Department of Research & Evaluation News

A new study led by Kaiser Permanente researchers compared how well 4 different types of glucose-lowering medications reduced the risk of heart attack and stroke for patients with type 2 diabetes, providing important new information for these patients and their physicians.

The study, published in JAMA Network Open in October, 2025, analyzed data collected on nearly 300,000 adults with type 2 diabetes who had recently been prescribed 1 of 4 types of diabetes medications: GLP-1 receptor agonists, SGLT2 inhibitors, sulfonylureas, and DPP4 inhibitors. Most patients had previously been on another diabetes medication, typically metformin.

“Our study reveals that, among adults with type 2 diabetes, the risk of major cardiovascular events differs greatly depending on the medication used,” said the study’s second author Jaejin An, PhD, a pharmacoepidemiologist with the Kaiser Permanente Southern California Department of Research & Evaluation.

Study identified drug with most benefit

The investigators followed close to 300,000 adults receiving care within 6 large U.S. health care delivery systems: Kaiser Permanente Southern California, Northern California, and Hawaii; Geisinger in Pennsylvania; Henry Ford Health System in Michigan; and HealthPartners in Minnesota and Wisconsin.

The researchers collected data from the patients’ electronic health records on their diagnosis, prescriptions, and outcomes. They then used advanced causal inference and statistical techniques to emulate large randomized clinical trials designed to compare the cardiovascular benefit of the 4 types of diabetes medications.

The researchers’ analyses showed that sustained use of

• GLP-1 receptor agonists offered the most protection against heart attacks and strokes.
• SGLT2 inhibitors were the second most effective.
• Less effective were sulfonylureas medications, followed by DPP4 inhibitors.

Age and other factors affected degree of benefit

When the researchers looked at specific subgroups, they found that patients who already had atherosclerotic cardiovascular disease or heart failure, were 65 or older, or had moderate kidney impairment, obtained more benefit from the GLP-1 receptor agonists than from the SGLT2 inhibitors. In adults under age 50, both types of drugs were about equally effective in decreasing cardiovascular risks.

“It is important to identify which drug provides the greatest benefit in real-world clinical settings,” Dr. An said. “These findings, which highlight differences in treatment benefits across patient subgroups, will be very helpful for clinicians and patients when choosing diabetes medications.”

Diabetes increases risk of heart attack

The study’s lead author, Romain S. Neugebauer, PhD, a research scientist at the Kaiser Permanente Division of Research noted, “People with type 2 diabetes are at high risk of experiencing or dying from a heart attack, stroke, and other forms of cardiovascular disease. It is important that physicians and patients are aware of which medications not only can effectively control diabetes but can also improve heart health.”

Kaiser Permanente co-authors include Andrew J. Karter, PhD, MA; Holly Finertie, MA; Maher Yassin, MPH; Sharon Lin, MA; Wendy Dyer, MS; Noel Pimentel, MA; Keanu Izadian, MA; and Luis Rodriguez, PhD, RD, MPH, of the Division of Research; Caryn Oshiro, PhD, RD, MS, of the Kaiser Permanente Hawaii Center for Integrated Health Care Research; Lisa Gilliam, MD, PhD, of The Permanente Medical Group.