DOI: https://doi.org/10.21203/rs.2.16671/v1
Background The cardiovascular effects of glucagon-like peptide-1 (GLP-1) receptor agonists are still controversial in the treatment of type 2 diabetes mellitus (T2DM) patients. The purpose of this study was to evaluate the risk of cardiovascular events of GLP-1 (albiglutide, exenatide, liraglutide and semaglutide) receptor agonists in T2DM patients.
Methods PubMed and Embase were searched to find relevant randomized controlled trials (RCTs) from inception to June 2019 that evaluated the effect of GLP-1 receptor agonists on cardiovascular events in patients with T2DM. The T2DM patients of all the eligible trials received either GLP-1 therapy or placebo, and the cardiovascular outcomes included death from cardiovascular causes, fatal or non-fatal myocardial infarction and fatal or non-fatal stroke.
Results We included 4 multinational double-blind randomized placebo-control trials that included a total of 36852 T2DM patients. The results indicated that GLP-1 receptor agonists reduced the risk of death from cardiovascular causes (RR: 0.86; 95% CI: 0.78–0.96; P = 0.005), fatal or non-fatal myocardial infarction (RR: 0.85; 95% CI: 0.74–0.98; P = 0.03) and fatal or non-fatal stroke (RR: 0.84; 95% CI: 0.75–0.95; P = 0.007) compared with the placebo controls.
Conclusion We concluded that GLP-1 receptor agonist therapy had a protective cardiovascular effect compared with the placebo in the treatment of T2DM patients in trials with cardiovascular outcomes.
Type 2 diabetes mellitus patients have a much higher risk of cardiovascular events, including death from cardiovascular causes, fatal or non-fatal myocardial infarction and fatal or non-fatal stroke [1]. The rates of cardiovascular death are 2- to 4-fold higher for patients with diabetes compared with the rates for those without diabetes [2]. GLP–1 receptor agonists, which are new glucose-lowering therapeutic agents in the treatment of type 2 diabetes mellitus, have been shown to affect the incidence of cardiovascular outcomes in patients with type 2 diabetes mellitus, although the results regarding GLP–1 receptor agonists remain inconsistent [3–4]. It is well known that GLP–1, as a peptide hormone, stimulates insulin secretion and inhibits glucagon secretion in a glucose-dependent manner [5]. An increasing number of studies have shown that glucagon-like peptide–1 (GLP–1) may improve endothelial functioning and may have direct effects in protecting the vascular system [6]. There are several GLP–1 receptor agonists that are used as therapeutic agents for treating type 2 diabetes mellitus patients in clinical fields. Recently, the GLP–1 receptor was believed to have an effect on individual cardiovascular outcomes in the treatment of diabetes, but not all GLP–1 receptor agonists showed the effect of reducing cardiovascular outcomes because of the varied effectiveness of the different GLP–1 drugs [3–4]. The use of GLP–1 receptor agonists to reduce cardiovascular outcomes in T2DM has become a new research and therapeutic area. Currently, no meta-analysis has concentrated on the long-term cardiovascular complications in GLP–1-treated T2DM patients. Previous studies have only focused on the short-term effects and safety of GLP–1 receptor agonists on T2DM patients [7,8].
Therefore, we performed a meta-analysis of double-blind randomized placebo-controlled clinical trials to investigate the cardiovascular complications of GLP–1 receptor agonists in T2DM patients. The cardiovascular outcomes included death from cardiovascular causes, fatal or non-fatal myocardial infarction and fatal or non-fatal stroke.
Data sources and search strategy
We comprehensively searched PubMed and Embase to find relevant randomized controlled trials (RCTs) from inception to June 2019 that evaluated the effect of GLP-1 receptor agonists on cardiovascular events in patients with T2DM. This meta-analysis was conducted and reported in accordance with the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analysis Statements[9]. The language was confined to English. The search terms were as follows: “incretin” OR “GLP-1” OR “glucagon-like peptide-1 analogue” OR “Liraglutide” OR “exenatide” OR “liraglutide” OR “lixisenatide” OR “albiglutide” OR “dulaglutide” OR “semaglutide” OR “taspoglutide” AND “type 2 diabetes mellitus” OR “T2DM” AND “randomized controlled trials” OR “RCT”. We also comprehensively screened the references of reviews and articles in order to find more eligible articles.
Data selection criteria
The literature search was screened independently by two authors; if there were some inconsistencies, we discussed within the group until a consensus was reached. The research titles and abstracts were initially screened, and then we screened the study design, interventions, control, and outcomes in detail to determine the included trials.
