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Randomized Controlled Trial
. 2023 May 1;6(5):e2314493.
doi: 10.1001/jamanetworkopen.2023.14493.

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

Aditi R Saxena  1 , Juan P Frias  2 , Lisa S Brown  3 , Donal N Gorman  4 , Szilard Vasas  5 , Nikolaos Tsamandouras  6 , Morris J Birnbaum  1
Affiliations
Randomized Controlled Trial

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

Aditi R Saxena et al. JAMA Netw Open. .

Abstract

Importance: Currently 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.

Objective: To 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 participants: A 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.

Interventions: Participants 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 measures: Change 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.

Results: Of 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 relevance: In 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 registration: ClinicalTrials.gov Identifier: NCT03985293.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Saxena reported being a coinventor of danuglipron and holding stocks in Pfizer outside the submitted work. Dr Frias reported receiving grants and personal fees from Pfizer for serving as an advisory board member during the conduct of the study and grants and personal fees from Eli Lilly, Novo Nordisk, Sanofi, and Boehringer Ingelheim outside the submitted work. Ms Brown reported holding stocks in Pfizer outside the submitted work. Dr Gorman reported holding stocks in Pfizer outside the submitted work. Dr Tsamandouras reported holding stocks in Pfizer outside the submitted work. Dr Birnbaum reported receiving consulting fees from Pfizer and holding stocks in Pfizer outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Disposition of Study Participants
If compliance was less than 89% (based on pill count) during the 2-week placebo run-in period, the participant was not randomized and was excluded from the remainder of the study. All treated participants contributed to both efficacy and safety analysis populations. Participants who discontinued treatment might still have continued in the study. The category “completed follow-up” includes participants who completed the double-blind treatment phase as well as those who did not if they continued in the study. Six of 411 participants discontinued for COVID-19–related reasons. AE indicates adverse event; LTFU, lost to follow-up; PD, protocol deviation; and NLMEC, no longer meets eligibility criteria. aOne participant was randomized to the 120-mg twice daily group but was not treated because of being randomized in error.
Figure 2.
Figure 2.. Least Squares (LS) Mean Change from Baseline Through the 16-Week Double-Blind Treatment Period for Glycated Hemoglobin (HbA1c), Fasting Plasma Glucose (FPG), and Body Weight
Data are for all randomized and treated participants. For participants who discontinued study medication and/or received glycemic rescue medication, all subsequent values were censored in the analysis. To convert HbA1c to proportion of hemoglobin, multiply by 0.01; to convert FPG to millimoles per liter, multiply by 0.0555.
See this image and copyright information in PMC

References

    1. Draznin B, Aroda VR, Bakris G, et al. ; American Diabetes Association Professional Practice Committee . 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2022. Diabetes Care. 2022;45(suppl 1):S125-S143. doi:10.2337/dc22-S009 - DOI - PubMed
    1. Buse JB, Wexler DJ, Tsapas A, et al. . 2019 update to: management of hyperglycemia in type 2 diabetes, 2018: a consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2020;43(2):487-493. doi:10.2337/dci19-0066 - DOI - PMC - PubMed
    1. Hussein H, Zaccardi F, Khunti K, et al. . Efficacy and tolerability of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists: a systematic review and network meta-analysis. Diabetes Obes Metab. 2020;22(7):1035-1046. doi:10.1111/dom.14008 - DOI - PubMed
    1. Cooke CE, Lee HY, Tong YP, Haines ST. Persistence with injectable antidiabetic agents in members with type 2 diabetes in a commercial managed care organization. Curr Med Res Opin. 2010;26(1):231-238. doi:10.1185/03007990903421994 - DOI - PubMed
    1. Sikirica MV, Martin AA, Wood R, Leith A, Piercy J, Higgins V. Reasons for discontinuation of GLP1 receptor agonists: data from a real-world cross-sectional survey of physicians and their patients with type 2 diabetes. Diabetes Metab Syndr Obes. 2017;10:403-412. doi:10.2147/DMSO.S141235 - DOI - PMC - PubMed

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