Phase 2 tirzepatide results published in The Lancet

In October 2018, results from mid-stage testing of a new kind of diabetes drug moved into the medical spotlight. The drug, then called LY3298176, was built to switch on two gut hormone receptors at once — GIP and GLP-1 — instead of just GLP-1 like the medicines already on the market ^[1]. It is the molecule now known as tirzepatide.

The detailed Phase 2 results reported by Frias and colleagues in The Lancet were not included in the source material available here, so the specific Phase 2 numbers are not described in this article. What is available is the companion paper published in Molecular Metabolism, which lays out the drug's path "from discovery to clinical proof of concept" — the laboratory work and first-in-human studies that justified testing it in larger trials ^[1].

What the early data showed

LY3298176 is a fatty-acid-modified peptide designed for once-weekly injection under the skin ^[1]. In laboratory cell lines it turned on both GIP and GLP-1 receptor signaling, and in mice it increased insulin release in a glucose-dependent way and improved glucose tolerance through both receptors ^[1]. With repeated dosing in mice, it lowered body weight and food intake more than a GLP-1 receptor agonist alone ^[1].

The human work was a Phase 1 study in three parts: a single-ascending-dose stage (0.25–8 mg) and a four-week multiple-ascending-dose stage (0.5–10 mg) in healthy subjects, followed by a four-week proof-of-concept study (0.5–15 mg) in people with type 2 diabetes ^[1]. Doses above 5 mg were reached by stepping up gradually. Dulaglutide, an existing once-weekly GLP-1 receptor agonist, served as an active comparator, and the main goal was safety and tolerability ^[1]. In total, 142 people received at least one dose of LY3298176, dulaglutide, or placebo ^[1].

In the diabetes group, the 10 mg and 15 mg doses significantly lowered fasting serum glucose versus placebo, by a least-squares mean difference of −49.12 mg/dL (95% CI −78.14 to −20.12) and −43.15 mg/dL (95% CI −73.06 to −13.21) ^[1].

Weight changes were also measured. In healthy subjects taking multiple doses, weight fell more than with placebo at 1.5 mg (−1.75 kg; 95% CI −3.38 to −0.12), 4.5 mg (−5.09 kg; 95% CI −6.72 to −3.46) and 10 mg (−4.61 kg; 95% CI −6.21 to −3.01) ^[1]. In people with type 2 diabetes, the 10 mg and 15 mg doses produced differences of −2.62 kg (95% CI −3.79 to −1.45) and −2.07 kg (95% CI −3.25 to −0.88) versus placebo ^[1]. The authors noted that weight loss was greater with LY3298176 than with dulaglutide in healthy humans ^[1].

The most common side effects were gastrointestinal — vomiting, nausea, decreased appetite, diarrhea and abdominal distension — in both healthy subjects and patients with diabetes. All were described as dose-dependent and mild to moderate in severity, and overall tolerability was reported as comparable to GLP-1 receptor agonists ^[1].

Why it matters for patients

These were small, short studies — four weeks of dosing, 142 people total across all groups — so they cannot say anything about long-term blood sugar control, long-term weight change, or rare risks ^[1]. What they did establish is the basic idea behind the drug: that adding GIP activity to GLP-1 activity might do more than GLP-1 alone, at least on weight ^[1].

The side-effect pattern seen here is the same one people taking GLP-1 medicines report today: nausea, vomiting, diarrhea and reduced appetite, worse at higher doses ^[1]. The gradual dose escalation used above 5 mg in these early studies reflects that reality ^[1].

The authors' conclusion was cautious: the data "warrant further clinical evaluation" for type 2 diabetes and potentially obesity ^[1]. Whether that promise held up depended on the larger Phase 2 and Phase 3 trials, which are not covered by this source.

What happens next

The Molecular Metabolism paper appeared in the December 2018 issue, pages 3–14 ^[1]. It is open access under a Creative Commons license ^[1]. The Phase 1b proof-of-concept study is registered as NCT02759107 ^[1].