Danuglipron helps with glucose control, weight loss in T2D

The glucagon-like peptide 1 receptor (GLP-1R) agonist danuglipron appears to be beneficial in the treatment of patients with type 2 diabetes (T2D), yielding reductions in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), and body weight, without fasting restrictions, as shown in the results of a phase IIb study.

Compared with placebo, all danuglipron doses were associated with significant decreases in HbA1c (mean change from baseline, −0.49 percent to −1.18 percent vs −0.02 percent) and FPG (mean change from baseline, −14.12 to −33.24 mg/dL vs 1.31 mg/dL) at week 16. [JAMA Netw Open 2023;6:e2314493]

Additionally, participants who received higher doses of danuglipron lost significantly more weight at week 16 than those who received placebo (80-mg twice daily vs placebo: −2.04 kg, 90 percent confidence interval [CI], −3.01 to −1.07; 120-mg twice daily vs placebo: −4.17 kg, 90 percent CI, −5.15 to −3.18).

The observed proportions of participants who achieved weight loss of at least 5 percent at week 16, relative to baseline, were 6 percent with danuglipron 2.5-mg twice daily, 10 percent with 10 mg twice daily, 18 percent with 40 mg twice daily, 22 percent with 80 mg twice daily, 47 percent with 120 mg twice daily, and 2 percent with placebo.

“There were no consistent trends in change from baseline for fasting insulin, HOMA-IR, and fasting glucagon across all treatment groups or differences to placebo relative to the danuglipron groups,” according to the investigators.

“Danuglipron was generally safe in [the T2D] population, with most participants receiving metformin background therapy, with a tolerability profile consistent with the mechanism of action,” they added. [Cell Metab 2018;27:740-756; Diabetes Obes Metab 2021;23:30-39]

The most common adverse events were nausea, diarrhoea, and vomiting.

Easy to administer

Unlike most currently available GLP-1R therapies that require subcutaneous administration, “the small-molecule GLP-1R agonist danuglipron … is administered orally, twice daily, with or without food,” the investigators noted. [J Med Chem 2022;65:8208-8226]

The administration route for danuglipron an advantage, given that “subcutaneous medications can be inconvenient or unsuitable for some patients and result in reduced uptake, adherence, and persistence, with patients generally preferring oral medicines,” they said. 

Among other peptidic GLP-1R agonists, semaglutide is currently the only one available for oral administration, although the drug has strict fasting requirements before and after administration. [Curr Med Res Opin 2010;26:231-238; Diabetes Metab Syndr Obes 2017;10:403-412; Diabetes Ther 2021;12:1915-1927]

Study details

The current phase IIb study included 411 participants with T2D (mean age 58.6 years, 51 percent men). They were randomly assigned to receive treatment with placebo or danuglipron at 2.5, 10, 40, 80, or 120 mg, all orally administered twice daily with food for 16 weeks, and a total of 316 participants (77 percent) completed treatment.

Of note, participants underwent weekly dose escalation steps to receive danuglipron 40 mg or more twice daily.

“At the time of study design, weekly dose escalation steps were considered an acceptable and efficient approach to assess glycaemic efficacy [for] 16 weeks, taking into account the half-life of danuglipron,” the investigators said. [J Med Chem 2022;65:8208-8226; Nat Med 2021;27:1079-1087] 

“Danuglipron doses were expected to reach pharmacokinetic steady state within the weekly timeframe, and weekly steps were of a longer duration than had been used previously. However, clinical data with peptidic GLP-1R agonists have demonstrated that longer dose escalation steps are more likely to result in better tolerability, particularly at higher doses, and monthly steps are used for many of the peptidic GLP-1R agonists in clinical use,” they pointed out. [Nat Med 2021;27:1079-1087; J Clin Invest 2017;127:4217-4227]