Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis
Open accessAbstract
Background Glucagon-like peptide-1 (GLP-1) receptor agonists are effective glucose-lowering drugs. Findings from cardiovascular outcome trials showed cardiovascular safety of GLP-1 receptor agonists, but results for cardiovascular efficacy were varied. We aimed to examine overall cardiovascular efficacy for lixisenatide, liraglutide, semaglutide, and extended-release exenatide.Methods In this systematic review and meta-analysis, we analysed data from eligible trials that assessed the safety and efficacy of GLP-1 receptor agonists compared with placebo in adult patients (aged 18 years or older) with type 2 diabetes and had a primary outcome including, but not limited to, cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke. We searched PubMed and MEDLINE without language restrictions up to Sept 18, 2017, for eligible trials. We did a meta-analysis of available trial data using a random-effects model to calculate overall hazard ratios (HRs) for cardiovascular efficacy outcomes and odds ratios for key safety outcomes.Findings Of 12 articles identified in our search and screened for eligibility, four trials of cardiovascular outcomes of GLP-1 receptor agonists were identified: ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN 6 (semaglutide), and EXSCEL (extended-release exenatide). Compared with placebo, GLP-1 receptor agonist treatment showed a significant 10% relative risk reduction in the three-point major adverse cardiovascular event primary outcome (cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke; HR 0·90, 95% CI 0·82-0·99; p=0·033), a 13% RRR in cardiovascular mortality (0·87, 0·79-0·96; p=0·007), and a 12% relative risk reduction in all-cause mortality (0·88, 0·81-0·95; p=0·002), with low-to-moderate between-trial statistical heterogeneity. No significant effect of GLP-1 receptor agonists was identified on fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, hospital admission for unstable angina, or hospital admission for heart failure. Overall, no significant differences were seen in severe hypoglycaemia, pancreatitis, pancreatic cancer, or medullary thyroid cancer reported between GLP-1 receptor agonist treatment and placebo.Interpretation Our findings show cardiovascular safety across all GLP-1 receptor agonist cardiovascular outcome trials and suggest that drugs in this class can reduce three-point major adverse cardiovascular events, cardiovascular mortality, and all-cause mortality risk, albeit to varying degrees for individual drugs, without significant safety concerns. GLP-1 receptor agonists have a favourable risk-benefit balance overall, which should allow the choice of drug to be individualised to each patient's needs.Funding Amylin Pharmaceuticals (AstraZeneca).
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GLP-1 RAs are indicated for the treatment of type 2 diabetes (all) and obesity (liraglutide and semaglutide only) and have beneficial effects on patient-important outcomes such as weight loss, cardiovascular and kidney events, hepatic steatosis, and mortality.
“Clinically, GLP-1 RAs are indicated for the treatment of type 2 diabetes (all) and obesity (liraglutide and semaglutide only) and have beneficial effects on patient-important outcomes such as weight loss, cardiovascular and kidney events, hepatic steatosis, and mortality.5,7–9,11,30”
From Glucagon-Like Peptide-1 Receptor Agonists and Thyroid Cancer: A Narrative Review (2024) · cites this paper as [5]
Pharmaceutical interventions of 1.5 to 3 years duration report HbA1c reductions of 0.2 to 1.0% with DPP-4 inhibitors, SGLT-2 inhibitors and GLP-1 agonists.
“Pharmaceutical interventions of 1.5 to 3 years duration report HbA1c reductions of 0.2 to 1.0% with DPP-4 inhibitors, SGLT-2 inhibitors and GLP-1 agonists (6, 7, 49).”
The cardioprotective impact of GLP-1RA therapy is established with several large cardiovascular outcome trials demonstrating clear benefits and suggest a class effect.
“The cardioprotective impact of GLP-1RA therapy is now established with several large cardiovascular outcome trials demonstrating clear benefits and together strongly suggest a class effect of GLP-1RA therapy.11,12”
From Randomised trial comparing weight loss through lifestyle and GLP-1 receptor agonist therapy in people with MASLD (2025) · cites this paper as [11]
Some animal models have demonstrated that GLP1 might have a direct impact on the hypothalamus-pituitary-testicular axis beyond weight reduction.
“Furthermore, some animal models have demonstrated that GLP1 might even have a direct impact on HPT that is beyond WR (10, 11, 12, 13, 14).”
From Effects of liraglutide on obesity-associated functional hypogonadism in men (2019) · cites this paper as [13]
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- Authors
- Bethel, M. A., Patel, R. A., Merrill, P., Lokhnygina, Y., Buse, J. B., Mentz, R. J., Pagidipati, N. J., Chan, J. C., Gustavson, S. M., Iqbal, N., Maggioni, A. P., Öhman, P., Poulter, N. R., Ramachandran, A., Zinman, B., Hernandez, A. F., & Holman, R. R.
- Affiliations
- University of Oxford (GB)
- Duke University (US)
- University of North Carolina at Chapel Hill (US)
- Chinese University of Hong Kong (HK)
- AstraZeneca (United States) (US)
- Associazione Nazionale Medici Cardiologi Ospedalieri (IT)
- Imperial College London (GB)
- India Diabetes Research Foundation (IN)
- Mount Sinai Hospital (CA)
- Corresponding author
- Bethel, M Angelyn
- ORCID
- Venue
- The Lancet Diabetes & Endocrinology
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 6
- Issue
- 2
- Pages
- 105-113
- ISSN
- 2213-8587 (ISSN-L)
- OpenAlex
- W2773969925
- Cited by
- 599
- References
- 8
- Citations by year
- 2026: 36 · 2025: 50 · 2024: 39 · 2023: 52 · 2022: 58 · 2021: 73 · 2020: 102 · 2019: 112 · 2018: 74 · 2017: 2
- FWCI
- 62.64
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- The Lancet Diabetes & Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Spiral (Imperial College London) (submittedVersion, cc-by-nc-nd)
- Funders
- Amylin Pharmaceuticals
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- GLP-1 receptor agonists, type 2 diabetes, cardiovascular outcomes, cardiovascular mortality, myocardial infarction, stroke, lixisenatide, liraglutide, semaglutide, major adverse cardiovascular events, all-cause mortality, hypoglycemia, heart failure, unstable angina, drug safety
- MeSH terms
- Glucagon-Like Peptide-1 Receptor Agonists, Cardiovascular Diseases, Cardiovascular System, Diabetes Mellitus, Type 2, Humans, Hypoglycemic Agents, Prognosis, Survival Rate
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Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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