Tirzepatide and SGLT2 drugs in HFpEF

A review published in September 2026 in Endocrinology, Diabetes & Metabolism puts tirzepatide side by side with the SGLT2 inhibitors for obesity-related heart failure with preserved ejection fraction (HFpEF) and lands on a deliberately unexciting conclusion. The two drug classes act through different physiology, they plausibly complement each other, and nobody has run the trial that would show whether adding one to the other actually helps^[1].

That gap matters because the two classes are already reaching the same patients. Someone with obesity, HFpEF and type-2 diabetes qualifies for tirzepatide and for an SGLT2 inhibitor on separate grounds, so the combination is in use ahead of the evidence that tests it.

What each class has actually shown

For tirzepatide, the anchor is SUMMIT. Packer and colleagues randomised 731 patients with an ejection fraction of 50% or higher and a body-mass index of 30 or higher to tirzepatide (up to 15 mg weekly by subcutaneous injection) or placebo, and followed them for a median of 104 weeks^[2]. The primary composite of cardiovascular death or worsening heart-failure events occurred in 9.9% of the tirzepatide group versus 15.3% on placebo (hazard ratio 0.62, 95% CI 0.41 to 0.95, P=0.026). Symptom burden improved too: the Kansas City Cardiomyopathy Questionnaire clinical summary score rose 19.5 points on tirzepatide against 12.7 on placebo at 52 weeks, a between-group difference of 6.9 points^[2].

For the SGLT2 inhibitors, two large trials carry the case. EMPEROR-Preserved randomised 5,988 patients with class II to IV heart failure and an ejection fraction above 40% to empagliflozin 10 mg daily or placebo. Over a median 26.2 months the composite of cardiovascular death or heart-failure hospitalisation occurred in 13.8% versus 17.1% (hazard ratio 0.79, 95% CI 0.69 to 0.90, P<0.001), driven mainly by fewer hospitalisations and consistent in patients with and without diabetes^[3]. DELIVER repeated the question with dapagliflozin 10 mg daily in 6,263 patients with an ejection fraction above 40% and reported 16.4% versus 19.5% over a median 2.3 years (hazard ratio 0.82, 95% CI 0.73 to 0.92, P<0.001)^[4].

Why the review calls the mechanisms complementary

The review's framing is that obesity drives HFpEF through expansion of epicardial adipose tissue, chronic low-grade inflammation and haemodynamic overload that ends in ventricular hypertrophy^[1]. On that account, tirzepatide works on the substrate. The authors point to weight loss above 20%, measurable reductions in epicardial and paracardiac fat, and the 19.5-point questionnaire gain seen in SUMMIT^[1].

The SGLT2 inhibitors are described as working on loading conditions and cardiac fuel handling instead: natriuresis (increased sodium and water excretion by the kidney), improved myocardial energetics, and a reduction in heart-failure hospitalisation that holds regardless of diabetes status, with kidney protection on top^[1]. Two different levers on the same disease is a reasonable argument for combining them. It is an argument, not a result.

The regulatory picture is not symmetrical

This is where the practical difference sits. On 30 January 2026 the European Medicines Agency finished assessing an application to extend Mounjaro to symptomatic chronic HFpEF in adults with obesity. The agency did not grant it. The published outcome states that although EMA did not recommend that a separate indication should be granted for the treatment of HFpEF, it agreed to include relevant data from the study submitted with the application in the medicine's product information, so that healthcare professionals have access to up-to-date data on the effects of Mounjaro in adults with chronic HFpEF and obesity^[5].

Empagliflozin sits in a different position. The EU indication for Jardiance reads that it is indicated in adults for the treatment of symptomatic chronic heart failure, with no ejection-fraction qualifier at all^[6]. So in the EU, one of these two classes can be prescribed for HFpEF on label and the other cannot. Tirzepatide remains authorised for type-2 diabetes and for weight management, and country-level status is on our tirzepatide regulation summary.

What has not been tested

The review is direct about its own limits, and the caveats belong in the what we do not know column. Combined use of the two classes is called mechanistically promising but has not been tested in a dedicated randomised controlled trial, and the authors say prospective studies are needed to establish safety and long-term efficacy in obesity-related HFpEF^[1]. They also warn against the comparison readers will reach for anyway: because SUMMIT and EMPEROR-Preserved differed in design and population, a direct head-to-head reading of the two hazard ratios is not statistically valid, and each agent should be judged on its own evidence base^[1].

One number inside SUMMIT deserves more attention than the headline gets. The composite benefit came from worsening heart-failure events (8.0% versus 14.2%, hazard ratio 0.54, 95% CI 0.34 to 0.85), not from mortality. Cardiovascular deaths were 8 on tirzepatide and 5 on placebo, a hazard ratio of 1.58 with a confidence interval running from 0.52 to 4.83^[2]. Those are small counts and the interval is wide enough to be uninformative in either direction, but it is not a mortality result and should not be read as one. Discontinuation for adverse events also ran higher on tirzepatide (6.3% versus 1.4%), which is consistent with the tolerability profile on our tirzepatide safety summary.

Be clear about what this publication is, too. It is a narrative review of trial and mechanistic literature from 2015 to 2026, written by a group based mainly at Somali National University. It adds no new patient data, and its value is the framing rather than any fresh number.

Practical context

The honest summary for readers following tirzepatide into cardiology: both classes have credible randomised evidence in preserved-ejection-fraction heart failure, only the SGLT2 inhibitors carry a licensed heart-failure indication in the EU, and the stacking question is open. That combination of prescription medicines and an unresolved evidence gap is a conversation for a cardiologist rather than a website. Our tirzepatide overview covers the wider trial programme, and the regulation section tracks the label by country.