Tirzepatide Meets Endpoints in All Five Phase 3 Trials, New Drug Application Expected This Year

On May 20, 2021, Eli Lilly and Company announced that tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, achieved its primary endpoint and all key secondary endpoints in the SURPASS-4 clinical trial. Compared with the active control, in adult patients with type 2 diabetes and increased cardiovascular (CV) risk, all three doses of tirzepatide significantly reduced patients' glycated hemoglobin (A1C) and body weight. In the group receiving the highest dose (15 mg), after 52 weeks of treatment, tirzepatide successfully normalized A1C levels in 43% of patients, with an average weight reduction of 11.7 kg. To date, tirzepatide has achieved its primary endpoint in all five global Phase 3 clinical trials.

Tirzepatide is an investigational once-weekly dual GIP and GLP-1 receptor agonist that integrates the effects of these two incretins into a single novel molecule, representing a novel therapeutic approach for type 2 diabetes. GIP is a hormone that may complement the actions of GLP-1 receptor agonists. Preclinical models have demonstrated that GIP reduces food intake and increases energy expenditure, thereby leading to weight loss. Furthermore, when GIP is used in combination with GLP-1 receptor agonists, it may exert a greater impact on patients' blood glucose levels and body weight. Tirzepatide is currently in Phase 3 clinical development for glycemic management in adults with type 2 diabetes and for chronic weight management. It is also being investigated as a potential therapy for nonalcoholic steatohepatitis (NASH) and heart failure with preserved ejection fraction (HFpEF).

The SURPASS-4 trial was designed to evaluate the efficacy and safety of three different doses of tirzepatide (5 mg, 10 mg, and 15 mg) in 2,002 patients with type 2 diabetes. The mean duration of diabetes in these patients was 11.8 years, with a baseline A1C of 8.52% and a baseline body weight of 90.3 kg; over 85% of the subjects had a history of cardiovascular events.

SURPASS-4 met its primary and key secondary endpoints. Trial results demonstrated that, compared with the insulin glargine control group, all three doses of tirzepatide (5 mg, 10 mg, and 15 mg) resulted in greater reductions in A1C and body weight. Among patients receiving the highest dose of tirzepatide (15 mg), mean A1C levels decreased by 2.41%, and mean body weight was reduced by 11.7 kg. Furthermore, 91% of patients achieved an A1C level below 7%, which is the target recommended by the American Diabetes Association for patients with diabetes. Additionally, 43% of patients reached an A1C level below 5.7%, corresponding to the levels observed in healthy individuals without diabetes.

▲ Efficacy data for tirzepatide at Week 52 in the SURPASS-4 clinical trial (Source: Reference [1])

The overall safety profile of tirzepatide is consistent with that of GLP-1 receptor agonists. Gastrointestinal side effects are the most frequently reported adverse events, typically mild to moderate in severity. These events generally occur during dose titration and tend to diminish over time. In the tirzepatide treatment groups, the incidence of nausea (11.9%, 15.9%, 22.2%), diarrhea (12.2%, 19.5%, 20.4%), and vomiting (4.9%, 8.2%, 8.3%) was higher than in the control group. Additionally, the treatment discontinuation rates due to adverse events were 8.2%, 7.3%, and 8.9%, respectively, compared with 2.9% in the control group.

Note: The original text has been abridged.

References:

[1] Lilly's tirzepatide achieves all primary and key secondary study outcomes against insulin glargine in adults with type 2 diabetes and increased cardiovascular risk in SURPASS-4 trial. May 20, 2021, from https://investor.lilly.com/news-releases/news-release-details/lillys-tirzepatide-achieves-all-primary-and-key-secondary-study

Note: This article is intended to present advances in medical and health research and does not constitute a recommendation for any treatment regimen. For professional guidance on treatment options, please consult a qualified healthcare provider at an accredited medical institution.

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