Received: 22 February 2022 Revised: 22 March 2022 Accepted: 30 March 2022

DOI: 10.1111/dom.14707

RESEARCH LETTER

Effect of glucagon-like peptide-1 receptor agonists

on cardiovascular events in overweight or obese adults
without diabetes: A meta-analysis of placebo-controlled
randomized trials

Ana Rita Leite1,2* | Anto
nio Angélico-Gonçalves1,2* |

voa
Francisco Vasques-No 1,2,3
| Marta Borges-Canha 1,2,4
|
1,2 1,2,4
Adelino Leite-Moreira | João Sérgio Neves | João Pedro Ferreira1,2,5

1
Cardiovascular R&D Center, Faculty of
Medicine, University of Porto, Porto, Portugal Abstract
2
Department of Surgery and Physiology, Our aim was to study the effect of glucagon-like peptide-1 receptor agonists (GLP-1
Faculty of Medicine, University of Porto,
RA) on the risk of any cardiovascular event in adults with overweight or obesity and
Porto, Portugal
3
Department of Internal Medicine, Centro without diabetes. We conducted a random-effects meta-analysis of placebo-
Hospitalar Universitário de São João, E.P.E, controlled randomized controlled trials. Nine trials were eligible and, in total, 11 430
Porto, Portugal
4
patients were included, of which 7702 (67%) were submitted to treatment with
Department of Endocrinology, Diabetes and
Metabolism, Centro Hospitalar Universitário GLP-1 RA. During follow-up, 673 participants receiving GLP-1 RA treatment (8.7%)
de São João, E.P.E, Porto, Portugal
and 416 participants receiving placebo (11.2%) had a cardiovascular event. Treatment
5
Centre d'Investigation Clinique-
Plurithématique INSERM CIC-P 1433,
with GLP-1 RA versus placebo resulted in a reduction in the risk of any cardiovascu-
INSERM U1116, CHRU Nancy Brabois, lar event (RR = 0.81, CI 0.70-0.92; p = .001). In overweight or obese adults without
F-CRIN INI-CRCT, Université de Lorraine,
Nancy, France
diabetes, treatment with GLP-1 RA reduced the risk of cardiovascular events. Our
findings support the use of GLP-1 RA for reducing the cardiovascular risk of these
Correspondence
Anto
nio Angélico-Gonçalves, Cardiovascular patients.
R&D Center, Faculty of Medicine, University
of Porto, Porto, Portugal.
Email: antoniogoncalves97@hotmail.com

1 | B A CKG R O U N D individual trials were underpowered to test the effect of GLP-1 RA on

cardiovascular events among overweight or obese people with-
Obesity is a major public health issue affecting approximately 39% of out T2D.
the adult population worldwide, and is associated with an increased Our aim was to assess the effect of GLP-1 RA on the risk of car-
risk of cardiovascular events.1 diovascular events in overweight or obese adults without T2D.
Glucagon-like peptide-1 receptor agonists (GLP-1 RA) have been
shown to reduce body weight, as adjuncts to lifestyle intervention. In
people with type 2 diabetes (T2D), GLP-1 RA reduced the risk of 2 | METHODS
major adverse cardiovascular events (MACE).2 Still, the potential car-
diovascular benefits of GLP-1 RA in obese people without T2D 2.1 | Study design
remains to be established, mainly because GLP-1 RA trials in obese
populations were small or had a short follow-up time; thus, the We conducted a meta-analysis of randomized controlled trials (RCTs)
in which treatment with GLP-1 RA in people with overweight or obe-
* Equally contributing first authors. sity and without T2D was evaluated.

1676 © 2022 John Wiley & Sons Ltd. wileyonlinelibrary.com/journal/dom Diabetes Obes Metab. 2022;24:1676–1680.
 LEITE ET AL.

