loss in HF (often reflecting cachexia or advanced disease) is consistently associated with adverse outcomes, whereas the impact of intentional weight reduction through structured interventions or pharmacotherapy remains incompletely defined [ 33, 34]. Emerging data, particularly in obesity-related HFpEF, suggest that GLP-1 RA-associated weight loss may improve symptoms and functional capacity. However, the relative contributions of weight-dependent versus direct cardiometabolic effects, as well as effects on hard clinical endpoints across HF phenotypes, remain areas of ongoing investigation [ 33]. Of note, more recently, findings from the SUMMIT trial have demonstrated that patients with HFpEF derived significant cardiovascular benefit even in the absence of marked weight reduction [ 35]. These observations challenge the notion that the therapeutic effects of GLP-1 based therapies are mediated exclusively through weight loss, suggesting that attributing their cardiovascular benefit solely to weight reduction represents an oversimplification. Background HF therapy is an important determinant of outcomes and should be considered when interpreting treatment effects [ 2]. The relatively low or inconsistent use of guideline-directed medical therapies observed in some of the included studies (refer to Table S2 for details) may reflect historical timing. Specific prognostic agents (such as SGLG2-i or angiotensin receptor-neprilysin inhibitors (ARNI)), as well as broader optimisation of quadruple therapy (beta-blockers, mineralocorticoid receptor antagonists (MRAs), renin–angiotensin system inhibition, and SGLT2-i) did not exist or were not indicated for use in HF management. Thus, several of the studies included in our analysis began recruitment before these therapies were licensed, incorporated into clinical guidelines, or widely adopted in routine practice. Even among more established therapies such as beta-blockers, MRAs, or loop diuretics, prescribing patterns and target-dose attainment were variably reported, thus limiting direct comparisons with contemporary standards of optimised HF care. In addition to the above, some therapies (including ARNI and certain SGLT2-i) are primarily indicated for specific HF subgroups such as HFrEF. As several trials enrolled heterogeneous HF populations or were not designed to target these subgroups, variability in background therapy use was expected. Differences in trial-era standards of care, HF phenotype distribution, and incomplete reporting of background medication intensity or dose optimisation may therefore have influenced observed treatment effects and should be considered when interpreting both efficacy and safety outcomes. In particular, the incremental benefit of GLP-1 based therapeutic agents may differ depending on whether they are evaluated as adjunctive therapy on top of fully optimised contemporary HF treatment versus in historical cohorts receiving less comprehensive neurohormonal blockade. Nonetheless, contemporary HF management increasingly emphasises the synergistic and additive benefits of combined prognostic therapies, and evidence from cardiovascular outcome trials suggests that combinations of cardiometabolic agents (for example, SGLT2-i together with GLP-1 RAs) provide incremental benefit in cardiovascular health [ 36]. This evolving therapeutic landscape underscores the importance of contextualising older trial data, as the treatment effects observed in earlier studies may not fully reflect the interaction profile or incremental value of GLP-1 based therapies when layered onto modern, guideline-directed, multidrug regimens. Future research should prioritise targeted trials evaluating different combinations of established HF prognostic therapies with these agents to better define the incremental and potentially synergistic effects of these multidrug strategies and to clarify their optimal use across different HF phenotypes. Considering the strengths of our study, a major advantage lies in the comprehensive strategy used to search across several trial databases, ensuring a broad and unbiased capture of relevant literature. Furthermore, this study aimed to assess a wide range of clinically meaningful outcomes, which were strictly limited to participants with clearly defined HF (with the majority classified into specific subgroups or having documented LVEF values). This is in contrast with the pooled results from patients with a poorly defined diagnosis of HF or no classification of its subtypes amongst participants. This important fact, which was observed in previous pre-specified analyses of original trial data as well as meta-analyses in this field, may have obscured the true effects of GLP-1 based treatments. With regard to the quality of the studies included, the overall risk of bias was generally low on detailed assessment, further reinforcing the credibility of the so-far conclusions. It should, however, be noted that because this review was intended to provide an exploratory, hypothesis-generating synthesis of the available evidence, a structured assessment of evidence was considered beyond its scope and was therefore not performed. Nevertheless, we acknowledge that factors such as indirectness, imprecision, and between-study heterogeneity may influence the overall certainty of the evidence. Formal certainty-of-evidence assessments may be valuable in future reviews and guidelines development as the evidence base continues to mature. Finally, every effort was made to avoid potential duplication of trial data by carefully distinguishing between original trial results and any relevant pre-specified or post-hoc analyses derived from the same dataset. A key limitation of our analysis is that we pooled data from different GLP-1 based therapies, including both GLP-1 RAs and the dual GIP analogue/GLP-1 RA tirzepatide. These agents differ in pharmacologic profile and magnitude of weight reduction, which may introduce clinical heterogeneity. Although no meaningful discrepancies in direction of effect were observed across agents in the available data, most individual drugs were represented by a limited number of studies, precluding adequately powered, agent-specific analyses. Consequently, our conclusions apply to GLP-1 based therapies as a class rather than to any single compound, and future studies with sufficient data for individual agents are needed to clarify potential differences in efficacy and underlying mechanisms. Furthermore, our analysis combines data from dedicated HF trials, with post-hoc and