Efficacy and Safety of Oral Small Molecule Glucagon-Like Peptide 1 Receptor Agonist Danuglipron for Glycemic Control Among Patients With Type 2 Diabetes

Abstract

ImportanceCurrently available glucagon-like peptide 1 receptor (GLP-1R) agonists for treating type 2 diabetes (T2D) are peptide agonists that require subcutaneous administration or strict fasting requirements before and after oral administration.ObjectiveTo investigate the efficacy, safety, and tolerability of multiple dose levels of the novel, oral, small molecule GLP-1R agonist danuglipron over 16 weeks.Design, Setting, and ParticipantsA phase 2b, double-blind, placebo-controlled, parallel-group, 6-group randomized clinical trial with 16-week double-blind treatment period and 4-week follow-up was conducted from July 7, 2020, to July 7, 2021. Adults with T2D inadequately controlled by diet and exercise, with or without metformin treatment, were enrolled from 97 clinical research sites in 8 countries or regions.InterventionsParticipants received placebo or danuglipron, 2.5, 10, 40, 80, or 120 mg, all orally administered twice daily with food for 16 weeks. Weekly dose escalation steps were incorporated to achieve danuglipron doses of 40 mg or more twice daily.Main Outcomes and MeasuresChange from baseline in glycated hemoglobin (HbA1c, primary end point), fasting plasma glucose (FPG), and body weight were assessed at week 16. Safety was monitored throughout the study period, including a 4-week follow-up period.ResultsOf 411 participants randomized and treated (mean [SD] age, 58.6 [9.3] years; 209 [51%] male), 316 (77%) completed treatment. For all danuglipron doses, HbA1c and FPG were statistically significantly reduced at week 16 vs placebo, with HbA1c reductions up to a least squares mean difference vs placebo of −1.16% (90% CI, −1.47% to −0.86%) for the 120-mg twice daily group and FPG reductions up to a least squares mean difference vs placebo of −33.24 mg/dL (90% CI, −45.63 to −20.84 mg/dL). Body weight was statistically significantly reduced at week 16 compared with placebo in the 80-mg twice daily and 120-mg twice daily groups only, with a least squares mean difference vs placebo of −2.04 kg (90% CI, −3.01 to −1.07 kg) for the 80-mg twice daily group and −4.17 kg (90% CI, −5.15 to −3.18 kg) for the 120-mg twice daily group. The most commonly reported adverse events were nausea, diarrhea, and vomiting.Conclusions and RelevanceIn adults with T2D, danuglipron reduced HbA1c, FPG, and body weight at week 16 compared with placebo, with a tolerability profile consistent with the mechanism of action.Trial RegistrationClinicalTrials.gov Identifier: NCT03985293

Development of Long-Acting Dipeptidyl Peptidase-4 Inhibitors: Structural Evolution and Long-Acting Determinants

“…An orally administered formulation of semaglutide was approved for the treatment of T2DM in 2019 . The oral small-molecule GLP-1R agonist danugliprone, developed by Pfizer, is currently in phase II clinical trials. , Recent clinical data showed that danugliprone reduced HbA1c, fasting plasma glucose (FPG), and body weight at week 16 . GLP-1R agonists have some advantages compared with DPP-4 inhibitors, including greater reductions in HbA1c, significant body weight loss, and lower risk of major adverse cardiovascular events. , As more oral GLP-1R agonists are approved, it is challenging to develop daily dosing DPP-4 inhibitors.…”

“…212 The oral small-molecule GLP-1R agonist danugliprone, developed by Pfizer, is currently in phase II clinical trials. 213,214 Recent clinical data showed that danugliprone reduced HbA1c, fasting plasma glucose (FPG), and body weight at week 16. 213 GLP-1R agonists have some advantages compared with DPP-4 inhibitors, including greater reductions in HbA1c, significant body weight loss, and lower risk of major adverse cardiovascular events.…”

“…213,214 Recent clinical data showed that danugliprone reduced HbA1c, fasting plasma glucose (FPG), and body weight at week 16. 213 GLP-1R agonists have some advantages compared with DPP-4 inhibitors, including greater reductions in HbA1c, significant body weight loss, and lower risk of major adverse cardiovascular events. 210,215 As more oral GLP-1R agonists are approved, it is challenging to develop daily dosing DPP-4 inhibitors.…”

Newer pharmacological interventions directed at gut hormones for obesity

“…A study conducted in Japanese patients with type 2 diabetes showed significant reduction in glycaemia and body weight (Ono et al, 2023). Patients with type 2 diabetes showed a significant reduction in glycaemia and body weight at 16 weeks (Saxena et al, 2023).…”

Effect of Renal Impairment on the Pharmacokinetics of a Single Oral Dose of Danuglipron in Participants With Type 2 Diabetes

“…Danuglipron has been found to stimulate glucose‐dependent insulin release and suppress food intake in nonclinical models 13,14 with an efficacy equivalent to that observed with injectable peptidic GLP‐1R agonists. Moreover, recent Phase 1 and Phase 2 studies in patients with T2D found that danuglipron, either on a background of metformin or as monotherapy, 14‐17 reduced glycemic indices and body weight with favorable safety and pharmacokinetic profiles. Drug disposition studies have shown that there is minimal excretion of unchanged danuglipron in urine (<0.1%) 14 .…”