Diabetes drugs such as semaglutide already have a reputation for lowering the risk of major cardiovascular events in people with type 2 diabetes.

What hasn’t been clear is whether tirzepatide, another similar drug, offers similar protection, and how the two stack up against each other outside of tightly controlled trials.

A new Mass General Brigham study delivers the first large, real-world, comprehensive look. The takeaway: both drugs cut the risk of heart attack, stroke, and death, with only small differences between them.

What the researchers set out to test

The team wanted to move beyond single-drug trials and ask a pragmatic question: in everyday clinical practice, do tirzepatide and semaglutide both reduce cardiovascular risk, and by how much compared with commonly used alternatives?

To answer that, they tapped national claims databases capturing nearly a million adults treated for type 2 diabetes, then compared outcomes among those prescribed tirzepatide, semaglutide, or other standard therapies.

“Randomized controlled trials are often considered the reference standard in the medical evidence generation process. However, not all questions can be answered using this time- and resource-intensive method,” said study first author Dr. Nils Krüger.

“Data generated in clinical practice and used secondarily for research allow us to address a wide range of clinically relevant questions time- and resource-effectively – when applied correctly.”

“Moreover, we can study patients who reflect the reality of everyday clinical care, in contrast to the highly selected participants of randomized experiments.”

Testing the diabetes medications

Rather than pitting the two medications directly in a randomized trial, the investigators used careful observational comparisons anchored to active comparators that have well-described cardiovascular profiles.

For semaglutide, they used sitagliptin – a drug considered neutral for cardiovascular risk – as the benchmark. For tirzepatide, they used dulaglutide, a long-standing GLP-1 receptor agonist.

These choices help contextualize risk reductions against realistic alternatives in routine care while reducing confounding from comparing drug users to non-users.

Heart benefits of diabetes drugs

The results point in a consistent direction. “Both drugs show strong cardioprotective effects. Our data also indicate that these benefits occur early, suggesting that their protective mechanisms go beyond weight loss alone,” Krüger said.

When benchmarked against sitagliptin, semaglutide was associated with an 18% lower risk of heart attack and stroke.

When benchmarked against dulaglutide, tirzepatide was linked to a 13% lower risk of heart attack, stroke, and death from any cause.

Because these medications are relatively new, mechanistic confirmation is still catching up. The precise biological mechanisms underlying such protective effects remain unknown.

However, the early separation of event curves suggests effects that are not purely mediated by long-term weight change.

Comparing the diabetes drugs

Manufacturers have promoted analyses implying that each company’s own product is superior for cardiovascular protection. The new real-world comparison doesn’t support sweeping claims of dominance.

“According to recently presented database analyses by the respective manufacturers, each company’s own drug appears to reduce cardiovascular risk much more effectively than the competitor’s,” said Krüger.

“However, our study found only small differences between tirzepatide and semaglutide in cardiovascular protection among populations at risk of adverse events, underscoring that both agents provide protective benefit and could be integrated into clinical cardiovascular practice.”

In other words, for patients with type 2 diabetes who carry cardiovascular risk, the choice between these two therapies may reasonably hinge on factors like tolerability, access, individual metabolic goals, and comorbidities.

Why this real-world approach matters

Claims data cannot replace randomized trials, but it can broaden the lens. It captures heterogeneous patients, polypharmacy, and the messy realities of adherence and comorbid illness.

The investigators leaned into transparency, with public preregistration and shared analytic code to invite scrutiny and replication.

“We hope that our study will help clinicians better understand how these new medications work in clinical practice,” said study senior author Shirley Wang.

“Our transparent and open science practices, including pre-registration of a public protocol and shared analytic code, are designed to support scientific discussion.”

What clinicians can do now

For people with type 2 diabetes at heightened cardiovascular risk, both tirzepatide and semaglutide look like strong options to lower the chance of heart attack or stroke, and to reduce mortality.

The signals appear early, which is clinically meaningful for patients already living with established atherosclerotic risk or multiple risk factors.

The findings also reinforce a broader shift: glucose-lowering therapies that deliver organ protection are becoming the standard of care, and treatment plans should weigh cardiovascular benefit.

What we still need to learn

Several questions remain. The study doesn’t pinpoint mechanisms, and it cannot control for every nuance of prescribing behavior or patient selection.

Head-to-head randomized outcome trials are still lacking, and longer follow-up will clarify durability, safety, and effects across subgroups such as older adults, those with heart failure, or patients with chronic kidney disease.

As more data accumulate, we’ll get sharper estimates of benefit and better tools to personalize therapy.

For now, the message is straightforward: in real-world practice, both agents protect the heart. The more important decision may be getting an effective, cardio-protective therapy started rather than chasing marginal differences between two strong contenders.

The research is published in the journal Nature Medicine and was presented at the American Heart Association Scientific Sessions 2025.

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