Background

Tirzepatide, a single-molecule dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor (R) agonist, has shown superiority in the reduction of blood glucose and body weight, above selective GLP-1R agonists, but the contribution of GIP to these effects remains incompletely understood.

Objectives

To characterize the preclinical and in-human effects of a long-acting GIPR agonist monotherapy in healthy participants and patients with type 2 diabetes (T2D).

Methods

A long-acting GIPR agonist (LY3537021) was characterized in vitro and in Long-Evans diet-induced obese rats and Wistar rats. Next, a phase 1, randomized, placebo-controlled, single ascending dose (SAD)/multiple ascending dose (MAD) study explored the safety, tolerability, pharmacokinetics, and pharmacodynamics of LY3537021 in healthy participants and participants with T2D in Singapore.

Results

In vitro, LY3537021 demonstrated potency greater than native GIP and selectivity for the GIPR. In vivo in rats, chronic treatment with LY3537021 resulted in weight loss and improved glycemic control during a glucose tolerance test. The phase 1 clinical study enrolled 85 healthy participants and patients with T2D (SAD, n = 47 [aged 25–64 years]; MAD, n = 38 [aged 25–69 years]; average baseline BMI was 25.9–27.0 kg/m² across the arms). During the MAD part, dose-dependent decreases in mean body weight were observed in all LY3537021 dose groups, regardless of T2D status, and persisted at 35 days after the last dose. For example, participants with T2D treated with 25 mg of LY3537021 lost a mean of 3.14 kg of body weight compared with 0.36 kg in the placebo group (p < 0.05) at day 57. Transient reductions in fasting glucose were observed in these participants, but the reductions were not sustained and not significantly different from placebo at day 29. The time to maximum observed drug concentrations varied across cohorts (8–96 h), and the half-life was estimated at approximately 12 days for non-T2D and T2D cohorts with the 25-mg dose, supporting once-weekly administration. There was no delay in gastric emptying following a single subcutaneous dose of 0.3–25 mg LY3537021. LY3537021 was well tolerated with infrequent gastrointestinal adverse events.

Conclusions

In vivo studies demonstrated that LY3537021 reduced body weight and improved glycemia during a glucose challenge in rats. The phase 1 study demonstrated that the long-acting GIPR agonist LY3537021 was well tolerated, induced weight loss, and improved glucose control in humans. These observations better define the therapeutic benefit of long-acting GIPR agonists and support a distinct contribution of GIP agonism to the benefits observed with multi-agonist peptides that act via the GIPR. Future studies are needed in more diverse populations and in cohorts with overweight/obesity to confirm these findings.