Eli Lilly Advances Weight-Loss Pipeline with Retatrutide Results and Orforglipron Stockpiling

Eli Lilly and Company announced positive topline results from the Phase 3 TRIUMPH-4 clinical trial evaluating retatrutide, a first-in-class GIP, GLP-1 and glucagon triple hormone receptor agonist, in adults with obesity or overweight and knee osteoarthritis. Each dose of retatrutide (9 mg and 12 mg) met all primary and key secondary endpoints, delivering significant weight loss and improvements in pain and physical function at 68 weeks.

In this global registration trial, where 84.0% of participants had a baseline BMI of ≥35 kg/m², retatrutide lowered weight by up to an average of 28.7% (71.2 lbs) and reduced pain by up to an average of 4.5 points (75.8%) using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score. For weight loss thresholds, 58.6% of patients on the 12 mg dose achieved ≥25% weight loss, 39.4% achieved ≥30% weight loss, and 23.7% achieved ≥35% weight loss, compared to 1.3%, 0.8%, and 0.0% with placebo, respectively.

Additionally, 67.7% to 73.0% of patients on retatrutide achieved ≥70% reduction in WOMAC pain compared to 26.2% on placebo. In a post-hoc analysis, 14.1% of patients on retatrutide 9 mg and 12.0% patients on retatrutide 12 mg were completely free of knee pain at 68 weeks compared to 4.2% on placebo. Retatrutide also reduced known markers of cardiovascular risk, including non-HDL cholesterol, triglycerides, and high-sensitivity C-reactive protein (hsCRP), and at the highest dose lowered systolic blood pressure by 14.0 mmHg.

For the treatment-regimen estimand, each dose level of retatrutide led to statistically significant improvements in both co-primary and all secondary endpoints. The treatment-regimen estimand results for the co-primary endpoints were: percent change in body weight of -20.0% (-22.9 kg; -50.5 lbs; 9 mg); -23.7% (-27.2 kg; -60.0 lbs; 12 mg) and -4.6% (-5.3 kg; -11.7 lbs; placebo), and change in WOMAC pain subscale score of -4.0 points (-67.2%; 9 mg), -3.7 points (-62.6%; 12 mg) and -2.1 points (-35.1%; placebo).

The most common adverse events among participants treated with retatrutide (9 mg and 12 mg, respectively) were nausea (38.1% and 43.2%) vs. 10.7% with placebo, diarrhea (34.7% and 33.1%) vs. 13.4% with placebo, constipation (21.8% and 25.0%) vs. 8.7% with placebo, vomiting (20.4% and 20.9%) vs. 0.0% with placebo, and decreased appetite (19.0% and 18.2%) vs. 9.4% with placebo. Dysesthesia occurred in 8.8% and 20.9% (9 mg and 12 mg, respectively) of patients treated with retatrutide, compared to 0.7% with placebo. These dysesthesia events were generally mild and rarely led to treatment discontinuation.

Overall treatment discontinuation rates were similar across the retatrutide and placebo treatment arms. Discontinuation rates due to adverse events were 12.2% and 18.2% with retatrutide 9 mg and 12 mg, respectively, compared to 4.0% with placebo. These rates were highly correlated with baseline BMI and included discontinuations for perceived excessive weight loss. For patients with a baseline BMI ≥35, discontinuation rates due to adverse events were 8.8% and 12.1% for the 9 mg and 12 mg doses, respectively. Seven additional Phase 3 readouts for retatrutide are expected in 2026.

Separately, Eli Lilly is stockpiling its oral GLP-1 drug orforglipron for obesity treatment while awaiting approval from the US Food and Drug Administration. As of December 31, the company had secured $1.5 billion in "advance purchase reserves." Eli Lilly aims to avoid a shortage of orforglipron upon market launch, as happened with its injectable diabetes and obesity drugs Mounjaro and Zepbound. Although Eli Lilly and its main competitor in the GLP-1 agonist field, Denmark's Novo Nordisk, have fully resolved supply issues, the initial shortages contributed to the emergence of an entire industry producing such drugs, which has proven difficult to control.

In November, Eli Lilly received a priority review voucher from the regulator for orforglipron. This procedure, aimed at significantly speeding up the review of products that "address US healthcare priorities," has already been criticized for its potential to facilitate corruption and undermine public trust in the FDA's review standards. Nevertheless, despite a promise to review the drug within one to two months, the target decision date for orforglipron has been moved to April 10th. If approved, orforglipron will immediately compete with the oral version of Novo Nordisk's Wegovy, sales of which began in the United States in January.

Analysts have recognized orforglipron as one of the most anticipated launches of 2026. According to forecasts from Evaluate, sales of Eli Lilly's new drug will reach $11.8 billion by 2032, which, however, falls short of the projected figure for Novo Nordisk's latest development, CagriSema.

The chief scientific and medical officer stated that the company achieved positive outcomes for nearly all R&D key events in 2025, a rare set of results in the industry. This includes not only progress in the company's weight management and diabetes therapies, but also advancements in cancer and Alzheimer's disease treatments. Eli Lilly also reported positive phase 3 results for its cancer drug Jaypirca and promising long-term data for its Alzheimer's disease treatment Kisunla. The company is also investing in artificial intelligence (AI) to further improve its clinical trial success rate, building what will become the industry's largest AI supercomputer.