LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept

Summary

Primary research, not a review. The paper combines cell and mouse pharmacology with a phase 1 human program for LY3298176, the development code for tirzepatide: a fatty-acid-modified peptide with dual GIP and GLP-1 receptor agonist activity, designed for once-weekly injection. The aim was to test whether GIP’s metabolic action adds to the benefits of selective GLP-1 receptor agonists in type 2 diabetes. In cells and mice the compound activated both receptors. With chronic dosing in mice it reduced body weight and food intake more than a GLP-1 receptor agonist. In the human program, 142 participants received at least one dose of LY3298176, dulaglutide, or placebo; over 4 weeks LY3298176 lowered fasting glucose and body weight versus placebo, with mainly gastrointestinal side effects.

Key Findings

• LY3298176 activated both GIP and GLP-1 receptor signaling in vitro; in mice it produced glucose-dependent insulin secretion and improved glucose tolerance by acting on both receptors
• With chronic administration in mice, it decreased body weight and food intake significantly more than a GLP-1 receptor agonist
• Pharmacokinetics across 0.25–15 mg supported once-weekly dosing
• In the 4-week phase 1b in type 2 diabetes, 10 mg and 15 mg reduced fasting serum glucose vs placebo (least-squares mean difference -49.12 and -43.15 mg/dL)
• Body weight fell vs placebo in healthy subjects at 1.5, 4.5 and 10 mg (-1.75, -5.09 and -4.61 kg), and in patients with type 2 diabetes at 10 and 15 mg (-2.62 and -2.07 kg)
• The most frequent side effects were gastrointestinal (vomiting, nausea, decreased appetite, diarrhoea, abdominal distension), all dose-dependent and mild to moderate

Methodology

In-vitro signaling and functional assays in cell lines expressing incretin receptors, plus mouse studies of body weight, food intake, insulin secretion, and glycemic profiles. The human phase 1 program (NCT02759107) was randomized, placebo-controlled, and double-blind, in three parts:

• a single-ascending-dose study (0.25–8 mg) in healthy subjects
• a 4-week multiple-ascending-dose study (0.5–10 mg) in healthy subjects
• a 4-week phase 1b proof-of-concept study (0.5–15 mg) in patients with type 2 diabetes

Doses above 5 mg were reached by titration, dulaglutide served as a positive control, and the primary objective was safety and tolerability.

Limitations

• Human exposure was short (4 weeks) and the program was small, with safety and tolerability as the primary objective
• The advantage over a GLP-1 receptor agonist on body weight and food intake was shown in mice, not in humans
• The abstract does not report a head-to-head human efficacy comparison with dulaglutide
• The abstract does not isolate how much of the human effect comes from the GIP component

Relevance to Content

The foundational mechanism paper for tirzepatide. It shows the molecule acts on both GIP and GLP-1 receptors, and that in mice dual agonism reduced weight and food intake more than GLP-1 agonism alone. Use it to explain the dual-agonist design, while noting that the head-to-head advantage here is preclinical; human efficacy comparisons come from later trials.

See Also

• Parent compound: Tirzepatide
• Semaglutide
• Retatrutide