BMJ openJan 9, 2025

Heart risk linked to glucagon-like peptide-1 receptor drugs compared to other common diabetes medicines in people with type 2 diabetes

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jan 20, 2026

Abstract

Approximately 67 million people are covered by the comprehensive national healthcare database in France used to evaluate GLP-1 receptor agonists.

Real-world data will be utilized to assess the effectiveness of GLP-1 receptor agonists combined with metformin on cardiovascular events and hospitalizations for heart failure in patients with type-2 diabetes.
Comparative analyses will be conducted against other diabetes treatments, including dipeptidyl peptidase IV inhibitors and sulfonylureas, while excluding sodium-glucose transport protein 2 inhibitors.
Cohorts of patients initiating GLP-1 receptor agonists will be matched with control groups based on treatment history and demographic factors.
Outcomes will be analyzed using hazard ratios and confidence intervals to estimate treatment effects on cardiovascular and mortality outcomes.

Simplified

INTRODUCTION: Several cardiovascular outcome trials have been conducted to assess the cardiovascular safety and efficacy of glucagon-like peptide-1 receptor agonists (GLP1-RAs) on cardiorenal outcomes in patients with type-2 diabetes (T2D). However, the strict requirements of randomised controlled trials to avoid most confounding factors are at the expense of external validity. Using national real-world data, we aimed to evaluate the effectiveness of GLP-1RAs in association with metformin especially on cardiovascular events, hospitalisation for heart failure and all-cause death in comparison with other diabetes treatment schemes using dipeptidyl peptidase IV inhibitors, sulfonylureas/glinides or insulin also associated with metformin. Sodium-glucose transport protein 2 inhibitors (SGLT-2i) will be excluded as comparators, as this class of oral hypoglycaemic agents just started in 2020 to be marketed in France.

METHODS AND ANALYSIS: The Système National des Données de Santé is a comprehensive nationwide administrative healthcare database in France that covers approximately 67 million people.Several cohorts of adult patients with T2D initiating any GLP1-RA in dual or triple therapies, as recommended by the French Health authorities, will be identified in this database over the period 2016-2021. These cohorts will be defined by the combination of glucose-lowering drugs prescribed simultaneously with GLP1-RA and diabetes treatment received over a 6-month period before GLP1-RA initiation. They will be first matched with T2D controls (1:3 ratio) based on the year of drug initiation and treatment regimens before and simultaneously with GLP1-RA in the different selected cohorts. Comparative analyses will be conducted versus these control groups, adjusting for cardiovascular event history and a propensity score considering age, sex, area of residence, deprivation index, comorbidities, duration of diabetes, use of lipid-lowering drugs, anticoagulants, antiplatelet therapies and blood pressure-lowering therapies. Comparative analyses will be conducted versus these control groups, using a high-dimensional propensity scores method and fixed baseline characteristics. Treatment effects on the different outcomes measured will be estimated for each GLP1-RA group, through HR and their corresponding CIs (95% CI) using Cox regressions and/or competitive risk regressions when necessary.

ETHICS AND DISSEMINATION: The study has been approved by an independent ethics committee (Comité éthique et scientifique pour les recherches, les études et les évaluations dans le domaine de la santé, Paris, France; reference: 8699786, dated 2 June 2022) and has been registered with the French National Data Protection Commission (Commission Nationale de l'Informatique et des Libertés, Paris, France; reference: 922161, dated 26 June 2022). The findings of this study will be published in peer-reviewed scientific journals and presented at international conferences.

TRIAL REGISTRATION NUMBER: F20220803152803.

Key numbers

14%

Reduction in MACE Risk

Based on a meta-analysis of cardiovascular outcome trials.

67 million

Population Coverage

The Système National des Données de Santé includes the majority of the French population.

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Competing interests

Competing interests: ND has received fees for giving talks or participating to advisory boards, or support for attending meetings from: Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Bouchara-Recordati, IBSA, Maincare, MSD, NovoNordisk, Pfizer, Servier, UCB and Vifor. GL has received fees and honoraria from Alnylam, Amarin, Amgen, Astra Zeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Boston Scientific, MSD, Novartis, Novo Nordisk, Organon, Pfizer, Recordati and Sanofi Aventis. MM has received fees and honoraria from Acticor Biotech, Astra Zeneca, Boehringer Ingelheim, Novartis, Novo Nordisk. KM has received consulting fees from Novo Nordisk; honoraria for lectures, presentations, or speaker bureaus from Novo Nordisk, Astra Zeneca, Boehringer-Ingelheim, Eli Lilly, Sanofi, Lifescan, Abbott, and Bayer; and participation to Advisory Board from Novo Nordisk, Sanofi and Amarin. FS has received research grants from and/or was speaker (with or without lecture fees) on a.o. (CME accredited) meetings sponsored by Amgen, Bayer, Novartis, Novo Nordisk, Sanofi Aventis, Recordati, Servier, Mylan and AstraZeneca. IS has received fees and honoraria from Novonordisk, Sanofi Synthé-Labo, Servier, Boheringer Ingelheim, Astra-Zeneca and Medtronic. AC, CE and CN are employees of CEMKA, a French heath care Clinical Research Organization. LV and CM are employees of NovoNordisk. BD has received fees from Astra-Zeneca, CEMKA, Novo-Nordisk, Abbott, Sanofi Winthrop Industry, Lumanity, Continuum+ and CERBA. LF has received consulting fees from AstraZeneca, Bayer, BMS/Pfizer, Boehringer Ingelheim, Novo and XO, and speaker activities for AstraZeneca, Bayer, BMS/Pfizer, Boehringer Ingelheim, Boston Scientific, Medtronic and Zoll.

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Heart risk linked to glucagon-like peptide-1 receptor drugs compared to other common diabetes medicines in people with type 2 diabetes

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