New Lilly combo tops tirzepatide for weight loss in diabetes

Eli Lilly's bid to dominate the next generation of weight-loss therapies has been strengthened by data on a new combination therapy that combines its GIP/GLP-1 agonist tirzepatide with amylin-targeting eloralintide.

The therapy – known as EloraTZP – achieved better weight loss over 48 weeks than tirzepatide, Lilly's multibillion-dollar incretin therapy sold as Mounjaro for type 2 diabetes (T2D) and Zepbound for weight loss alone, in the head-to-head phase 2 trial, which enrolled 367 adults with T2D and obesity or overweight.

The result presented at the EASD congress in Milan, Italy, adds another strand to Lilly's bow in incretin therapies for cardiometabolic disorders and intensifies its rivalry with Novo in the category, and comes shortly after it reported strong results with another triple therapy – retatrutide – at the conference.

Subjects taking a 9 mg weekly injection of EloraTZP lost up to 23.3% of their body weight, compared to 14.8% with a high (15 mg) weekly dose of tirzepatide. The triple agonist was also more effective at reducing blood glucose levels, reducing the biomarker HbA1c by an average of 2.9% over the 48-week follow-up period, versus 2.4% with tirzepatide.

Analysts at Citi said the results show "strong combination proof-of-concept and broaden Lilly's cardiometabolic portfolio beyond today's incretin standards," with the efficacy in this T2D population "comparable to tirzepatide in patients without T2D." That is a significant finding, as weight-loss therapies are typically less effective in people with diabetes.

Lilly is losing no time in advancing EloraTZP into phase 3 testing on the back of the mid-stage result, and said pivotal trials will start before the end of the year. The company has suggested that EloraTZP could improve on the impressive weight loss seen with retatrutide in non-diabetic and diabetic people with obesity or overweight.

"Obesity and type 2 diabetes are interconnected, and we are seeing the potential benefit of targeting multiple hormonal pathways to address both," said Liana Billings of Endeavor Health in the US, who was the lead author in the study.

"Across the dose combinations studied with eloralintide and tirzepatide, participants had substantial weight loss alongside meaningful reductions in A1C," she added. "These are outcomes that matter to patients."

One issue that could undermine the new triple is tolerability, as the treatment discontinuation rate for the most effective dose was 27% – mainly due to gastrointestinal side effects – which compared to 2.9% with tirzepatide and 16.7% with placebo.

Lilly also intends to continue running trials of eloralintide alone, after seeing weight reduction of 11% to 12% when used as a monotherapy in the study, with a discontinuation rate of 10.8% overall.

Analysts are giving Lilly the edge over Novo as the next generation of incretin-based obesity and diabetes therapies approach the market, as the Danish company's amylin and GLP-1-targeted CagriSema (cagrilintide and semaglutide) – already filed for approval – has failed to differentiate itself from Zepbound in clinical testing.

Longer term, Novo is planning to launch a cagrilintide-only product and a high-dose version of CagriSema in 2028, and a single-molecule follow-up, zenagamtide (formerly amycretin), which is being developed in both injectable and oral formulations.

Cardiovascular data with Foundayo

Also at EASD, Lilly reported the results of the ACHIEVE-4 cardiovascular outcomes study with its oral GLP-1 agonist Foundayo (orforglipron), showing that the risk of cardiovascular death, heart attack, stroke, or hospitalisation for unstable sudden chest pain (MACE-4) was 16% lower for Foundayo compared to the active control therapy, insulin glargine, in adults with T2D and obesity/overweight who were at increased cardiovascular risk.

Patients taking Lilly's drug also had a 23% lower risk of cardiovascular death, heart attack, or stroke (MACE-3), with additional improvements in weight, body composition, and blood glucose control and a 57% lower risk of all-cause death.

The results could help build momentum for Foundayo, which has lagged behind Novo's rival Wegovy pill (semaglutide) since launch.

Photo by Sincerely Media on Unsplash