The new clinical trials were funded by Eli Lilly, and the results have not yet been published in a peer-reviewed journal.
“This medication could become one of the most effective pharmacologic options we have for obesity,” says Christine Bonarrigo, PharmD, a weight management pharmacist at Tufts Medical Center in Boston. “However, it’s important to remember that the goal isn’t simply weight loss. It’s reducing obesity-related disease and improving long-term health.”
Results from an earlier retatrutide trial, TRIUMPH-1 — which helped some adults lose as much as 30 percent of their starting body weight — have got people talking, says Mir Ali, MD, the medical director of MemorialCare Surgical Weight Loss Center at Orange Coast Medical Center in Fountain Valley, California. “Even though it’s not yet FDA-approved, some patients are aware of retatrutide and are already asking about it.”
Retatrutide Works Differently Than Other GLP-1s
Retatrutide is different from FDA-approved GLP-1 medications like semaglutide (Wegovy, Ozempic) and tirzepatide (Zepbound, Mounjaro). This is a triple-agonist medication that acts on three different hormone receptors in the body: glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP), and glucagon (GCG), Dr. Ali explains. As a result, it’s been dubbed a “triple G” medication.
Semaglutide works on one receptor (GLP-1) while tirzepatide works on two receptors (GLP-1 and GIP).
Like semaglutide and tirzepatide, retatrutide is taken once a week via injection. It reduces appetite and slows digestion to support weight loss, says Ali.
“There’s no one medication that works for every person, which is why finding more medications that may be beneficial to treat a range of health conditions is always ideal,” he adds.
Adults With Type 2 Diabetes Lost Almost 20 Percent of Their Weight on Retatrutide
Participants were randomized to receive a placebo (dummy medication) or retatrutide in doses of 4, 9, or 12 milligrams (mg). The 80-week trial was double-blinded, meaning neither the participants nor the researchers knew which treatment the participants received.
People assigned to receive higher doses started at 2 mg and increased the amount incrementally every four weeks until reaching the target dose (this step-up dosing is called titration).
At the end of the 80-week trial, the average results showed:
- Participants on a 4 mg dose lost 29.8 pounds (lb), or about 12.7 percent of their starting body weight.
- Those on a 9 mg dose lost 45.4 lb, about 19.1 percent of starting weight.
- Those on a 12 mg dose lost 49.6 lb, about 20.8 percent of starting weight.
The participants also saw 1.6 percent average drop in A1C levels, a measurement that estimates average blood sugar levels over the previous two to three months.
“People with type 2 diabetes have historically lost less weight on obesity medications than those without diabetes,” Dr. Bonarrigo says. “Even in that population, retatrutide demonstrated nearly 21 percent average weight loss at the highest dose, which is remarkable.”
Retatrutide Also Delivered Significant Results for People With Severe Obesity and Heart Disease
The other trial, TRIUMPH-3, included nearly 2,000 adults with severe obesity (defined as a BMI of 40 or higher) and cardiovascular disease; some participants also had type 2 diabetes.
Researchers randomly assigned trial members to receive a placebo or 9 or 12 mg doses of retatrutide. Like TRIUMPH-2, this trial was also double-blind. Participants who received retatrutide also started at 2 mg and titrated up to their target dose.
At the end of the 80-week trial, the average results showed:
- Adults taking a 9 mg dose lost 52.7 lb, about 21.6 percent of their starting weight.
- Those on a 12 mg dose lost 55.8 lb, about 22.6 percent of starting weight.
During the study period, there were 27 major adverse cardiovascular events, including heart attack and stroke, among people who received retatrutide, compared with 23 events in the placebo group.
Participants taking the highest dose of retatrutide saw, on average, the following health improvements: these average reductions in cardiovascular disease risk factors:
- 37 percent reduction in triglycerides, or fats in the blood
- 16.5 percent reduction in non-HDL “bad” cholesterol
- 9.3 mmHg reduction in systolic blood pressure, the pressure in the arteries when the heart beats
- 7.5-inch reduction in waist circumference
- 51.2 percent reduction in high-sensitivity C-reactive protein, a measurement of inflammation in the body
Side Effects Led More Than 1 in 10 Participants to Drop Out
Side-effect rates differed between the two trials. In the diabetes TRIUMPH-2 trial, reported side effects included:
- Diarrhea (around 27 to 34 percent of participants, depending on the dose)
- Nausea (14 to 28 percent)
- Constipation (14 to 17 percent)
- Decreased appetite (6 to 17 percent)
- Vomiting (6 to 16 percent)
In the TRIUMPH-3 trial for adults with severe obesity and heart disease, participants reported:
- Diarrhea (around 24 to 30 percent of participants, depending on the dose)
- Nausea (22 percent)
- Constipation (16 to 18 percent)
- Decreased appetite (14 to 15 percent)
- Hyperglycemia, or high blood sugar (3 to 4 percent)
The high rates of diarrhea surprised Ali. “We don’t usually see that much diarrhea with the GLP-1 medications,” he says. “Their main side effects are usually nausea and vomiting.”
In TRIUMPH-2, up to 11.6 percent of participants using retatrutide stopped the drug before the end of the trial due to side effects, compared with 4.9 percent of the placebo group. In TRIUMPH-3, up to 13.5 percent of participants using retatrutide stopped early, compared with 4.8 percent taking a placebo. By comparison, 4.9 percent of participants taking retatrutide dropped out of the TRIUMPH-1 trial.
“Most of the time, patients drop out because of side effects,” Ali says. “These side effects may be prohibitive, but it’s hard to say. Everybody responds differently.”
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