The long-term cardiovascular safety and efficacy of glucagon-like peptide-1 (GLP-1) receptor agonists in high-risk cardiovascular populations: A systematic review and meta-analysis

The long-term cardiovascular safety and efficacy of glucagon-like peptide-1 (GLP-1) receptor agonists in high-risk cardiovascular populations: A systematic review and meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The long-term cardiovascular safety and efficacy of glucagon-like peptide-1 (GLP-1) receptor agonists in high-risk cardiovascular populations: A systematic review and meta-analysis Kezia Peter, Ocin Roka, Emma Sepp, Maya Warburton, Jufen Zhang, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8788582/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 May, 2026 Read the published version in Cardiovascular Diabetology – Endocrinology Reports → Version 1 posted 16 You are reading this latest preprint version Abstract Background Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for the management of type 2 diabetes and obesity, yet their long-term cardiovascular effects in high-risk populations continue to be actively evaluated. Given emerging evidence of both metabolic and direct cardiovascular actions, a comprehensive synthesis of cardiovascular outcome trial data is required to clarify the efficacy and safety of this drug class. Methods We conducted a systematic review and meta-analysis of randomised, placebo-controlled cardiovascular outcome trials evaluating GLP-1RAs in adults at high cardiovascular risk. Searches of PubMed, Embase (via OVID), and the Cochrane Library were performed for studies published between January 2015 and May 2025, in accordance with PRISMA 2020 guidelines. Eligible trials included ≥ 3,000 participants with a minimum follow-up of 12 months. The primary outcome was major adverse cardiovascular events (MACE). Secondary outcomes included cardiovascular mortality, all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, hospitalisation for heart failure, and adverse events. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using random-effects meta-analysis. Risk of bias was assessed using the Cochrane RoB 2 tool, and certainty of evidence was evaluated using GRADE. Results Eleven cardiovascular outcome trials comprising 91,490 participants were included, with a mean follow-up of 2.7 years. GLP-1RA treatment was associated with a significant reduction in MACE compared with placebo (HR 0.87, 95% CI 0.81–0.92). Meta-analysis also demonstrated significant reductions in cardiovascular mortality, all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, and hospitalisation for heart failure. GLP-1RAs did not materially increase the risk of severe hypoglycaemia or acute pancreatitis, while gastrointestinal adverse effects were consistently more frequent. Conclusions GLP-1 receptor agonists significantly reduce major cardiovascular events and mortality in high-risk populations, with a favourable long-term safety profile. These findings support the broader integration of GLP-1RAs into cardiovascular risk reduction strategies beyond glycaemic control. Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide, accounting for approximately 17.9 million deaths annually, representing around 32% of all global deaths (World Health Organisation, 2025 ). Despite preventative strategies and advances in medical interventions, the prevalence of CVDs is continuing to rise, particularly among high-risk populations (Yang et al., 2025 ). The UK’s National Institute for Health and Care Excellence (NICE) defines high-risk individuals as those with a 10-year risk of a first cardiovascular event of 10% or above, often calculated using tools such as QRISK3 (National Institute for Health and Care Excellence, 2023 ). One of the promising emerging therapeutic drug classes with potential benefits in these high-risk populations are glucagon-like peptide (GLP-1) receptor agonists (GLP-1RAs). Originally developed for the treatment of type 2 diabetes, but now also licensed for the treatment of obesity, these medications act by mimicking the endogenous incretin hormone GLP-1, enhancing insulin secretion, satiety and weight loss. Agents in this class include liraglutide, semaglutide, dulaglutide and exenatide which have been demonstrated to reduce HbA1c levels and help with weight management in large-scale clinical trials (Alfaris et al., 2024 ) . GLP-1 receptors (GLP-1R) have been identified in murine and human heart tissue (McLean et al, 2022 , Baggio et al, 2018 ) as well as in brain regions associated with autonomic control of the cardiovascular system, such as the paraventricular nucleus and rostroventrolateral medulla (Cork et al, 2015 ). Furthermore, administration of the GLP-1R agonist Exendin-4 leads to direct effects on heart rate in mice (Holt et al, 2020 ). That GLP-1 seems to have a direct physiological effect on the cardiovascular system, as well as its role in improving metabolic health, has increased interest in its possible therapeutic use in cardiovascular disease. This systematic review aims to investigate the literature around the use of GLP-1R agonists and their effects on major adverse cardiovascular events (MACE). Methodology Study Design This study is a systematic review and meta-analysis of cardiovascular outcome trials (CVOTs) evaluating the long-term safety and efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in populations at high cardiovascular risk. The protocol [Supplementary Appendix A] was developed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines (Page et al, 2021) and has been published on PROSPERO (ID: CRD420251051447) Literature Search A comprehensive literature search was conducted in May 2025 across PubMed, Embase via OVID and the Cochrane Library from 01 January 2015 to 12 May 2025. Search terms included a combination of Medical Subject Headings (MeSH) and free-text terms, such as ‘GLP-1 receptor agonist’, ‘semaglutide’, ‘liraglutide’, ‘dulaglutide’, ‘cardiovascular outcomes’ and ‘major adverse cardiovascular events. The complete search strategy can be found in [Supplementary Appendix B]. To streamline the review process, Covidence (Covidence, 2025 ), an automation tool for systematic reviews, was used to manage reference screening and selection. All retrieved citations were imported into Covidence, where duplicates were automatically removed. Additional duplicates were identified and removed manually using RefWorks. Eligibility Criteria Studies were included if they met the following criteria, according to the PICOS framework: Population Adults (≥ 18 years) only at high risk for cardiovascular disease (CVD) or with established CVD (coronary artery disease, heart failure, prior myocardial infarction, stroke). Patients with comorbid conditions associated with cardiovascular risk - type 2 diabetes, obesity, hypertension, dyslipidaemia. Intervention Studies evaluating GLP-1 receptor agonists (Liraglutide, Lixisenatide, Semaglutide, Exenatide, Albiglutide, Dulaglutide, Efpeglenatide). Comparator Placebo Outcome Primary: Cardiovascular outcomes - major adverse cardiovascular events [MACE] Secondary: cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, heart failure Adverse Effects: Safety outcomes (severe hypoglycaemia, pancreatitis, GI side effects). Study Design Randomised controlled trial (RCT) Minimum total sample size of 3000 participants. Minimum follow-up period of 12 months to evaluate long-term outcomes. Other Peer-reviewed articles, published in English. Studies published within the last 10 years to reflect current clinical practices and drug development. Study Selection Two reviewers (KP and OR) independently screened all titles and abstracts, followed by full-text assessment of potentially eligible studies. Conflicts were resolved through discussion and referral to third person (SCC) as necessary. The study selection process is illustrated using PRISMA 2020 flow diagram (Fig. 1 ) Data Extraction and Synthesis A detailed data extraction table was developed on Microsoft Excel and data on key study characteristics and outcomes were collected. For each included study, data was extracted on study design, baseline population characteristics, intervention details (type and dose of GLP-1 receptor agonists), comparator, mean follow-up duration and reported cardiovascular outcomes. This included MACE, cardiovascular mortality, all-cause mortality, myocardial infarction, stroke, hospitalisation for heart failure and adverse effects, including acute pancreatitis, severe hypoglycaemia and gastrointestinal side-effects [Table 1 ] Table 1 Data extraction table for cardiovascular outcome trials, covering study design, intervention details, baseline characteristics and outcomes. Basic Info Study Design Intervention Details Baseline Characteristics Outcomes and Conclusions - see notes to fill in RCT Trial Sample Size Intervention (n) Comparator (n) Median Duration (yrs) Population Drug Dose Age (mean) Gender (% female) HbA1c (%) CVD (%) Statistical Test Used Primary Outcomes Incidents (Primary - Intervention) Incidents (Primary - Comparator) Hazard Ratio Secondary Outcomes Incidents (Secondary - Intervention) Incidents (Secondary - Comparator) Hazard Ratio Severe Hypoglycaemia (%) Pancreatitis (%) GI Side effects (%) LEADER 9340 4668 4672 3.8 Mean diabetes duration 13 years; T2DM at high CV risk Liraglutide 1.8mg or max tolerated dose 64 36 8.7 81 Cox regression model including only treatment group as covariate Composite CV outcome (MACE): CV death, MI, stroke 608 694 0.87 (95% Cl: 0.78–0.97); P < 0.001 noninferiority; P = 0.01 superiority CV death, all-cause death, MI, stroke, HF hosp. CV death: 219; all cause death: 381 CV death: 278; all cause death: 447 CV death (0.78; 95% CI: 0.66–0.93; P = 0.007), all-cause death (0.85; 95% CI: 0.74–0.97; P = 0.02) 2.4 (liraglutide); 3.3 (placebo); P = 0.02 0.4 (liraglutide); 0.5 (placebo); P = 0.44 9.5 (liraglutide), 7.3 (placebo); P < 0.001 ELIXA 6068 3034 3034 2.1 T2DM and recent ACS Lixisenatide 10-20mcg S/C once daily 60 31 7.7 100 Cox proportional-hazards model with study group and geographocal region as covariates Composite CV outcome (MACE): CV death, MI, stroke 406 399 1.02 (95% Cl: 0.89–1.17); P < 0.001 noninferiority; P = 0.81 superiority HF hosp., all-cause death CV death: 156; MI: 270; stroke: 67; HF hosp.: 456 CV death: 158; MI: 261; stroke: 60; HF hosp.: 469 HF hosp. (HR 0.96; 95% Cl: 0.75–1.23), all-cause death (HR 0.94; 95% Cl: 0.78–1.13) 0.5 (lixisenatide), 0.8 (placebo) 0.2 (lixisenatide), 0.3 (placebo) 4.9 (lixisenatide), 1.2 (placebo); P < 0.001 SUSTAIN-6 3297 1648 1649 2.1 T2DM on standard care regimen Semaglutide S/C 0.5mg or 1mg once weekly for 104 wks 65 39 8.7 83 Cox proportional-hazards model with pooled treatment as a fixed factor Composite CV outcome (MACE): CV death, MI, stroke 108 146 0.74 (95% Cl: 0.58–0.95); P < 0.001 noninferiority Non-fatal MI, non-fatal stroke, CV death Non-fatal MI: 47; Non-fatal stroke: 27; CV death: 44 Non-fatal MI: 64; Non-fatal stroke: 27; CV death: 46 Nonfatal MI: 0.74 (95% CI: 0.51–1.08; P = 0.12), Nonfatal Stroke: 0.61 (95% CI: 0.38–0.99; P = 0.04), CV death: 0.98 (95% CI: 0.65–1.48; P = 0.92) 22.1 (semaglutide), 21.2 (placebo) 0.5 (semaglutide), 0.7 (placebo) 52 (semaglutide), 35 (placebo) EXSCEL 14752 7356 7396 3.2 T2DM with or without CVD Exenatide S/C extended release 2mg once weekly 62 38 8 73 Cox proportional-hazards model Composite CV outcome (MACE): CV death, MI, stroke 839 905 0.91 (95% Cl: 0.83-1.00); P < 0.001 for noninferiority; P = 0.06 superiority All-cause death, CV death, stroke, HF hosp. All-cause death:507; CV death: 340; MI: 483; Stroke: 187; HF hosp.: 219 All-cause death:584; CV death: 383; MI: 493; Stroke: 218; HF hosp.: 231 Non-fatal MI: 0.91 (95% CI: 0.81–1.02), Non-fatal Stroke: 0.90 (95% CI: 0.75–1.08), HF hosp.: 0.99 (95% CI: 0.79–1.24), ACS: 1.00 (95% CI: 0.81–1.24) 3.4 (exenatide), 3.0 (placebo) 0.4 (exenatide), 0.3 (placebo) Not recorded HARMONY Outcomes 9463 4731 4732 1.6 T2DM and CVD Albiglutide 30-50mg based on glycaemic response and tolerability 64 30 8.7 100 Cox proportional hazards regression, with treatment group as the only explanatory variable Composite cardiovascular events (CV death, MI, stroke) 338 428 0.78 (95% CI: 0.68–0.90); P < 0.0001 noninferiority; P = 0.0006 superiority CV death, MI, Stroke, All cause death CV death:122; MI: 181; Stroke: 94; all cause death: 196 CV death:130; MI: 240; Stroke: 108; all cause death: 205 MI: 0.75 (95% CI: 0.61–0.90; P = 0.003), stroke: 0.86 (95% CI: 0.66–1.14; P = 0.3), CV death: 0.93 (95% CI: 0.73–1.19; P = 0.578) 1.0 (albiglutide), 1.0 (placebo < 0.1 (albiglutide), < 0.1 (placebo) 2.0 (albiglutide), 2.0 (placebo) PIONEER-6 3183 1591 1592 1.3 ≥50 years old with established CV or chronic kidney disease, or ≥60 years old with CV risk factors only Semaglutide Oral 14mg max daily dose 66 32 8.2 85 A stratified Cox proportional-hazards model was used for the primary outcome analysis, with trial group as a fixed factor. Composite cardiovascular events (CV death, MI, stroke) 61 76 0.79 (95% CI: 0.57–1.11); P < 0.001 noninferiority CV death, nonfatal MI, nonfatal stroke, all-cause death all-cause death: 23; CV death: 15; non-fatal MI: 37; non-fatal stroke: 12; HF hosp.:21 all-cause death: 45; CV death: 30; non-fatal MI: 31; non-fatal stroke: 16; HF hosp.:24 CV death: 0.49 (95% CI: 0.27–0.92); Nonfatal MI: 1.18 (95% CI: 0.73–1.90); Nonfatal stroke: 0.74 (95% CI: 0.35–1.57); all-cause death: 0.51 (95% CI: 0.31–0.84) 1.4 (semaglutide), 0.8 (placebo) 0.1 (semaglutide), 0.2 (placebo) 6.8 (semaglutide), 1.6 (placebo) REWIND 9901 4949 4952 5.4 T2DM with/ without CVD or risk factors;≥ 50 years old Dulaglutide 1.5mg S/C once a week 66 46 7.3 31 Kaplan-Meier estimates used to generate