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Effects of glucagon-like peptide-1 receptor agonists on cardiovascular outcomes in high-risk type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials

Diabetology & Metabolic Syndrome volume 16, Article number: 251 (2024) Cite this article

Abstract

Background

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been shown to provide cardiovascular benefits in patients with type 2 diabetes mellitus (T2DM). However, their cardiovascular protective efficacy in high-risk T2DM patients, particularly those with a history of cardiovascular events or severe chronic kidney disease, remains uncertain.

Methods

A comprehensive search was conducted in PubMed, Embase, Web of Science, and The Cochrane Library to identify randomized controlled trials (RCTs) that evaluated the effects of GLP-1 RAs on cardiovascular outcomes in high-risk patients with T2DM. A random-effects model was used to calculate pooled hazard ratios (HRs) for cardiovascular outcomes. Subgroup analyses and GRADE assessment were also performed.

Results

Nine RCTs involving 63,613 patients were included. GLP-1 RAs significantly reduced the risk of the primary composite outcome (HR: 0.86, 95% CI: 0.80–0.92), cardiovascular death (HR: 0.85, 95% CI: 0.78–0.93), all-cause death (HR: 0.87, 95% CI: 0.82–0.93), myocardial infarction (HR: 0.90, 95% CI: 0.82–0.98), stroke (HR: 0.85, 95% CI: 0.77–0.95), and heart failure (HF) hospitalization (HR: 0.90, 95% CI: 0.83–0.97). No significant difference in unstable angina (UA) hospitalization was observed (HR: 1.04, 95% CI: 0.95–1.15). Subgroup analyses indicated greater benefits with combination therapy, particularly in patients with chronic kidney disease. The quality of evidence was rated as “High” for six outcomes and “Moderate” for UA hospitalization.

Conclusions

GLP-1 RAs significantly reduce cardiovascular risk in high-risk T2DM patients, especially with combination therapy and in those with chronic kidney disease. However, further research is needed to confirm their long-term effects.

Introduction

Type 2 diabetes mellitus (T2DM) is a highly common chronic metabolic disease globally, with its incidence and prevalence rapidly increasing [1]. T2DM is not only characterized by hyperglycemia but also by a significant risk of cardiovascular disease. Cardiovascular complications, including myocardial infarction, heart failure, and stroke, are the leading causes of death among patients with T2DM [2, 3]. While controlling blood glucose levels is crucial for these high-risk patients, it has limited effectiveness in reducing cardiovascular events, highlighting the need for additional therapeutic strategies [4, 5].

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a novel class of antidiabetic agents that have gained considerable attention for their dual role in managing T2DM. These agents markedly enhance glycemic control by boosting insulin secretion, reducing glucagon release, and slowing gastric emptying [6, 7]. Additionally, emerging evidence suggests that GLP-1 RAs offer unique cardiovascular protective effects, potentially slowing the progression of cardiovascular disease through mechanisms such as improving endothelial function, exerting anti-inflammatory effects, and reducing blood pressure [8].

Several meta-analyses have evaluated the effect of GLP-1 RAs on cardiovascular outcomes in the general or low-to-moderate risk T2DM population [9,10,11]. However, the effects of GLP-1 RAs on cardiovascular outcomes in high-risk T2DM patients—particularly those with a history of cardiovascular events or severe chronic kidney disease—remain insufficiently studied. Given the pre-existing cardiovascular or renal damage in these patients, their need for cardiovascular protective therapies is more urgent, and their response to GLP-1 RAs may differ.

This study systematically reviewed and performed a meta-analysis to assess the effect of GLP-1 RAs on cardiovascular outcomes in patients with high-risk T2DM. We integrated data from all published RCTs to determine the efficacy of these agents in reducing cardiovascular events and mortality. Confirming the cardiovascular protective effects of these drugs in high-risk T2DM patients could have significant implications for clinical management, potentially altering treatment strategies and improving long-term prognosis for these patients.

