Beyond Ozempic: Eli Lilly’s Experimental Drug Delivers Up to 28% Weight Loss

Eli Lilly’s experimental weight-loss drug retatrutide is drawing attention after producing significant weight reductions in late-stage clinical trials.

At the highest dose, participants without diabetes and with overweight or obesity lost an average of 28.3% of their body weight over 80 weeks in a Phase 3 trial.

The drug has been nicknamed the “Godzilla” of obesity treatments because of the scale of weight loss reported in trials. However, retatrutide is still investigational and has not been approved for public use. There has also been no direct head-to-head trial comparing it with Ozempic.

What Is Retatrutide?

Retatrutide is a once-weekly investigational injection designed to activate three hormone pathways: GLP-1, GIP and glucagon. Because it targets all three, it is known as a triple agonist.

Ozempic contains semaglutide, which primarily activates the GLP-1 receptor. GLP-1 medicines help regulate appetite and blood sugar, while retatrutide’s additional activity on GIP and glucagon pathways is intended to influence metabolism and energy expenditure.

How Is Retatrutide Different From Ozempic?

The key difference is the number of hormonal pathways targeted.

Retatrutide activates GLP-1, GIP and glucagon receptors, potentially influencing appetite, glucose control and energy expenditure through multiple mechanisms. Semaglutide, the active ingredient in Ozempic and Wegovy, acts on the GLP-1 pathway.

This multi-pathway approach is one reason researchers are investigating whether retatrutide can produce greater weight loss than existing GLP-1-based medicines.

How Much Weight Can Retatrutide Reduce?

Results have varied depending on the trial population and dose.

In the Phase 3 TRIUMPH-2 trial, which involved adults with overweight or obesity and type 2 diabetes, participants receiving the highest 12 mg dose lost an average of 20.8% of their body weight after 80 weeks. Those receiving 9 mg lost 19.1%, while the 4 mg group recorded an average reduction of 12.7%.

The study also reported improvements in HbA1c, with reductions of up to 1.6 percentage points.

An earlier Phase 3 study, TRIUMPH-1, involved people with overweight or obesity who did not have diabetes. At 80 weeks, those receiving 12 mg lost an average of 28.3% of their body weight.

In a selected extension group with a BMI of at least 35, average weight loss reached 30.3% after 104 weeks.

Is Retatrutide More Effective Than Ozempic?

The available numbers should not be interpreted as a direct comparison.

The retatrutide and semaglutide results come from separate clinical trials involving different participants, doses, study designs and treatment periods. There has not yet been a head-to-head trial directly comparing retatrutide with Ozempic.

Earlier semaglutide studies have generally reported smaller average weight reductions than those observed in Lilly’s Phase 3 retatrutide trials. However, comparing percentages from separate studies cannot establish that one drug is exactly twice as effective as another.

A Phase 3 head-to-head trial comparing retatrutide with tirzepatide is also underway, which could provide a more direct comparison with another leading obesity treatment.

What Side Effects Have Been Reported?

Retatrutide remains an investigational medicine, so its safety profile is still being studied.

Gastrointestinal problems have been among the most frequently reported side effects. In the diabetes trial, diarrhea, nausea, constipation and vomiting occurred more often at higher doses.

Researchers are also examining changes in body composition, including how much weight lost during treatment comes from fat versus lean tissue. This is an important consideration as increasingly powerful weight-loss medicines are developed.

Eli Lilly has said it plans to seek US regulatory approval for retatrutide in 2027. Until regulatory approval, the drug is not available as an approved prescription treatment.

What Could Retatrutide Mean for Obesity Treatment?

The clinical-trial results suggest that multi-hormone medicines could produce substantial reductions in body weight. For people living with obesity and related health conditions, significant weight loss may also be associated with improvements in metabolic health and other health outcomes.

However, the current findings remain clinical-trial data. Longer-term safety, effectiveness in broader populations and changes in muscle and fat mass will be important factors if retatrutide is eventually approved.

Cost, access, long-term treatment requirements and lifestyle support will also influence how the medicine is used in routine care.

For now, retatrutide remains an investigational drug, but its three-pathway mechanism and the large weight reductions reported in Phase 3 trials have made it one of the most closely watched developments in obesity treatment.