56-OR: A Long-Acting Glucose-Dependent Insulinotropic Polypeptide Receptor Agonist Shows Weight Loss without Nausea or Vomiting

The contributions of glucose-dependent insulinotropic polypeptide (GIP) to overall metabolic and weight effects of incretin therapies are unclear. Weight loss efficacy has been observed with glucagon-like peptide 1 (GLP-1) and GIP receptor agonist tirzepatide, but weight loss efficacy has also been observed with GLP-1 agonism mixed with GIP antagonism.

LY3537021 (LY), a selective, long-acting GIP receptor agonist, was tested in single [SAD, LY vs placebo (PBO)] and multiple ascending doses (MAD, LY vs PBO once weekly for 4 weeks) to evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics.

In SAD, healthy participants (N=39) had a mean age of 43.5 yrs and mean weight of 74.4 kg. People with T2D (N=6) had a mean age of 58.5 yrs and mean weight of 75.1 kg. Median Tmax was 12 to 84 hrs post dose and mean terminal T½ was approximately 11 to 14 days. PK in people with T2D appeared comparable to healthy participants. In MAD, healthy participants (N=18) had a mean age of 38.3 yrs and mean weight of 75.4 kg. People with T2D (N=18) had a mean age of 57.1 yrs and mean weight of 74.3 kg. In healthy MAD participants at day 57, numerically greater mean weight loss was reported in those who received LY (-1.1 to -2.2 kg) versus PBO (-0.4 kg). In people with T2D, numerically greater mean weight loss was reported for those receiving LY (-1.9 to -3.1 kg) versus PBO (-0.4 kg). LY did not result in gastric emptying delay. No serious adverse events or hypoglycemia occurred. Study participants had few mild gastrointestinal (GI) adverse events. Study findings included decreased appetite (LY: n=4, PBO: n=1), abdominal pain (LY: n=1, PBO: n=0) and diarrhea (LY: n=1, PBO: n=2). No nausea or vomiting was observed.

Repeated dosing of a long-acting GIP receptor agonist, once weekly for 4 weeks, induced weight loss without gastric emptying delay or nausea and vomiting. The results suggest that GIP agonism can contribute to weight loss effects seen with multi-agonist incretins such as tirzepatide.