Methods

Protocol registration

This meta-analysis adhered to the Cochrane Handbook and PRISMA 2020 guidelines [12], and was registered prospectively in PROSPERO (CRD42024581477). The PRISMA 2020 checklist is provided in Supplementary Table S1.

Search strategy

A thorough literature search was carried out in PubMed, Embase, Web of Science, and The Cochrane Library up to August 14, 2024. The search strategy was followed the PICOS framework (Population, Intervention, Comparison, Outcome, and Study Design) with keywords including:

For population

“T2DM” AND (“Cardiovascular Diseases” OR “Chronic Kidney Disease”);

For intervention

“glucagon-like peptide-1 receptor agonist” OR “GLP-1 Receptor Agonists” OR “albiglutide,” “dulaglutide,” “efpeglenatide,” “exenatide,” “liraglutide,” “lixisenatide,” and “semaglutide”;

For study design

“randomized controlled trial” OR “RCT” OR “Clinical Trial”.

To avoid missing relevant studies, we did not restrict outcome or comparison keywords. The detailed search strategy is provided in Supplementary Table S2.

Inclusion and exclusion criteria

Studies were selected based on the following PICOS criteria:

  1. (i)

    Population: High-risk patients with T2DM, including those with a history of cardiovascular events (e.g., coronary artery disease, myocardial infarction, stroke, or heart failure) or severe chronic kidney disease, defined as an eGFR < 60 mL/min/1.73 m² or urinary albumin excretion rate > 300 mg/24 hours.

  2. (ii)

    Intervention: GLP-1 RAs used as monotherapy or in combination with other glucose-lowering therapies, including oral hypoglycemic agents and injectable treatments.

  3. (iii)

    Comparison: Placebo, other antidiabetic drugs, or placebo combined with other antidiabetic drugs.

  4. (iv)

    Outcomes: Primary composite outcome, all-cause death, cardiovascular death, myocardial infarction, stroke, HF hospitalization, and UA hospitalization.

  5. (v)

    Study Design: Published randomized controlled trials.

Exclusion criteria included observational studies, reviews, letters, editorials, conference abstracts, case reports, pediatric studies, unpublished articles, and articles not in English. In cases of overlapping populations, we used data from the study with the largest sample size or longest follow-up. No studies were excluded based on follow-up duration or sample size.

Literature screening, data extraction

Two researchers (XMC and XGZ) independently extracted data, resolving discrepancies through discussion or with input from a third author (XX) to achieve consensus. Extracted data included the first author, publication year, country/region, study design, registration number, median study duration, median follow-up time, sample size, age, gender, T2DM duration, baseline comorbidities, type and dosage of GLP-1 RAs, and control type. When continuous variables were presented as medians with ranges or interquartile ranges, we converted them to mean ± standard deviation using validated methods [13].

Outcome definition

The primary composite outcome was defined as the first occurrence of major adverse cardiovascular events, including cardiovascular death (which encompasses deaths from undetermined causes potentially related to cardiovascular events), non-fatal stroke, non-fatal myocardial infarction (including silent myocardial infarction), or UA hospitalization. In addition to the primary composite outcome, the cardiovascular outcomes assessed in this meta-analysis included all-cause death, cardiovascular death, myocardial infarction, stroke, HF hospitalization, and UA hospitalization.

Quality Assessment

We evaluated the study quality using the Cochrane Collaboration’s Risk of Bias tool [14]. This tool assesses seven aspects: random sequence generation, allocation concealment, participant blinding, outcome assessment blinding, incomplete data handling, selective reporting, and other biases. Based on these criteria, studies were classified as having a “low risk of bias,” “unclear risk of bias,” or “high risk of bias.” Two authors independently evaluated the risk of bias, and any disagreements were resolved through discussion with a third author.

Data Analysis

Data were synthesized using Review Manager version 5.4 (Cochrane Collaboration, Oxford, UK). For cardiovascular outcomes, including the primary composite outcome, all-cause death, cardiovascular death, myocardial infarction, stroke, HF hospitalization, and UA hospitalization, effect estimates were reported as HRs with 95% CIs. HRs were selected because they are appropriate for time-to-event data, which are crucial for assessing the long-term impact of GLP-1RAs on cardiovascular outcomes.

