Glucagon-Like Peptide-1 Receptor Agonists Across the Heart Failure Spectrum: A Systematic Review and Meta-Analysis

Figures

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  Figure 1. PRISMA 2020 flow diagram of study selection A total of 1087 records were identified across PubMed (n=697), Cochrane CENTRAL (n=356), and ClinicalTrials.gov (n=34). After removing 198 duplicates, 889 unique records underwent title and abstract screening. 200 reports were sought for full-text assessment, 186 were excluded with reasons, and 14 studies were included in quantitative synthesis. HF, heart failure; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses

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  Figure 2. RoB 2 assessment of included studies (composite) Panel A - RoB 2 traffic-light plot by study and domain. Panel B - RoB 2 domain summary across all 14 included studies. Studies displayed (left to right, top to bottom in Panel A): STEP-HFpEF [9], STEP-HFpEF-DM [10], SUMMIT [11], FIGHT [12], Harmony Outcomes (HF post hoc) [24], LIVE [23], Albiglutide HFrEF [25], SELECT (HF subgroup) [26], SOUL (HF analysis) [27], FLOW (HF subgroup) [28], EXSCEL (by EF) [29], EXSCEL (by HF status) [30], LEADER (HF subgroup) [31], and REWIND (HF post hoc) [32]. Color coding: green (low risk), amber (some concerns), red (high risk), and grey (not applicable). RoB, risk of bias; HFpEF, heart failure with preserved ejection fraction; HF, heart failure

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  Figure 3. Forest plot of the primary composite outcome (CV death and first HF hospitalization) HRs with 95% CIs from a random-effects meta-analysis (REML + HKSJ). Studies displayed (top to bottom): SUMMIT [11], FIGHT [12], SELECT (HF subgroup) [26], SOUL (HF analysis) [27], FLOW (HF subgroup) [28], Harmony Outcomes (HF post hoc) [24], LEADER (HF subgroup) [31], and REWIND (HF post hoc) [32]. The diamond represents the pooled estimate. CI, confidence interval; CV, cardiovascular; HF, heart failure; HKSJ, Hartung-Knapp-Sidik-Jonkman; HR, hazard ratio; REML, restricted maximum likelihood; GLP-1RA, glucagon-like peptide-1 receptor agonist

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  Figure 4. Forest plot of ACM Pooled HR 0.86 (95% CI 0.79 to 0.95; I²=0%) across seven studies. Studies displayed (top to bottom): SUMMIT [11], FIGHT [12], LIVE [23], SELECT (HF subgroup) [26], SOUL (HF analysis) [27], LEADER (HF subgroup) [31], and EXSCEL (by EF) [29]. ACM, all-cause mortality; CI, confidence interval; HR, hazard ratio; GLP-1RA, glucagon-like peptide-1 receptor agonist

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  Figure 5. Forest plot of MACE Pooled HR 0.80 (95% CI 0.69 to 0.93; I²=0%) across 4 studies. Studies displayed (top to bottom): SELECT (HF subgroup) [26], FLOW (HF subgroup) [28], LEADER (HF subgroup) [31], EXSCEL (by EF) [29]. MACE, major adverse cardiovascular events; CI, confidence interval; HR, hazard ratio

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  Figure 6. Forest plot of HF hospitalization Pooled HR 0.87 (95% CI 0.62 to 1.22; I²=59%) across five studies. Studies displayed (top to bottom): SUMMIT [11], FIGHT [12], FLOW (HF subgroup) [28], Harmony Outcomes (HF post-hoc) [24], EXSCEL (by EF) [29]. HF, heart failure; CI, confidence interval; HR, hazard ratio; GLP-1RA, glucagon-like peptide-1 receptor agonist; HF, heart failure; EF, ejection fraction

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  Figure 7. Forest plot of CV death HRs with 95% CIs from random-effects meta-analysis (REML+HKSJ). Pooled HR 0.79 (95% CI 0.53 to 1.19; I²=0%) across three studies. Studies displayed (top to bottom): SUMMIT [11], SELECT (HF subgroup) [26], SOUL (HF analysis) [27]. CV, cardiovascular; CI, confidence interval; HR, hazard ratio; HKSJ, Hartung-Knapp-Sidik-Jonkman; REML, restricted maximum likelihood; GLP-1RA, glucagon-like peptide-1 receptor agonist; HF, heart failure

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  Figure 8. Forest plot of KCCQ-CSS Pooled mean difference +7.4 points (95% CI 6.3 to 8.5; I²=0%) across three studies. Studies displayed (top to bottom): SUMMIT [11], STEP-HFpEF [9], STEP-HFpEF-DM [10]. KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score; CI, confidence interval; MD, mean difference; GLP-1RA, glucagon-like peptide-1 receptor agonist; HFpEF, heart failure with preserved ejection fraction; DM, diabetes mellitus

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  Figure 9. Forest plot of 6MWD Pooled mean difference +17.6 m (95% CI 13.4 to 21.7; I²=0%) across four studies. Studies displayed (top to bottom): SUMMIT [11], STEP-HFpEF [9], STEP-HFpEF-DM [10], Albiglutide HFrEF [25]. 6MWD, 6-minute walk distance; CI, confidence interval; MD, mean difference; GLP-1RA, glucagon-like peptide-1 receptor agonist; HFpEF, heart failure with preserved ejection fraction; DM, diabetes mellitus

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  Figure 10. Forest plot of LVEF change Mean differences with 95% CIs from random-effects meta-analysis (REML+HKSJ). Pooled MD 0.8% (95% CI: -24.5 to 26.0; I²=73%) across two studies. Studies displayed (top to bottom): LIVE [23], Albiglutide HFrEF [25]. LVEF, left ventricular ejection fraction; CI, confidence interval; MD, mean difference; HKSJ, Hartung-Knapp-Sidik-Jonkman; REML, restricted maximum likelihood; GLP-1RA, glucagon-like peptide-1 receptor agonist; HFrEF, heart failure with reduced ejection fraction

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  Figure 11. Forest plot of body weight change Mean differences with 95% CIs from random-effects meta-analysis (REML+HKSJ). Pooled MD −9.3 kg (95% CI -15.8 to -2.7; I²=94%) across three studies. Studies displayed (top to bottom): SUMMIT [11], STEP-HFpEF [9], STEP-HFpEF-DM [10]. CI, confidence interval; MD, mean difference; HKSJ, Hartung-Knapp-Sidik-Jonkman; REML, restricted maximum likelihood; HFpEF, heart failure with preserved ejection; fraction; GLP-1RA, glucagon-like peptide-1 receptor agonist; DM, diabetes mellitus

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  Figure 12. Forest plot of SAE RRs from Mantel-Haenszel random-effects meta-analysis. Pooled RR 0.74 (95% CI 0.43 to 1.29; I²=78%) across four studies. Studies displayed (top to bottom): SUMMIT [11], STEP-HFpEF [9], STEP-HFpEF-DM [10], FIGHT [12]. SAE, serious adverse event; CI, confidence interval; RR, risk ratio; GLP-1RA, glucagon-like peptide-1 receptor agonist; HFpEF, heart failure with preserved ejection fraction; DM, diabetes mellitus