subgroup analyses derived from cardiovascular outcome trials. This is an important limitation, given the fact that HF phenotypes were not always uniformly defined across studies. It may have affected cross-trial comparability, which may have introduced heterogeneity in our study design. Nonetheless, it should also be noted that Cochran’s Q test and Inconsistency Index showed relatively low variation in most results. Variability and incomplete reporting of background HF therapies across trials, which have been discussed above, represent additional limitations. Several studies were conducted before the widespread adoption of contemporary guideline-directed medical therapy, and information regarding medication intensity and dose optimisation was inconsistently reported. Consequently, the observed treatment effects of GLP-1 based therapies may not fully reflect their incremental benefit when added to modern HF treatment regimens. Finally, variations in reported outcomes were influenced by differences in the metrics used across studies. 5. Conclusions In the era of precision cardiology, and given the heterogeneity of HF as a syndrome, our findings suggest that GLP-1 based therapies (GLP-1 RAs and tirzepatide) may have differential effects across specific HF phenotypes and should potentially be targeted to specific patient subgroups rather than applied universally across all HF populations. However, these findings should be interpreted cautiously given the limited data available for some subgroup analyses, the absence of consistently significant interaction tests, and variability in the reporting of background heart failure therapies across the included trials. As such, our results should be considered hypothesis-generating and may contribute to future research aimed at clarifying whether a more phenotype-specific approach to the use of these agents in HF management is warranted. Supplementary Materials The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/jcm15124450/s1, Figure S1: Risk of bias assessment for all included studies using the revised Cochrane assessment tool. (A) traffic light plot for individual studies and (B) summary plot [ 7, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25]; Figure S2: Publication bias assessment—funnel plot for heart failure hospitalisations [ 7, 13, 15, 16, 17, 18, 19, 20, 22, 23]; Table S1: PRISMA checklist [ 37]; Table S2: Characteristics of studies used in the meta-analysis [ 7, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25]. Author Contributions Conceptualisation, T.C., G.N. and S.B.; methodology, T.C., G.N., S.B., G.F. and D.P.; validation, G.N., S.C., K.I. and M.K.; formal analysis, T.C., G.N., G.F., S.B. and D.P.; investigation, T.C., G.N., S.B., G.F., D.P., S.C., K.I. and M.K.; data curation, T.C., G.F. and G.N.; writing—original draft preparation, T.C.; writing—review and editing, T.C., G.N., S.B., G.F., D.P., S.C., K.I. and M.K.; visualisation, G.N. and S.B.; software, G.N.; supervision, G.N.; project administration, G.N. All authors have read and agreed to the published version of the manuscript. Funding This research received no external funding. Institutional Review Board Statement Not applicable—this systematic review relied solely on previously published data and did not involve the collection of new data from human participants. Informed Consent Statement Not applicable. Data Availability Statement The data extracted from the included studies, along with the analysis code, are available from the corresponding authors upon request. Conflicts of Interest The authors declare no conflicts of interest. Abbreviations The following abbreviations are used in this manuscript: ACS Acute coronary syndromes ARNI Angiotensin receptor-neprilysin inhibitors BMI Body mass index CAD Coronary artery disease CI(s) Confidence interval(s) CV Cardiovascular DM Diabetes mellitus exp(ES) Exponentiated effect size GIP Glucose-dependent insulinotropic polypeptide GLP-1 Glucagon-like peptide-1 GLP-1 RA(s) Glucagon-like peptide-1 receptor agonist(s) HF Heart failure HFH Heart failure hospitalisations HFmrEF Heart failure with mildly reduced ejection fraction HFpEF Heart failure with preserved ejection fraction HFrEF Heart failure with reduced ejection fraction HR(s) Hazard ratio(s) ITT Intention-to-treat LVEF Left ventricular ejection fraction MRA(s) Mineralocorticoid Receptor Antagonist(s) NYHA New York Heart Association PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses RCT(s) Randomised controlled trial(s) REML Restricted maximum likelihood RR(s) Relative risk(s) SGLT2-i Sodium-glucose co-transporter 2 inhibitors References Giamouzis, G.; Xanthopoulos, A.; Boudoulas, K.D.; Karagiannis, G.; Skoularigis, J.; Triposkiadis, F. 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Share and Cite MDPI and ACS Style Christophides, T.; Figlioli, G.; Christoforou, S.; Ioannou, K.; Kounnafi, M.; Piovani, D.; Bonovas, S.; Nikolopoulos, G. The Efficacy of Glucagon-like Peptide-1 Based Therapies in Heart Failure Across the Spectrum of Left Ventricular Ejection Fraction: A Systematic Review and Meta-Analysis. J. Clin. Med. 2026, 15, 4450. https://doi.org/10.3390/jcm15124450 AMA Style Christophides T, Figlioli G, Christoforou S, Ioannou K, Kounnafi M, Piovani D, Bonovas S, Nikolopoulos G. The Efficacy of Glucagon-like Peptide-1 Based Therapies in Heart Failure Across the Spectrum of Left Ventricular Ejection Fraction: A Systematic Review and Meta-Analysis. Journal of Clinical Medicine. 2026; 15(12):4450. https://doi.org/10.3390/jcm15124450 Chicago/Turabian Style Christophides, Theodoros, Gisella Figlioli, Sotiris Christoforou, Kyriacos Ioannou, Maria Kounnafi, Daniele Piovani, Stefanos Bonovas, and Georgios Nikolopoulos. 2026. "The Efficacy of Glucagon-like Peptide-1 Based Therapies in Heart Failure Across the Spectrum of Left Ventricular Ejection Fraction: A Systematic Review and Meta-Analysis" Journal of Clinical Medicine 15, no. 12: 4450. https://doi.org/10.3390/jcm15124450 APA Style Christophides, T., Figlioli, G., Christoforou, S., Ioannou, K., Kounnafi, M., Piovani, D., Bonovas, S., & Nikolopoulos, G. (2026). The Efficacy of Glucagon-like Peptide-1 Based Therapies in Heart Failure Across the Spectrum of Left Ventricular Ejection Fraction: A Systematic Review and Meta-Analysis. Journal of Clinical Medicine, 15(12), 4450. https://doi.org/10.3390/jcm15124450 Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here. Article Metrics Article metric data becomes available approximately 24 hours after publication online.
