Triple Threat: Novel Agent Shows Potent T2D Weight Loss

STOCKHOLM — First came the GLP-1 receptor agonists as treatments for patients with type 2 diabetes, then came tirzepatide (Mounjaro) which added a second incretin agonism for the receptor to the glucose-dependent insulinotropic polypeptide (GIP). Now coming onto the clinical scene is a molecule with triple agonism to the GLP-1 receptor, the GIP receptor, and to the glucagon receptor.

That molecule, LY3437943, showed reasonable safety and tolerability and an apparent incremental uptick in weight loss compared with the approved incretin-based agents for people with type 2 diabetes in a 12-week, dose-ranging study involving 52 patients with type 2 diabetes who received the new agent.

The 12 people who uptitrated for a total of 12 weeks and reached the highest tested dose of LY3437943, 12 mg, injected once weekly during the final 4 weeks, showed an average weight loss of 8.65 kg, while the 11 patients who maxed out at a weekly dose of 6 mg of LY3437943 had an average 12-week weight loss of 7.52 kg, Zvonko Milicevic, MD, reported at the annual meeting of the European Association for the Study of Diabetes.

Fifteen more participants received placebo and five received a comparator GLP-1 receptor agonist. All 72 patients in the study were also already on treatment with metformin when they entered, and they were maintained on metformin throughout the study period.

The new agent showed “greater weight loss efficacy than currently approved medications,” said Milicevic, a staff researcher who works in Vienna for Eli Lilly, the company developing LY3437943.

Really Impressive Weight Loss

Martin Haluzik, MD, who chaired the session where Milicevic spoke, agreed. “The data, especially for weight reduction, were really impressive,” Haluzik said in an interview. “It looks stronger than the best we have at the moment,” the dual incretin agonist tirzepatide, he added.

Cross-study comparisons are very unreliable, but to put the weight loss seen with LY3437943 in perspective, the 12-week weight reduction that occurred with the highest dose of tirzepatide tested (15 mg/weekly) in the pivotal SURPASS-2 trial with 1,879 randomized patients with type 2 diabetes was an average of roughly 5 kg, while the comparator of 1 mg weekly of semaglutide (Ozempic) tested in the same study produced an average weight loss of about 4 kg.

Other notable efficacy results for LY3437943 after 12 weeks on treatment included an average reduction in hemoglobin A1c from baseline of 1.90%, achieved in the group that received 6 mg weekly as their maximum dose for 8 weeks after a 4-week run-in at a lower dose; a reduction in systolic blood pressure of 7.99 mm Hg on the 6-mg maximum weekly dose and of 12.06 mm Hg on the maximum 12-mg weekly dose; and “robust” reductions in lipids including cuts from baseline of about 40% for both triglycerides and very-LDL cholesterol, Milicevic reported.

Adverse Effects Resemble Approved Incretin-Based Agents

The study, which ran at four U.S. sites, had a primary objective of safety assessment, and Milicevic said the results showed acceptable safety and tolerability consistent with the glucagon-like peptide-1 (GLP-1) receptor agonists and tirzepatide. Like those agents, LY3437943 caused primarily mild gastrointestinal adverse effects such as nausea and diarrhea. Of the 52 patients in the study who received the triple agonist, 4 discontinued treatment because of a treatment-emergent adverse effect, including 1 patient in the subgroup who received the maximum dose.

The only concerning adverse effect noted by Haluzik was the average increase in heart rate from baseline of 10.26 beats/min in the subgroup that received the maximum dose, roughly twice the increase seen with tirzepatide and semaglutide in SURPASS-2. The average heart rate increase was about half that, 5.30 beats/min compared with baseline, in the subgroup that received a maximum weekly dose of 6 mg.

Overall, the results showed “no major adverse effects that might hamper use,” said Haluzik, an endocrinologist and professor at Charles University in Prague.

Two phase 2 studies of LY3437943 are underway and are scheduled to finish before the end of 2022. They include a study of about 300 people with type 2 diabetes that’s running at 43 U.S. sites, and a second study of about 500 people with overweight or obesity running at 28 U.S. sites.

The study was sponsored by Eli Lilly, the company developing LY3437943. Milicevic is an employee of and stockholder of Eli Lilly. Haluzik has been an adviser to, consultant to, and received honoraria and research support from Eli Lilly. He has had similar relationships with Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Johnson & Johnson, Mundipharma, Novo Nordisk, and Sanofi.

This article originally appeared on, part of the Medscape Professional Network.

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