cumulative risks. Cox proportional hazards models used for effect of intervention on outcome and to estimate HRs and 95% CIs. Composite cardiovascular events (CV death, MI, stroke) 594 663 0.88 (95% CI: 0.79–0.99); P = 0.026) CV death, nonfatal MI, nonfatal stroke MI: 223; stroke: 158; cvs death: 317; all-cause death: 536; HF: 213 MI: 231; stroke: 205; cvs death: 346; all-cause death: 592; HF: 226 CV death: 0.91 (95% CI: 0.78–1.06; P = 0.21); Nonfatal MI: 0.96 (95% CI: 0.79–1.16; P = 0.65); Nonfatal stroke: 0.76 (95% CI: 0.61–0.95; P = 0.017); all-cause death: 0.90 (95% CI: 0.80–1.01; P = 0.067) 1.3 (dulaglutide), 1.5 (placebo) 0.5 (dulaglutide), 0.3 (placebo) 47.4 (dulaglutide), 34.1 (placebo) AMPLITUDE-O 4076 2717 1359 1.8 T2DM and CVD or renal disease Efpeglenatide 4mg or 6mg 65 33 8.9 76 Kaplan–Meier curves for cumulative risks. Cox proportional-hazards models adjusted for geographic region. Randomisation stratification factor to estimate HR and 95% CI for effect of efpeglenatide (dose groups combined) on outcomes. Composite cardiovascular events (CV death, MI, stroke) 189 125 0.73 (95% CI: 0.58–0.92); P < 0.001 noninferiority; P = 0.007 superiority [double checked and this is correct] Non-fatal MI, non-fatal stroke, HF, CV death, all-cause death MI: 91; Stroke: 47; CV death: 75; all-cause mortality: 111; HF: 40 MI: 58; Stroke: 31; CV death: 50; all-cause mortality: 69; HF: 31 Non-fatal MI: 0.78 (95% CI: 0.55–1.10), non-fatal stroke: 0.80 (95% CI: 0.48–1.31), HF: 0.61 (95% CI: 0.38–0.98), CV death: 0.72 (95% CI: 0.50–1.03), all-cause death: 0.78 (95% CI: 0.58–1.06) 0.9 (efpeglenatide), 1.0 (placebo) 0.4 (efpeglenatide), 0.5 (placebo) 3.3 (efpeglenatide), 1.8 (pacebo) ITCA 650 4156 2075 2081 1.8 T2DM and either a history of CVD or current kidney disease (eGFR: 25.0–59.9 ml/ min/ 1.73 m2 body-surface area) plus ≥ 1 CV risk factor Efpeglenatide S/C 4mg or 6mg once weekly 63 37.5 (ITCA); 35.9 placebo 8 76 HRs, 95% CIs and P values for time-to-event analyses were derived from a stratified Cox proportional hazards model. First MACE (nonfatal MI, nonfatal stroke, or death from CV or undetermined causes) 95 79 1.21 (95% CI: 0.90–1.63); P = 0.004 non-inferiority All-cause mortality, cvs death, non-fatal MI, non-fatal stroke; HF hosp. all-cause mortality: 49; cvs death: 28; non-fatal MI: 37; non-fatal stroke: 23; HF hosp. 16 all-cause mortality: 41; cvs death: 23; non-fatal MI: 28; non-fatal stroke: 23; HF hosp. 17 CV death:1.22 (95% CI: 0.70–2.12); non-fatal MI: 1.33 (95% CI: 0.82–2.17); non-fatal stroke: 1.00 (95% CI: 0.56–1.79); all-cause mortality: 1.20 (95% CI: 0.79–1.81); HF hosp.: 0.95 (95% CI: 0.48–1.88) 0.4 (ITCA 650), 0.2 (placebo) 0.4 (ITCA 650), 0.1 (placebo) Nausea − 20.6 (ITCA 650), 3.6 (placebo); Vomiting − 13.5 (ITCA 650), 1.2 (placebo); diarrhoea − 7.8 (ITCA 650), 3.5 (placebo) SELECT 17604 8803 8801 3.3 ≥ 45 year old; pre-existing CVD and BMI ≥ 27; no history of diabetes Semaglutide S/C 2.4mg once weekly 62 28 5.8 > 75 previous MI; ~25 chronic HF Cause-specific HRs and 95% CI using Cox proportional hazards model with randomised assignment (semaglutide or placebo) as fixed factor. One-sided P values from score test. Composite cardiovascular events (CV death, MI, stroke) 569 701 0.80 (95% CI: 0.72–0.90); P < 0.001 noninferiority; P = 0.046 superiority CV death, HF, all- cause death, non-fatal MI, non-fatal stroke, HF hosp. cvs death: 223; HF: 300; all-cause death: 375; non-fatal MI: 234; non-fatal stroke: 154; HF hosp.: 109 cvs death: 262; HF: 361; all-cause death: 458; non-fatal MI: 322; non-fatal stroke: 165; HF hosp.: 122 CV death: 0.85 (95% CI: 0.71–1.01; P = 0.07), HF: 0.82 (95% CI: 0.71–0.96), all-cause death: 0.81 (95% CI: 0.71–0.93) Not recorded 0.2 (semaglutide), 0.3 (placebo) 10.0 (semaglutide), 2.0 (placebo) SOUL 9650 4825 4825 4.1 ≥ 50 years old, had T2DM with a glycated Hb level 6.5–10.0%, atherosclerotic CV disease, CKD, or both Semaglutide Oral Once daily 14mg max dose 66 28.90 8 57 Cox proportional-hazards model with randomized group assignment as a fixed factor MACE (death from CV causes, nonfatal MI, or nonfatal stroke), assessed in a time-to-first-event analysis 579 668 0.86; 95% confidence interval, 0.77 to 0.96; P = 0.006 CV death, MI, Stroke, All cause death, HF CV death: 301; MI: 200; stroke: 164; all-cause death: 528; HF: 146 CV death: 320; MI: 268; stroke: 171; all-cause death: 577; HF: 167 CV death: 0.93 (95% CI: 0.80–1.09), MI: 0.73 (95% CI: 0.61–0.88), stroke: 0.95 (95% CI: 0.76–1.17), all-cause death: 0.91 (95% CI: 0.80–1.02) 1.6 (semaglutide), 1.7 (placebo) 0.4 (semaglutide), 0.4 (placebo) 5.0 (semaglutide), 4.4 (placebo) Two reviewers (KP and OR) independently extracted the data. Discrepancies were resolved through discussion and referral to third person (SCC) as necessary. Results were grouped according to primary and secondary outcomes. A narrative synthesis was conducted to summarise findings across studies. Statistical analysis was conducted using Stata version 18 statistical software. Hazard Ratio (HR) with 95% CI were used to assess the outcomes between the two treatment groups. Heterogeneity was assessed using chi-squared tests as well as I-squared test. Forest plots are used to represent the results generated from the random-effects meta-analysis graphically. The pooled HR and the degree of heterogeneity are presented. Publication bias was minimised by comprehensive literature searching. Risk of Bias and Quality Assessment The quality of each included study and outcomes was independently assessed by reviewers (KP and OR) Discrepancies were resolved through discussion and referral to third person (SCC) as necessary. The Cochrane Risk of Bias 2 (RoB2) tool (Sterne et al, 2019 ) was used to evaluate bias across five domains: randomisation process, deviations from the intended interventions, missing outcome data, measurement of the outcome and selection of the reported result. Each study was assigned a risk of bias rating of ‘low risk’, ‘some concerns’ or ‘high risk’ in each domain and an overall rating. The overall rating for risk of bias obtained through the RoB2 tool was included as part of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach (Schünemann et al, 2013 ). The GRADE approach assessed the quality of the evidence for each outcome across five domains: risk of bias, inconsistency, indirectness, imprecision and publication bias. Each outcome was rated as very low, low, moderate and high certainty. A detailed summary of findings table was constructed to present the quality of evidence across the included outcomes and studies [Supplementary Appendix C]. Results Study Selection A total of 645 studies were identified through database searches in PubMed, Ovid and The Cochrane Library. After removing duplicates and screening the titles and abstracts of these studies, 49 full-text studies were assessed for eligibility. Following this, 11 studies met the inclusion criteria and data extracted for the systematic review. A PRISMA flow diagram (Page et al, 2021) illustrating the selection process can be found in Fig. 1 . Study Characteristics The included studies were published between 2016 and 2025, with sample sizes ranging from 3183 and 17604 participants. All eleven studies were randomised placebo-controlled trials investigating GLP-1 receptor agonists in adults with high cardiovascular risk. Drugs investigated across these studies include: Liraglutide (n = 1); Lixisenatide (n = 1); Semaglutide (n = 4); Exenatide (n = 1); Albiglutide (n = 1); Dulaglutide (n = 1); Efpeglenatide (n = 1). The COX proportional hazards model was used by all eleven studies to determine the effect of the intervention on the outcome and to estimate hazard ratios and 95% confidence intervals. All studies are cardiovascular outcome trials (CVOTs) and reported on MACE as their primary outcomes. The studies reported on secondary outcomes, including all-cause mortality, fatal and non-fatal myocardial infarction (MI) and stroke, as well as hospitalisation for heart failure. Adverse events were also reported, including acute pancreatitis, severe hypoglycaemia and gastrointestinal side effects. A detailed summary of study characteristics is presented in a data extraction table [Table 1 ]. Outcomes The primary outcome, MACE, was reported in 11 studies with statistically significant reduction in MACE observed in 7 of the 11 studies. Three studies, ELIXA (Pfeffer et al, 2015 ), ITCA 650 (Ruff et al, 2021 ) and PIONEER-6 (Husain et al, 2019 ) trials, were identified as non-significant for superiority but met criteria for non-inferiority (P values: <0.001; 0.004; <0.001, respectively). One study, the EXSCEL trial, reported a borderline result for superiority (HR 0.91 (95% Cl: 0.83-1.00); P < 0.001 for non-inferiority; P = 0.06 for superiority). In the meta-analysis, there are 91,490 patients with 4386 events in the intervention group and 4884 events in the placebo group. The mean duration of follow-up in the studies was 2.7 years. The HR (95%CI) for MACE is 0.87 (0.81–0.92) in favour of GLP-1 receptor agonists [Figure 4 ]. Secondary outcomes included cardiovascular mortality, all-cause mortality, non-fatal myocardial infarction (MI) and stroke, as well as hospitalisation for heart failure. Cardiovascular mortality was observed in 9 of the 11 studies. Two studies, LEADER (Marso et al, 2016 ) and PIONEER-6, reported a statistically significant reduction in cardiovascular mortality (HR (95%CI): 0.78 (0.66–0.93); 0.49 (0.27–0.92) respectively). Six studies, SUSTAIN-6 (Marso et al, 2016 ), HARMONY Outcomes (Thorpe et al, 2018 ), REWIND (Basile et al, 2019 ), AMPLITUDE-O (Gerstein et al, 2021 ), SELECT (Lincoff et al, 2023 ) and SOUL (McGuire et al, 2025 ), showed non-significant trends toward benefit with hazard ratios close to 1 and confidence intervals that crossed 1 (HR (95%CI): 0.98 (0.65–1.48); 0.93 (0.73–1.19); 0.91 (0.78–1.06); 0.72 (0.50–1.03); 0.85 (0.71–1.01); 0.93 (0.80–1.09) respectively). One study, ITCA 650, reported a non-significant potential increase in cardiovascular mortality (1.22 (95% CI:0.70–2.12)). All-cause mortality was reported in 8 of the 11 studies. Three studies, LEADER, PIONEER-6 and SELECT, demonstrated a statistically significant reduction in all-cause mortality (HR (95%CI): 0.85(0.74–0.97); 0.51 (0.31–0.84); 0.81 (0.71–0.93) respectively). Four studies, ELIXA, REWIND, AMPLITUDE-O and SOUL, indicated non-significant trends toward benefit with hazard ratios close to 1 and confidence intervals that crossed 1 (HR (95%CI): 0.94 (0.78–1.13); 0.90 (0.80–1.01); 0.78 (0.58–1.06); 0.91 (0.80–1.02) respectively). One study, ITCA 650, reported a non-significant potential increase in all-cause mortality (HR 1.20 (95% CI: 0.79–1.81)). Non-fatal MI was reported in 8 of the 11 studies. Two studies, HARMONY Outcomes and SOUL, reported a statistically significant reduction in non-fatal MI (HR (95%CI): 0.75 (0.61–0.90); 0.73 (0.61–0.88) respectively). Four studies, SUSTAIN-6, EXSCEL, REWIND and AMPLITUDE-O, reported non-significant trends toward benefit with hazard ratios close to 1 and confidence intervals that crossed 1 (HR (95%CI): 0.74 (0.51–1.08); 0.90 (0.75–1.08); 0.96 (0.79–1.16); 0.78 (0.55–1.10) respectively). Two studies, PIONEER-6 and ITCA 650, revealed a non-significant increase in non-fatal MI (HR (95%CI): 1.18 (0.73–1.90); 1.33 (0.82–2.17) respectively). Non-fatal stroke was reported in 8 of the 11 studies. Two studies, SUSTAIN-6 and REWIND, reported a statistically significant reduction in non-fatal stroke (HR (95%CI): 0.61 (0.38–0.99); 0.76 (0.61–0.95) respectively). Five studies, EXSCEL, HARMONY Outcomes, PIONEER-6, AMPLITUDE-O and SOUL, reported non-significant trends toward benefit with hazard ratios close to 1 and confidence intervals that crossed 1 (HR (95%CI): 0.90 (0.75–1.08); 0.86 (0.66–1.14); 0.74 (0.35–1.57); 0.80 (0.48–1.31); 0.95 (0.76–1.17) respectively). One study, ITCA 650, showed a non-significant increase in non-fatal stroke (HR 1.00 (95% CI: 0.56–1.79)). Hospitalisation for heart failure was reported in 5 of the 11 studies. Two studies, AMPLITUDE-O and SELECT, reported a statistically significant reduction in hospitalisation for heart failure (HR (95%CI): 0.61 (0.38–0.98); 0.82 (0.71–0.96) respectively). Three studies, ELIXA, EXSCEL and ITCA 650, reported non-significant trends toward benefit with hazard ratios close to 1 and confidence intervals that crossed 1 (HR (95%CI): 0.96 (0.75–1.23); 0.99 (0.79–1.24); 0.95 (0.48–1.88) respectively. The meta-analysis shows that use of GLP-1 receptor agonists was associated with a reduction of the outcomes (HR (95%CI): 0.87 (0.81–0.94) for all-cause mortality; 0.87 (0.80–0.94) for CV death, 0.88 (0.77–0.99) for HF hospitalization, 0.85 (0.76–0.96) for non-fatal MI and 0.85 (0.77–0.95) for non-fatal stroke, [Supplementary Appendix D]. Adverse effects included Severe hypoglycaemia, acute pancreatitis and Gastrointestinal side effects. Severe hypoglycaemia was investigated in ten of out eleven studies. One study (SELECT) did not report this. When expressed as absolute risk differences (ARD), the rates of severe hypoglycaemia with intervention groups compared against placebo groups ranged from − 0.9% (LEADER) to + 0.9% (SUSTAIN-6), with most studies showing negligible differences (–0.3% to + 0.2%). Four of the ten studies identified higher rates of severe hypoglycaemia compared to the placebo group (SUSTAIN-6, EXSCEL, PIONEER-6, ITCA 650). Five of the ten studies reported to have lower rates of severe hypoglycaemia compared to the placebo group (LEADER, ELIXA, REWIND, AMPLITUDE-O, SOUL). One study found no difference between the intervention and placebo groups (HARMONY outcomes). This suggests that the use of GLP-1 RAs does not materially increase the risk of severe hypoglycaemia, in contrast to