Coskun T, Urva S, Roell WC, et al. (2022). LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. Cell Metab, 34(9):1234-1247.e9.
AnimalPMID 35985340DOI↩
What is retatrutide?
Retatrutide is an experimental weight-loss and diabetes medicine from Eli Lilly, tested in trials under the code name LY3437943. It’s a single lab-made peptide that switches on three different hormone receptors at once: those for GIP, GLP-1, and glucagon [1].
That’s why it’s often called a “triple agonist.” The first generation of hormone-based weight-loss drugs copied GLP-1, a gut hormone released after meals. A second generation added GIP, a partner hormone, with remarkable results [2]. Retatrutide adds a third hormone, glucagon, to the mix [1].
It’s given as an injection under the skin once a week [3]. Retatrutide has now finished several large phase 3 trials, the final stage of testing before a drug can be approved [4, 5]. It isn’t approved yet, but copies are already sold online [S1].
How might it work?
- Eating less (GLP-1 and GIP). In animal studies, signals through the GLP-1 and GIP receptors reduced how much food was eaten [1]. Retatrutide also slows how quickly the stomach empties [6].
- Burning more (glucagon). Glucagon is best known for raising blood sugar, but it also helps the liver burn fat and, at least in animals, increases the energy the body burns. Pairing it with GLP-1, which lowers blood sugar, keeps blood sugar in check [7]. In obese mice, adding glucagon activity boosted weight loss beyond what eating less alone achieved [1].
- Lasting all week. Retatrutide stays in the body with a half-life of about six days, which is why one injection a week is enough [3].
What has research found?
Weight loss
- Phase 2: In 338 adults with obesity, the highest dose (12 mg) led to an average weight loss of 24.2% after 48 weeks, compared with 2.1% on placebo. At that dose, 83% of people lost at least 15% of their body weight [8].
- Phase 3 (TRIUMPH-1): In 2,339 adults with obesity but without diabetes, people lost an average of 17.6%, 23.7%, and 25.0% of their body weight at the three doses over 80 weeks, compared with 3.9% on placebo [4].
- With type 2 diabetes (TRIUMPH-2): In 1,152 adults with obesity and type 2 diabetes, weight loss reached 18.8% at the highest dose, compared with 5.1% on placebo [5].
- How it compares: A 2026 review of the major trials found that retatrutide’s weight loss beyond placebo (about 22%) was numerically larger than that of today’s approved shots, such as semaglutide and tirzepatide. Those comparisons come from separate trials, though, not head-to-head testing [9].
Blood sugar and diabetes
- Phase 2: In people with type 2 diabetes, retatrutide lowered HbA1c, a measure of long-term blood sugar, by up to 2 percentage points. Higher doses beat an established diabetes drug, dulaglutide [10].
- Phase 3 (TRANSCEND-T2D-1): Used on its own, retatrutide lowered HbA1c by 1.7 to 1.9 percentage points over 40 weeks, compared with 0.8 on placebo. People also lost 11.5% to 15.3% of their body weight, and no one had severe low blood sugar [11].
Joints, sleep, and the liver
- Knee arthritis: In people with knee osteoarthritis, retatrutide reduced knee pain more than placebo [4].
- Sleep apnea: In people with obstructive sleep apnea, breathing interruptions fell by about 22 to 34 events per hour, compared with about 10 on placebo [4].
- Fatty liver: In people with fatty liver disease, the higher doses cut liver fat by more than 80% in 24 weeks, and 86% of people on the top dose reached a normal liver fat level [12].
Heart, kidney, and body composition
- Heart risk markers: Retatrutide lowered blood pressure and cholesterol [13]. In one phase 2 study, it also reduced a key marker of inflammation by about half [14].
- Kidneys: Higher doses reduced protein leaking into the urine, an early sign of kidney stress [15].
- Fat vs. muscle: In people with type 2 diabetes, retatrutide cut total body fat by up to about a quarter. People also lost some lean mass, but in a similar proportion to other obesity treatments [16].
In animals
- Cancer: In obese mice, retatrutide slowed the growth of pancreatic and lung tumors, and its benefit for pancreatic tumors was larger than semaglutide’s [17]. That’s an intriguing lead, but it hasn’t been tested in people.
How strong is the evidence?
| What we know so far | What we still don’t know |
|---|---|
| Large phase 3 trials show major weight loss over 80 weeks [4, 5] | Whether it lowers the risk of heart attacks, strokes, or death, which hasn’t been shown yet [18] |
| It improves blood sugar in type 2 diabetes [10, 11] | How it compares head-to-head with approved drugs [9, 18] |
| It eased knee pain and sleep apnea in people with obesity [4] | The long-term effects of continuously switching on the glucagon receptor [7] |
| Side effects are similar to those of other GLP-1 drugs [5, 11] | Whether products sold online contain what they claim [19, 20] |
A few more things to keep in mind:
- Strong trials, one sponsor. The key trials are large, randomized, and placebo-controlled, which is the gold standard. All of them were funded by Eli Lilly, and many authors are company employees [4, 5, 11].
- Some comparisons are still uncertain. A 2026 analysis rated the evidence comparing newer drugs like retatrutide with established ones as very low to low certainty [18].
Safety: what we know
- Stomach upset is common. Nausea and diarrhea were the most frequent side effects. They were mostly mild to moderate, depended on dose, and were less common when people started on a lower dose [8]. In TRIUMPH-2, diarrhea affected about a third of people on the higher doses, compared with 13% on placebo [5].
- Faster heart rate. Heart rate rose with dose, peaked around 24 weeks, and then declined [8].
- Skin sensations and low blood pressure. Some people reported unusual skin sensations such as tingling or burning (dysesthesia), and some had low blood pressure. Both were more common than on placebo [5]. Similar skin sensations have been reported with other GLP-1 drugs [21].
- Stopping treatment. At the higher doses in TRIUMPH-2, 8% to 12% of people stopped treatment because of side effects, compared with 5% on placebo [5].
- Online products carry extra risk. A man with type 1 diabetes became seriously ill, nearly developing a dangerous condition called diabetic ketoacidosis, after injecting a product bought online as retatrutide. He also had a gut infection, so the exact cause was unclear [19]. Doctors warn that unregulated injectables can be contaminated, impure, or wrongly dosed [20].
Legal status
- Not yet approved. Retatrutide is still in clinical development [11]. FDA says it hasn’t been found safe and effective for any condition [S1]. Lilly plans to apply for FDA approval in early 2027 [S2].
- United States: Retatrutide can’t legally be used by pharmacies to make compounded drugs. FDA has warned companies selling it as “for research purposes” or “not for human consumption,” as well as telehealth companies marketing it [S1].
- Sports: Retatrutide isn’t named on the World Anti-Doping Agency’s 2026 banned list, but the list bans at all times any drug still in development without government approval for human use [S3]. Anti-doping labs have developed a blood test that detected it for about 56 days after a dose [22].
The bottom line
Retatrutide is one of the most powerful weight-loss medicines yet tested. By copying three hormones at once, it helped people on the highest dose lose about a quarter of their body weight in large trials, while also improving blood sugar, liver fat, knee pain, and sleep apnea. It’s a striking example of how far peptide-based medicine has come in just a few years.
It isn’t approved yet, though, and its long-term effects on the heart and other organs are still being studied. The safest way to benefit from this research is to wait for regulators to review the full data, rather than turning to unregulated products online.