Lilly paper describes LY3298176, the dual GIP and GLP-1 drug now called tirzepatide

On October 3, 2018, Eli Lilly researchers published a paper in the journal Molecular Metabolism describing LY3298176, a dual GIP and GLP-1 receptor agonist — the molecule now known as tirzepatide — together with the first human tests of it ^[1][2]. The paper reports laboratory and mouse work plus a three-part Phase 1 program in which 142 people received at least one dose of the drug, the comparison drug dulaglutide, or a placebo ^[1].

A peptide built to hit two receptors

LY3298176 is a fatty acid modified peptide designed for once-weekly injection under the skin ^[1]. The researchers set out to test whether the metabolic action of GIP would add to the established benefits of selective GLP-1 receptor agonists in type 2 diabetes ^[1]. The paper describes binding constants of 0.135 nM at the GIP receptor and 4.23 nM at the GLP-1 receptor ^[1].

In mice, the drug activated both receptors, produced glucose-dependent insulin secretion, and improved glucose tolerance. Given over time, it lowered body weight and food intake by amounts significantly greater than a selective GLP-1 receptor agonist did ^[1].

The human study (ClinicalTrials.gov number NCT02759107) had three parts: a single-ascending-dose stage from 0.25 to 8 mg, and a four-week multiple-ascending-dose stage from 0.5 to 10 mg, both in healthy volunteers, followed by a four-week Phase 1b proof-of-concept stage from 0.5 to 15 mg in patients with type 2 diabetes. Doses above 5 mg were reached through titration. Dulaglutide served as a positive control, and the primary objective was safety and tolerability ^[1].

What the first human data showed

In the diabetes cohort, the 10 mg and 15 mg doses significantly reduced fasting blood sugar compared with placebo, by 49.12 mg/dL (95% confidence interval −78.14 to −20.12) and 43.15 mg/dL (95% confidence interval −73.06 to −13.21) ^[1].

Weight reductions were significantly greater than placebo with the 1.5 mg, 4.5 mg and 10 mg doses in healthy volunteers: 1.75 kg, 5.09 kg and 4.61 kg respectively. In patients with type 2 diabetes, the 10 mg and 15 mg doses had a relevant effect on weight, with reductions of 2.62 kg and 2.07 kg versus placebo ^[1].

The most frequent side effects were gastrointestinal — vomiting, nausea, decreased appetite, diarrhea and abdominal distension. All were dose-dependent and considered mild to moderate in severity in both healthy volunteers and patients with type 2 diabetes ^[1].

Why it matters for patients

The medicines most people know as GLP-1 drugs act on a single receptor. This paper was an early test of whether adding a second hormone pathway, GIP, changes what the drug does. In this study, the answer in the short term was measurable drops in fasting blood sugar and weight, along with a side-effect profile the authors described as comparable to GLP-1 receptor agonists ^[1].

There are limits to what these numbers mean. Phase 1 studies are small and short by design, and the stated primary objective here was safety and tolerability, not proof that the drug prevents complications or sustains weight loss ^[1]. The paper itself says the data "warrant further clinical evaluation" of LY3298176 for type 2 diabetes and potentially obesity — in other words, larger trials were still needed when the paper appeared ^[1].

The paper does not report cardiovascular outcomes, how long any weight change lasted, or what happened to participants after treatment stopped. It also does not describe the drug's later development, any approval decisions, or when it might reach patients. Those things are not addressed in this publication ^[1].

What happens next

The paper's conclusion is that the drug's pharmacology translated from animal studies to humans and that the results justify more clinical testing ^[1]. The specific later-stage trials, their timing, and any regulatory milestones are not reported in this paper ^[1].