concerns raised for other glucose-lowering therapies. Similarly, for acute pancreatitis, absolute risk differences reported in cardiovascular outcome trials are typically < 0.1%, indicating no consistent excess risk compared with placebo. Acute pancreatitis was reported in all eleven studies. Across these studies, the ARD for pancreatitis between the intervention and placebo groups were minimal, ranging from − 0.2% (SUSTAIN-6) to + 0.3% (ITCA 650). The event rates were consistently below 1%, with no statistically significant risk identified. Three of the eleven studies reported higher rates of acute pancreatis in the intervention group compared to the placebo group (EXSCEL, REWIND, ITCA 650). Six of the eleven studies reported lower rates of acute pancreatitis in the intervention group compared to the placebo group (LEADER, ELIXA, SUSTAIN-6, PIONEER-6, AMPLITUDE-O, SELECT). Two of the eleven studies reported no difference between the groups (HARMONY outcomes, SOUL). These findings reinforce that while pancreatitis has been a theoretical concern, the clinical evidence demonstrates that GLP-1 RAs do not confer a meaningful increase in risk compared with placebo. Gastrointestinal side effects were reported in ten of eleven studies. One study did not report gastrointestinal effects (EXSCEL). When expressed as ARD, the intervention group was consistently associated with a higher incidence of gastrointestinal side effects compared to the placebo group. The differences ranged from + 0.6% (SOUL) to + 17% (SUSTAIN-6; nausea in ITCA 650). ITCA 650 reported statistically significant increased risk of the gastrointestinal side effects: nausea (+ 17%), vomiting (+ 12.3%) and diarrhoea (+ 4.3%). Two of the eleven studies, with ARD values greater than 10%, found stronger evidence for higher rates of gastrointestinal side effects in the intervention group compared against the placebo group (SUSATAIN-6, REWIND). Five of the eleven studies reported, with ARD values less than 10%, reported statistically significant increased incidence of gastrointestinal side effects in the intervention group compared against the placebo group (LEADER, ELIXA, PIONEER-6, AMPLITUDE-O, SELECT). One study reported less statistically significant higher rates of gastrointestinal side effects in the intervention group compared against the placebo group (SOUL). One study showed no differences between the two groups (HARMONY outcomes). These findings confirm that while the GLP-1 RAs does not materially increase rare adverse events such as pancreatitis and severe hypoglycaemia, gastrointestinal side effects represent a predictable and clinically relevant class effect that often limits tolerability. Risk of Bias Ten of eleven studies were judged to be at low risk of bias across all RoB2 (Sterne et al, 2019 ) domains, including randomisation and allocation (D1), deviations from intervention (D2), missing outcome data (D3), measurement of outcome (D4) and selection of reported results (D5). One study (ITCA 650) reported as ‘some concerns’ overall due to risk of bias in D2 due to concerns regarding the implantable device affecting the blinding of the procedure, which may have influenced how the intervention was administered. This has been illustrated in Fig. 2 . Certainty of Evidence All primary and secondary outcomes were judged to have high certainty of evidence across all GRADE approach (Schünemann et al, 2013 ) domains, including risk of bias (D1), inconsistency (D2), indirectness (D3), imprecision (D4), publication bias (D5). As ITCA 650 contributed minimally to the pooled estimate, its potential bias did not materially affect the overall assessment. Therefore, D1 was judged as ‘high certainty’ overall for each outcome. This has been illustrated in Fig. 3 . Discussion Despite recent advancements in cardiovascular prevention and treatment, cardiovascular disease remains the leading cause of death worldwide, especially amongst high-risk populations such as those with type 2 diabetes and/or hypertension (WHO, 2025). The persistently elevated risk amongst these trial populations demonstrates the limitations of current management strategies and highlights the need for new and improved therapies that can address the link between metabolic disease and direct cardiovascular pathology. The results of this systematic review and meta-analysis demonstrate that glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce the risk of major adverse cardiovascular events (MACE). The benefits of these drugs likely extend beyond their current use in the treatment of diabetes and obesity as a way to manage glycaemic control, as reductions were observed even in populations with near target HbA1c at baseline. GLP-1RAs therefore function as a dual-action therapy; lowering metabolic risk factors such as type 2 diabetes and hyperglycaemia, whilst also generating cardiovascular benefits that cannot solely be explained by the metabolic effects alone. Research involving preclinical and translational studies provides plausible explanations for the cardiovascular effects observed in the trials analysed in our meta-analysis. GLP-1 receptors have been identified within myocardial tissue and autonomic centres (McLean et al, 2022 , Baggio et al, 2018 , Cork et al, 2015 ), with murine studies demonstrating effects on heart rate, endothelial function and regulation of the autonomic nervous system (Baggio et al, 2017 , Holt et al, 2020 , Gaspari et al, 2011 ). These effects work alongside indirect benefits including weight loss, reduced blood pressure and improved lipid metabolism, which in turn may enhance protection against atherosclerotic disease. These combined direct and indirect effects provide a rationale for the observed reduction of MACE in our meta-analysis. Our meta-analysis confirms a significant reduction in MACE, consistent with lower cardiovascular and all-cause mortality with the introduction of GLP-1 RAs. While several studies demonstrated non-significant or borderline effects on endpoints such as myocardial infarction, stroke or cardiovascular death, pooling the data revealed significant reductions in MACE and all-cause mortality. The combined evidence from various trials also demonstrated a consistent benefit across various trial designs, drug formulations and patient populations, supporting the conclusion that cardiovascular benefit is not an isolated finding but rather an effect seen by the class of drug. Safety is a critical factor to consider when evaluating long-term cardiometabolic therapies. Evidence from the cardiovascular outcome trials included in our review consistently demonstrates that GLP-1 RAs do not increase the risk of severe hypoglycaemia or acute pancreatitis. These findings directly address the long-standing safety concerns that have been raised regarding this drug class. The incidence of severe hypoglycaemia was minimal and did not change substantially from placebo, indicating the glucose-dependent mechanism of GLP-1 RAs, in contrast to the increased risk linked to insulin and sulfonylureas. Likewise, while pancreatitis has been a theoretical concern, trial data has consistently shown that the occurrence rates are very low (< 1%) and there is no significant increase in risk compared to placebo. (Marso et al, 2016 , Gerstein et al, 2021 , Ussher & Drucker, 2023 ) Conversely, patients receiving GLP-1 RAs were consistently more likely to report experiencing gastrointestinal side effects. The predominant complaints were nausea, vomiting and diarrhoea; in some trials, the incidence was more than 10% higher compared to placebo. (Marso et al, 2016 ). These adverse effects are well-recognised class-specific reactions that may restrict tolerance and adherence in clinical practice. To maximise the cardiovascular benefits of GLP-1 RAs at a population level, strategies can be used to improve tolerability, such as patient counselling, gradual dose escalation and the use of long-acting formulations (Nauck & Meier, 2019 ). Overall, GLP-1 RAs have a favourable safety profile, with benefits that significantly outweigh their manageable side effects. Looking ahead, the accumulating body of evidence supporting the cardiovascular benefits of GLP-1 RAs highlights the need to integrate them more widely into routine clinical practice. These therapies should be regarded as key components of larger cardiovascular risk reduction strategies, especially for patients with established heart disease or Type II Diabetes, in addition to being used as treatments for glycaemic control. High-risk individuals may receive more long-term cardiovascular protection if GLP-1 RAs are initiated earlier. Additional cardiovascular benefits may be provided by combination therapy with other antidiabetic medications, such as SGLT2 inhibitors. Overcoming barriers such as availability, affordability and clinical awareness could broaden implementation in clinical practice. Incorporating GLP-1 RAs into standard treatment pathways has the potential to substantially lower cardiovascular morbidity and mortality among high-risk populations. Declarations Funding There is no funding associated with this article. Author Contribution KP, OR, ES and MW conceptualised the project, produced the methodology analysed the data and drafted the manuscriptJZ undertook the meta analysisSCC supervised the project and drafted the manuscriptAll authors agreed to the final manuscript Data Availability All data is available in the manuscript and associated supplementary files. 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Supplementary Files SupplementaryAppendixA.docx SupplementaryAppendixB.docx SupplementaryAppendixC.docx SupplementaryAppendixD.docx Cite Share Download PDF Status: Published Journal Publication published 01 May, 2026 Read the published version in Cardiovascular Diabetology – Endocrinology Reports → Version 1 posted Editorial decision: Revision requested 17 Feb, 2026 Reviews received at journal 17 Feb, 2026 Reviews received at journal 14 Feb, 2026 Reviews received at journal 08 Feb, 2026 Reviewers agreed at journal 06 Feb, 2026 Reviewers agreed at journal 06 Feb, 2026 Reviewers agreed at journal 06 Feb, 2026 Reviewers agreed at journal 06 Feb, 2026 Reviewers agreed at journal 06 Feb, 2026 Reviewers agreed at journal 06 Feb, 2026 Reviewers agreed at journal 06 Feb, 2026 Reviewers agreed at journal 06 Feb, 2026 Reviewers invited by journal 06 Feb, 2026 Editor assigned by journal 06 Feb, 2026 Submission checks completed at journal 06 Feb, 2026 First submitted to journal 04 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8788582","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":587757026,"identity":"40e2ea9a-a428-442a-b860-a93bfdd5d7f3","order_by":0,"name":"Kezia Peter","email":"","orcid":"","institution":"Anglia Ruskin University","correspondingAuthor":false,"prefix":"","firstName":"Kezia","middleName":"","lastName":"Peter","suffix":""},{"id":587757029,"identity":"29a97f99-618f-4a12-b95f-2e18558a35b8","order_by":1,"name":"Ocin Roka","email":"","orcid":"","institution":"Anglia Ruskin University","correspondingAuthor":false,"prefix":"","firstName":"Ocin","middleName":"","lastName":"Roka","suffix":""},{"id":587757030,"identity":"d6a48c17-a44a-4285-a811-290e6e9d6b2c","order_by":2,"name":"Emma Sepp","email":"","orcid":"","institution":"Anglia Ruskin University","correspondingAuthor":false,"prefix":"","firstName":"Emma","middleName":"","lastName":"Sepp","suffix":""},{"id":587757032,"identity":"be2175bf-a63b-486f-9590-33f60e13dc69","order_by":3,"name":"Maya Warburton","email":"","orcid":"","institution":"Anglia Ruskin University","correspondingAuthor":false,"prefix":"","firstName":"Maya","middleName":"","lastName":"Warburton","suffix":""},{"id":587757033,"identity":"c92fff82-6107-45f1-aef8-3d54dc44ef7b","order_by":4,"name":"Jufen Zhang","email":"","orcid":"","institution":"Anglia Ruskin University","correspondingAuthor":false,"prefix":"","firstName":"Jufen","middleName":"","lastName":"Zhang","suffix":""},{"id":587757034,"identity":"b229250f-67cb-4ab5-a320-1e0d508f0c39","order_by":5,"name":"Simon C. Cork","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzklEQVRIiWNgGAWjYDACZhiDh/kAhhghLWwJRGqBAx4eA+K0yLdzJz4uYLCTM+858/FzZRuDPH8Dj7EBPi0Gh3k3G89gSDaWOdu7WfJsG4PhjAM8xgl4tTDzbpPmYTiQOIOfd4NkYxsD4wYGHuMDeB3WDNfC8/gnUIs9QS0Mh2FaeHvYQLYkgrTgdxjILzwGycYSPMfMLBvOSSTPOMxWjNf78v1nNz7mqbCTk+BJfnyzoczGtr+9ebMEXodB7IKzJIiPyFEwCkbBKBgFuAEAXRw6YGqVHWgAAAAASUVORK5CYII=","orcid":"","institution":"Anglia Ruskin University","correspondingAuthor":true,"prefix":"","firstName":"Simon","middleName":"C.","lastName":"Cork","suffix":""}],"badges":[],"createdAt":"2026-02-04 16:08:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8788582/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8788582/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s40842-026-00295-3","type":"published","date":"2026-05-01T15:57:13+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":102746284,"identity":"134f55b9-ddb6-46b0-94b6-48000412d9c8","added_by":"auto","created_at":"2026-02-16 08:56:26","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":92746,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 flowchart illustrating literature searching methods (Page et al, 2021).\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8788582/v1/4ec1c18b61e83e3fbd1acfbe.jpeg"},{"id":102439918,"identity":"785ed852-f382-436c-9a25-b448fe961f84","added_by":"auto","created_at":"2026-02-11 16:44:23","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":773042,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRisk of bias assessment results using Cochrane’s RoB-2 tool for each cardiovascular outcome trial and a key on the right to explain ratings across domains (D1: randomisation process, D2: deviations from the intended interventions, D3: missing outcome data, D4: measurement of the outcome and D5: selection of the reported result) (Sterne et al., 2019).