Effects of Liraglutide on Left Ventricular Function: A Meta-Analysis of Randomized, Placebo-Controlled Trials

Background The effects of liraglutide treatment on the left ventricular systolic and diastolic function remain unclear. Methods This meta-analysis was conducted according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement. All relevant randomized, placebo-controlled trials (RCTs) were identified by searching PubMed, EMBASE, Cochrane Library, and ISI Web of Science from the establishment to January 2021 without language limitations. The weighted mean difference (WMD) with 95% confidence intervals (CIs) was calculated. Results Ten placebo-controlled RCTs involving a total of 732 cases were included in the meta-analysis. Compared with the placebo group, liraglutide therapy showed no beneficial effect on the left ventricular ejection fraction (LVEF) at the end of the study (WMD: 2.120, 95% CI: −0.688 to 4.929, P=0.139) and ΔLVEF during the trial period (WMD: −0.651, 95% CI: −1.649 to 0.348, P=0.202). Similarly, no statistical differences were noted in diastolic function parameters between the two groups, including the value early diastolic filling velocity (E)/the mitral annular early diastolic velocity (e′) (WMD: −0.763, 95% CI: −2.157 to 0.630, P=0.283), Δe′ (WMD: −0.069, 95% CI: −0.481 to 0.343, P=0.742), and ΔE/e′ (WMD: −0.683, 95% CI: −1.663 to 0.298, P=0.172). Conclusions Liraglutide treatment did not improve the left ventricular systolic and diastolic function. Given the study's limitations, further investigation may be warranted.


Introduction
Glucagon-like peptide-1 (GLP-1) is a gut-derived hormone that can stimulate glucose-dependent insulin secretion from pancreatic beta cells in response to intake [1,2]. Since GLP-1 is degraded rapidly by the enzyme dipeptidyl peptidase-4 (DPP-4), GLP-1 receptor agonists with natural or modified structures resistant to the inactivation by DPP-4 were developed [3]. Among the GLP-1 receptor agonists, liraglutide was proved to be associated with a lower incidence of cardiovascular disease (CVD) events compared to placebo [4]. e potential mechanisms may involve improving postprandial lipid metabolism [5] and anti-inflammatory effects [6], leading to benefits on other cardiometabolic risk factors [7].
However, the effects of liraglutide on cardiac function remain unclear. In the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial [8], liraglutide treatment failed to reach the statistical significance on the endpoint of hospitalization for heart failure. On the contrary, in a recent meta-analysis, GLP-1 receptor agonists did show beneficial effects on heart failure outcomes, though the explanation for the results was still pending [9]. Many other studies showed similar controversial results. To further clarify the effects of liraglutide on left ventricular function, we performed this meta-analysis with randomized, placebo-controlled trials (RCTs).

Search Strategy.
is meta-analysis was conducted according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement [10]. All published RCTs comparing the effects of liraglutide and placebo on left ventricular function were identified by searching PubMed, EMBASE, Cochrane Library, and ISI Web of Science from the establishment to January 2021 without language restrictions. e search formula was performed as (liraglutide) AND (left ventricular) AND (randomized). Two authors went through the titles and abstracts of the records and identified eligible articles independently. Disagreements were resolved by discussion or referring to the third author (S.-Y.X.).

Inclusion and Exclusion Criteria.
e inclusion criteria contained the following: (1) RCT, (2) liraglutide therapy was administered and compared with the placebo-controlled group, and (3) reported at least one of the following outcomes: for systolic function, the left ventricular ejection fraction (LVEF) at the end of the study or the changes of LVEF during the study (ΔLVEF); for diastolic function, the mitral annular early diastolic velocity (e ′ ), the value early diastolic filling velocity (E)/e ′ , or the changes of the two indicators during the trial (Δe ′ and ΔE/e ′ ). Duplicated publications, reviews, meeting abstracts, and case reports were excluded.

Data Extraction and Quality Assessment.
Two authors used a predesigned structured form to extract data from each study independently. e data elements included (1) study information, such as the first author's name, publication year, sample size, intervention strategies, and follow-up information; (2) patient characteristics, such as the mean age, the proportion of hypertension, diabetes, and smokers; (3) measurement of the baseline LVEF, e ′ , and E/e ′ ; (4) outcomes as listed above. e methodological qualities of the included trials were assessed by two independent authors using the modified Jadad scale [11]. e disagreements were resolved by discussion or referring to the third author (S.-Y.X.).

Statistical Analysis.
We calculated the weighted mean difference (WMD) with 95% confidence intervals (CIs) for continuous outcomes. e I 2 statistic was used to measure the heterogeneity across the included studies, and a randomeffect (RE) model was applied for all pooled outcomes regardless of heterogeneity [12]. In the case of significant heterogeneity, the sensitivity or subgroup analysis would be considered. e publication bias was evaluated by funnel plots with Begg's test [13]. Two-sided P < 0.05 indicated a statistical significance. All analyses were completed using Stata v12.0 (Stata Corp, College Station, TX, USA) with the metan function.