Heterogeneity across studies was evaluated using Cochran’s Q test and the I² statistic. Significant heterogeneity was indicated by a p-value below 0.10 for Cochran’s Q or an I² exceeding 50%. Given the potential variability within and between studies, a random-effects model was used to pool the effect estimates.

We conducted sensitivity analyses to test the robustness of the results by systematically excluding studies with a high risk of bias and reanalyzing the pooled effect estimates. Subgroup analyses were also performed to explore potential sources of heterogeneity based on predefined factors, such as intervention type, patient characteristics, control group type, follow-up duration, and sample size.

Funnel plots were created with Review Manager version 5.4, and publication bias was evaluated using Egger’s regression test in Stata version 17.0 MP 64-bit (StataCorp, College Station, TX, USA). Funnel plots were used for visual inspection, and Egger’s test was applied to outcomes with three or more studies. A p-value below 0.05 was interpreted as evidence of significant publication bias.

GRADE Assessment

Evidence quality for each cardiovascular outcome was evaluated using the GRADE system (Grading of Recommendations, Assessment, Development, and Evaluations) [15]. The GRADE system categorizes evidence quality into four levels—High, Moderate, Low, or Very Low—based on study design, risk of bias, consistency, directness, precision, and publication bias.

Results

Literature search and study characteristics

The flowchart detailing the systematic literature search and selection process is presented in Fig. 1. The search identified 3,697 relevant articles across PubMed (n = 338), Embase (n = 2,160), Web of Science (n = 369), and The Cochrane Library (n = 830). After removing duplicates, 2,696 articles remained for title and abstract screening. The full texts of 19 articles were reviewed, resulting in the exclusion of 5 conference abstracts, 1 post-hoc analysis of an RCT, 3 articles with duplicate data, and 1 article that did not fit the population criteria. In total, 9 studies were included in the meta-analysis [16,17,18,19,20,21,22,23,24].

Fig. 1
figure 1

Flowchart of the systematic search and selection process

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Tables 1 and 2 present the characteristics of the included studies and patient populations. All 9 studies were multicenter, randomized, double-blind, controlled trials, encompassing 63,613 patients in total (GLP-1RAs group: 32,461; control group: 31,152). Sample sizes ranged from 3,183 to 14,752 patients, with the average age of participants between 60.1 and 66.6 years. The proportion of male participants ranged from 38 to 70%, and the median follow-up duration ranged from 1.3 to 5.4 years. The GLP-1RAs evaluated included albiglutide, dulaglutide, lixisenatide, liraglutide, semaglutide, exenatide, and efpeglenatide. Among the 9 studies, 1 study incorporated standard treatment for T2DM in both the treatment and control groups [20], and another study included SGLT2 inhibitors in part of the treatment and control groups [22]. The remaining 7 studies were placebo-controlled trials of GLP-1RAs monotherapy.

Table 1 Baseline characteristics of the included studies
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Table 2 Patients’ demographic and clinical characteristics
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Quality Assessment results

The Cochrane Collaboration’s Risk of Bias tool was used to evaluate the bias risk in all included studies. The assessment indicated that all studies had a low risk of bias in key areas, including random sequence generation, allocation concealment, and blinding. Overall, the methodological quality was rated as high (Supplementary Figure S1).

Primary composite outcome

Eight studies, encompassing 60,080 patients in total, were analyzed to evaluate the impact of GLP-1 RAs on the primary composite outcome. During the follow-up period, 3,136 of 30,694 patients in the GLP-1 RAs group (10.2%) experienced a primary composite outcome, compared to 3,443 of 29,386 patients in the control group (11.7%). The forest plot (Fig. 2A) displays the HRs and their 95% CIs for each study. The pooled analysis revealed that GLP-1 RAs notably lowered the risk of the primary composite outcome (HR: 0.86; 95% CI: 0.80–0.92, P < 0.0001), with no significant heterogeneity was detected (I² = 46%, P = 0.08). The funnel plot (Supplementary Figure S2A) and Egger’s test indicated no significant publication bias (P = 0.154).