\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8788582/v1/92dee665e492816a608260b8.jpeg"},{"id":102439922,"identity":"e699d954-a79f-4a7e-b04f-d559245a3e46","added_by":"auto","created_at":"2026-02-11 16:44:23","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":860530,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach results to illustrate quality of evidence across outcomes. Key on the right to explain ratings across domains (D1: risk of bias, D2: inconsistency, D3: indirectness, D4: imprecision and D5: publication bias) (Schünemann et al, 2013).\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8788582/v1/037d2b4439e68ad1c74a2dcf.jpeg"},{"id":102439921,"identity":"9a48d164-43a5-4e16-a5e3-c7ca690c9446","added_by":"auto","created_at":"2026-02-11 16:44:23","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":42307,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plot diagram between GLP-1 receptor agonists and placebo for MACE events according to random effects analysis.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8788582/v1/648416048be95777b7f61425.png"},{"id":108438022,"identity":"48a385ab-34de-4015-9385-ab1bdb21fac0","added_by":"auto","created_at":"2026-05-04 16:05:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2077236,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8788582/v1/d0dd14be-82af-484e-8db3-db89c8fbbc06.pdf"},{"id":102745473,"identity":"1a4510b3-e2cb-44ea-9ed4-40c3aad06b9e","added_by":"auto","created_at":"2026-02-16 08:50:59","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":42800,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryAppendixA.docx","url":"https://assets-eu.researchsquare.com/files/rs-8788582/v1/5d8a2c8d40d33ff23a0cd9ba.docx"},{"id":102439924,"identity":"0b9d3bb4-bcd3-4647-90d6-b5fcf8dfb47f","added_by":"auto","created_at":"2026-02-11 16:44:24","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":30701,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryAppendixB.docx","url":"https://assets-eu.researchsquare.com/files/rs-8788582/v1/850d7b91cbdb3162b5755d39.docx"},{"id":102439923,"identity":"26b54578-42b1-4491-8c7a-7c7093a1a102","added_by":"auto","created_at":"2026-02-11 16:44:23","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":124508,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryAppendixC.docx","url":"https://assets-eu.researchsquare.com/files/rs-8788582/v1/626dc4bbc623790420ed06d0.docx"},{"id":102439920,"identity":"61753731-0fed-4b3c-9f76-05b49d86b18b","added_by":"auto","created_at":"2026-02-11 16:44:23","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":409858,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryAppendixD.docx","url":"https://assets-eu.researchsquare.com/files/rs-8788582/v1/6c2c53ef3f67b6d4941f8e71.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The long-term cardiovascular safety and efficacy of glucagon-like peptide-1 (GLP-1) receptor agonists in high-risk cardiovascular populations: A systematic review and meta-analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCardiovascular diseases (CVDs) remain the leading cause of mortality worldwide, accounting for approximately 17.9\u0026nbsp;million deaths annually, representing around 32% of all global deaths (World Health Organisation, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). Despite preventative strategies and advances in medical interventions, the prevalence of CVDs is continuing to rise, particularly among high-risk populations (Yang et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). The UK\u0026rsquo;s National Institute for Health and Care Excellence (NICE) defines high-risk individuals as those with a 10-year risk of a first cardiovascular event of 10% or above, often calculated using tools such as QRISK3 (National Institute for Health and Care Excellence, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2023\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOne of the promising emerging therapeutic drug classes with potential benefits in these high-risk populations are glucagon-like peptide (GLP-1) receptor agonists (GLP-1RAs). Originally developed for the treatment of type 2 diabetes, but now also licensed for the treatment of obesity, these medications act by mimicking the endogenous incretin hormone GLP-1, enhancing insulin secretion, satiety and weight loss. Agents in this class include liraglutide, semaglutide, dulaglutide and exenatide which have been demonstrated to reduce HbA1c levels and help with weight management in large-scale clinical trials (Alfaris et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2024\u003c/span\u003e) .\u003c/p\u003e \u003cp\u003eGLP-1 receptors (GLP-1R) have been identified in murine and human heart tissue (McLean et al, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2022\u003c/span\u003e, Baggio et al, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2018\u003c/span\u003e) as well as in brain regions associated with autonomic control of the cardiovascular system, such as the paraventricular nucleus and rostroventrolateral medulla (Cork et al, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). Furthermore, administration of the GLP-1R agonist Exendin-4 leads to direct effects on heart rate in mice (Holt et al, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2020\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThat GLP-1 seems to have a direct physiological effect on the cardiovascular system, as well as its role in improving metabolic health, has increased interest in its possible therapeutic use in cardiovascular disease. This systematic review aims to investigate the literature around the use of GLP-1R agonists and their effects on major adverse cardiovascular events (MACE).\u003c/p\u003e"},{"header":"Methodology","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eThis study is a systematic review and meta-analysis of cardiovascular outcome trials (CVOTs) evaluating the long-term safety and efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in populations at high cardiovascular risk. The protocol [Supplementary Appendix A] was developed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines (Page et al, 2021) and has been published on PROSPERO (ID: CRD420251051447)\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eLiterature Search\u003c/h3\u003e\n\u003cp\u003eA comprehensive literature search was conducted in May 2025 across PubMed, Embase via OVID and the Cochrane Library from 01 January 2015 to 12 May 2025. Search terms included a combination of Medical Subject Headings (MeSH) and free-text terms, such as \u0026lsquo;GLP-1 receptor agonist\u0026rsquo;, \u0026lsquo;semaglutide\u0026rsquo;, \u0026lsquo;liraglutide\u0026rsquo;, \u0026lsquo;dulaglutide\u0026rsquo;, \u0026lsquo;cardiovascular outcomes\u0026rsquo; and \u0026lsquo;major adverse cardiovascular events. The complete search strategy can be found in [Supplementary Appendix B].\u003c/p\u003e \u003cp\u003eTo streamline the review process, Covidence (Covidence, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2025\u003c/span\u003e), an automation tool for systematic reviews, was used to manage reference screening and selection. All retrieved citations were imported into Covidence, where duplicates were automatically removed. Additional duplicates were identified and removed manually using RefWorks.\u003c/p\u003e\n\u003ch3\u003eEligibility Criteria\u003c/h3\u003e\n\u003cp\u003eStudies were included if they met the following criteria, according to the PICOS framework:\u003c/p\u003e\n\u003ch3\u003ePopulation\u003c/h3\u003e\n\u003cp\u003eAdults (\u0026ge;\u0026thinsp;18 years) only at high risk for cardiovascular disease (CVD) or with established CVD (coronary artery disease, heart failure, prior myocardial infarction, stroke).\u003c/p\u003e \u003cp\u003ePatients with comorbid conditions associated with cardiovascular risk - type 2 diabetes, obesity, hypertension, dyslipidaemia.\u003c/p\u003e\n\u003ch3\u003eIntervention\u003c/h3\u003e\n\u003cp\u003eStudies evaluating GLP-1 receptor agonists (Liraglutide, Lixisenatide, Semaglutide, Exenatide, Albiglutide, Dulaglutide, Efpeglenatide).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eComparator\u003c/h2\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eOutcome\u003c/h3\u003e\n\u003cp\u003ePrimary: Cardiovascular outcomes - major adverse cardiovascular events [MACE]\u003c/p\u003e \u003cp\u003eSecondary: cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, heart failure\u003c/p\u003e \u003cp\u003eAdverse Effects: Safety outcomes (severe hypoglycaemia, pancreatitis, GI side effects).\u003c/p\u003e\n\u003ch3\u003eStudy Design\u003c/h3\u003e\n\u003cp\u003eRandomised controlled trial (RCT)\u003c/p\u003e \u003cp\u003eMinimum total sample size of 3000 participants.\u003c/p\u003e \u003cp\u003eMinimum follow-up period of 12 months to evaluate long-term outcomes.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eOther\u003c/h2\u003e \u003cp\u003ePeer-reviewed articles, published in English.\u003c/p\u003e \u003cp\u003eStudies published within the last 10 years to reflect current clinical practices and drug development.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eStudy Selection\u003c/h2\u003e \u003cp\u003eTwo reviewers (KP and OR) independently screened all titles and abstracts, followed by full-text assessment of potentially eligible studies. Conflicts were resolved through discussion and referral to third person (SCC) as necessary. The study selection process is illustrated using PRISMA 2020 flow diagram (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eData Extraction and Synthesis\u003c/h2\u003e \u003cp\u003eA detailed data extraction table was developed on Microsoft Excel and data on key study characteristics and outcomes were collected. For each included study, data was extracted on study design, baseline population characteristics, intervention details (type and dose of GLP-1 receptor agonists), comparator, mean follow-up duration and reported cardiovascular outcomes. This included MACE, cardiovascular mortality, all-cause mortality, myocardial infarction, stroke, hospitalisation for heart failure and adverse effects, including acute pancreatitis, severe hypoglycaemia and gastrointestinal side-effects [Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eData extraction table for cardiovascular outcome trials, covering study design, intervention details, baseline characteristics and outcomes.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"24\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c15\" colnum=\"15\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c16\" colnum=\"16\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c17\" colnum=\"17\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c18\" colnum=\"18\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c19\" colnum=\"19\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c20\" colnum=\"20\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c21\" colnum=\"21\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c22\" colnum=\"22\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c23\" colnum=\"23\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c24\" colnum=\"24\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBasic Info\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c6\" namest=\"c2\"\u003e \u003cp\u003eStudy Design\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eIntervention Details\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c12\" namest=\"c9\"\u003e \u003cp\u003eBaseline Characteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"12\" nameend=\"c24\" namest=\"c13\"\u003e \u003cp\u003eOutcomes and Conclusions - see notes to fill in\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRCT Trial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSample Size\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIntervention (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eComparator (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMedian Duration (yrs)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePopulation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eDrug\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAge (mean)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eGender (% female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eHbA1c (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eCVD (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eStatistical Test Used\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003ePrimary Outcomes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003eIncidents (Primary - Intervention)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003eIncidents (Primary - Comparator)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cp\u003eHazard Ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cp\u003eSecondary Outcomes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cp\u003eIncidents (Secondary - Intervention)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c20\"\u003e \u003cp\u003eIncidents (Secondary - Comparator)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c21\"\u003e \u003cp\u003eHazard Ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c22\"\u003e \u003cp\u003eSevere Hypoglycaemia (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c23\"\u003e \u003cp\u003ePancreatitis (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c24\"\u003e \u003cp\u003eGI Side effects (%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLEADER\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9340\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4668\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4672\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMean diabetes duration 13 years; T2DM at high CV risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLiraglutide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.8mg or max tolerated dose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e8.