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. 2025 Oct 1;8(10):e2536100.
doi: 10.1001/jamanetworkopen.2025.36100.

Glucose-Lowering Medication Classes and Cardiovascular Outcomes in Patients With Type 2 Diabetes

Romain Neugebauer  1 , Jaejin An  2 , Sarah Krahe Dombrowski  3 , Caryn Oshiro  4 , Andrea Cassidy-Bushrow  5   6   7 , Lisa Gilliam  8 , Gregg Simonson  9 , Andrew J Karter  1 , Richard Bergenstal  9 , Holly Finertie  1 , Maher M Yassin  1 , Greg Knowlton  10 , Sharon R Lin  1 , Wendy Dyer  1 , Noel Pimentel  1 , Keanu Izadian  1 , Julie Schmittdiel  1 , Tainayah W Thomas  11 , Stephanie A Hooker  10 , Margaret B Nolan  10 , Eric Wright  3 , Lindsey Aurora  12 , Luis A Rodriguez  1 , Jasleen Kaur  13 , Alyce S Adams  11   14 , Mark J van der Laan  15 , Patrick J O'Connor  10
Affiliations

Glucose-Lowering Medication Classes and Cardiovascular Outcomes in Patients With Type 2 Diabetes

Romain Neugebauer et al. JAMA Netw Open. .

Abstract

Importance: Major adverse cardiovascular events (MACEs) are primary causes of morbidity and mortality in adults with type 2 diabetes (T2D), yet few head-to-head randomized trials have compared the effects of glucose-lowering medications on MACEs, and most observational analyses are limited by inadequate bias adjustment methods.

Objective: To compare the effectiveness of sustained exposure to 4 classes of glucose-lowering medications (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 using modern causal methods combined with machine learning.

Design, setting, and participants: This comparative effectiveness study included adults with T2D who were members of 6 large US health care delivery systems and initiated treatment with 1 of 4 medication classes (sulfonylureas, DPP4is, SGLT2is, and GLP-1RAs) between January 1, 2014, and December 31, 2021. Data analysis was conducted from May 1 to December 31, 2024.

Exposure: New use of a sulfonylurea, DPP4i, SGLT2i, or GLP-1RA based on filled prescriptions.

Main outcomes and measures: The primary outcome was MACEs defined as nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Analyses were conducted using targeted learning within a trial emulation framework. Heterogeneity of treatment effects was assessed for prespecified subgroups.

Results: This study included 296 676 adults. The cohort for emulating a 4-arm trial included a subset of 241 981 adults (mean [SD] age, 57.2 [12.9] years; 54.3% male) with T2D. In adjusted analyses, 2.5-year MACE risk was lowest in patients with sustained exposure to GLP-1RAs, followed by SGLT2is , sulfonylureas, and DPP4is. Comparing DPP4is with sulfonylureas and SGLT2is with GLP-1RAs, the 2.5-year cumulative risk difference was 1.9% (95% CI, 1.1%-2.7%) and 1.5% (1.1%-1.9%), respectively. Risk differences in patients with vs without atherosclerotic cardiovascular disease (ASCVD) were similar in direction but typically much smaller for patients without ASCVD. Evidence of a benefit of GLP-1RAs over SGLT2is was most pronounced in patients with baseline ASCVD or heart failure (HF), age 65 years or older, or low to moderate kidney impairment but was not found in patients younger than 50 years.

Conclusions and relevance: In this study, MACE risk varied significantly by medication class, with most protection achieved with sustained treatment with GLP-1RAs followed by SGLT2is, sulfonylureas, and DPP4is. The magnitude of benefit of GLP-1RAs over SGLT2is depended on baseline age, ASCVD, HF, and kidney impairment. These results, along with consideration of cost, availability, and collateral clinical benefits, may inform treatment decisions for adults with T2D.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Neugebauer reported receiving grants from the Patient Centered Outcomes Research Institute (PCORI) and the National Institutes of Health (NIH) during the conduct of the study. Dr An reported receiving grants (to Kaiser Permanente Southern California) from PCORI during the conduct of the study and grants from AstraZeneca, Merck LLC, and Bayer outside the submitted work. Dr Dombrowski reported receiving grants from PCORI during the conduct of the study. Dr Oshiro reported receiving grants from PCORI during the conduct of the study. Dr Simonson reported receiving grants from HealthPartners Institute during the conduct of the study and grants from Novo Nordisk, Abbott Diabetes Care, Dexcom, and Sanofi outside the submitted work. Dr Karter reported receiving grants from PCORI during the conduct of the study. Dr Bergenstal reported receiving grants (to HealthPartners Institute) from Abbott Diabetes Care, Eli Lilly, Novo Nordisk, DexCom, and Zealand outside the submitted work. In additional, Dr Bergenstal reported consulting for or serving on advisory boards (with support to HealthPartners Institute) to Abbott Diabetes Care, Eli Lilly, Novo Nordisk, DexCom, Zealand, Sanofi, and Roche outside the submitted work. Mr Yassin reported receiving grants from PCORI during the conduct of the study. Ms Dyer reported receiving grants from PCORI during the conduct of the study. Dr Schmittdiel reported receiving grants from PCORI during the conduct of the study. Dr Thomas reported receiving grants from PCORI during the conduct of the study and grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institute of Minority Health and Disparities outside the submitted work. Dr Wright reported receiving grants from PCORI during the conduct of the study and personal fees from AstraZeneca outside the submitted work. Dr Adams reported receiving grants from PCORI and the NIDDK during the conduct of the study. Dr O’Connor reported receiving grants from the NIH outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flow Diagram
Inclusion and exclusion counts leading to creation of the cohort for emulating the 4-arm randomized clinical trial, along with sample sizes and counts for each observed end of follow-up in each treatment arm. New fills represents the count of patients who initiated 1 of the 4 medication classes compared and for whom there was no evidence of a dispensing for any of these 4 medication classes in the prior 2 years. ALT indicates alanine transaminase; DPP4i, dipeptidyl peptidase-4 inhibitor; eGFR, estimated glomerular filtration rate; GLP-1RA glucagon-like peptide-1 receptor agonist; HbA1c, hemoglobin A1c; MACE, major adverse cardiovascular event; SGLT2i, sodium-glucose cotransporter-2 inhibitor.
Figure 2.
Figure 2.. Cumulative Incidence Curves for Major Adverse Cardiovascular Events (MACEs) for Glucose-Lowering Medications
A to H, Each plot represents unadjusted (A) or adjusted (B-H) estimates of cumulative incidence curves for MACEs derived with targeted learning (ie, targeted minimum loss–based estimation with super learning estimates of propensity scores) and no weight truncation. A and B, The plots emulate inferences (PP analyses) from 4-arm randomized clinical trials (RCTs) for comparing sulfonylureas, dipeptidyl peptidase-4 inhibitors (DPP4is), sodium-glucose cotransporter-2 inhibitors (SGLT2i), and glucagon-like peptide-1 receptor agonists (GLP-1RA) before (A) and after (B) covariate adjustment. C to H, The plots emulate inferences (PP analyses) from one of six 2-arm RCTs after covariate adjustment to compare sulfonylureas to DPP4is (C), SGLT2is to sulfonylureas (D), GLP-1RAs to sulfonylureas (E), SGLT2is to DPP4is (F), GLP-1RAs to DPP4is (G), and GLP-1RAs to SGLT2is (H). Plots emulating inferences from 2-arm RCTs display a P value for the test that the average risk difference through 2.5 years of follow-up (30 months) is 0.
See this image and copyright information in PMC

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