Lilly gets first heart outcomes readout with tirzepatide

Eli Lilly's dual GLP-1/GIP agonist tirzepatide has been shown to reduce the risk of worsening disease in people with heart failure and obesity in a phase 3 trial, the first to show a benefit on cardiovascular outcomes with the drug.

The result from the SUMMIT study helps Lilly close the gap with Novo Nordisk, whose GLP-1 agonist semaglutide is already approved to reduce the risk of serious cardiovascular conditions in people who are overweight or obese and showed a benefit in heart failure in a late-stage trial reported last year.

Lilly now plans to file for approval to add the heart failure indication to the label for tirzepatide, which is already sold as Mounjaro for type 2 diabetes and Zepbound for obesity, later this year.

The SUMMIT trial enrolled obese patients with heart failure with preserved ejection fraction (HFpEF) – a particularly hard-to-treat form that accounts for around half of all cases of heart failure and has few approved therapies – with or without diabetes.

Treatment with tirzepatide reduced the risk of heart failure outcomes – specifically a heart failure urgent visit or hospitalisation, oral diuretic intensification, or cardiovascular death – by 38% compared to placebo after 52 weeks.

Lilly's drug also significantly improved heart failure symptoms and physical limitations measured using the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) compared to placebo, and achieved 15.7% weight loss compared to a 2.2% loss in the control group.

A key difference between SUMMIT and Novo Nordisk's STEP-HFpEF study of semaglutide is that it included hard cardiovascular outcomes as the primary endpoint. In contrast, Novo Nordisk's study looked at KCCQ-CSS measures and weight loss only.

"Previous incretin studies in this population focused on symptoms and physical limitations," said Jeff Emmick, senior vice president of product development at Lilly. "In a first-of-its-kind trial, tirzepatide reduced severity of symptoms and improved heart failure outcomes in people with HFpEF and obesity."

It's not clear how GLP-1 drugs exert their beneficial effects in cardiovascular diseases, but studies have suggested that it could be more than just a consequence of weight loss – or a reduction in fat around the heart in the case of heart failure patients.

A recent analysis of data from the SELECT trial of semaglutide in overweight or obese patients found that the cardiovascular benefits of the drug seemed to accrue regardless of how much weight people taking the drug lost, and even if they lost no weight at all. The authors suggested other factors were coming into play, possibly reductions in blood sugar levels or inflammation or some other direct effect on the cardiovascular system.

What is apparent is that GLP-1 agonists look poised to have an impact across a lengthening list of diseases. Semaglutide has been shown to reduce the risk of complications in patients with chronic kidney disease, an indication for which it has been filed for approval, while tirzepatide has been shown to improve obstructive sleep apnoea associated with obesity.

Meanwhile, GLP-1 drugs have also shown signs of efficacy in metabolic dysfunction-associated steatohepatitis (MASH), obesity-related cancers, Parkinson's, Alzheimer's, and nicotine addiction.