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eCox regression model including only treatment group as covariate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eComposite CV outcome (MACE): CV death, MI, stroke\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e608\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e694\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cp\u003e0.87 (95% Cl: 0.78\u0026ndash;0.97); P\u0026thinsp;\u0026lt;\u0026thinsp;0.001 noninferiority; P\u0026thinsp;=\u0026thinsp;0.01\u003c/p\u003e \u003cp\u003esuperiority\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cp\u003eCV death, all-cause death, MI, stroke, HF hosp.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cp\u003eCV death: 219; all cause death: 381\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c20\"\u003e \u003cp\u003eCV death: 278; all cause death: 447\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c21\"\u003e \u003cp\u003eCV death (0.78; 95% CI: 0.66\u0026ndash;0.93; P\u0026thinsp;=\u0026thinsp;0.007), all-cause death (0.85; 95% CI: 0.74\u0026ndash;0.97; P\u0026thinsp;=\u0026thinsp;0.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c22\"\u003e \u003cp\u003e2.4 (liraglutide); 3.3 (placebo); P\u0026thinsp;=\u0026thinsp;0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c23\"\u003e \u003cp\u003e0.4 (liraglutide); 0.5 (placebo); P\u0026thinsp;=\u0026thinsp;0.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c24\"\u003e \u003cp\u003e9.5 (liraglutide), 7.3 (placebo); P\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eELIXA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6068\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eT2DM and recent ACS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLixisenatide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e10-20mcg S/C once daily\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e7.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eCox proportional-hazards model with study group and geographocal region as covariates\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eComposite CV outcome (MACE): CV death, MI, stroke\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e406\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e399\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cp\u003e1.02 (95% Cl: 0.89\u0026ndash;1.17); P\u0026thinsp;\u0026lt;\u0026thinsp;0.001 noninferiority; P\u0026thinsp;=\u0026thinsp;0.81\u003c/p\u003e \u003cp\u003esuperiority\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cp\u003eHF hosp., all-cause death\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cp\u003eCV death: 156; MI: 270; stroke: 67; HF hosp.: 456\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c20\"\u003e \u003cp\u003eCV death: 158; MI: 261; stroke: 60; HF hosp.: 469\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c21\"\u003e \u003cp\u003eHF hosp. (HR 0.96; 95% Cl: 0.75\u0026ndash;1.23), all-cause death (HR 0.94; 95% Cl: 0.78\u0026ndash;1.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c22\"\u003e \u003cp\u003e0.5 (lixisenatide), 0.8 (placebo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c23\"\u003e \u003cp\u003e0.2 (lixisenatide), 0.3 (placebo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c24\"\u003e \u003cp\u003e4.9 (lixisenatide), 1.2 (placebo); P\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSUSTAIN-6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3297\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1648\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1649\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eT2DM on standard care regimen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSemaglutide S/C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.5mg or 1mg once weekly for 104 wks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e8.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eCox proportional-hazards model with pooled treatment as a fixed factor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eComposite CV outcome (MACE): CV death, MI, stroke\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e108\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e146\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cp\u003e0.74 (95% Cl: 0.58\u0026ndash;0.95); P\u0026thinsp;\u0026lt;\u0026thinsp;0.001 noninferiority\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cp\u003eNon-fatal MI, non-fatal stroke, CV death\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cp\u003eNon-fatal MI: 47; Non-fatal stroke: 27; CV death: 44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c20\"\u003e \u003cp\u003eNon-fatal MI: 64; Non-fatal stroke: 27; CV death: 46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c21\"\u003e \u003cp\u003eNonfatal MI: 0.74 (95% CI: 0.51\u0026ndash;1.08; P\u0026thinsp;=\u0026thinsp;0.12), Nonfatal Stroke: 0.61 (95% CI: 0.38\u0026ndash;0.99; P\u0026thinsp;=\u0026thinsp;0.04), CV death: 0.98 (95% CI: 0.65\u0026ndash;1.48; P\u0026thinsp;=\u0026thinsp;0.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c22\"\u003e \u003cp\u003e22.1 (semaglutide), 21.2 (placebo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c23\"\u003e \u003cp\u003e0.5 (semaglutide), 0.7 (placebo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c24\"\u003e \u003cp\u003e\u003cb\u003e52\u003c/b\u003e (semaglutide), 35 (placebo)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEXSCEL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14752\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7356\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7396\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eT2DM with or without CVD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eExenatide S/C extended release\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2mg once weekly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eCox proportional-hazards model\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eComposite CV outcome (MACE): CV death, MI, stroke\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e839\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e905\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cp\u003e0.91 (95% Cl: 0.83-1.00); P\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for noninferiority; P\u0026thinsp;=\u0026thinsp;0.06\u003c/p\u003e \u003cp\u003esuperiority\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cp\u003eAll-cause death, CV death, stroke, HF hosp.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cp\u003eAll-cause death:507; CV death: 340; MI: 483; Stroke: 187; HF hosp.: 219\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c20\"\u003e \u003cp\u003eAll-cause death:584; CV death: 383; MI: 493; Stroke: 218; HF hosp.: 231\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c21\"\u003e \u003cp\u003eNon-fatal MI: 0.91 (95% CI: 0.81\u0026ndash;1.02), Non-fatal Stroke: 0.90 (95% CI: 0.75\u0026ndash;1.08), HF hosp.: 0.99 (95% CI: 0.79\u0026ndash;1.24), ACS: 1.00 (95% CI: 0.81\u0026ndash;1.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c22\"\u003e \u003cp\u003e3.4 (exenatide), 3.0 (placebo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c23\"\u003e \u003cp\u003e0.4 (exenatide), 0.3 (placebo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c24\"\u003e \u003cp\u003eNot recorded\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHARMONY Outcomes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9463\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4731\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4732\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eT2DM and CVD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAlbiglutide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e30-50mg based on glycaemic response and tolerability\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e8.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eCox proportional hazards regression, with treatment group as the only explanatory variable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eComposite cardiovascular events (CV death, MI, stroke)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e338\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e428\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cp\u003e0.78 (95% CI: 0.68\u0026ndash;0.90); P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 noninferiority; P\u0026thinsp;=\u0026thinsp;0.0006\u003c/p\u003e \u003cp\u003esuperiority\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cp\u003eCV death, MI, Stroke, All cause death\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cp\u003eCV death:122; MI: 181; Stroke: 94; all cause death: 196\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c20\"\u003e \u003cp\u003eCV death:130; MI: 240; Stroke: 108; all cause death: 205\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c21\"\u003e \u003cp\u003eMI: 0.75 (95% CI: 0.61\u0026ndash;0.90; P\u0026thinsp;=\u0026thinsp;0.003), stroke: 0.86 (95% CI: 0.66\u0026ndash;1.14; P\u0026thinsp;=\u0026thinsp;0.3), CV death: 0.93 (95% CI: 0.73\u0026ndash;1.19; P\u0026thinsp;=\u0026thinsp;0.578)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c22\"\u003e \u003cp\u003e1.0 (albiglutide), 1.0 (placebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c23\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.1 (albiglutide), \u0026lt;\u0026thinsp;0.1 (placebo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c24\"\u003e \u003cp\u003e2.0 (albiglutide), 2.0 (placebo)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePIONEER-6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3183\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1591\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1592\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026ge;50 years old with established CV or chronic kidney disease, or \u0026ge;60 years old with CV risk factors only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSemaglutide Oral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e14mg max daily dose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e8.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eA stratified Cox proportional-hazards model was used for the primary outcome analysis, with trial group as a fixed factor.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eComposite cardiovascular events (CV death, MI, stroke)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cp\u003e0.79 (95% CI: 0.57\u0026ndash;1.11); P\u0026thinsp;\u0026lt;\u0026thinsp;0.001 noninferiority\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cp\u003eCV death, nonfatal MI, nonfatal stroke, all-cause death\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cp\u003eall-cause death: 23; CV death: 15; non-fatal MI: 37; non-fatal stroke: 12; HF hosp.:21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c20\"\u003e \u003cp\u003eall-cause death: 45; CV death: 30; non-fatal MI: 31; non-fatal stroke: 16; HF hosp.:24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c21\"\u003e \u003cp\u003eCV death: 0.49 (95% CI: 0.27\u0026ndash;0.92); Nonfatal MI: 1.18 (95% CI: 0.73\u0026ndash;1.90); Nonfatal stroke: 0.74 (95% CI: 0.35\u0026ndash;1.57); all-cause death: 0.51 (95% CI: 0.31\u0026ndash;0.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c22\"\u003e \u003cp\u003e1.4 (semaglutide), 0.8 (placebo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c23\"\u003e \u003cp\u003e0.1 (semaglutide), 0.2 (placebo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c24\"\u003e \u003cp\u003e6.8 (semaglutide), 1.6 (placebo)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eREWIND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9901\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4949\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4952\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eT2DM with/ without CVD or risk factors;\u0026ge; 50 years old\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eDulaglutide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.5mg S/C once a week\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e7.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eKaplan-Meier estimates used to generate cumulative risks. Cox proportional hazards models used for effect of intervention on outcome and to estimate HRs and 95% CIs.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eComposite cardiovascular events (CV death, MI, stroke)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e594\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e663\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cp\u003e0.88 (95% CI: 0.79\u0026ndash;0.99); P\u0026thinsp;=\u0026thinsp;0.026)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cp\u003eCV death, nonfatal MI, nonfatal stroke\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cp\u003eMI: 223; stroke: 158; cvs death: 317; all-cause death: 536; HF: 213\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c20\"\u003e \u003cp\u003eMI: 231; stroke: 205; cvs death: 346; all-cause death: 592; HF: 226\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c21\"\u003e \u003cp\u003eCV death: 0.91 (95% CI: 0.78\u0026ndash;1.06; P\u0026thinsp;=\u0026thinsp;0.21); Nonfatal MI: 0.96 (95% CI: 0.79\u0026ndash;1.16; P\u0026thinsp;=\u0026thinsp;0.65); Nonfatal stroke: 0.76 (95% CI: 0.61\u0026ndash;0.95; P\u0026thinsp;=\u0026thinsp;0.017); all-cause death: 0.90 (95% CI: 0.80\u0026ndash;1.01; P\u0026thinsp;=\u0026thinsp;0.067)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c22\"\u003e \u003cp\u003e1.3 (dulaglutide), 1.5 (placebo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c23\"\u003e \u003cp\u003e0.5 (dulaglutide), 0.3 (placebo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c24\"\u003e \u003cp\u003e47.4 (dulaglutide), 34.1 (placebo)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAMPLITUDE-O\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4076\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2717\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1359\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eT2DM and CVD or renal disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eEfpeglenatide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4mg or 6mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e8.