Million-Patient Study: Heart Risk Cut by GLP-1 Drugs

A new large-scale analysis from Mass General Brigham has directly compared two of the most talked-about diabetes medicines—tirzepatide and semaglutide—and found both appear to lower the risk of major cardiovascular events. Drawing on nearly one million patients' real-world health records, the study offers fresh, clinically useful evidence about how these drugs perform outside randomized trials.

Real-world data reveals early heart protection

Researchers analyzed national health claims for adults treated for type 2 diabetes with tirzepatide, semaglutide, or other commonly prescribed agents. Published in Nature Medicine and presented at the 2025 American Heart Association Scientific Sessions, the study shows both agents are linked to meaningful reductions in heart attack, stroke and all-cause mortality compared with other therapies.

Specifically, semaglutide was associated with an 18% lower combined risk of stroke and heart attack versus sitagliptin, a drug considered cardiovascularly neutral. Tirzepatide also produced a significant benefit—about a 13% reduction in the combined risk of stroke, heart attack and death compared with dulaglutide, an established GLP-1 receptor agonist. These effects were evident early after treatment initiation, suggesting benefits may extend beyond weight loss alone.

Why real-world evidence matters

Randomized controlled trials are the gold standard for determining drug efficacy, but they can take years and often enroll narrowly defined populations. This study used routinely collected clinical and claims data to capture outcomes among patients who better represent everyday clinical practice. As Nils Krüger, MD, one of the lead investigators, explained, using real-world data can answer time-sensitive questions and help clinicians understand how newer drugs behave in typical patients.

How tirzepatide and semaglutide compare—and what remains uncertain

Tirzepatide and semaglutide both act on pathways that influence insulin, appetite and metabolism. Semaglutide is a GLP-1 receptor agonist; tirzepatide combines GLP-1 activity with a second glucose-lowering mechanism (GIP agonism). While earlier trials had already suggested semaglutide reduces cardiovascular events, direct comparisons between the two agents were scarce until now.

The new analysis found only modest differences in cardioprotection between tirzepatide and semaglutide among patients at elevated cardiovascular risk. That implies both drugs can be considered heart-protective treatment options in routine care, rather than one clearly superior agent across all populations. Still, the precise biological mechanisms that produce these early cardiovascular benefits are not fully understood and warrant further research.

Implications for clinicians and patients

• Clinicians now have stronger real-world evidence that prescribing semaglutide or tirzepatide may reduce cardiovascular events in people with type 2 diabetes who are at risk.
• Benefits appear early, so early therapeutic decisions could influence short-term risk as well as long-term outcomes.
• Choice of agent should factor in individual patient needs—weight loss goals, side-effect profile, cost and access—since both drugs offer cardioprotective potential.

Shirley Wang, PhD, a senior epidemiologist on the team, emphasized the study's commitment to transparency: the researchers preregistered their protocol and shared analytic code to foster open scientific discussion. That approach helps clinicians and policy makers evaluate findings in context and supports reproducibility.

Expert Insight

"Large observational studies like this don’t replace randomized trials, but they provide an important complementary view of how therapies perform in everyday practice," says Dr. Karen Mitchell, a fictional clinical cardiologist and diabetes specialist. "For patients who are eligible, these results strengthen the case for considering GLP-1–based therapies as part of a cardiovascular risk–reduction strategy, alongside lifestyle measures and other risk-factor treatments."

Future work will need to dissect mechanisms—are the cardioprotective effects driven by changes in blood glucose, blood pressure, inflammation, clotting, or direct actions on the vascular system? Ongoing and planned randomized studies, mechanistic trials, and continued real-world monitoring will be essential to answer those questions and to guide precise, personalized use of these promising drugs.

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