Many people with type 2 diabetes (T2D) take medications to control blood sugar after initial treatment with metformin. But not all options may be equal when it comes to heart health. A large study published in JAMA Network Open looked at whether three common diabetes medicines affect the risk of serious heart problems, including heart attack, stroke, heart failure, and heart-related death.
Why Researchers Looked at Diabetes Drugs and Heart Health
People with T2D have a higher chance of developing heart and blood vessel diseases. As a result, doctors try to choose medicines that both control blood sugar and lower heart risk.
Some older medicines called sulfonylureas (including glipizide, glimepiride, and glyburide) are widely used because they lower blood sugar effectively and cost less. Another class, DPP-4 inhibitors (DPP4is), is also used as a second option after metformin.
But there have been questions and mixed evidence about whether sulfonylureas may raise the risk of heart problems compared with DPP4is. To address this, researchers used detailed health records to compare real-world outcomes for people taking these drugs.
How the Study Compared Medications
The research team looked at health records from 48,165 adults with T2D who were starting a second medicine after metformin from 2014 to 2023. All had moderate cardiovascular risk, meaning they were at risk for heart-related events but were not too sick at baseline.
Participants were grouped based on which medicine they started:
- Glipizide: 18,147 people
- Glimepiride: 14,282 people
- Glyburide: 1,887 people
- DPP4 inhibitor (DPP4i): 13,849 people
All groups were similar in age, sex, and basic health measures like hemoglobin A1C and cholesterol.
Researchers followed patients for about three years on average, tracking major cardiovascular events:
- Heart attack
- Stroke
- Hospitalization for heart failure
- Cardiovascular death
These events were combined into a single measure called MACE-4 (major adverse cardiovascular events).
What the Results Revealed
Over the follow-up period, 6.6% of individuals experienced at least one major cardiovascular event. When researchers compared the risk among medications, they found:
- DPP4i group (reference): 8.1% risk over 5 years
- Glyburide: 8.4% risk (similar to DPP4i)
- Glimepiride: 8.6% risk (slightly higher but not clearly different)
- Glipizide: 9.1% risk — highest among the drugs studied
Compared with DPP4is, glipizide was associated with a 13% higher risk of major cardiovascular events over five years. The differences for glyburide and glimepiride were smaller and less precise, meaning researchers could not be as confident about those comparisons.
In simpler terms:
- People taking glipizide had a higher chance of heart problems than those taking DPP4i drugs.
- The other sulfonylureas did not show clear increases in risk in this study.
Why These Findings Matter for You
This study is important because it uses real-world data from tens of thousands of patients, not just a single clinical trial. It suggests that when doctors choose a second diabetes medication after metformin, heart risk should be part of the conversation.
Here’s what this could mean:
- If you have type 2 diabetes and moderate heart risk, some diabetes medicines may be safer for your heart than others.
- DPP4 inhibitors appeared to have a lower risk of major heart events compared with glipizide.
- Not all drugs in the same class behave the same way — even within sulfonylureas, differences exist.
Doctors already monitor heart risk with diabetes management. This study may help shift practice toward safer glycemic medicines for patients with heart concerns.
What Patients Should Talk About With Their Care Team
If you are taking or considering a sulfonylurea such as glipizide, glyburide, or glimepiride, it may be worth discussing:
- Your personal heart risk profile
- Alternative medicines such as DPP4 inhibitors or other second-line agents
- Whether switching medications could lower your chance of heart complications
- The role of lifestyle changes (diet, exercise, blood pressure control) in reducing overall risk
Medication choice is always personal and should consider blood sugar control, side effects, cost, and long-term health goals. This study adds important context to that shared decision-making process.
Source:
Turchin A, Petito LC, Hegermiller E, Carnahan R, DeVries A, Goel S, et al. Cardiovascular events in individuals treated with sulfonylureas or dipeptidyl peptidase-4 inhibitors: a comparative effectiveness research study. JAMA Netw Open. 2025;8(7):e2523067. Accessed by: https://pubmed.ncbi.nlm.nih.gov/40674376/
