Eli Lilly's LY3537021, a GIP-only drug, produced weight loss without nausea in an early trial
A small phase 1 study suggests a drug that targets only the GIP receptor can produce modest weight loss without nausea or vomiting, though larger trials have not been reported.
A once-weekly experimental drug that acts only on the GIP receptor produced modest weight loss over four weeks without nausea or vomiting, according to early-stage results presented June 20, 2023 at the American Diabetes Association's Scientific Sessions and published in the journal Diabetes [1].
The drug, LY3537021, is a selective, long-acting GIP receptor agonist. The study authors include several employees of Eli Lilly and Company, and the disclosure statement lists Lilly stock ownership for them [1]. GIP, or glucose-dependent insulinotropic polypeptide, is one of the two incretin hormones targeted by existing weight-loss medicines; the other is GLP-1.
The abstract describes two parts of a phase 1 trial. In the single-dose part, 39 healthy participants (average age 43.5 years, average weight 74.4 kg) and six people with type 2 diabetes (average age 58.5 years, average weight 75.1 kg) received the drug or a placebo [1]. In the multiple-dose part, participants received LY3537021 or placebo once a week for four weeks: 18 healthy participants (average age 38.3 years, average weight 75.4 kg) and 18 people with type 2 diabetes (average age 57.1 years, average weight 74.3 kg) [1].
Blood levels peaked 12 to 84 hours after dosing, and the drug's average terminal half-life was about 11 to 14 days. Pharmacokinetics in people with type 2 diabetes appeared comparable to those in healthy participants [1].
By day 57, average weight loss was numerically greater in people who received LY3537021 than in those who received placebo. In healthy participants, the drug groups lost 1.1 to 2.2 kg versus 0.4 kg for placebo. In people with type 2 diabetes, the drug groups lost 1.9 to 3.1 kg versus 0.4 kg for placebo [1].
LY3537021 did not delay gastric emptying. No serious adverse events and no hypoglycemia occurred. Gastrointestinal side effects were few and mild: decreased appetite in four people on the drug versus one on placebo, abdominal pain in one person on the drug versus none on placebo, and diarrhea in one person on the drug versus two on placebo. No nausea or vomiting was observed [1].
Why the result drew attention: how much GIP contributes to the weight effects of incretin drugs has been unclear. Weight loss has been seen with tirzepatide, which activates both GLP-1 and GIP receptors, but also with treatments that combine GLP-1 agonism with GIP blockade, a contradiction the field has not resolved [1]. The authors write that their findings suggest GIP agonism can contribute to the weight loss seen with multi-agonist incretins such as tirzepatide [1].
Why it matters for patients
The question behind this study is whether weight loss can be separated from the nausea and vomiting that can come with incretin-based treatment. In this trial, no participant who received the drug reported nausea or vomiting, and there was no sign of slowed stomach emptying [1]. Whether that pattern holds in larger and longer studies is not yet known.
The weight loss reported here was small and measured after only four weeks. The abstract describes the differences from placebo as "numerically greater" and does not state whether they were statistically significant [1]. The number of participants in each dose group is not given, and the trial did not compare LY3537021 with any approved GLP-1 or dual-agonist medicine, so how it stacks up against them has not been reported [1].
LY3537021 is not approved by the Food and Drug Administration and is not available by prescription. People taking semaglutide (Ozempic, Wegovy, Rybelsus), tirzepatide (Mounjaro, Zepbound) or any other GLP-1 medicine are not affected by this finding, and no data in the abstract speak to switching between products.
What happens next
The abstract does not say whether a phase 2 trial of LY3537021 is planned, when one might start, or what dose would be studied next. No follow-up timelines have been disclosed [1]. Results beyond day 57, including whether weight loss continues with longer treatment, have not been reported [1].
Sources
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