Too much of a good thing?
Participants taking the highest dose of Eli Lilly’s new GLP-1 drug lost an average of 28.7% of their body weight in a late-stage trial, putting it on track to be a heavyweight in the crowded world of weight-loss and diabetes treatments.
But in a surprising twist, top-line results show higher dropout rates than in earlier trials, with at least some participants worried about just how slim they were becoming.
Like Lilly’s other diabetes and obesity drugs, Mounjaro and Zepbound, retatrutide mimics GLP-1 and GIP, hormones the body produces naturally to curb appetite, slow digestion, and lower blood sugar.
But this experimental drug goes a step further by adding a third hormone, glucagon, earning it the nickname “Triple G.”
In the Phase 3 “Triumph-4” trial, Lilly tested two doses of retatrutide against a placebo in 445 people who were obese or overweight and also had knee osteoarthritis.
After 68 weeks of once-weekly injections, patients who completed the higher 12mg dose lost an average of 71.2 pounds. Those who finished the lower 9mg dose lost 64.2 pounds on average, or 26.4% of their body weight.
That’s notably more than current weight-loss drugs on the market. For comparison, once weekly injections of Lilly’s Zepbound has helped participants shed 15% to 21% of their starting weight after 72 weeks in clinical trials.
“This is beyond what we see with any other medication on the market, and it is what we see with some bariatric surgeries,” Dr. Jennah Siwak, an obesity medicine expert, said in a TikTok last December after the trial’s topline results dropped. “This is insane.”
But not everyone made it to the finish line.
A whopping 18.2% of participants on the 12mg dose dropped out due to adverse events, while 12.2% of those on the 9mg dose left early. By comparison, just 4% of the placebo group quit before the study wrapped up.
For context, in a previous Phase 3 trial of Zepbound, the highest-dose group saw a dropout rate of only 6.2% due to adverse events.
The full data hasn’t been published yet, so it’s unclear why each patient left. Lilly noted, however, that dropouts were “highly correlated with baseline BMI and included discontinuations for perceived excessive weight loss.”
The company also pointed out that participants with a higher BMI were less likely to drop out.
Limiting the analysis to those with a BMI of 35 or higher brought dropout rates down to 8.8% for the low dose and 12.1% for the high dose, compared with 4.8% for placebo — closer to the rates seen in Zepbound trials, but still higher.
The Post has reached out to Eli Lilly for comment on the participants who dropped out of the trial.
Other side effects were reported as well. Dysesthesia, an unpleasant tingling or burning sensation in the skin, affected about 1 in 5 patients on the 12mg dose and 1 in 13 on the 9mg dose — though Lilly said most cases were mild and rarely caused participants to drop out.
Gastrointestinal issues were common, including diarrhea, constipation, vomiting and decreased appetite, which are often seen with GLP-1 drugs.
But retatrutide also showed some extra perks beyond its jaw-dropping weight-loss results. The experimental drug also appeared to ease knee pain, with both doses showing about a 75% drop in pain scores, compared with a 40% decline in the placebo group.
“People with obesity and knee osteoarthritis often live with pain and restricted mobility, and may eventually require total joint replacement,” Dr. Kenneth Custer, executive vice president and president od Lilly Cardiometabolic Health, said in a statement last year announcing the trial results.
“With seven additional Phase 3 readouts expected in 2026, we believe retatrutide could become an important option for patients with significant weight loss needs and certain complications, including knee osteoarthritis.”
