Indianapolis, Indiana, is on a roll lately. On December 6, the Indiana Hoosiers beat the Ohio State Buckeyes to win their first Big 10 championship since 1967. Less than a week later, Indianapolis-based pharmaceutical giant Eli Lilly announced shocking results for a 68-week trial of their new weight loss drug, retatrutide.

How shocking? Those at the highest dosage who completed the trial experienced an average 28.7% weight reduction! Even counting those who dropped out before the trial ended, weight loss was 23.7%. The numbers were better than expected, sending the company’s stock up 3%. Weight loss drugs are expected to be a $100 billion dollar annual market by 2030.

What’s in retatrutide that makes it different from other GLP-1 receptor agonist drugs? Retatrutide is a blend of three different hunger-regulating hormones: A GLP-1 drug, A GIP drug, and glucagon.

Eli Lilly is the manufacturer of Zepbound for weight loss, based on a blend of the GLP-1 drug tirzepatide and a GIP drug. They also make Mounjaro for type 2 diabetes, a blend of a GLP-1 drug and a GIP drug. The addition of glucagon makes retatrutide a “three-G” drug, with the best weight loss results of any of the GLP-1 drugs to date.

In July of this year, researchers from the Kalpana Chawla Government Medical College in Karnal, India, conducted a systematic review of clinical trials involving retatrutide. The studies involved 510 people receiving weekly injections of retatrutide and 130 who received a placebo.

The conclusions of the systematic review provide a vague endorsement for continued trials of retatrutide, without citing any average weight loss percentages:

Weekly subcutaneous injections of retatrutide in obese patients resulted in significant weight loss and metabolic improvements compared to a placebo.

A similar finding came from a systematic review of clinical trials involving retatrutide published last year by Metabolism Open. Researchers there commented on the side effects: “an increase in non-severe gastrointestinal and hypersensitivity adverse events.”

Eli Lilly reports that 18% of test subjects on the highest dosage of retatrutide stopped treatment due to the side effects. JPMorgan pharmaceutical industry analyst Chris Schott told CNBC that patient tolerability was “somewhat worse versus Zepbound.”

A phase 2 trial of retatrutide for obesity published in The New England Journal of Medicine in June 2023 provides further details on the weight-shedding power of this triple-G drug. After 48 weeks of weekly injections, here is the average weight loss obese patients experienced:

• 1 mg group lost 8.7%
• 4 mg group lost 17.1%
• 8 mg group lost 22.8%
• 12 mg group lost 24.2%
• placebo group lost 2.1%

For the 4 mg group, 75% of participants lost 10% or more of body weight. For the 8 mg group, that number jumps to 91%. For the 12 mg group, it improves to 93%. “Body-weight reductions of 20% or more and 25% or more were more common among the participants who received retatrutide at a dose of at least 4 mg,” researchers note.

The adverse side effects were mostly gastrointestinal and, researchers say, proportional to dosage levels. “Discontinuation of retatrutide or placebo due to adverse events occurred in 6 to 16% of the participants who received retatrutide and in none of the participants who received placebo,” they write, summarizing:

The most frequently reported adverse events were gastrointestinal (nausea, diarrhea, vomiting, and constipation)… Gastrointestinal adverse events in the retatrutide groups occurred primarily during dose escalation, were predominantly mild to moderate in severity, were more frequent in higher-dose groups, were partially mitigated by the use of a lower starting dose (2 mg vs. 4 mg), and were the most common adverse events leading to treatment discontinuation.

In the new Eli Lilly study, 18% of those in the highest dosage group stopped due to the side effects. Of those with a BMI above 35 taking the highest dosage, 12% dropped out of the trial. “Around 43% of patients on the highest dose experienced nausea,” while roughly 33% had diarrhea and 21% experienced vomiting. According to analyst Chris Schott, those rates are on par with Zepbound and Wegovy.

The response of the medical community to the new Eli Lilly study is enthusiastic. Dr. Caroline Apovian, co-director of the Center for Weight Management and Wellness at Brigham and Women’s Hospital in Boston, told CNBC, “Now we have a drug that rivals the weight loss benefits of surgery.”

One of the more astonishing results in Eli Lilly’s new study is the effect of retatrutide on knee osteoarthritis. “More than 1 in 8 patients who took the drug were completely free from knee pain by the end of the trial,” Eli Lilly told CNBC, with an average pain reduction of 62.6%.

It remains to be tested whether retatrutide is effective with other addictions besides eating addiction. There may soon be another three-G drug competing with retatrutide. Novo Nordisk, maker of the GLP-1 drugs Ozempic and Wegovy, is developing its own three-G drug in collaboration with United Laboratories International, a Chinese pharmaceutical giant.

Written by Steve O’Keefe. First published December 18, 2025.

Sources:

“Eli Lilly’s next-generation obesity drug delivers strong weight loss, reduces knee pain in late-stage trial,” CNBC, December 11, 2025.

“Efficacy and safety of retatrutide for the treatment of obesity: a systematic review of clinical trials,” Journal of Basic and Clinical Physiology and Pharmacology, July 21, 2025.

“Effects of once-weekly subcutaneous retatrutide on weight and metabolic markers: A systematic review and meta-analysis of randomized controlled trials,” Metabolism Open, December 2024.

“Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial,” The New England Journal of Medicine, June 26, 2023.

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