Basic Characteristics of Included Studies.
A total of 136 records were initially identified by our search strategy, in which 56 duplicates were removed. After a title and abstract screening, another 60 citations were excluded as reviews, meeting abstracts, commentaries, case reports, or irrelevant studies. Among the 20 full-text review articles, ten were further excluded for reasons such as substudy [14], registering as one trial [15], comparing with other drugs, or no available data for pooling [16,17]. Finally, ten placebocontrolled RCTs [18][19][20][21][22][23][24][25][26][27] involving a total of 732 cases were included in the meta-analysis. e detailed flowchart is shown in Figure 1. e baseline characteristics of the studies are presented in Tables 1 and 2. e sensitivity analyses and publication assessments for each endpoint are listed in the Supplementary Materials (online suppl. Figures 1 and 2). No publication bias was found.

Methodological Quality Assessment.
e methodological quality was assessed by the modified Jadad scale, composed of randomization, double blinding, withdrawals and dropouts, and allocation concealment [11]. e modified Jadad scores of the enrolled trials ranged from 5 to 7, as presented in Table 3.

Discussion
In this meta-analysis of placebo-controlled RCTs, we examined the effect of liraglutide treatment on left ventricular function, with or without diabetes, heart failure, and coronary artery disease. e parameters of LVEF, e ′ , and E/e ′ were measured by echocardiography, magnetic resonance, or the pulse indicator continuous cardiac output (PICCO) system. e results showed that liraglutide did not affect the left ventricular systolic or diastolic function.
GLP-1 receptor agonists demonstrated beneficial effects on CVD events and mortality in several studies [28]. e potential mechanisms may involve improving postprandial lipid metabolism [5], endothelial function and anti-136 records identified through PubMed (n = 36), EMBASE (n = 56), Cochrane library (n = 3), and web of science (n = 41) 80 records after duplicates removed 60 records removed for metaanalyses, reviews, meeting abstracts, commentaries, case reports, or citations not related to the study 20 potential full-text articles for further assessment 10 excluded 2 for substudy or registered as one trial 6 for comparing with other drugs 2 for data ineligible for pooling 10 RCTs finally included   (37) LG: liraglutide group; CG: control group; NR: not reported.
International Journal of Endocrinology 3 inflammatory effects [29,30], and other benefits directly on the coronary blood flow and myocardial energy metabolism [31][32][33]. However, the effects of GLP-1 receptor agonists on left ventricular function remain to be established. In previous studies, GLP-1 was associated with improved left ventricular systolic function [34][35][36]. As a primary GLP-1 receptor agonist, liraglutide showed beneficial effects on LVEF as well, even in patients without diabetes [25,37]. Nevertheless, most of the studies' population was relatively small or not placebo-matched. In the LEADER trial, liraglutide showed no effect on hospitalization for heart failure, and many other studies showed similar controversial results [8].
To clarify this issue, we conducted the present study, and the results showed that liraglutide had no positive effects on LVEF. In our study, the outcome of LVEF at the end of the study showed significant heterogeneity (I 2 � 70.7%). We performed the sensitivity analysis, and the results are listed in the Supplementary Materials (online suppl. Figure 1). Due to the limited number of enrolled studies, the subgroup analysis was not carried out. Given the influence on statistical power, we would prefer to regard LVEF at the end of the study as an ancillary finding to ΔLVEF. Furthermore, though not included in the meta-analysis due to the data format, the Functional Impact of GLP-1 for Heart Failure Treatment (FIGHT) trial also showed comparable results between liraglutide and placebo on left ventricular systolic function [16]. Consequently, as hypothesized by some scholars, the beneficial effect of GLP-1 receptor agonists on hospital admission for heart failure may attribute to the reduction in myocardial infarction rather than immediate improvement in systolic function [9]. e effects of liraglutide on left ventricular diastolic function were also investigated. Lambadiari et al. reported   [22]. e present meta-analysis further confirmed that liraglutide had no benefits on left ventricular diastolic function. e potential explanations may be multiple. Several studies reported that GLP-1 receptor agonists, including liraglutide, were associated with a significant increase in heart rate [40,41], which means adverse effects on left ventricular function [42] and cardiovascular mortality [43]. e mechanisms may involve sympathetic activity stimulation [44] and immediate effect    International Journal of Endocrinology on GLP-1 receptors in the sinoatrial node [45]. It was hypothesized that beta blocker or other heart rate-lowering drugs might blunt this potential adverse effect [18]. However, in the LIVE study, an increase in heart rate was still observed in patients treating with maximum tolerable beta-blocker dose [24].
As far as we know, the present study is the first metaanalysis assessing the effect of liraglutide treatment on left ventricular systolic and diastolic function parameters using placebo-controlled RCTs. However, the potential limitations of the study should not be ignored. Due to the limited study number and population size, the power of the funnel plot asymmetry test for publication bias might be restricted, and we did not perform the subgroup analyses based on patients with or without diabetes, heart failure, and coronary disease, which might be responsible for the inconsistent findings across the enrolled studies. Furthermore, though highquality RCTs were enrolled, few data were available for pooling analysis, such as cardiac index, global longitudinal strain, and E/A ratio. Despite this, LVEF, e′, and E/e ′ were the most representative indicators for left ventricular function assessment, and the change in E/e ′ was associated with the NT-proBNP level [14]. Finally, the meta-analysis contained studies with different follow-up periods, intervention regimens, and patient's clinical features, which may also affect the analysis power. erefore, the study results should be interpreted with caution and may warrant further investigation.

Conclusion
e present study demonstrated that liraglutide treatment did not improve left ventricular function, irrespective of systolic or diastolic parameters. Given the study's limitations, the results should be interpreted cautiously, and further investigation may be needed.

Data Availability
All the data that support the findings of this study are included within the article.

Supplementary Materials
Online suppl.