‘This raises the bar’: Phase 2 data show 24% weight loss with triple-agonist retatrutide
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Key takeaways:
- Retatrutide, a triple-hormone agonist, was associated with 24.2% weight loss at the highest dose for people with obesity.
- The GLP-1/GIP/glucagon agonist also reduced HbA1c and body weight in type 2 diabetes.
SAN DIEGO — Adults with obesity who received the highest dose of a once-weekly injection of retatrutide lost an average of 24.2% of their body weight at 48 weeks compared with placebo, data from a phase 2 study show.
With the highest 12 mg dose of retatrutide (Eli Lilly) — an investigational GLP-1, glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptor agonist — nearly two-thirds of participants lost 20% or more of their body weight, half of participants lost 25% of their body weight and one-quarter of participants lost more than 30% of their body weight, according to Ania M. Jastreboff, MD, PhD, associate professor of medicine and pediatrics (endocrinology) at Yale University School of Medicine, director of weight management and obesity prevention at the Yale Stress Center and co-director of the Yale Center for Weight Management.
“We have not seen results like this before in a trial of less than 1-year duration with an anti-obesity medication,” Jastreboff said during a press conference at the American Diabetes association Scientific Sessions.
The results, if confirmed in a larger phase 3 study, could be revolutionary for people with obesity, Carel Le Roux, MD, PhD, professor of experimental pathology at University College Dublin, said during a panel discussion at a press conference.
“This raises the bar. This is way beyond my wildest dreams,” Le Roux said. “To see something like this in my lifetime is impressive.”
Weight loss continued at 48 weeks
Jastreboff and colleagues analyzed data from 338 adults without diabetes who had a BMI of 30 kg/m2 or greater or BMI of 27 kg/m2 to 30 kg/m2 with at least one weight-related condition. Researchers randomly assigned participants to 1 mg, 4 mg, 8 mg or 12 mg retatrutide or placebo once weekly for 48 weeks. The primary endpoint was percent change in body weight from baseline to 24 weeks. Secondary endpoints included percent change in body weight from baseline to 48 weeks and a weight reduction of at least 5%, 10% or 15%. Researchers also assessed safety.
The weight-loss findings were simultaneously published in The New England Journal of Medicine.
At 24 weeks, the least squares mean percentage change in body weight with retatrutide was –7.2% for the 1 mg group, –12.9% for the combined 4 mg group, –17.3% for the combined 8 mg group and –17.5% for the 12 mg group, compared with –1.6% for the placebo group.
At 48 weeks, the least squares mean percentage change with retatrutide was –8.7% for the 1 mg group, –17.1% for the combined 4 mg group, –22.8% for the combined 8 mg group and –24.2% for the 12 mg group, compared with –2.1% for the placebo group.
At 48 weeks, weight reductions of at least 5%, 10% and 15% occurred for 100%, 93% and 83% of participants, respectively, among those who received the 12 mg dose, Jastreboff said.
“Please note, at this point [48 weeks] the weight-loss curve had not yet plateaued,” Jastreboff said during the press conference. “Meaning that participants were losing weight at the time the trial product was discontinued.”
In results stratified by sex, the mean percentage change in body weight was greater for women vs. men, Jastreboff said, with mean weight loss of 28.5% vs. 21.9% for women and men, respectively.
“There have been post hoc analyses on this, and it looks like women have been losing more weight than men,” Jastreboff said. “Now we have to look at the mechanisms, what may be contributing to these findings.”
While presenting cardiometabolic outcomes, Jastreboff said participants who received the 12 mg dose of retatrutide also experienced a mean 40% reduction in triglyceride levels and a mean 22% reduction in LDL cholesterol at 48 weeks, in addition to reductions in HbA1c and blood pressure.
The most common adverse events reported by participants in the retatrutide group were gastrointestinal, dose-related and were mostly mild to moderate in severity. Jastreboff said gastrointestinal-related adverse events were partially mitigated with a lower starting dose, such as 2 mg vs. 4 mg.
Researchers also observed a dose-dependent increase in heart rate for some participants that peaked at 24 weeks and then declined thereafter.
Achieving normoglycemia, 17% weight loss in diabetes
Data from a second phase 2 study that compared retatrutide with placebo and the GLP-1 receptor agonist dulaglutide (Trulicity, Eli Lilly) demonstrated a robust reduction in HbA1c for people with type 2 diabetes and overweight or obesity, with approximately 80% of participants assigned retatrutide reaching a target HbA1c of 7%, Julio Rosenstock, MD, FACE, director of the Dallas Diabetes Research Center at Medical City Dallas and clinical professor of medicine at the University of Texas Southwestern Medical Center, said during the presentation. Researchers also observed a 17% body weight reduction for the 8 mg and 12 mg doses of retatrutide.
