Eloralintide boosts tirzepatide weight loss to 23% in T2D

Clinical takeaway: Phase 3 trials are planned to start by the end of 2026 for a co-formulation of the two drugs with an optimized escalation schedule. Side effects and related discontinuations continue to be an issue, so watch for that. 

Clinicians treating obesity in patients with type 2 diabetes face a group in which substantial, sustained weight loss has been difficult to reach. Tirzepatide, a dual incretin agonist approved for both conditions, is now being tested with a second hormone pathway layered on top. 

Eloralintide, a selective amylin receptor agonist, has the potential to cut calorie intake, likely by promoting fullness. Tirzepatide activates receptors for two gut hormones, glucose-dependent insulinotropic polypeptide (GIP) and GLP-1, which are released after eating and help regulate hunger and blood sugar. An earlier phase 2 study in adults with obesity but without diabetes reported weight loss. This phase 2b trial extends that work to patients who have diabetes, testing eloralintide alongside tirzepatide. 

Participants on the highest dose combination, eloralintide 9 mg plus tirzepatide 15 mg, lost an average of 23.3% of body weight (54.1 lbs) at 48 weeks, if they stayed on treatment throughout. Tirzepatide 15 mg alone produced 14.8% (34.4 lbs), a secondary comparison. Placebo, the primary comparator, produced 3.0%. The lowest dose combination, which paired eloralintide 3 mg with tirzepatide 5 mg, reached 13.2%, below tirzepatide 15 mg alone. A1C fell an average of 2.9 percentage points on the highest combination from a baseline of 8.1%, versus 2.4 percentage points on tirzepatide alone. 

Gastrointestinal events were the most common adverse effects, mostly mild or moderate and concentrated in dose escalation. They occurred more often in the combination arms than with either drug alone. Discontinuation because of adverse events ranged from 10.8% to 27.0% across the combination arms, versus 0% to 10.8% on eloralintide alone and 2.9% on tirzepatide alone. The rate with placebo rate was 16.7%.

The phase 2b trial randomized 367 adults in the US and Argentina who had obesity or overweight and type 2 diabetes. It was double-blind and compared four eloralintide and tirzepatide combinations with eloralintide alone, tirzepatide 15 mg alone, and placebo. The primary endpoint was percent change in body weight versus placebo at 48 weeks, with A1C change as a secondary endpoint. 

This is not the only late-stage investigational approach across multiple mechanisms within weight loss. CagriSema, which pairs the amylin analogue cagrilintide with semaglutide, awaits an FDA decision expected by late 2026. It missed noninferiority to tirzepatide 15 mg in an open-label phase 3 trial but beat low-dose tirzepatide in topline results in type 2 diabetes. Retatrutide, a triple hormone receptor agonist, produced substantial weight loss and glycemic improvement in adults with obesity or overweight and type 2 diabetes. Amgen's maridebart cafraglutide, a monthly injection that activates the GLP-1 receptor while blocking the GIP receptor, is in phase 3 trials that include adults with type 2 diabetes. 

"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, MD, director of clinical and genetics research in diabetes and cardiometabolic disease at Endeavor Health, and the trial's lead author. "Across the dose combinations studied with eloralintide and tirzepatide, participants had substantial weight loss alongside meaningful reductions in A1C." 

Source: Eli Lilly and Company. (2026 Sep 30). Lilly's EloraTZP (combination of eloralintide and tirzepatide) delivered greater weight loss and A1C reduction vs. tirzepatide 15 mg in adults with obesity and type 2 diabetes