Eli Lilly's 3-Target Drug Achieves New Weight Loss Milestone

A drug candidate from Eli Lilly, designed to target three metabolic pathways, has demonstrated significant weight loss in a late-stage clinical trial. Participants experienced an average reduction of 28.7% in body weight, marking a new benchmark in the competitive field of next-generation obesity medications.

However, preliminary Phase 3 results also indicated a high percentage of patients discontinuing the treatment. This will be an important factor to monitor in the coming year for retatrutide, the weekly injectable medication. The data, released on Thursday, represents the initial findings from a comprehensive clinical trial program, with seven additional Phase 3 trial readouts anticipated in 2026.

Lilly has established itself as a prominent player in the obesity drug market with Zepbound, a weekly injectable whose main component is a peptide engineered to bind to and activate two gut receptors, GLP-1 and GIP. Retatrutide impacts these two targets, with the addition of a third, the glucagon receptor. Health tracking apps like Shotlee can help monitor the changes in body composition during this kind of treatment.

Study Details and Results

The results made public Thursday are from a 68-week Phase 3 trial involving two dose levels of retatrutide in adults who were obese or overweight. The 445 participants in the study did not have diabetes but did have knee osteoarthritis. In addition to assessing the drug's impact on weight loss, the study also evaluated its effect on pain and joint movement as a co-primary endpoint. All participants began with a 2 mg weekly dose, which was increased every four weeks until the target dose was achieved.

The 28.7% average weight loss (32.3 kg or 71.2 pounds) was observed with the 12 mg dose, which was the larger of the two doses assessed. Weight loss in the placebo group averaged 2.1% (2.1 kg or 4.6 pounds). According to a measurement scale for pain, where higher scores indicate greater discomfort and disability, the treatment resulted in an average 4.4 point decrease in score (74.3%), while the placebo group saw an average decrease of 2.4 points (40.3%).

Adverse Events and Discontinuation Rates

The most frequently reported adverse events in the study were nausea, diarrhea, constipation, and decreased appetite. These side effects are consistent with those of currently available obesity medications. The discontinuation rate for the high dose was 18.2%, compared to 4% for the placebo. Lilly reported that discontinuations were strongly linked to participants' initial body mass index and included discontinuations due to perceived excessive weight loss. The company intends to present more detailed clinical trial results at a future medical conference and in a peer-reviewed publication.

Analyst Perspectives

Leerink Partners analyst David Risinger noted in a research report that the retatrutide results aligned with the firm's expectations for weight loss in the mid-to-high 20% range. In comparison, the Phase 3 trial of Zepbound demonstrated a 22% absolute weight loss for the 15 mg dose, measured at 68 weeks. Risinger indicated that the gastrointestinal adverse events observed in the retatrutide study were comparable to those seen with Zepbound, but also highlighted the higher rate of discontinuations: 18.2% for retatrutide versus 6.2% for 15 mg Zepbound.

He concluded that retatrutide provides additional benefits for patients and raises the standard for future competitors to tirzepatide.

Ongoing Clinical Trials

Retatrutide's extensive Phase 3 program has enrolled over 5,800 participants. These trials are evaluating the drug's impact on obesity along with at least one weight-related health issue, such as type 2 diabetes, knee osteoarthritis, moderate-to-severe obstructive sleep apnea, chronic low back pain, cardiovascular and renal outcomes, and metabolic dysfunction-associated steatotic liver disease.