Fig. 2
figure 2

Forest plot of pooled HRs for cardiovascular outcomes: (A) Primary composite outcome, (B) Cardiovascular death, (C) All-cause death, and (D) Myocardial infarction

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Cardiovascular death

Nine studies, encompassing 63,613 patients in total, were analyzed to evaluate the impact of GLP-1 RAs on cardiovascular death. During the follow-up period, 1,413 of 32,461 patients in the GLP-1 RAs group (4.4%) experienced cardiovascular death, compared to 1,588 of 31,152 patients in the control group (5.1%). The forest plot (Fig. 2B) displays the HRs and their 95% CIs for each study. The pooled analysis demonstrated that GLP-1 RAs significantly reduced cardiovascular death risk (HR: 0.85; 95% CI: 0.78–0.93, P = 0.0002), with no significant heterogeneity detected (I² = 26%, P = 0.22). Funnel plot analysis (Supplementary Figure S2B) and Egger’s test indicated no significant publication bias (P = 0.293).

All-cause death

Nine studies, encompassing 63,613 patients in total, were analyzed to assess the effect of GLP-1 RAs on all-cause death. During the follow-up period, 2,266 of 32,461 patients in the GLP-1 RAs group (7.0%) experienced all-cause death, compared to 2,456 of 31,152 patients in the control group (7.9%). The forest plot (Fig. 2C) displays the HRs and their 95% CIs for each study. The pooled analysis demonstrated that GLP-1 RAs significantly reduced the risk of all-cause death (HR: 0.87; 95% CI: 0.82–0.93, P < 0.00001), with no significant heterogeneity detected (I² = 10%, P = 0.35). Analysis using the funnel plot (Supplementary Figure S2C) and Egger’s test showed no significant publication bias (P = 0.410).

Myocardial infarction

Nine studies, encompassing 63,613 patients in total, were analyzed to assess the effect of GLP-1 RAs on myocardial infarction. During the follow-up period, 1,667 of 32,461 patients in the GLP-1 RAs group (5.1%) experienced myocardial infarction, compared to 1,790 of 31,152 patients in the control group (5.8%). The forest plot (Fig. 2D) displays the HRs and their 95% CIs for each study. The pooled analysis demonstrated that GLP-1 RAs significantly reduced myocardial infarction risk (HR: 0.90; 95% CI: 0.82–0.98, P = 0.02), with no notable heterogeneity observed (I² = 28%, P = 0.19). Funnel plot analysis (Supplementary Figure S2D) and Egger’s test showed no significant publication bias (P = 0.350).

Stroke

Nine studies, encompassing 63,613 patients in total, were analyzed to evaluate the impact of GLP-1 RAs on stroke. During the follow-up period, 821 of 32,461 patients in the GLP-1 RAs group (2.5%) experienced a stroke, compared to 939 of 31,152 patients in the control group (3.0%). The forest plot (Fig. 3A) displays the HRs and their 95% CIs for each study. Pooled analysis revealed that GLP-1 RAs significantly lowered stroke risk (HR: 0.85; 95% CI: 0.77–0.95, P = 0.003), with no notable heterogeneity observed (I² = 16%, P = 0.30). Funnel plot analysis (Supplementary Figure S3A) and Egger’s test showed no evidence of significant publication bias (P = 0.931).

Fig. 3
figure 3

Forest plot of pooled hrs for cardiovascular outcomes: (A) stroke, (B) HF hospitalization, and (C) UA hospitalization

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HF hospitalization

Nine studies, encompassing 63,613 patients in total, were analyzed to evaluate the impact of GLP-1 RAs on HF hospitalization. During the follow-up period, 1,218 of 32,461 patients in the GLP-1 RAs group (3.8%) experienced HF hospitalization, compared to 1,329 of 31,152 patients in the control group (4.3%). The forest plot (Fig. 3B) displays the HRs and their 95% CIs for each study. Pooled analysis revealed that GLP-1 RAs significantly lowered HF hospitalization risk (HR: 0.90; 95% CI: 0.83–0.97, P = 0.005), with no notable heterogeneity observed (I² = 0%, P = 0.54). Funnel plot analysis (Supplementary Figure S3B) and Egger’s test showed no significant publication bias (P = 0.587).