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eKaplan\u0026ndash;Meier curves for cumulative risks. Cox proportional-hazards models adjusted for geographic region. Randomisation stratification factor to estimate HR and 95% CI for effect of efpeglenatide (dose groups combined) on outcomes.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eComposite cardiovascular events (CV death, MI, stroke)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e189\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cp\u003e0.73 (95% CI: 0.58\u0026ndash;0.92); P\u0026thinsp;\u0026lt;\u0026thinsp;0.001 noninferiority; P\u0026thinsp;=\u0026thinsp;0.007 superiority [double checked and this is correct]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cp\u003eNon-fatal MI, non-fatal stroke, HF, CV death, all-cause death\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cp\u003eMI: 91; Stroke: 47; CV death: 75; all-cause mortality: 111; HF: 40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c20\"\u003e \u003cp\u003eMI: 58; Stroke: 31; CV death: 50; all-cause mortality: 69; HF: 31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c21\"\u003e \u003cp\u003eNon-fatal MI: 0.78 (95% CI: 0.55\u0026ndash;1.10), non-fatal stroke: 0.80 (95% CI: 0.48\u0026ndash;1.31), HF: 0.61 (95% CI: 0.38\u0026ndash;0.98), CV death: 0.72 (95% CI: 0.50\u0026ndash;1.03), all-cause death: 0.78 (95% CI: 0.58\u0026ndash;1.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c22\"\u003e \u003cp\u003e0.9 (efpeglenatide), 1.0 (placebo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c23\"\u003e \u003cp\u003e0.4 (efpeglenatide), 0.5 (placebo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c24\"\u003e \u003cp\u003e3.3 (efpeglenatide), 1.8 (pacebo)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eITCA 650\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4156\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2075\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2081\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eT2DM and either a history of CVD or current kidney disease (eGFR: 25.0\u0026ndash;59.9 ml/ min/ 1.73 m2 body-surface area) plus\u0026thinsp;\u0026ge;\u0026thinsp;1 CV risk factor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eEfpeglenatide S/C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4mg or 6mg once weekly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e37.5 (ITCA); 35.9 placebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eHRs, 95% CIs and P values for time-to-event analyses were derived from a stratified Cox proportional hazards model.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eFirst MACE (nonfatal MI, nonfatal stroke, or death from CV or undetermined causes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cp\u003e1.21 (95% CI: 0.90\u0026ndash;1.63); P\u0026thinsp;=\u0026thinsp;0.004 non-inferiority\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cp\u003eAll-cause mortality, cvs death, non-fatal MI, non-fatal stroke; HF hosp.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cp\u003eall-cause mortality: 49; cvs death: 28; non-fatal MI: 37; non-fatal stroke: 23; HF hosp. 16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c20\"\u003e \u003cp\u003eall-cause mortality: 41; cvs death: 23; non-fatal MI: 28; non-fatal stroke: 23; HF hosp. 17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c21\"\u003e \u003cp\u003eCV death:1.22 (95% CI: 0.70\u0026ndash;2.12); non-fatal MI: 1.33 (95% CI: 0.82\u0026ndash;2.17); non-fatal stroke: 1.00 (95% CI: 0.56\u0026ndash;1.79); all-cause mortality: 1.20 (95% CI: 0.79\u0026ndash;1.81); HF hosp.: 0.95 (95% CI: 0.48\u0026ndash;1.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c22\"\u003e \u003cp\u003e0.4 (ITCA 650), 0.2 (placebo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c23\"\u003e \u003cp\u003e0.4 (ITCA 650), 0.1 (placebo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c24\"\u003e \u003cp\u003eNausea\u0026thinsp;\u0026minus;\u0026thinsp;20.6 (ITCA 650), 3.6 (placebo); Vomiting\u0026thinsp;\u0026minus;\u0026thinsp;13.5 (ITCA 650), 1.2 (placebo); diarrhoea\u0026thinsp;\u0026minus;\u0026thinsp;7.8 (ITCA 650), 3.5 (placebo)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSELECT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17604\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8803\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8801\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;45 year old; pre-existing CVD and BMI\u0026thinsp;\u0026ge;\u0026thinsp;27; no history of diabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSemaglutide S/C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.4mg once weekly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e5.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;75 previous MI; ~25 chronic HF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eCause-specific HRs and 95% CI using Cox proportional hazards model with randomised assignment (semaglutide or placebo) as fixed factor. One-sided P values from score test.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eComposite cardiovascular events (CV death, MI, stroke)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e569\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e701\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cp\u003e0.80 (95% CI: 0.72\u0026ndash;0.90); P\u0026thinsp;\u0026lt;\u0026thinsp;0.001 noninferiority; P\u0026thinsp;=\u0026thinsp;0.046 superiority\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cp\u003eCV death, HF, all- cause death, non-fatal MI, non-fatal stroke, HF hosp.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cp\u003ecvs death: 223; HF: 300; all-cause death: 375; non-fatal MI: 234; non-fatal stroke: 154; HF hosp.: 109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c20\"\u003e \u003cp\u003ecvs death: 262; HF: 361; all-cause death: 458; non-fatal MI: 322; non-fatal stroke: 165; HF hosp.: 122\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c21\"\u003e \u003cp\u003eCV death: 0.85 (95% CI: 0.71\u0026ndash;1.01; P\u0026thinsp;=\u0026thinsp;0.07), HF: 0.82 (95% CI: 0.71\u0026ndash;0.96), all-cause death: 0.81 (95% CI: 0.71\u0026ndash;0.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c22\"\u003e \u003cp\u003eNot recorded\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c23\"\u003e \u003cp\u003e0.2 (semaglutide), 0.3 (placebo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c24\"\u003e \u003cp\u003e10.0 (semaglutide), 2.0 (placebo)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSOUL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9650\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4825\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4825\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;50 years old, had T2DM with a glycated Hb level 6.5\u0026ndash;10.0%, atherosclerotic CV disease, CKD, or both\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSemaglutide Oral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eOnce daily 14mg max dose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e28.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eCox proportional-hazards model with randomized group assignment as a fixed factor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eMACE (death from CV causes, nonfatal MI, or nonfatal stroke), assessed in a time-to-first-event analysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e579\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e668\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cp\u003e0.86; 95% confidence interval, 0.77 to 0.96; P\u0026thinsp;=\u0026thinsp;0.006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cp\u003eCV death, MI, Stroke, All cause death, HF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cp\u003eCV death: 301; MI: 200; stroke: 164; all-cause death: 528; HF: 146\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c20\"\u003e \u003cp\u003eCV death: 320; MI: 268; stroke: 171; all-cause death: 577; HF: 167\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c21\"\u003e \u003cp\u003eCV death: 0.93 (95% CI: 0.80\u0026ndash;1.09), MI: 0.73 (95% CI: 0.61\u0026ndash;0.88), stroke: 0.95 (95% CI: 0.76\u0026ndash;1.17), all-cause death: 0.91 (95% CI: 0.80\u0026ndash;1.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c22\"\u003e \u003cp\u003e1.6 (semaglutide), 1.7 (placebo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c23\"\u003e \u003cp\u003e0.4 (semaglutide), 0.4 (placebo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c24\"\u003e \u003cp\u003e5.0 (semaglutide), 4.4 (placebo)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTwo reviewers (KP and OR) independently extracted the data. Discrepancies were resolved through discussion and referral to third person (SCC) as necessary. Results were grouped according to primary and secondary outcomes. A narrative synthesis was conducted to summarise findings across studies. Statistical analysis was conducted using Stata version 18 statistical software. Hazard Ratio (HR) with 95% CI were used to assess the outcomes between the two treatment groups. Heterogeneity was assessed using chi-squared tests as well as I-squared test. Forest plots are used to represent the results generated from the random-effects meta-analysis graphically. The pooled HR and the degree of heterogeneity are presented. Publication bias was minimised by comprehensive literature searching.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eRisk of Bias and Quality Assessment\u003c/h2\u003e \u003cp\u003e The quality of each included study and outcomes was independently assessed by reviewers (KP and OR) Discrepancies were resolved through discussion and referral to third person (SCC) as necessary. The Cochrane Risk of Bias 2 (RoB2) tool (Sterne et al, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2019\u003c/span\u003e) was used to evaluate bias across five domains: randomisation process, deviations from the intended interventions, missing outcome data, measurement of the outcome and selection of the reported result. Each study was assigned a risk of bias rating of \u0026lsquo;low risk\u0026rsquo;, \u0026lsquo;some concerns\u0026rsquo; or \u0026lsquo;high risk\u0026rsquo; in each domain and an overall rating.\u003c/p\u003e \u003cp\u003eThe overall rating for risk of bias obtained through the RoB2 tool was included as part of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach (Sch\u0026uuml;nemann et al, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). The GRADE approach assessed the quality of the evidence for each outcome across five domains: risk of bias, inconsistency, indirectness, imprecision and publication bias. Each outcome was rated as very low, low, moderate and high certainty. A detailed summary of findings table was constructed to present the quality of evidence across the included outcomes and studies [Supplementary Appendix C].\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eStudy Selection\u003c/h2\u003e \u003cp\u003eA total of 645 studies were identified through database searches in PubMed, Ovid and The Cochrane Library. After removing duplicates and screening the titles and abstracts of these studies, 49 full-text studies were assessed for eligibility. Following this, 11 studies met the inclusion criteria and data extracted for the systematic review. A PRISMA flow diagram (Page et al, 2021) illustrating the selection process can be found in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eStudy Characteristics\u003c/h2\u003e \u003cp\u003eThe included studies were published between 2016 and 2025, with sample sizes ranging from 3183 and 17604 participants. All eleven studies were randomised placebo-controlled trials investigating GLP-1 receptor agonists in adults with high cardiovascular risk. Drugs investigated across these studies include: Liraglutide (n\u0026thinsp;=\u0026thinsp;1); Lixisenatide (n\u0026thinsp;=\u0026thinsp;1); Semaglutide (n\u0026thinsp;=\u0026thinsp;4); Exenatide (n\u0026thinsp;=\u0026thinsp;1); Albiglutide (n\u0026thinsp;=\u0026thinsp;1); Dulaglutide (n\u0026thinsp;=\u0026thinsp;1); Efpeglenatide (n\u0026thinsp;=\u0026thinsp;1).