Eli Lilly’s ‘triple G’ agonist, retatrutide, has secured another late-stage win in obesity, though analysts question whether the drug will outcompete the company’s market-leading medication, tirzepatide.
In the Phase III TRIUMPH-1 study (NCT05929066) which is one of the seven trials in retatrutide’s late-stage programme, Lilly pitted three doses (4mg, 9mg and 12mg) of the triple glucagon, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) agonist against placebo in obese adults with at least one weight-related comorbidity. The study met its primary and key secondary endpoints.
After 80 weeks of treatment, patients randomised to the respective doses of retatrutide all experienced significant weight loss from baseline over placebo, with those given the highest dose of the drug losing 28.3% of their body weight compared with the 2.2% average in the placebo group. According to senior GlobalData analyst, Shehroz Mahmood, this result establishes retatrutide as “the highest-efficacy pharmacological weight loss agent to date in a large pivotal trial”.
The 12mg dose of retatrutide also prompted 45.3% of patients to lose more than 30% of their body weight – an outcome Lilly says is commonly associated with weight loss surgery. 37.9% and 15.3% of patients on the medium and low doses, respectively, achieved this result.
The results come after retatrutide met its primary endpoints in a Phase III diabetes trial readout in March 2026.
Alongside its weight loss efficacy, retatrutide offered significant baseline reductions in cardiovascular risk factors, including waist circumference, triglyceride levels, systolic blood pressure, non-HDL cholesterol and high-sensitivity C-reactive protein (hsCRP). Lilly is yet to share specific data around these secondary endpoints.
Retatrutide's tolerability raises questions
While the triple G agonist was proven generally tolerable and safe, 11.3% of the high-dose cohort did discontinue treatment due to adverse events (AEs), versus 4.9% in the placebo group – highlighting potential concerns around the number of side effects at high doses. According to William Blair analysts, retatrutide’s tolerability profile could confine the drug to use in patients at the higher end of the BMI spectrum, while Lilly’s best-selling injectable, tirzepatide, will “continue to serve as the go-to medication, due to its balanced efficacy and tolerability profile.”
Lilly sells tirzepatide under the brand name Zepbound in the US for obesity. In international markets, it is known as Mounjaro for both obesity and diabetes. In 2025, Mounjaro generated approximately $23bn in 2025, while Zepbound made $13.5bn.
Will retatrutide shift the injectable weight loss paradigm?
Though Mahmood highlights the TRIUMPH-1 results as generally “very impressive”, he notes that the further data Lilly plans to present at the 2026 American Diabetes Association (ADA) congress will be critical in determining the drug’s potential future on the obesity market.
This is because the industry is yet to see if the drug’s weight loss efficacy will translate into broader cardiometabolic benefit without adverse effects on lean body mass or bone mineral density – endpoints he says are attracting increasing scrutiny as the obesity field matures beyond weight loss as a standalone outcome.
Based on retatrutide’s efficacy in the TRIUMPH-1 study, Mahmood says the drug holds the potential to be a game-changer in obesity, though adoption may not be as strong as peer therapies like Zepbound or Novo Nordisk’s Wegovy (semaglutide), since many patients and doctors are already familiar with these drugs.
However, Mahmood points to retatrutide’s differentiated, three-pronged approach to weight loss that could hold the potential to better address obesity-related comorbidities like metabolic dysfunction-associated steatohepatitis (MASH), as the glucagon component could offer advantages that neither Zepbound or Wegovy can achieve through GLP-1 or GIP pathway modulation alone.