UA hospitalization

Seven studies, encompassing 50,617 patients in total, were analyzed to evaluate the impact of GLP-1 RAs on UA hospitalization. During the follow-up period, 861 of 25,963 patients in the GLP-1 RAs group (3.3%) experienced UA hospitalization, compared to 820 of 24,654 patients in the control group (3.3%). The forest plot (Fig. 3C) displays the HRs and their 95% CIs for each study. The pooled analysis indicated that UA hospitalization risk was not significantly different between the GLP-1 RAs and control groups (HR: 1.04; 95% CI: 0.95–1.15, P = 0.38), with no notable heterogeneity observed (I² = 0%, P = 0.84). Funnel plot analysis (Supplementary Figure S3C) and Egger’s test showed no significant publication bias (P = 0.698).

Subgroup analysis

We performed a subgroup analysis on cardiovascular outcomes, categorizing by intervention type, patient characteristics, control group type, follow-up duration, and sample size. The results indicated that monotherapy led to a significant decrease in the risk of all-cause death and stroke, but its effects on cardiovascular death and myocardial infarction were limited. In contrast, combination therapy demonstrated more pronounced risk reductions in cardiovascular death, all-cause death, and HF hospitalization. Among patients with chronic kidney disease, GLP-1 RAs notably decreased the risk of cardiovascular death, all-cause death, and HF hospitalization. In studies with long-term follow-up (≥ 2 years), GLP-1 RAs showed more significant effects in reducing the risks of all-cause death, HF hospitalization, and stroke. Additionally, studies with larger sample sizes demonstrated that GLP-1 RAs provided significant protective effects across multiple cardiovascular outcomes (Table 3).

Table 3A Subgroup analysis of cardiovascular outcomes: primary composite outcome, cardiovascular death, all-cause death, myocardial infarction
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Table 3B Subgroup analysis of cardiovascular outcomes: HF Hospitalization, Stroke, UA Hospitalization
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Sensitivity analysis

Sensitivity analyses were conducted for each cardiovascular outcome to assess the influence of individual studies on the pooled HRs. This was achieved by excluding one study at a time and observing the changes in the pooled HRs. The results demonstrated that the exclusion of any single study did not significantly alter the pooled HRs for the composite outcome, cardiovascular death, all-cause death, stroke, HF hospitalization, or UA hospitalization, indicating the robustness of the findings. For myocardial infarction, sensitivity analysis showed that excluding the studies by Hernandez 2018 and Marso 2016a had some impact on the overall effect and heterogeneity, but the overall stability of the results remained consistent. This indicates that GLP-1 RAs generally have consistent effects on myocardial infarction across studies, despite some variability in specific trials (Supplementary Figures S4-S5).

GRADE assessment

In the GRADE assessment, the evidence quality for UA hospitalization was downgraded to “Moderate” due to imprecision, as the HR effect was not statistically significant. For the other cardiovascular outcomes, including the primary composite outcome, all-cause death, cardiovascular death, myocardial infarction, HF hospitalization, and stroke, no serious risk of bias, inconsistency, indirectness, or imprecision was detected, and no publication bias was identified. Reasonable confounding factors did not significantly affect the validity of the results, and the evidence quality for these outcomes was rated as “High” (Table 4).

