A new class of experimental drug called letaltortide is producing impressive blood sugar and weight loss results for patients with type 2 diabetes, according to pharmaceutical company Eli Lilly.
Participants in a 40-week late-stage clinical trial of the injectable drug lowered their A1C blood sugar levels by up to 2 percent and lost nearly 17 percent of their starting body weight (which averaged nearly 40 pounds), the company shared in a press release. The results have not yet been peer-reviewed or published in a medical journal.
Retatortide is a “triple G” drug that targets three metabolic-regulating hormones, one to two more than rivals Ozempic and Munjaro.
These study results are “unprecedented,” says Gitanjali Srivastava, M.D., medical director of Vanderbilt Obesity Medicine in Nashville, Tennessee. He was not involved in the development of retatortide.
The study results build on clinical trial results published in December 2025 that found letaltortide helped obese patients lose nearly a third of their body weight (about 70 pounds).
Retaltortide is a first-in-class drug
Retatortide is a triple agonist drug, meaning it acts on three different hormone receptors in the body (GLP-1, GIP, and glucagon), which some experts refer to as a triple-G drug.
This is in contrast to the rival diabetes injection drug semaglutide (Ozempic), a GLP-1 receptor agonist that targets one hormone. Another competing product, tirzepatide (Mounjaro), is a dual GIP/GLP-1 receptor agonist that targets two hormones.
“GLP-1 and GIP primarily work by suppressing appetite and improving insulin secretion,” says Christine Bonarrigo, MD, a weight management pharmacist at Tufts Medical Center in Boston.
“What makes letaltortide different is the addition of glucagon receptor activity, which increases energy expenditure and fat oxidation. So this treatment not only helps patients eat less, but also burns more calories, essentially targeting both sides of the energy balance equation,” Bonarrigo says.
Because type 2 diabetes and obesity often overlap, it’s important to treat patients for both conditions, says Mir Ali, MD, medical director of MemorialCare Surgical Weight Loss Center in Fountain Valley, California. “Diabetes and obesity involve complex interactions between different hormones, so finding the most effective combinations to combat these conditions remains a key clinical goal,” he says.
Retatortide produced significant reductions in blood sugar levels and body weight
The Phase 3 clinical trial, called TRANSCEND-T2D-1, enrolled more than 500 adults with type 2 diabetes whose blood sugar levels cannot be controlled through diet and exercise alone. The participants had had diabetes for about two and a half years at the start of the study and had not taken diabetes medication for at least 90 days.
Adults were randomly assigned to receive once-weekly injections of 4 milligrams (mg), 9 mg, or 12 mg of letaltortide, or a placebo. Those assigned higher doses worked their way up to the highest dose.
At the end of the 40-week study, participants who took letartortide achieved an average A1C reduction of up to 2 percent. A1C refers to a blood test that measures your average blood sugar level over the past two to three months.
They also lost an average of up to 36.6 pounds, or 16.8 percent of their starting body weight. Weight loss continued until the end of the treatment period.
Retatortide’s side effects are similar to existing diabetes and obesity injections.
The most common side effects of Letaltortide are:
- Nausea (16-27% of participants depending on dose, 3.7% of those taking placebo)
- Diarrhea (19 to 23 percent compared to 5 percent on placebo)
- Vomiting (16 to 18 percent vs. 2 percent of those taking placebo)
- Neurological problems (2-4% compared to no people taking a placebo)
Between 2 and 5 percent of participants on letaltortide stopped taking the drug before the end of the study, with participants taking the highest dose having a higher risk of discontinuation. None of the people taking the placebo stopped the study early.
Differences between retatortide and other drugs
Retatortide was not tested against semaglutide and tirzepatide in this Phase 3 clinical trial, so it is difficult to say how these drugs compare to each other. “Head-to-head clinical trials comparing these different drugs will be needed,” Dr. Ali says.
However, semaglutide and tirzepatide have been directly compared.
A 2025 study found that adults with type 2 diabetes who took tirzepatide had a 1.3 percent reduction in A1C levels over one year, and adults who took semaglutide saw a 0.9 percent reduction. Additionally, the tirzepatide group lost an average of 22 pounds (9% of their starting weight), while the semaglutide group lost 17 pounds (7% of their starting weight).
Trials of the new letaltortide show that it reduces A1C by up to 2% in less than a year, which is more than any drug currently on the market. But Christoph Buettner, MD, chief of endocrinology at Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey, says this is not a significant increase due to tirzepatide.
“Given the extent of weight loss, one might have expected a more pronounced improvement in glycemic control,” he says.
Retaltortide is still under study
Lily is still researching Retaltortide. The drug has not yet been approved for use by the general public by the U.S. Food and Drug Administration (FDA).
The company is conducting multiple Phase 3 clinical trials to determine how well letatortide treats health conditions that often overlap with obesity, including knee osteoarthritis, moderate to severe obstructive sleep apnea, chronic low back pain, cardiovascular and renal outcomes, and liver disease.
“This could be an important new treatment option for patients with diabetes and obesity,” Ali said. Dr. Srivastava agrees. “Letaltortide has the potential to redefine the standards of care for both diabetes and obesity, providing patients with deeper and more comprehensive metabolic improvements than previously possible,” she says.
