Tirzepatide shows benefits for T2D

The novel dual GIP* and GLP-1** receptor agonist tirzepatide demonstrated clinically meaningful improvements in glycaemic control and weight loss in patients with type 2 diabetes (T2D), according to data presented at EASD 2019.

Researchers sought to evaluate the 12-week efficacy and tolerability of once-weekly tirzepatide 12 and 15 mg against placebo in individuals with T2D (n=111; mean age 57.4 years, HbA_1c 8.4 percent, body mass index 31.9 kg/m²). The dose-escalation algorithm for the 12-mg arm (T12) was 4, 8, and 12 mg through weeks 4, 8, and 12, respectively. The first 15-mg arm (T15-1) started at 2.5 mg for the first 2 weeks, increasing to 5 mg in the ensuing 2 weeks, then to 10 and 15 mg through weeks 8 and 12, respectively. The algorithm for the second 15-mg arm (T15-2) was 2.5, 7.5, and 15 mg for weeks 4, 8, and 12, respectively. [EASD 2019, abstract OP114]

The results were also compared against a phase IIb study evaluating T15 at a starting dose of 5 mg, increasing to 10 mg (6-week dose-escalation phase) and then to 15 mg thereafter through week 26. [Lancet 2018;392:2180-2193]

At 12 weeks, change in HbA_1c from baseline was significantly greater with tirzepatide vs placebo (-1.7 percent [T12], -2.0 percent [T15-1], and -1.8 percent [T15-2] vs +0.2 percent; p<0.001 for all). The current findings for T15 collectively resulted in a -2.1 percent change in HBA_1c, which was similar to the phase IIb study results (-2.4 percent), supporting the efficacy of tirzepatide in glycaemic control.

Reductions in body weight were also greater with tirzepatide vs placebo (-5.3 kg [T12], -5.5 kg [T15-1], and -5.7 kg [T15 -2] vs -0.5 kg; p<0.001 for all). Although the phase IIb study demonstrated a numerically greater weight reduction than the current trial (-11.3 vs -7.7 kg), the tirzepatide arms in both studies demonstrated significant reductions when compared with their respective placebo arms (-0.9 vs -0.4; p<0.001 for both).

“[Participants of both studies] have not been exposed to the same amount of tirzepatide [given] the lower [starting] dose … and the slower uptitration … We believe this is on the same page [as] the previous study,” explained study investigator Dr Michael Nauck from the Ruhr-University Bochum in Bochum, Germany.

The incidence of treatment-emergent AEs (TEAEs) was higher with tirzepatide vs placebo (79.3 percent [T12], 67.9 percent [T15-1], and 85.7 percent [T15-2] vs 50 percent), the most frequent being nausea, diarrhoea, reduced appetite, and vomiting. However, these were mild to moderate in intensity and lower than those found in the phase IIb study, noted Nauck. “[Our findings suggest that] initiating incretin hormone receptor agonist therapy at a low dose with gradual dose escalation may improve gastrointestinal (GI) tolerability.”

Overall treatment discontinuation rates were lower with tirzepatide vs placebo (6.9 percent, 21.4 percent, and 7.1 percent for T12, T15-1, and T15-2, respectively, vs 23.1 percent). Treatment discontinuation due to AEs were similar across all arms (3.4, 3.6, and 0 percent vs 3.8 percent).

However, the limited dose-escalation period is a potential limitation, noted Nauck. “Longer dose escalation may even be better in preventing the incidence of [GI AEs].” Nonetheless, the reductions in AEs and treatment cessation with tirzepatide suggest improved tolerability, said Nauck.

“[Our objective is to try] to save high doses [of tirzepatide] for phase III trials and further use by trying to modify the initial exposure to the drug and the uptitration schedule … [Our findings may provide] insight to help inform a starting dose and dose-escalation regimen of tirzepatide for phase III clinical trials,” said Nauck.

Adding further insight into the issue of reduced appetite and weight loss, Nauck noted that it would be advisable to investigate whether individuals with reduced appetite lose more weight than those with no appetite issues. “Maybe there is some biology to it … I can only speculate that [it could be] a social problem … [This] is interesting and should be explored.”