Table 4 GRADE evidence profile
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Discussion

Based on current RCT evidence, our meta-analysis revealed that GLP-1 RAs significantly reduce the risk of primary composite outcome, all-cause death, cardiovascular death, stroke, myocardial infarction, and HF hospitalization in high-risk patients with T2DM. Subgroup analysis revealed that GLP-1 RAs are particularly effective in reducing all-cause death and stroke when used as monotherapy, although their impact on cardiovascular death and myocardial infarction is more modest. Combination therapy provided stronger cardiovascular protection, especially in reducing all-cause death, cardiovascular death, and HF hospitalization. The absence of significant heterogeneity further supported the reliability and consistency of these findings. Sensitivity analyses confirmed the robustness of our results. Based on the GRADE system, the evidence quality was classified as “High” for six cardiovascular outcomes, except for UA hospitalization, which was rated as “Moderate”.

Compared to previous studies, our analysis not only confirmed the cardiovascular protective effects of GLP-1 RAs in the general or low-to-moderate risk T2DM population [25] but also provided the first systematic evaluation of their efficacy in high-risk T2DM subgroups [26]. Bethel et al. [9] (2018) conducted a meta-analysis involving four RCTs and reported that GLP-1 RAs reduced the risk of all-cause mortality, major adverse cardiovascular events, and cardiovascular mortality in T2DM patients. Similarly, Pulipati et al. [11] included seven RCTs in their meta-analysis, showing significant reductions in all-cause mortality, cardiovascular mortality, major composite endpoints, and non-fatal stroke with GLP-1 RAs in T2DM patients. However, these studies primarily focused on low-or moderate-risk T2DM patients and did not adequately address the specific needs of high-risk subgroups.

Our study is one of the first to systematically evaluate the efficacy of GLP-1 RAs in high-risk T2DM patients with a history of cardiovascular events or severe chronic kidney disease. Our findings suggest that GLP-1 RAs offer enhanced cardiovascular protection in these high-risk patients, likely related to the distinct pathophysiological characteristics of this population. Subgroup analysis revealed that GLP-1 RAs significantly reduced all-cause death and stroke when used as monotherapy, although their impact on cardiovascular death and myocardial infarction was less pronounced. In contrast, combination therapy offered stronger cardiovascular protection, particularly in reducing cardiovascular death, all-cause death, and HF hospitalization. Additionally, studies with long-term follow-up (≥ 2 years) indicated that GLP-1 RAs exert a more pronounced effect in reducing all-cause death, HF hospitalization, and stroke. Larger sample size studies further corroborated the substantial protective effects of GLP-1 RAs across various cardiovascular outcomes.

GLP-1 RAs provide cardiovascular protection through multiple mechanisms [27]. First, they improve insulin sensitivity and reduce blood glucose levels, which is particularly important for high-risk patients with severe insulin resistance [28]. Second, GLP-1 RAs have anti-inflammatory properties, suppressing pro-inflammatory cytokine release and mitigating chronic inflammation, thereby lowering the risk of atherosclerosis and cardiovascular events. Additionally, GLP-1 RAs enhance lipid profiles by reducing levels of triglycerides and low-density lipoprotein, raising high-density lipoprotein, and significantly lowering blood pressure in patients with resistant hypertension [29]. The heart-protective effects of GLP-1 RAs may also involve the activation of the eNOS pathway, improved endothelial function, enhanced coronary blood flow, and the inhibition of myocardial apoptosis and fibrosis [30, 31]. These mechanisms explain the superior cardiovascular protection provided by GLP-1 RAs in high-risk T2DM patients and offer evidence-based support for their use in this population.

This study’s findings carry significant clinical implications. This is the first comprehensive meta-analysis of RCTs reporting cardiovascular outcomes in high-risk T2DM patients receiving GLP-1 RAs. The results support prioritizing GLP-1 RAs in the management of high-risk T2DM patients, particularly those with a history of cardiovascular events or severe chronic kidney disease. Our findings provide high-quality evidence for the clinical application of GLP-1 RAs in reducing major cardiovascular events and mortality, offering valuable guidance for clinicians in developing treatment strategies. Although GLP-1 RAs showed significant effects in reducing various cardiovascular outcomes, they did not demonstrate a statistically significant reduction in the risk of UA hospitalization. This lack of significance may be due to the different pathophysiological mechanisms of UA hospitalization compared to other cardiovascular events. Additionally, the sample size may have been insufficient to detect a difference in this outcome. Future research should explore the mechanisms of GLP-1 RAs in UA and validate these findings in larger studies.

