Top-line data suggest improved outcomes, symptoms with tirzepatide for HFpEF and obesity

Erin D. Michos, MD, MHS, FACC, FAHA, FASE, FASPC

HFpEF is starting to overtake HF with reduced EF as the most common type of HF. Patients with the obesity phenotype represent the majority of those with HFpEF and generally have a worse prognosis. Individuals with the obesity phenotype of HFpEF have more concentric left ventricular remodeling, a high prevalence of hypertension, more right ventricular dysfunction, increased epicardial fat thickness, greater increased plasma volume and stressed blood volume. As such, patients with the obesity phenotype of HFpEF are more diuretic resistant, have a greater symptom burden, poorer functional capacity and more severely impaired quality of life. However, prior to SGLT2 inhibitors, there were no effective therapies for HFpEF. Then the STEP-HFpEF trial first demonstrated that a GLP-1 receptor agonist — semaglutide (Wegovy, Novo Nordisk) — could significantly improve quality of life in patients with HFpEF and BMI of 30 kg/m2 or more, opening the door for another avenue of therapy for HFpEF management.  

And now this exciting top-line data released from SUMMIT phase 3 clinical trial confirmed that the dual GLP-1/GIP agonist tirzepatide also significantly improved quality of life, HF symptoms and physical limitations, as captured by the KCCQ-CSS, compared with placebo in patients with obesity and HFpEF, while conferring a 16% weight loss. Notably, in the coprimary endpoint, tirzepatide significantly reduced a composite HF outcome endpoint of HF urgent visit or hospitalization, oral diuretic dose or CV death by 38% compared with placebo. This is really clinically meaningful and offers great promise of new hope for HFpEF patients with obesity, with or without diabetes. Exercise capacity as captured by the 6-minute walk test distance was also improved, as well as reduction in inflammation as measured by high-sensitivity C-reactive protein. We await the full publication for more details.

One key question is whether the HF benefit seen with GLP-1 receptor agonist therapy — first with semaglutide and now with tirzepatide — is simply due to weight loss or whether GLP-1 receptor agonist therapy is actually modifying the disease itself. Secondary analyses from HFpEF suggest the latter — with improvements in biomarkers like N-terminal pro-B-type natriuretic peptide despite weight loss, and that subgroups with a worse HF phenotype had greater improvement in quality of life despite similar weight loss.

So now following the heels of the STEP-HFpEF trials with semaglutide, we have another confirmatory trial with SUMMIT investigating tirzepatide that incretin-based therapies make a substantial difference in the lives of patients with the obesity phenotype of HFpEF. These data debunk the old “obesity paradox,” confirming a major difference between unintentional and intentional weight loss, with intentional weight loss with incretin-based therapies demonstrating clinical benefit, at least for HFpEF. Current guidelines have already given SGLT2 inhibitors a class IIa indication for HFpEF treatment. We will need to see more data regarding the combination of SGTL2 inhibitors and GLP-1 receptor agonists in HF patients, but given their different mechanisms of action, patients with HFpEF and obesity will likely benefit from both therapies together to improve physical limitations, symptoms, exercise function, and reduce clinical events.

In sum, overweight and obesity are not mere bystanders but, in fact, play a causal role in the pathogenesis and progression of HFpEF. While prevention and treatment of obesity upstream remains the primary goal to prevent progression down the cardio-kidney-metabolic spectrum, for those who have already developed HF, at least we have some new hope on the “SUMMIT” that we can offer patients with obesity and HFpEF with incretin-based therapy.