\u003c/p\u003e \u003cp\u003eThe COX proportional hazards model was used by all eleven studies to determine the effect of the intervention on the outcome and to estimate hazard ratios and 95% confidence intervals. All studies are cardiovascular outcome trials (CVOTs) and reported on MACE as their primary outcomes. The studies reported on secondary outcomes, including all-cause mortality, fatal and non-fatal myocardial infarction (MI) and stroke, as well as hospitalisation for heart failure. Adverse events were also reported, including acute pancreatitis, severe hypoglycaemia and gastrointestinal side effects. A detailed summary of study characteristics is presented in a data extraction table [Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes\u003c/h2\u003e \u003cp\u003eThe primary outcome, MACE, was reported in 11 studies with statistically significant reduction in MACE observed in 7 of the 11 studies. Three studies, ELIXA (Pfeffer et al, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2015\u003c/span\u003e), ITCA 650 (Ruff et al, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2021\u003c/span\u003e) and PIONEER-6 (Husain et al, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2019\u003c/span\u003e) trials, were identified as non-significant for superiority but met criteria for non-inferiority (P values: \u0026lt;0.001; 0.004; \u0026lt;0.001, respectively). One study, the EXSCEL trial, reported a borderline result for superiority (HR 0.91 (95% Cl: 0.83-1.00); P\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for non-inferiority; P\u0026thinsp;=\u0026thinsp;0.06 for superiority). In the meta-analysis, there are 91,490 patients with 4386 events in the intervention group and 4884 events in the placebo group. The mean duration of follow-up in the studies was 2.7 years. The HR (95%CI) for MACE is 0.87 (0.81\u0026ndash;0.92) in favour of GLP-1 receptor agonists [Figure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e4\u003c/span\u003e]. Secondary outcomes included cardiovascular mortality, all-cause mortality, non-fatal myocardial infarction (MI) and stroke, as well as hospitalisation for heart failure.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eCardiovascular mortality was observed in 9 of the 11 studies. Two studies, LEADER (Marso et al, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2016\u003c/span\u003e) and PIONEER-6, reported a statistically significant reduction in cardiovascular mortality (HR (95%CI): 0.78 (0.66\u0026ndash;0.93); 0.49 (0.27\u0026ndash;0.92) respectively). Six studies, SUSTAIN-6 (Marso et al, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2016\u003c/span\u003e), HARMONY Outcomes (Thorpe et al, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2018\u003c/span\u003e), REWIND (Basile et al, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2019\u003c/span\u003e), AMPLITUDE-O (Gerstein et al, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2021\u003c/span\u003e), SELECT (Lincoff et al, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2023\u003c/span\u003e) and SOUL (McGuire et al, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2025\u003c/span\u003e), showed non-significant trends toward benefit with hazard ratios close to 1 and confidence intervals that crossed 1 (HR (95%CI): 0.98 (0.65\u0026ndash;1.48); 0.93 (0.73\u0026ndash;1.19); 0.91 (0.78\u0026ndash;1.06); 0.72 (0.50\u0026ndash;1.03); 0.85 (0.71\u0026ndash;1.01); 0.93 (0.80\u0026ndash;1.09) respectively). One study, ITCA 650, reported a non-significant potential increase in cardiovascular mortality (1.22 (95% CI:0.70\u0026ndash;2.12)).\u003c/p\u003e \u003cp\u003eAll-cause mortality was reported in 8 of the 11 studies. Three studies, LEADER, PIONEER-6 and SELECT, demonstrated a statistically significant reduction in all-cause mortality (HR (95%CI): 0.85(0.74\u0026ndash;0.97); 0.51 (0.31\u0026ndash;0.84); 0.81 (0.71\u0026ndash;0.93) respectively). Four studies, ELIXA, REWIND, AMPLITUDE-O and SOUL, indicated non-significant trends toward benefit with hazard ratios close to 1 and confidence intervals that crossed 1 (HR (95%CI): 0.94 (0.78\u0026ndash;1.13); 0.90 (0.80\u0026ndash;1.01); 0.78 (0.58\u0026ndash;1.06); 0.91 (0.80\u0026ndash;1.02) respectively). One study, ITCA 650, reported a non-significant potential increase in all-cause mortality (HR 1.20 (95% CI: 0.79\u0026ndash;1.81)).\u003c/p\u003e \u003cp\u003eNon-fatal MI was reported in 8 of the 11 studies. Two studies, HARMONY Outcomes and SOUL, reported a statistically significant reduction in non-fatal MI (HR (95%CI): 0.75 (0.61\u0026ndash;0.90); 0.73 (0.61\u0026ndash;0.88) respectively). Four studies, SUSTAIN-6, EXSCEL, REWIND and AMPLITUDE-O, reported non-significant trends toward benefit with hazard ratios close to 1 and confidence intervals that crossed 1 (HR (95%CI): 0.74 (0.51\u0026ndash;1.08); 0.90 (0.75\u0026ndash;1.08); 0.96 (0.79\u0026ndash;1.16); 0.78 (0.55\u0026ndash;1.10) respectively). Two studies, PIONEER-6 and ITCA 650, revealed a non-significant increase in non-fatal MI (HR (95%CI): 1.18 (0.73\u0026ndash;1.90); 1.33 (0.82\u0026ndash;2.17) respectively).\u003c/p\u003e \u003cp\u003eNon-fatal stroke was reported in 8 of the 11 studies. Two studies, SUSTAIN-6 and REWIND, reported a statistically significant reduction in non-fatal stroke (HR (95%CI): 0.61 (0.38\u0026ndash;0.99); 0.76 (0.61\u0026ndash;0.95) respectively). Five studies, EXSCEL, HARMONY Outcomes, PIONEER-6, AMPLITUDE-O and SOUL, reported non-significant trends toward benefit with hazard ratios close to 1 and confidence intervals that crossed 1 (HR (95%CI): 0.90 (0.75\u0026ndash;1.08); 0.86 (0.66\u0026ndash;1.14); 0.74 (0.35\u0026ndash;1.57); 0.80 (0.48\u0026ndash;1.31); 0.95 (0.76\u0026ndash;1.17) respectively). One study, ITCA 650, showed a non-significant increase in non-fatal stroke (HR 1.00 (95% CI: 0.56\u0026ndash;1.79)).\u003c/p\u003e \u003cp\u003eHospitalisation for heart failure was reported in 5 of the 11 studies. Two studies, AMPLITUDE-O and SELECT, reported a statistically significant reduction in hospitalisation for heart failure (HR (95%CI): 0.61 (0.38\u0026ndash;0.98); 0.82 (0.71\u0026ndash;0.96) respectively). Three studies, ELIXA, EXSCEL and ITCA 650, reported non-significant trends toward benefit with hazard ratios close to 1 and confidence intervals that crossed 1 (HR (95%CI): 0.96 (0.75\u0026ndash;1.23); 0.99 (0.79\u0026ndash;1.24); 0.95 (0.48\u0026ndash;1.88) respectively.\u003c/p\u003e \u003cp\u003eThe meta-analysis shows that use of GLP-1 receptor agonists was associated with a reduction of the outcomes (HR (95%CI): 0.87 (0.81\u0026ndash;0.94) for all-cause mortality; 0.87 (0.80\u0026ndash;0.94) for CV death, 0.88 (0.77\u0026ndash;0.99) for HF hospitalization, 0.85 (0.76\u0026ndash;0.96) for non-fatal MI and 0.85 (0.77\u0026ndash;0.95) for non-fatal stroke, [Supplementary Appendix D].\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eAdverse effects included\u003c/strong\u003e \u003cp\u003e \u003cem\u003eSevere hypoglycaemia, acute pancreatitis and Gastrointestinal side effects.\u003c/em\u003e \u003c/p\u003e \u003c/p\u003e \u003cp\u003eSevere hypoglycaemia was investigated in ten of out eleven studies. One study (SELECT) did not report this. When expressed as absolute risk differences (ARD), the rates of severe hypoglycaemia with intervention groups compared against placebo groups ranged from \u0026minus;\u0026thinsp;0.9% (LEADER) to +\u0026thinsp;0.9% (SUSTAIN-6), with most studies showing negligible differences (\u0026ndash;0.3% to +\u0026thinsp;0.2%). Four of the ten studies identified higher rates of severe hypoglycaemia compared to the placebo group (SUSTAIN-6, EXSCEL, PIONEER-6, ITCA 650). Five of the ten studies reported to have lower rates of severe hypoglycaemia compared to the placebo group (LEADER, ELIXA, REWIND, AMPLITUDE-O, SOUL). One study found no difference between the intervention and placebo groups (HARMONY outcomes). This suggests that the use of GLP-1 RAs does not materially increase the risk of severe hypoglycaemia, in contrast to concerns raised for other glucose-lowering therapies. Similarly, for acute pancreatitis, absolute risk differences reported in cardiovascular outcome trials are typically\u0026thinsp;\u0026lt;\u0026thinsp;0.1%, indicating no consistent excess risk compared with placebo.\u003c/p\u003e \u003cp\u003eAcute pancreatitis was reported in all eleven studies. Across these studies, the ARD for pancreatitis between the intervention and placebo groups were minimal, ranging from \u0026minus;\u0026thinsp;0.2% (SUSTAIN-6) to +\u0026thinsp;0.3% (ITCA 650). The event rates were consistently below 1%, with no statistically significant risk identified. Three of the eleven studies reported higher rates of acute pancreatis in the intervention group compared to the placebo group (EXSCEL, REWIND, ITCA 650). Six of the eleven studies reported lower rates of acute pancreatitis in the intervention group compared to the placebo group (LEADER, ELIXA, SUSTAIN-6, PIONEER-6, AMPLITUDE-O, SELECT). Two of the eleven studies reported no difference between the groups (HARMONY outcomes, SOUL). These findings reinforce that while pancreatitis has been a theoretical concern, the clinical evidence demonstrates that GLP-1 RAs do not confer a meaningful increase in risk compared with placebo.\u003c/p\u003e \u003cp\u003eGastrointestinal side effects were reported in ten of eleven studies. One study did not report gastrointestinal effects (EXSCEL). When expressed as ARD, the intervention group was consistently associated with a higher incidence of gastrointestinal side effects compared to the placebo group. The differences ranged from +\u0026thinsp;0.6% (SOUL) to +\u0026thinsp;17% (SUSTAIN-6; nausea in ITCA 650). ITCA 650 reported statistically significant increased risk of the gastrointestinal side effects: nausea (+\u0026thinsp;17%), vomiting (+\u0026thinsp;12.3%) and diarrhoea (+\u0026thinsp;4.3%). Two of the eleven studies, with ARD values greater than 10%, found stronger evidence for higher rates of gastrointestinal side effects in the intervention group compared against the placebo group (SUSATAIN-6, REWIND). Five of the eleven studies reported, with ARD values less than 10%, reported statistically significant increased incidence of gastrointestinal side effects in the intervention group compared against the placebo group (LEADER, ELIXA, PIONEER-6, AMPLITUDE-O, SELECT). One study reported less statistically significant higher rates of gastrointestinal side effects in the intervention group compared against the placebo group (SOUL). One study showed no differences between the two groups (HARMONY outcomes). These findings confirm that while the GLP-1 RAs does not materially increase rare adverse events such as pancreatitis and severe hypoglycaemia, gastrointestinal side effects represent a predictable and clinically relevant class effect that often limits tolerability.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eRisk of Bias\u003c/h2\u003e \u003cp\u003eTen of eleven studies were judged to be at low risk of bias across all RoB2 (Sterne et al, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2019\u003c/span\u003e) domains, including randomisation and allocation (D1), deviations from intervention (D2), missing outcome data (D3), measurement of outcome (D4) and selection of reported results (D5). One study (ITCA 650) reported as \u0026lsquo;some concerns\u0026rsquo; overall due to risk of bias in D2 due to concerns regarding the implantable device affecting the blinding of the procedure, which may have influenced how the intervention was administered. This has been illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eCertainty of Evidence\u003c/h2\u003e \u003cp\u003eAll primary and secondary outcomes were judged to have high certainty of evidence across all GRADE approach (Sch\u0026uuml;nemann et al, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2013\u003c/span\u003e) domains, including risk of bias (D1), inconsistency (D2), indirectness (D3), imprecision (D4), publication bias (D5). As ITCA 650 contributed minimally to the pooled estimate, its potential bias did not materially affect the overall assessment. Therefore, D1 was judged as \u0026lsquo;high certainty\u0026rsquo; overall for each outcome. This has been illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eDespite recent advancements in cardiovascular prevention and treatment, cardiovascular disease remains the leading cause of death worldwide, especially amongst high-risk populations such as those with type 2 diabetes and/or hypertension (WHO, 2025). The persistently elevated risk amongst these trial populations demonstrates the limitations of current management strategies and highlights the need for new and improved therapies that can address the link between metabolic disease and direct cardiovascular pathology.\u003c/p\u003e \u003cp\u003eThe results of this systematic review and meta-analysis demonstrate that glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce the risk of major adverse cardiovascular events (MACE). The benefits of these drugs likely extend beyond their current use in the treatment of diabetes and obesity as a way to manage glycaemic control, as reductions were observed even in populations with near target HbA1c at baseline. GLP-1RAs therefore function as a dual-action therapy; lowering metabolic risk factors such as type 2 diabetes and hyperglycaemia, whilst also generating cardiovascular benefits that cannot solely be explained by the metabolic effects alone.\u003c/p\u003e \u003cp\u003eResearch involving preclinical and translational studies provides plausible explanations for the cardiovascular effects observed in the trials analysed in our meta-analysis. GLP-1 receptors have been identified within myocardial tissue and autonomic centres (McLean et al, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2022\u003c/span\u003e, Baggio et al, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2018\u003c/span\u003e, Cork et al, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2015\u003c/span\u003e), with murine studies demonstrating effects on heart rate, endothelial function and regulation of the autonomic nervous system (Baggio et al, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2017\u003c/span\u003e, Holt et al, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2020\u003c/span\u003e, Gaspari et al, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). These effects work alongside indirect benefits including weight loss, reduced blood pressure and improved lipid metabolism, which in turn may enhance protection against atherosclerotic disease. These combined direct and indirect effects provide a rationale for the observed reduction of MACE in our meta-analysis.