This study also has some limitations. First, the sample size for certain outcomes, particularly UA hospitalization, may have been too small to detect significant differences, potentially impacting the reliability of this result. Second, although we observed minimal heterogeneity across most outcomes, variations in study design, patient populations, follow-up duration, and the use of concomitant medications (e.g., SGLT2 inhibitors) may limit the generalizability of our findings to broader clinical settings. Third, differences in the pharmacokinetics and properties of the GLP-1 RAs studied were not fully accounted for, which could influence their cardiovascular effects. Fourth, many included studies did not stratify outcomes by important patient characteristics such as insulin resistance severity, heart failure subtype, or chronic kidney disease stage, which may limit the relevance of the findings to specific subgroups. Finally, the relatively short follow-up periods in most trials may not adequately capture the long-term cardiovascular effects of GLP-1 RAs, underscoring the need for further research with extended follow-up to confirm the durability of these benefits.

Future research should focus on assessing the differential efficacy of GLP-1 RAs across various high-risk T2DM subgroups, particularly those with distinct pathophysiological profiles, such as prior cardiovascular events, severe chronic kidney disease, and varying degrees of cardiac function [32, 33]. Long-term studies with larger sample sizes are required to validate the cardiovascular benefits observed in this meta-analysis and to enhance the statistical power for detecting significant effects in less common outcomes. Additionally, research should aim to develop personalized treatment strategies that optimize the use of GLP-1 RAs, potentially in combination with other therapies, to improve outcomes in patients with high-risk T2DM. Finally, real-world studies are essential to verify the efficacy and safety of GLP-1 RAs in broader clinical settings, ensuring their effective implementation in routine practice.

Conclusion

GLP-1 RAs significantly reduce cardiovascular risk in high-risk patients with T2DM, particularly improving primary composite outcome, all-cause death, cardiovascular death, myocardial infarction, stroke, and HF hospitalization. The benefits are especially pronounced with combination therapy and in patients with chronic kidney disease. However, no significant reduction was observed in the risk of UA hospitalization. These findings suggest that GLP-1 RAs could be an important therapeutic option for cardiovascular risk reduction in this population, but further investigation is needed to confirm their long-term effects and clarify their role in managing UA and other cardiovascular outcomes.

Data availability

The datasets generated and/or analysed during this study are available from the corresponding author upon reasonable request.

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  1. Xiaomei Chen and Xuge Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, Dazhou Second People’s Hospital, No. 1, Longquan Road, Dazhou, 635000, Sichuan, China

    Xiaomei Chen, Xiang Fang & Shenghong Feng

  2. Department of Otorhinolaryngology Head and Neck Surgery, Dazhou Second People’s Hospital, Dazhou, 635000, Sichuan, China

    Xuge Zhang

  3. Department of Critical Care Medicine, Chengdu Fifth People’s Hospital, Chengdu, 611130, China

    Xiang Xiang

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  1. Xiaomei Chen
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Contributions

XMC contributed to conceptualization, methodology, investigation, data curation, visualization, formal analysis, writing the original draft, writing-review and editing, and project administration. XGZ contributed to methodology, investigation, data curation, formal analysis, writing the original draft, and writing-review and editing. XX contributed to investigation, data curation, formal analysis, and writing-review and editing. XF and SHF contributed to resources, validation, supervision, and writing-review and editing. All authors reviewed and approved the final manuscript.

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Correspondence to Xiaomei Chen.

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Chen, X., Zhang, X., Xiang, X. et al. Effects of glucagon-like peptide-1 receptor agonists on cardiovascular outcomes in high-risk type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabetol Metab Syndr 16, 251 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13098-024-01497-4

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13098-024-01497-4

Keywords

Diabetology & Metabolic Syndrome

ISSN: 1758-5996

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