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Glucose-Lowering Medication Classes and Cardiovascular Outcomes in Patients With Type 2 Diabetes
Romain Neugebauer1, Jaejin An2, Sarah Krahe Dombrowski3
1Division of Research, Kaiser Permanente Northern California, Pleasanton.
JAMA Network Open
|October 15, 2025
Summary
Major adverse cardiovascular events (MACEs) risk is lowest with glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) in type 2 diabetes (T2D) patients. Benefits vary by patient characteristics, informing personalized treatment strategies.
Area of Science:
- Cardiology
- Endocrinology
- Pharmacology
Background:
- Major adverse cardiovascular events (MACEs) are a leading cause of death in type 2 diabetes (T2D).
- Limited head-to-head trials and inadequate bias adjustment in observational studies hinder comparative effectiveness research of glucose-lowering medications on MACEs.
Purpose of the Study:
- To compare the effectiveness of four glucose-lowering medication classes—sulfonylureas, dipeptidyl peptidase-4 inhibitors (DPP4is), sodium-glucose cotransporter-2 inhibitors (SGLT2is), and glucagon-like peptide-1 receptor agonists (GLP-1RAs)—on MACEs in US adults with T2D.
- To utilize modern causal inference methods and machine learning for robust bias adjustment in this comparative effectiveness study.
Main Methods:
- A comparative effectiveness study involving 241,981 adults with T2D initiated on one of four medication classes (sulfonylureas, DPP4is, SGLT2is, GLP-1RAs) between 2014-2021.
- Employed targeted learning within a trial emulation framework to analyze MACEs (nonfatal myocardial infarction, nonfatal stroke, cardiovascular death).
- Assessed heterogeneity of treatment effects across prespecified subgroups.
Main Results:
- Sustained exposure to GLP-1RAs was associated with the lowest 2.5-year MACE risk, followed by SGLT2is, sulfonylureas, and DPP4is.
- The cumulative risk difference between SGLT2is and GLP-1RAs was 1.5% (95% CI, 1.1%-1.9%).
- Benefits of GLP-1RAs over SGLT2is were most pronounced in patients with baseline atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), older age (≥65 years), or moderate kidney impairment.
Conclusions:
- Medication class significantly impacts MACE risk in T2D patients, with GLP-1RAs and SGLT2is offering the most protection.
- The comparative benefit of GLP-1RAs versus SGLT2is is influenced by patient factors like age, ASCVD, HF, and kidney function.
- These findings, alongside cost and clinical considerations, can guide personalized treatment decisions for T2D management.
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