Lilly's Tirzepatide Demonstrates Superior Glycemic Control and Weight Loss in Phase 3 Trial Published in The Lancet

On October 19, 2021, Eli Lilly and Company announced that the detailed results of a Phase 3 clinical trial of tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, were published in the prestigious academic journal *The Lancet*. The trial met its primary endpoint at week 52, demonstrating that in adult patients with type 2 diabetes and increased cardiovascular (CV) risk, all three doses of tirzepatide exhibited superior efficacy compared with insulin glargine, achieving greater reductions in glycated hemoglobin (A1C) levels (maximum dose: 2.58% vs. 1.44%) and body weight (maximum dose: -11.7 kg vs. +1.9 kg), and demonstrating sustained efficacy over a 2-year period.

Tirzepatide is a multifunctional peptide derived from the native GIP sequence that integrates the actions of two incretins into a single molecule, enabling simultaneous binding to both GIP and GLP-1 receptors. With an average half-life of 5 days, it allows for once-weekly injections. In preclinical models, GIP reduces food intake and increases energy expenditure, leading to weight loss. When combined with GLP-1 receptor agonists, GIP may exert a greater impact on glycemic control and body weight. Tirzepatide is currently in Phase 3 clinical development for the treatment of adults with type 2 diabetes and patients with obesity. It is also under clinical investigation for the treatment of nonalcoholic steatohepatitis (NASH) and heart failure with preserved ejection fraction (HFpEF).

This open-label Phase 3 clinical trial was conducted in adult patients with type 2 diabetes (n=2,002) who had previously received oral antidiabetic medications but had inadequate glycemic control; 1,819 patients (91%) completed the 52-week visit, with a median study duration of 85 weeks, and 202 patients (10%) completed the 2-year study.

▲Introduction to Tirzepatide (Image source: Eli Lilly official website)

The trial met its primary and key secondary endpoints. At the Week 52 primary endpoint, compared with insulin glargine, all three doses of tirzepatide (5 mg, 10 mg, and 15 mg) resulted in statistically significant and superior reductions in A1C and body weight. The specific results are shown below:

A1C reduction: -2.24% (5 mg), -2.43% (10 mg), -2.58% (15 mg), and -1.44% in the insulin glargine group.

Change in body weight: -7.1 kg (-8.1%, 5 mg), -9.5 kg (-10.7%, 10 mg), -11.7 kg (-13.0%, 15 mg), and +1.9 kg (+2.2%) in the insulin glargine group.

Percentage of subjects achieving A1C <7%: 81% (5 mg), 88% (10 mg), 91% (15 mg), 51% in the insulin glargine group

During the 2-year treatment period, subjects receiving tirzepatide maintained A1C and weight control.

In an additional exploratory endpoint, all three doses of tirzepatide resulted in favorable changes from baseline in fasting lipids at Week 52, including reductions in total cholesterol and triglycerides, and increases in "good cholesterol" high-density lipoprotein (HDL) cholesterol.

The most frequently reported adverse events in the tirzepatide group were gastrointestinal adverse events, typically mild to moderate in severity.

References:

[1] Tirzepatide results published in The Lancet show superior A1C and body weight reductions compared to insulin glargine in adults with type 2 diabetes with increased cardiovascular risk. Retrieved October 19, 2021, from https://investor.lilly.com/news-releases/news-release-details/tirzepatide-results-published-lancet-show-superior-a1c-and-body

(Original text abridged)

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