The criteria for including eligible studies were as follows: (1) the studies were double-blind, randomized placebo-controlled trials; (2) the RCTs were evaluating GLP-1 versus placebo in T2DM patients; (3) there was a comparison of cardiovascular risk between GLP-1 receptor agonists and placebo in T2DM patients with or without cardiovascular diseases; and (4) a risk ratio (RR) with corresponding 95% confidence intervals (CIs) or data was reported.
Regarding the exclusion criteria, we excluded studies with the following criteria: (1) the case and control patients included other T2DM complications; (2) the controls received other conventional antidiabetic agents; and (3) duplicate publications, animal experimental studies, reviews, conference abstracts, or meta-analyses.
Data extraction and quality assessment
The following data were extracted from the included RCTs by two authors independently: first author’s name; publication year, country, sample size, study design, intervention, glycated haemoglobin, duration of diabetes and the follow-up periods. The quality of the included studies was assessed by the Cochrane Collaboration tool for the risk of bias [10]. The randomization, blinding, withdrawals, generation of random numbers, and concealment of allocation were essential components for each RCT. The quality of each results was assessed according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system [11].
Data synthesis and statistical analysis
This meta-analysis was performed using Review Manager 5.3 software (RevMan), The Cochrane Collaboration, Copenhagen. For the cardiovascular events in our study, we calculated the the risk ratio (RR) with 95% confidence intervals (CIs) to standardize the differences between the GLP-1 receptor agonist and placebo. The forest plots were conducted using a fixed-effect model if there was no obvious heterogeneity or using a random-effect model when heterogeneity of the included studies was obvious [12-13]. Additionally, the chi-squared (χ2) test and the I2 test were used to assess the heterogeneity between studies. When P ≤ 0.10 and I2 > 50%, the heterogeneity between those included studies was defined as obvious heterogeneity [14]. Moreover, if the I2 test value was 25–50%, it was defined as mild heterogeneity, 50–75% as moderate heterogeneity, and 75% as severe heterogeneity. To measure publication bias, we performed a funnel plot and Egger’s tests. A funnel plot was used to qualitatively measure the publication bias [15,16], and P ≤ 0.05 was considered significant publication bias in this meta-analysis.
We obtained 1928 articles after searching PubMed and Embase from 2011 to June 2019. Then, we screened the titles and abstracts and removed the duplicate articles, reviews and conference abstracts, and 14 articles remained for evaluating the details of the full text to determine whether they met the inclusion criteria. Finally, 4 trials were included in this meta-analysis (Fig. 1). The Cochrane Collaboration tool was applied to evaluate the quality of the included trials. The results regarding the individual quality of the included trials are shown in Fig. 2.3.4.
The selected studies were published between 2016 and 2018. The GLP-1 receptor agonist arms included 18403 patients, and the placebo control arms included 18449 patients. The main characteristics of the included trials are presented in Table 1. The control treatment in the included trials was placebo according to the experimental trial treatment. The cardiovascular outcomes included death from cardiovascular causes, fatal or non-fatal myocardial infarction and fatal or non-fatal stroke.
There was no obvious heterogeneity in the four included studies (I2 = 0%, Cochran Q test P = 0.57) (Fig. 2) regarding the risk of death from cardiovascular causes. Therefore, we used the fixed effect model in the RevMan software. GLP-1 receptor agonists reduced the risk of death from cardiovascular causes compared with the placebo (RR: 0.86; 95% CI: 0.78 – 0.96; P = 0.005) according to the results of the meta-analysis.
There was mild heterogeneity (I2 = 55%, Cochran Q test P = 0.08) (Fig. 3) regarding the risk of fatal or non-fatal myocardial infarction in the included studies. Therefore, we used the random effect model in the RevMan software. The results showed that GLP-1 receptor agonists reduced the risk of fatal or non-fatal myocardial infarction compared with the placebo controls (RR: 0.85; 95% CI: 0.74 – 0.98; P = 0.03).
There was also no evidence of heterogeneity observed across the included trials regarding fatal or non-fatal stroke (I2 = 0%, Cochran Q test P = 0.59) (see Fig. 4). The fixed effect model was applied in the RevMan software. The results of the meta-analysis indicated that GLP-1 receptor agonists reduced the risk of fatal or non-fatal stroke compared with the placebo (RR: 0.84; 95% CI: 0.75 – 0.95; P = 0.007).
