Real-world study suggests tirzepatide may outperform dulaglutide in treating HFpEF, but randomised trials are still needed

A large observational study indicates tirzepatide could offer superior outcomes over dulaglutide for patients with heart failure with preserved ejection fraction, sparking interest in further clinical trials.

A large real-world study has found tirzepatide was associated with better outcomes than dulaglutide in people with heart failure with preserved ejection fraction, or HFpEF, although the findings come from observational data rather than a randomised head-to-head trial.

Researchers using the TriNetX US Collaborative Network identified more than 35,000 patients starting tirzepatide and nearly 53,000 starting dulaglutide. After propensity score matching, the analysis compared 24,305 patients in each group and found that tirzepatide was linked with lower all-cause mortality, fewer hospital admissions, fewer strokes, fewer major cardiovascular events and fewer major kidney events over both 1 year and 3 years. Myocardial infarction and hypoglycaemia did not differ meaningfully between the two drugs, while atrial fibrillation was slightly more common with tirzepatide and acute pancreatitis was less frequent.

The study adds to a growing body of evidence suggesting that incretin-based therapies may have a role beyond glucose control in HFpEF, a syndrome that accounts for more than half of heart failure cases and has long lacked treatments that consistently improve hard outcomes. Recent trial data have already shown tirzepatide can help patients with HFpEF and obesity, including reductions in cardiovascular death or worsening heart failure in the SUMMIT trial. A Nature report on a secondary analysis of that study said tirzepatide also reduced circulatory overload and end-organ damage.

At the same time, the broader incretin landscape is still taking shape. A separate claims-based analysis published in PubMed and covering cardiometabolic HFpEF found both semaglutide and tirzepatide were associated with lower risks of heart-failure hospitalisation or death versus a placebo proxy, but tirzepatide did not appear to offer a clear advantage over semaglutide. That suggests the class may be beneficial in this population, while the best agent for different patients remains unsettled.

The new TriNetX analysis is notable because it directly compares tirzepatide with dulaglutide, a drug with an established cardiovascular profile from the REWIND trial and wide use in type 2 diabetes. A post hoc analysis of SURPASS-CVOT, meanwhile, has suggested tirzepatide may lower combined cardiovascular and kidney events compared with dulaglutide in patients with diabetes and cardiovascular disease. Taken together, the evidence points to tirzepatide as a potentially stronger option in some patients, but the authors of the new study stress that randomised trials in HFpEF are still needed before firm treatment conclusions can be drawn.