MACE risk in type 2 diabetes varies by choice of glucose-lowering agent

medwireNews: The risk for major adverse cardiovascular events (MACE) among people with type 2 diabetes varies significantly according to the type of glucose-lowering medication they are using, US study findings indicate.

Glucagon-like peptide (GLP)-1 receptor agonists offer the greatest protection, but the magnitude of benefit depends on baseline factors such as age, and the presence of atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and kidney impairment, report Romain Neugebauer (Kaiser Permanente Northern California, Pleasanton) and co-authors in JAMA Network Open.

They explain that although MACE – defined as nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death – are a primary cause of morbidity and mortality in adults with type 2 diabetes, few head-to-head randomized trials have compared the effects of glucose-lowering medications on these events.

Neugebauer and team therefore used machine learning methods to emulate a comparative effectiveness clinical trial among 241,981 adults (mean age 57 years, 54% men) with type 2 diabetes who were members of six large US healthcare delivery systems and initiated treatment with a sulfonylurea (86.7%), sodium–glucose cotransporter (SGLT)2 inhibitor (6.1%), GLP-1 receptor agonist (3.8%), or a dipeptidyl peptidase (DPP)-4 inhibitor (2.4%) between 2014 and 2021.

In adjusted analyses, the risk for MACE during 2.5 years of follow-up varied substantially across the four classes of glucose-lowering medication. Individuals with sustained exposure to GLP-1 receptor agonists had the lowest risk, followed by those using SGLT2 inhibitors, sulfonylureas, and DPP-4 inhibitors, with cumulative incidence ranging from approximately 1.3–4.5%.

The researchers also carried out six different emulated two-way comparisons. Among them, the 2.5-year cumulative incidence of MACE was 3.2% with GLP-1 receptor agonists and 4.7% with SGLT2 inhibitors, giving a significant risk difference of 1.5 percentage points.

For sulfonylureas versus DPP-4 inhibitors, the risk difference for MACE was a significant 1.9 percentage points in favor of sulfonylureas, with cumulative incidence at 3.9% and 5.8%, respectively.

Of note, the adjusted 2.5-year risk difference estimates also favored GLP-1 receptor agonists over SGLT2 inhibitors among patients with ASCVD (7.6 vs 12.9%) and without ASCVD (2.5 vs 3.4%), and this was also true for sulfonylureas over DPP-4 inhibitors (14.3 vs 16.7% and 2.7 vs 4.3%, respectively), with rates of MACE generally much larger for patients with than without ASCVD.

Overall, the benefit of GLP-1 receptor agonists over SGLT2 inhibitors for MACE risk reduction was “most pronounced” in patients with baseline ASCVD or HF, those aged 65 years or older, and those with low to moderate kidney impairment, the investigators say.

Conversely, there was no significant difference between the two treatments among patients younger than 50 years. There was also no difference in MACE risk between sustained users of the GLP-1 receptor agonists exenatide, liraglutide, and semaglutide. These three agents accounted for 90% of GLP-1 receptor agonist use in the study and “therefore, our results may underestimate benefits obtainable with newer incretin mimetics,” the authors observe.

Neugebauer et al conclude: “These results, along with consideration of cost, availability, and collateral clinical benefits, may inform treatment decisions for adults with [type 2 diabetes].”

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JAMA Netw Open 2025; 8: e2536100