Two phase 3 trials with dual GIP/GLP-1RA in T2DM meet primary and key secondary endpoints

Tirzepatide, a dual glucose-dependent insulinotropic peptide/GLP-1 receptor agonist (GIP/GLP-1RA), significantly improved glycemic control and reduced body weight in patients with T2DM.

Two randomized phase 3 trials, SURPASS-3 and SURPASS-5 trials, showed that treatment of tirzepatide reduced hemoglobin A1c (HbA1c) and body weight from baseline to week 52 or week 40, respectively.

Tirzepatide is a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist (GLP-1RA) that integrates the actions of both incretins into a single molecule. GIP has been shown to decrease food intake and increase energy expenditure in preclinical studies, resulting in weight loss. GIP combined with GLP-1RA may result in greater effects on glucose and body weight. Tirzepatide is in phase 3 development for blood glucose management in adults with T2DMand for chronic weight management. It is also being studied as a potential drug for the treatment of non-alcoholic steatohepatitis (NASH).

The SURPASS-3 trial was a multicenter, randomized, open-label trial that enrolled adults with T2DM (n=1444) who had inadequate glycemic control despite metformin treatment in the presence or absence of an SGLT2 inhibitor. Participants were randomized (1:1:1:1) to receive either tirzepatide 5 mg, 10 mg or 15 mg or titrated insulin degludec. The primary endpoint was HbA1C reduction from baseline after 52 weeks for the two higher doses (10 mg and 15 mg). All studied tirzepatide doses led to significant HbA1C and body weight reductions compared to titrated insulin degludec. The highest dose of tirzepatide (15 mg) reduced HbA1C by 2.37%. Across the three tirzepatide groups, 82.4% (5mg), 89.7% (10 mg), and 92.6% (15 mg) achieved HbA1C <7%, which is the American Diabetic Association’s (ADA) recommended target for individuals with diabetes, compared to 61.3% on insulin degludec. Patients on tirzepatide also had a significant weight reduction compared to participants on insulin degludec (15 mg tirzepatide: -12.9 kg vs. insulin degludec: +2.3 kg).

The SURPASS-5 trial was a randomized, double-blind, placebo-controlled, phase 3 trial that compared the efficacy and safety of tirzepatide with placebo. Participants with T2DM (n=475) were randomized (1:1:1:1) to 5 mg, 10 mg, or 15 mg of tirzepatide or placebo as an add on to insulin glargine, with or without metformin. The primary endpoint of the study was change in HbA1c from baseline to week 40. The highest dose of tirzepatide (15 mg) reduced HbA1C by 2.59%. All three doses reduced Hb1Ac significantly, with 93.0% (5mg), 97.4% (10 mg), and 94.0% (15 mg) of participants achieving the recommended <7% HbA1c goal compared to 33.9% in the placebo group. Moreover, 26.1% (5mg), 47.8% (10 mg), and 62.4% (15 mg) of participants achieved an HbA1c of less than 5.7% compared to 2.5% in the placebo group. All three tirzepatide treatment groups had a significant weight reduction from baseline compared to placebo.

The overall safety profile in both trials was comparable to that of the established GLP-1RA class. Most reported adverse events in patients using tirzepatide were gastrointestinal related side effects (nausea, diarrhea, vomiting, and constipation).

The complete SURPASS-3 and SURPASS-5 clinical results will be presented at the American Diabetes Association’s annual Scientific Sessions.

Source: Eli Lilly and Company, February 17, 2021