Retatrutide's phase 2 data show 24.2% weight loss, the biggest yet

Eli Lilly said on June 26, 2023 that its investigational obesity drug retatrutide produced a mean weight reduction of up to 17.5% at 24 weeks, the trial's main goal, and up to 24.2% at 48 weeks in a secondary measure ^[1]. The phase 2 results were presented at the American Diabetes Association's 83rd Scientific Sessions in San Diego and published the same day in The New England Journal of Medicine ^[1][2].

Retatrutide is a once-weekly injection that acts on three hormone receptors — GLP-1, GIP and glucagon — which is why Lilly has nicknamed it "triple G" ^[2]. That is one more target than tirzepatide (Mounjaro/Zepbound), which acts on GLP-1 and GIP, and two more than semaglutide (Ozempic/Wegovy/Rybelsus), which acts on GLP-1 alone ^[2].

What the trial measured

The study (NCT04881760) randomized 338 adults in the United States who had obesity, or overweight with a weight-related condition, but not type 2 diabetes ^[1]. Participants needed a body mass index of at least 27 to qualify as overweight for the trial ^[1]. They were assigned to placebo or to retatrutide at 1 mg, 4 mg, 8 mg or 12 mg, using different starting doses and escalation schedules, injected under the skin once a week for 48 weeks ^[1]. The primary endpoint was percent change in body weight at 24 weeks ^[1].

The 17.5% average at 24 weeks worked out to about 41.2 pounds (18.7 kg) ^[1]. The 48-week figure of 24.2% translated to roughly 57.8 pounds (26.2 kg) ^[1]. Both numbers are least-squares means from an analysis that excluded data collected after a participant permanently stopped treatment ^[1].

Lilly said the safety profile looked similar to other incretin-based drugs ^[1]. Gastrointestinal side effects were the most commonly reported adverse events, were generally mild to moderate, and usually happened while doses were being increased ^[1]. Reuters reported those effects included nausea and vomiting ^[2]. As exploratory endpoints, the trial also recorded improvements at weeks 24 and 48 in systolic and diastolic blood pressure, triglycerides, LDL cholesterol, total cholesterol, HbA1c, and fasting glucose and insulin ^[1].

Ania Jastreboff, MD, PhD, of Yale School of Medicine, said participants on the highest dose lost an average of about 58 pounds over 11 months and "had not yet reached a weight plateau at the time the study ended," suggesting "full weight reduction efficacy was not yet attained" ^[1].

Why it matters for patients

For context, Lilly reported in 2022 that a trial of tirzepatide in people with obesity or overweight produced 22.5% weight loss after 72 weeks ^[2]. Retatrutide's 24.2% came after 48 weeks, though the two results come from separate trials and were not compared head-to-head in any study described in these sources ^[1][2].

Just as important is what this data does not settle. Phase 2 trials are mid-stage studies designed mainly to test doses, safety signals and early effectiveness in a few hundred people. This one enrolled 338 participants and excluded people with type 2 diabetes ^[1]. Longer and larger trials are needed to know whether the weight loss holds, how many people can tolerate the higher doses over time, and whether rarer risks emerge. Lilly's own release cautions there is no guarantee retatrutide will prove safe and effective, or that it will win regulatory approval ^[1].

The drug was not available by prescription at the time of this announcement, and these sources give no timeline for a filing or launch. Anyone hearing about retatrutide in 2023 was hearing about a research compound, not a pharmacy option.

What happens next

Lilly said it would move retatrutide into the TRIUMPH phase 3 program, which goes beyond weight alone ^[1][2]. TRIUMPH-1 covers adults without type 2 diabetes who have obesity or overweight, including those with obstructive sleep apnea and osteoarthritis; TRIUMPH-2 covers people with type 2 diabetes; TRIUMPH-3 focuses on Class II or Class III obesity with established cardiovascular disease; and TRIUMPH-4 focuses on osteoarthritis ^[1]. Readout dates for those trials were not given in these sources ^[1].