Because only four trials were included, which is less than ten, we have no evidence of publication bias in this meta-analysis by the funnel plot. No individual study had a significant effect on the pooled effect size according to the results of the sensitivity analysis at all end points.
The objective of this meta-analysis was to explore the effect of GLP-1 receptor agonists on cardiovascular outcomes in type 2 diabetes mellitus patients. The results of this meta-analysis suggest that GLP-1 therapy has a significant impact on the incidence of death from cardiovascular causes, fatal or non-fatal myocardial infarction and fatal or non-fatal stroke in T2DM patients. There was no heterogeneity in these four included studies in their assessment of the effect of GLP-1 receptor agonists on the risk of death from cardiovascular causes and fatal or non-fatal stroke; however, there was mild heterogeneity regarding the risk of fatal or non-fatal myocardial infarction in the included studies, and the reasons may be the specific medicine molecule and GLP-1 receptor agonist dose tested, differences in the randomized patients (such as medical history and baseline characteristics), duration of follow-up years and adherence to treatment. As our findings are based on good-quality studies that were all multinational double-blind randomized placebo-control trials and our meta-analysis was based on a mean follow-up of 2.65 years (minimum 1.5 year – maximum 3.8 years), the confounding and attrition bias are controlled, so the risk of unreliable results is diminished.
Similar to our results, some studies [17,18] also indicated that GLP-1 receptor agonists had a positive effect on the heart and enhanced cardiac function. GLP-1 receptor agonists have had cardiovascular protection effects in cardiovascular trials, which might be mediated through antiatherogenic mechanisms that contain direct and indirect effects on anti-inflammatory pathways, endothelial function and common cardiovascular risk factors (such as blood pressure) [19].
Some previous studies [20] found a lower incidence of cardiovascular disease (CVD) events when GLP-1 receptor agonists were compared with placebo. However, a comparison meta-analysis [21-23] indicated that there was no significant reduction in CVD events by GLP-1 receptor agonists. Similarly, Inzucchi et al. [24] believed that the evidence of GLP-1 receptor agonist cardiovascular protection was still limited, and the cardiovascular system benefits related to GLP-1 receptor agonists may be independent of its glucose, lipid, or energy metabolism effects.
The cardiovascular effects of GLP-1 receptor agonists might be mediated via antiatherogenic mechanisms that decrease cardiovascular risk over time. These mechanisms might include direct and indirect effects of GLP-1 receptor agonists on common cardiovascular risk factors (e.g., decreased blood pressure), anti-inflammatory pathways, cardiac output, ischaemic conditioning and endothelial function.
This meta-analysis has several strengths: (1) Only RCTs were included, so this meta-analysis eliminated the potential control group biases; (2) The large sample size of the 4 included trials allowed us to quantitatively evaluate the GLP-1 receptor agonist effects in T2DM patients; (3) A wide range of patient characteristics was represented, which ensured a comprehensive assessment of the effect of GLP-1 receptor agonists in the treatment of patients with T2DM.
This study has some limitations. First, the publication bias is an inevitable problem in any meta-analysis. Second, T2DM patients who received various GLP-1 receptor agonist drugs, such as albiglutide, exenatide, liraglutide and semaglutide, might have biased the meta-analysis results. Third, a more detailed analysis was restricted because the meta-analysis used pooled data.
The findings of this study indicated that GLP-1 receptor agonist therapy reduced the incidence of death from cardiovascular causes, fatal or non-fatal myocardial infarction and fatal or non-fatal stroke in the treatment of T2DM patients. We need additional large RCTs in the future to evaluate the treatment effects of GLP-1 receptor agonists in T2DM.
Ethics approval and consent to participate: “Not applicable”
Consent for publication: “Not applicable”
Availability of data and materials: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Competing interests: All authors declare that there are no conflict of interests or special relationships with industry in this meta-analysis.
Funding: “No funding”
Authors' contributions: Li Song is the corresponding author of this study. She collected and analyzed data, wrote the manuscript and made the decision to submit and publish the manuscript.Jing Qin is the first author for the meta-analysis, including study design, collected and analyzed data, and wrote the manuscript.
Acknowledgements: "Not applicable”
GLP-1 Glucagon-like peptide 1 receptor agonists
T2DM type 2 diabetes mellitus
RCTs randomized controlled trials
GRADE Grading of Recommendations, Assessment, Development, and Evaluation
CVD cardiovascular diseases
RR risk ratio
CIs confidence intervals
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