Kaiser Permanente study findings could help inform treatment decisions for adults with type 2 diabetes
A new study led by Kaiser Permanente researchers that compared how well 4 different types of glucose-lowering medications reduce the risk of heart attack and stroke provides important new information for patients with type 2 diabetes.
“People with type 2 diabetes are at high risk of experiencing or dying from a heart attack, stroke, and other forms of cardiovascular disease,” said first author Romain S. Neugebauer, PhD, a research scientist at the Kaiser Permanente Division of Research (DOR). “It is important that physicians and patients are aware of which medications not only can effectively control diabetes but can also improve heart health.”
The comparative effectiveness study, published in JAMA Network Open, analyzed data collected on close to 300,000 adults with type 2 diabetes who had recently been prescribed one 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.
The researchers’ analyses showed that sustained use of GLP-1 receptor agonists — such as liraglutide and semaglutide — offered the most protection against heart attacks and strokes. SGLT2 inhibitors — such as empagliflozin — were the second most effective. Less effective were sulfonylureas medications — such as glipizide or glimepiride — followed by DPP4 inhibitors, such as sitagliptin and linagliptin.
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.
“There are millions of Americans with type 2 diabetes and many different medications they can be prescribed to treat it,” said senior author Patrick O’Connor, MD, an investigator at HealthPartners Institute. “Because of the size of our study, we were able to provide information to inform medication choices for adults with type 2 diabetes who may already have heart disease as well as for those for whom the goal is to prevent heart problems from developing.”
Unique comparative analysis
The investigators received funding in 2021 to study close to 300,000 adults receiving care within 6 large U.S. health care delivery systems: Kaiser Permanente of Northern California, Southern 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.
“It would be very expensive, and it would take many years, to conduct several large, randomized trials to compare these 4 types of medications to one another,” said Neugebauer. “Our analysis provided a rigorous alternative to help patients with type 2 diabetes and their clinicians identify glucose-lowering medication regimens that have the most favorable effects on heart health and other outcomes that are important to patients.”
The study’s wide range of stakeholders was another unique aspect of its design. “We had 19 stakeholders who met twice a year to guide how the research was conducted and to provide context for the findings,” said study co-author Julie Schmittdiel, PhD, associate director for Health Care Delivery and Policy at DOR. “Many of these stakeholders were patients, and this meant a patient perspective informed the outcomes we studied, and the types of analyses we did. It also ensured our work would provide the most benefit possible to patients with type 2 diabetes.”
O’Connor noted that the study’s findings have worldwide implications. “The advantage of the GLP-1 receptor agonists over the SGLP-2 inhibitors will be important for people in countries like the U.S., where these medications are more available,” he said. “For clinicians and patients in lower- and middle-income countries, where these medications are less commonly used, the finding that, on average, and when used continuously, sulfonylureas medications appeared to be more effective than DDP4 inhibitors is also useful information.”
The study was funded by the Patient-Centered Outcomes Research Institute.
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 Kaiser Permanente Division of Research; Jaejin An, PhD, of the Kaiser Permanente Southern California Department of Research & Evaluation; Sarah Krahe Dombrowski, PharmD, BCACP, and Eric Wright, PharmD, MPH, of the Geisinger Center for Pharmacy Innovation and Outcomes; Caryn Oshiro, PhD, RD, MS, of the Kaiser Permanente Hawaii Center for Integrated Health Care Research; Andrea Cassidy-Bushrow, PhD, and Lindsey Aurora, MD, of Henry Ford Health; Lisa Gilliam, MD, PhD, of The Permanente Medical Group; Gregg Simonson, PhD, Richard Bergenstal, MD, Greg Knowlton, MS, Stephanie A. Hooker, PhD, MPH, MS, and Maggie Nolan, MD, MS, of HealthPartners Institute; Tainayah Thomas, PhD, MPH, and Alyce S. Adams, PhD, MPP, of Stanford University School of Medicine; Jasleen Kaur, MD, of HealthPartners, and Mark van der Laan, PhD, MA, of the University of California, Berkeley.
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About the Kaiser Permanente Division of Research
The Kaiser Permanente Division of Research conducts, publishes, and disseminates epidemiologic and health services research to improve the health and medical care of Kaiser Permanente members and society at large. KPDOR seeks to understand the determinants of illness and well-being and to improve the quality and cost-effectiveness of health care. Currently, DOR’s 720-plus staff, including 73 research and staff scientists, are working on nearly 630 epidemiological and health services research projects. For more information, visit divisionofresearch.kp.org or follow us @KPDOR.
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