TABLE 1 Baseline clinical characteristics of the patients included in the trials

SCALE obesity SCALE obesity SCALE

SCALE sleep
Trial STEP8 20225 STEP1 20218 STEP3 20217 STEP4 20216 O'Neil, et al. 20181,a and prediabetes and prediabetes maintenance
apnea 201610
20179 201511 201312
ClinicalTrials. NCT04074161 NCT03548935 NCT03611582 NCT03548987 NCT02453711 NCT01272219 NCT01557166 NCT01272219 NCT00781937
govID
Total, n 338 1961 611 803 957 2248 359 3731 422
Intervention Once-weekly Once-weekly Once-weekly Once-weekly Once-daily subcutaneous Once-daily Once-daily Once-daily Once-daily
subcutaneous subcutaneous subcutaneous subcutaneous semaglutide (0.05 mg, subcutaneous subcutaneous subcutaneous subcutaneous
semaglutide 2.4 mg or semaglutide semaglutide semaglutide 0.1 mg, 0.2 mg, 0.3 mg, liraglutide liraglutide liraglutide liraglutide
once-daily 2.4 mg 2.4 mg 2.4 mg 0.4 mg) or 3.0 mg 3.0 mg 3.0 mg 3.0 mg
subcutaneous liraglutide (3.0 mg)
liraglutide 3.0 mg
Comparator Placebo Placebo Placebo Placebo Placebo Placebo Placebo Placebo Placebo
Caucasian, n 249 (74) 1472 (75) 465 (76) 672 (84) 700 (73) 1884 (84) 265 (74) 3168 (85) 355 (84)
(%)
Women, n (%) 265 (78) 1453 (74) 495 (81) 634 (79) 619 (65) 1714 (76) 101 (28) 2928 (78) 344 (82)
Mean age, 49 46 46 47 47 47 49 45 46
years
Mean BMI, 37.5 37.9 38.0 34.4 39.3 38.9 39.1 38.3 37.9
kg/m2
Allocation 3:1:3:1b 2:1 2:1 2:1 6:1 2:1 1:1 2:1 1:1
ratio
Treatment 68 68 68 48c 52 160 32 56 56
duration,
weeks

Abbreviations: BMI, body mass index; ID, identifier.

a
Phase 2 trial.
b
Allocation ratio was three patients to the semaglutide group for one patient to the liraglutide group and three patients to the semaglutide group for one patient to the placebo group.
c
Trial included a run-in period of 20 weeks in which all the participants received once-weekly subcutaneous semaglutide. After this period, 803 participants were randomized to 48 weeks of subcutaneous
semaglutide or switched to placebo.
1677
1678
This meta-analysis is in accordance with the Preferred Reporting
Items for Systematic Reviews and Meta-analyses (PRISMA) reporting
3
guideline.
2.2 | Search strategy and selection criteria
We performed a search of the literature in PubMed and ClinicalTrials.
gov, from inception to January 2022. The search used terms related
to overweight and obesity, GLP-1 RA and RCTs (Supplementary
Appendix, Appendix 2).
Eligible RCTs had to fulfil the following criteria: (a) enrolled adult
participants (>18 years old) with overweight or obesity [body mass
index (BMI) ≥27 kg/m2 with at least one weight-related comorbidity
or BMI ≥30 kg/m2] and without type 1 diabetes or T2D, in which
(b) GLP-1 RA were the active treatment (controls had to be treated
with placebo). For studies that evaluated multiple doses or different
GLP-1 RA drugs, all groups treated with GLP-1 RA were combined
and compared with the control group.
Two independent reviewers (ARL and AAG) evaluated trial eligi-
bility and extracted data on study identifiers, study design and setting,
participant characteristics at baseline, reported outcomes and adverse
events.
2.3 | Outcomes
The primary outcome was the occurrence of any cardiovascular
event during the follow-up. The cardiovascular events included in
the primary outcome* in the Supplementary Appendix, Table S1.
The secondary outcomes included (a) MACE, including cardiovas-
cular death, non-fatal stroke or non-fatal myocardial infarction,
and (b) events of myocardial ischaemia, defined as the occurrence
of an acute coronary syndrome, or the need for percutaneous cor-
onary intervention or surgical revascularization. For both primary
and secondary outcomes, only the first event was considered.
2.4 | Statistical analysis
We performed a random-effects meta-analysis. The heterogeneity
was assessed using the Cochran Q-test statistic and Higgins and
2 2
Thompson I , and was considered as low, moderate or high if I was
<25%, 25-75% or >75%, respectively. The results of the meta-analysis
are presented as risk ratios (RR) with 95% confidence intervals (CI).
Only when three or more articles were available, did we undertake
subgroup analysis based on the drug and dosage (semaglutide 2.4 mg
and liraglutide 3.0 mg). We assessed publication bias by visual inspec-
tion of funnel plots, with the ascertainment for potential asymmetry
of published results by Egger's regression test and Duval and
Tweedie's trim-and-fill method. The statistical analyses were
*were reported with basis on the MedDRA documentation and are described.
LEITE ET AL.
performed using Stata® (StataCorp. 2021. Stata Statistical Software:
Release 17; StataCorp LLC, College Station, TX, USA). Two-sided
p < .05 was considered significant. The risk of bias of the included tri-
als was assessed with the RoB 2 tool.4
3 | RE SU LT S
Of the 847 articles identified, 802 were excluded at first screening
because they did not meet the eligibility criteria. After full-text analy-
sis, 30 articles were further excluded, leading to the final inclusion of
nine studies (Supplementary Appendix, Figure S1).1,5-12
The baseline characteristics of the participants from the eligible
RCTs are shown in Table 1. In total, 11 430 patients were included, of
which 7702 (67%) were submitted to treatment with GLP-1 RA
(liraglutide or semaglutide). The duration of follow-up ranged from
32 to 160 weeks. The mean age of all trial participants was 46 years;
75% were women and the mean BMI was 38.1 kg/m2.
The number of participants with any cardiovascular event (pri-
mary outcome), MACE and myocardial ischaemia event (secondary
outcomes) are presented in the Supplementary Appendix, Table S2.
During follow-up, 673 participants receiving GLP-1 RA treatment
(8.7%) and 416 participants receiving placebo (11.2%) had a cardiovas-
cular event. The treatment effect of GLP-1 RA versus placebo
resulted in a statistically significant reduction in the risk of any cardio-
vascular event (RR = 0.81, CI 0.70-0.92; p = .001) (Figure 1).
Treatment with GLP-1 RA was not associated with a decrease in
the risk of MACE (RR = 0.58, CI 0.23-1.45; Supplementary Appendix,
Figure S2). Semaglutide 2.4 mg and liraglutide 3.0 mg were individually
associated with a trend for a decrease in the risk of any cardiovascular
event (semaglutide 2.4 mg: RR = 0.73, CI 0.51-1.04; liraglutide 3.0 mg:
RR = 0.87, CI 0.76-1.00; Supplementary Appendix, Figures S3 and S4).
The assessment of the risk of bias by visual inspection of funnel
plots (Supplementary Appendix, Figures S5) and quantitative assess-
ment suggested no indication of publication bias.
4 | DI SCU SSION
Our results showed that treatment with GLP-1 RA reduced cardiovas-
cular events in overweight or obese adults without diabetes.
GLP-1 RA are known to improve cardiovascular outcomes in
patients with T2D,2 promoting glycaemic control and body weight
reduction, among other beneficial cardiometabolic effects.13 Similar
improvements in cardiovascular risk factors were recently reported in
overweight or obese patients.7,9-11 In a former post-hoc analysis,
liraglutide 3.0 mg was not associated with excess cardiovascular risk
and a potential benefit was proposed.14
This is the first meta-analysis documenting a decrease in the risk
of cardiovascular events in adults with overweight or obesity and
without diabetes treated with GLP-1 RA. These results strengthen the
hypothesis that GLP-1 RAs reduce cardiovascular events on top of
weight reduction. On the other hand, our analysis was underpowered
LEITE ET AL. 1679