\u003c/p\u003e \u003cp\u003eOur meta-analysis confirms a significant reduction in MACE, consistent with lower cardiovascular and all-cause mortality with the introduction of GLP-1 RAs. While several studies demonstrated non-significant or borderline effects on endpoints such as myocardial infarction, stroke or cardiovascular death, pooling the data revealed significant reductions in MACE and all-cause mortality. The combined evidence from various trials also demonstrated a consistent benefit across various trial designs, drug formulations and patient populations, supporting the conclusion that cardiovascular benefit is not an isolated finding but rather an effect seen by the class of drug.\u003c/p\u003e \u003cp\u003eSafety is a critical factor to consider when evaluating long-term cardiometabolic therapies. Evidence from the cardiovascular outcome trials included in our review consistently demonstrates that GLP-1 RAs do not increase the risk of severe hypoglycaemia or acute pancreatitis. These findings directly address the long-standing safety concerns that have been raised regarding this drug class. The incidence of severe hypoglycaemia was minimal and did not change substantially from placebo, indicating the glucose-dependent mechanism of GLP-1 RAs, in contrast to the increased risk linked to insulin and sulfonylureas. Likewise, while pancreatitis has been a theoretical concern, trial data has consistently shown that the occurrence rates are very low (\u0026lt;\u0026thinsp;1%) and there is no significant increase in risk compared to placebo. (Marso et al, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2016\u003c/span\u003e, Gerstein et al, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2021\u003c/span\u003e, Ussher \u0026amp; Drucker, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2023\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eConversely, patients receiving GLP-1 RAs were consistently more likely to report experiencing gastrointestinal side effects. The predominant complaints were nausea, vomiting and diarrhoea; in some trials, the incidence was more than 10% higher compared to placebo. (Marso et al, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). These adverse effects are well-recognised class-specific reactions that may restrict tolerance and adherence in clinical practice. To maximise the cardiovascular benefits of GLP-1 RAs at a population level, strategies can be used to improve tolerability, such as patient counselling, gradual dose escalation and the use of long-acting formulations (Nauck \u0026amp; Meier, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Overall, GLP-1 RAs have a favourable safety profile, with benefits that significantly outweigh their manageable side effects.\u003c/p\u003e \u003cp\u003eLooking ahead, the accumulating body of evidence supporting the cardiovascular benefits of GLP-1 RAs highlights the need to integrate them more widely into routine clinical practice. These therapies should be regarded as key components of larger cardiovascular risk reduction strategies, especially for patients with established heart disease or Type II Diabetes, in addition to being used as treatments for glycaemic control. High-risk individuals may receive more long-term cardiovascular protection if GLP-1 RAs are initiated earlier. Additional cardiovascular benefits may be provided by combination therapy with other antidiabetic medications, such as SGLT2 inhibitors. Overcoming barriers such as availability, affordability and clinical awareness could broaden implementation in clinical practice. Incorporating GLP-1 RAs into standard treatment pathways has the potential to substantially lower cardiovascular morbidity and mortality among high-risk populations.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThere is no funding associated with this article.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eKP, OR, ES and MW conceptualised the project, produced the methodology analysed the data and drafted the manuscriptJZ undertook the meta analysisSCC supervised the project and drafted the manuscriptAll authors agreed to the final manuscript\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eAll data is available in the manuscript and associated supplementary files.\u003c/p\u003e\u003ch2\u003eEthics and Consent to Participate declarations:\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003enot applicable\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAlfaris, N., Waldrop, S., Johnson, V., Boaventura, B., Kendrick, K. \u0026amp; Stanford, F.C. 2024, \u0026quot;GLP-1 single, dual, and triple receptor agonists for treating type 2 diabetes and obesity: a narrative review\u0026quot;, \u003cem\u003eEClinicalMedicine, \u003c/em\u003evol. 75. \u003c/li\u003e\n\u003cli\u003eBaggio LL, Ussher JR, McLean BA, Cao X, Kabir MG, Mulvihill EE, Mighiu AS, Zhang H, Ludwig A, Seeley RJ, Heximer SP, Drucker DJ. 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Glucagon-like Peptide-1 receptor Tie2+ cells are essential for the cardioprotective actions of liraglutide in mice with experimental myocardial infarction. \u003cem\u003eMolecular metabolism\u003c/em\u003e, \u003cem\u003e66\u003c/em\u003e, 101641. https://doi.org/10.1016/j.molmet.2022.101641 \u003c/li\u003e\n\u003cli\u003eNational Institute for Health and Care Excellence (2023) Cardiovascular disease: risk assessment and reduction, including lipid modification. Available at: https://www.nice.org.uk/guidance/ng238 [Accessed 12 May 2025] \u003c/li\u003e\n\u003cli\u003eNauck MA, Meier JJ. MANAGEMENT OF ENDOCRINE DISEASE: Are all GLP-1 agonists equal in the treatment of type 2 diabetes? Eur J Endocrinol. 2019 Dec;181(6):R211-R234. doi: 10.1530/EJE-19-0566. PMID: 31600725. \u003c/li\u003e\n\u003cli\u003ePage, M.J., McKenzie, J.E., Bossuyt, P.M., Boutron, I., Hoffmann, T.C., Mulrow, C.D., Shamseer, L., Tetzlaff, J.M., Akl, E.A., Brennan, S.E., Chou, R., Glanville, J., Grimshaw, J.M., Hr\u0026oacute;bjartsson, A., Lalu, M.M., Li, T., Loder, E.W., Mayo-Wilson, E., McDonald, S., McGuinness, L.A., Stewart, L.A., Thomas, J., Tricco, A.C., Welch, V.A., Whiting, P. and Moher, D., 2021. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ, [e-journal] 372, pp.n71\u0026ndash;n71. 10.1136/bmj.n71. \u0026lt;https://bmj.com/content/372/bmj.n71.full\u0026gt;. \u003c/li\u003e\n\u003cli\u003ePfeffer, M.A., Claggett, B., Diaz, R., Dickstein, K., Gerstein, H.C., K\u0026oslash;ber, L.V., Lawson, F.C., Ping, L., Wei, X., Lewis, E.F., Maggioni, A.P., McMurray, J.J.V., Probstfield, J.L., Riddle, M.C., Solomon, S.D. and Tardif, J., 2015. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. 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Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. The Lancet, [e-journal] 392 (10157), pp.1519\u0026ndash;1529. 10.1016/s0140-6736(18)32261-x. \u003c/li\u003e\n\u003cli\u003eUssher, J.R. and Drucker, D.J. (2023) \u0026apos;Glucagon-like peptide 1 receptor agonists: cardiovascular benefits and mechanisms of action\u0026apos;, Nature Reviews Cardiology, 20(7), pp. 463\u0026ndash;474 Available at: 10.1038/s41569-023-00849-3.[ Accessed 12 May 2025] \u003c/li\u003e\n\u003cli\u003eWorld Health Organisation (2025) Cardiovascular Diseases. Available at: https://www.who.int/health-topics/cardiovascular-diseases#tab=tab_1 [Accessed 11 May 2025] \u003c/li\u003e\n\u003cli\u003eYang, H., Qinghua, M., Han, L. \u0026amp; Liu, H. 2025, \u0026quot;A global prediction of cardiovascular disease from 2020 to 2030\u0026quot;, \u003cem\u003eFrontiers in Cardiovascular Medicine, \u003c/em\u003evol. 12, pp. 1462705 \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":false,"email":"","identity":"cardiovascular-diabetology-endocrinology-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Cardiovascular Diabetology – Endocrinology Reports","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"Unsupported Journal","inReviewEnabled":false,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8788582/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8788582/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for the management of type 2 diabetes and obesity, yet their long-term cardiovascular effects in high-risk populations continue to be actively evaluated. Given emerging evidence of both metabolic and direct cardiovascular actions, a comprehensive synthesis of cardiovascular outcome trial data is required to clarify the efficacy and safety of this drug class.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a systematic review and meta-analysis of randomised, placebo-controlled cardiovascular outcome trials evaluating GLP-1RAs in adults at high cardiovascular risk. Searches of PubMed, Embase (via OVID), and the Cochrane Library were performed for studies published between January 2015 and May 2025, in accordance with PRISMA 2020 guidelines. Eligible trials included\u0026thinsp;\u0026ge;\u0026thinsp;3,000 participants with a minimum follow-up of 12 months. The primary outcome was major adverse cardiovascular events (MACE). Secondary outcomes included cardiovascular mortality, all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, hospitalisation for heart failure, and adverse events. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using random-effects meta-analysis. Risk of bias was assessed using the Cochrane RoB 2 tool, and certainty of evidence was evaluated using GRADE.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eEleven cardiovascular outcome trials comprising 91,490 participants were included, with a mean follow-up of 2.7 years. GLP-1RA treatment was associated with a significant reduction in MACE compared with placebo (HR 0.87, 95% CI 0.81\u0026ndash;0.92). Meta-analysis also demonstrated significant reductions in cardiovascular mortality, all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, and hospitalisation for heart failure. GLP-1RAs did not materially increase the risk of severe hypoglycaemia or acute pancreatitis, while gastrointestinal adverse effects were consistently more frequent.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eGLP-1 receptor agonists significantly reduce major cardiovascular events and mortality in high-risk populations, with a favourable long-term safety profile. These findings support the broader integration of GLP-1RAs into cardiovascular risk reduction strategies beyond glycaemic control.\u003c/p\u003e","manuscriptTitle":"The long-term cardiovascular safety and efficacy of glucagon-like peptide-1 (GLP-1) receptor agonists in high-risk cardiovascular populations: A systematic review and meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-11 16:44:17","doi":"10.21203/rs.3.rs-8788582/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-17T13:53:04+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-17T06:07:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-14T09:29:20+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-08T16:02:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"120983368877722326502225317392021394641","date":"2026-02-06T15:05:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"220412623460795455792935845307298902276","date":"2026-02-06T14:45:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"267023632464364633202563363477528601549","date":"2026-02-06T14:10:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"186833301398204374192953154609336773514","date":"2026-02-06T13:30:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"160293095120618440638015467285016054397","date":"2026-02-06T13:25:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"141428114841746163588375441595275349914","date":"2026-02-06T13:19:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"60328238697742825318838813841619682050","date":"2026-02-06T12:55:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"295086785394368906146831922184756768847","date":"2026-02-06T12:43:24+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-06T12:18:18+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-06T11:04:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-06T10:57:05+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cardiovascular Diabetology – Endocrinology Reports","date":"2026-02-04T15:50:43+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":false,"email":"","identity":"cardiovascular-diabetology-endocrinology-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Cardiovascular Diabetology – Endocrinology Reports","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"Unsupported Journal","inReviewEnabled":false,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"41ec07f5-296b-4ade-8580-d5944770d7a7","owner":[],"postedDate":"February 11th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-05-04T16:05:28+00:00","versionOfRecord":{"articleIdentity":"rs-8788582","link":"https://doi.org/10.1186/s40842-026-00295-3","journal":{"identity":"cardiovascular-diabetology-endocrinology-reports","isVorOnly":false,"title":"Cardiovascular Diabetology – Endocrinology Reports"},"publishedOn":"2026-05-01 15:57:13","publishedOnDateReadable":"May 1st, 2026"},"versionCreatedAt":"2026-02-11 16:44:17","video":"","vorDoi":"10.1186/s40842-026-00295-3","vorDoiUrl":"https://doi.org/10.1186/s40842-026-00295-3","workflowStages":[]},"version":"v1","identity":"rs-8788582","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8788582","identity":"rs-8788582","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}