“This is something you have never seen in type 2 diabetes,” Rosenstock said during the press conference. “Not a single drug has achieved 17% [in people with diabetes]. And, you haven’t seen anything yet, because you can see that at 36 weeks, you continue to lose weight. It is conceivable that we can get to 20%.”
For the second study, Rosenstock and colleagues analyzed data from 281 adults with type 2 diabetes, an HbA1c between 7% and 10.5% and a BMI of 25 kg/m2 to 50 kg/m2. Researchers randomly assigned participants to retatrutide doses of 0.5 mg (n = 47), 4 mg with slow- and fast-escalation subgroups (n = 47), 8 mg with slow- and fast-escalation subgroups (n = 50), 12 mg (n = 46), 1.5 mg dulaglutide (n = 46) or placebo (n = 45). The mean age of participants was 56 years; mean diabetes duration was 8.1 years; 56% were women and 84% were white. The primary endpoint was change in HbA1c from baseline to 24 weeks, and secondary endpoints included change in HbA1c and body weight at 36 weeks.
“This was a very carefully designed phase 2 trial; a dose-ranging study to try and find the dosages for phase 3,” Rosenstock said.
The findings were simultaneously published in The Lancet.
At 24 weeks, least squares mean changes from baseline in HbA1c with retatrutide were –0.43% for the 0.5 mg group, –1.39% and –1.3% for the slow- and fast-escalation 4 mg dose groups, –1.99% and –1.88% for the slow- and fast-escalation 8 mg dose groups, and –2.02% for the 12 mg group, compared with –1.41% for the dulaglutide group and –0.01% for the placebo group.
HbA1c reductions with retatrutide were greater than placebo for all dose groups except 0.5 mg (P < .0001) and greater than the dulaglutide group for those in the 8 mg (P = .0019) and 12 mg groups (P = .0002). Findings persisted at 36 weeks.
Body weight decreased in a dose-dependent manner with retatrutide at 36 weeks, with a mean 16.94% reduction for participants in the 12 mg group compared with a mean 3% reduction in the placebo group and 2.02% in the dulaglutide group.
Decreases in body weight were greater than placebo for all doses of retatrutide 4 mg and higher (P = .0017 for the 4 mg escalation group and P < .0001 for all others) and greater than dulaglutide (P < .0001 for all).
There were no reports of hypoglycemia and no deaths during the study, Rosenstock said.
“This is [a drug] that has a lot of promise in the future,” Rosenstock said. “Getting one-third of patients reversing to [diabetes] metrics where the glucose is normal.”
Retatrutide not ‘magic pill’
Jastreboff said the results, while impressive, should not supplant those of similar drugs like semaglutide (Ozempic/Wegovy, Novo Nordisk) or tirzepatide (Mounjaro, Eli Lilly). Data have shown that not every person with obesity responds to a therapy; a small group of nonresponders may lose little to no weight when prescribed certain drugs.
“We do not yet know who will respond to which therapies, and just like for other diseases, like in diabetes, we do not have one medicine to treat everyone,” Jastreboff said. “We have to think about all the tools that we have. Different people will respond to different therapies. This medication has the potential of a different mechanism because it has glucagon. Some may respond better to various mechanisms.
“It is not [about] one medicine, one injection or one magic pill,” Jastreboff said. “It is all the different therapies. It is pairing it with bariatric surgery. It is combining therapies.”
Le Roux agreed, noting that drugs like retatrutide must be taken for life to maintain any weight loss. That will present a challenge for clinicians and patients alike, he said.
“These are treatments for the disease of obesity. They are not cures for the disease of obesity,” Le Roux said. “The minute we discontinue the treatments, the disease relapses. That will be a challenge for us, because patients want to start these treatments, but the next question is, how do we keep these patients on these treatments for the rest of their lives?”
References:
- Jastreboff A, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2301972.
- Rosenstock J, et al. Lancet. 2023;doi:10.1016/S0140-6736(23)01053-x.
Perspective
Back to TopSteven B. Heymsfield, MD, FTOS
In the obesity medicine space, we have semaglutide, tirzepatide and now retatrutide, all coming out within the space of about a year or so. This is a remarkable paradigm change — and I do not use that phrase often. These agents will make obesity management a major issue in clinical medicine. Having worked in drug development for many years, there is no question that there are responders, nonresponders and partial responders to these various therapies. Retatrutide is no different. Although these agents are largely in the same class, we will have to see over time if people respond more to one vs. another. There will certainly be studies going forward comparing these agents against each other. There are also other drugs in the pipeline, including the human monoclonal antibody bimagrumab (Versanis Bio) and cagrilintide (Novo Nordisk). This will be an interesting time going forward.
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Jastreboff A, et al. Retatrutide (LY3437943), a novel GIP/GLP-1/glucagon receptor triagonist – Obesity, NAFLD, and T2D phase 2 trial results. Presented at: American Diabetes Association Scientific Sessions; June 23-26, 2023; San Diego.
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