F I G U R E 1 GLP-1 RA treatment effects on the number of participants with a CV event during the follow-up period. CV, cardiovascular; GLP-1
RA, glucagon-like peptide-1 receptor agonists; REML, restricted maximum likelihood

to detect a significant effect on MACE. The low number of events is PE ER RE VIEW

probably explained by the young age of the population and the short The peer review history for this article is available at https://publons.
follow-up time of most studies included. com/publon/10.1111/dom.14707.
Our data were obtained from the safety analysis of RCTs that stud-
ied. The results of the ongoing Semaglutide Effects on Heart Disease DATA AVAILABILITY STAT EMEN T
and Stroke in Patients With Overweight or Obesity (SELECT) trial The data that supports the findings of this study are available in the
(NCT03574597) will study the effect of the GLP-1 RA semaglutide on supplementary material of this article.
cardiovascular outcomes in participants with overweight or obesity. The
main limitation of our study is that the cardiovascular events were
OR CID
ascertained according to the MedDRA documentation, which includes a
Ana Rita Leite https://orcid.org/0000-0002-4111-3787
broad range of cardiovascular events, as described in the Supplementary Ant

onio Angélico-Gonçalves https://orcid.org/0000-0003-2765-
Appendix, Table S1. Still, all the MedDRA cardiovascular events are clini- 1738
cally important and their reduction results in an important clinical benefit
voa
Francisco Vasques-No https://orcid.org/0000-0001-9701-8538
for people with obesity. Furthermore, we were unable to perform a
Marta Borges-Canha https://orcid.org/0000-0003-2929-3751
time-to-event analysis because of lack of data in the included articles. Adelino Leite-Moreira https://orcid.org/0000-0001-7808-3596
João Sérgio Neves https://orcid.org/0000-0002-8173-8255
João Pedro Ferreira https://orcid.org/0000-0002-2304-6138
5 | C O N CL U S I O N
RE FE RE NCE S
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SUPPORTING INF ORMATION
Additional supporting information may be found in the online version
of the article at the publisher's website.
How to cite this article: Leite AR, Angélico-Gonçalves A,

voa F, et al. Effect of glucagon-like peptide-1
Vasques-No
receptor agonists on cardiovascular events in overweight or
obese adults without diabetes: A meta-analysis of placebo-
controlled randomized trials. Diabetes Obes Metab. 2022;24(8):
1676‐1680. doi:10.1111/dom.14707