Higher investigational doses of oral semaglutide — 25 mg and 50 mg — were found to be superior to the 14-mg dose for reducing hemoglobin A1c (HbA1c) among patients with inadequately controlled type 2 diabetes, according to study results published in The Lancet.
Investigators assessed the efficacy, safety, and tolerability of oral semaglutide at higher investigational doses compared with the highest currently approved dose (14 mg) among adults with inadequately controlled type 2 diabetes.
The investigators conducted a 68-week, active-controlled, international, multicenter, randomized, phase 3b trial (PIONEER PLUS; ClinicalTrials.gov Identifier: NCT04707469) across 177 sites in 14 countries.
Eligible patients were those aged at least 18 years diagnosed with type 2 diabetes with HbA1c levels between 8.0% and 10.5%, a body mass index (BMI) of at least 25.0 kg/m2, and a diabetes treatment regimen comprising stable daily doses of 1 to 3 oral glucose-lowering drugs.
Patients were randomly assigned 1:1:1 to receive a 14-mg, 25-mg, or 50-mg daily oral maintenance dose of semaglutide, in addition to their glucose-lowering medications.
All patients were initiated on a 3-mg dose of once-daily oral semaglutide, which was escalated to higher doses at week 4 (7 mg) and week 8 (14 mg). Patients assigned to receive the 25-mg dose initiated the increased dose at week 12. Patients assigned to treatment with the 50-mg dose received the 25-mg dose at week 12 and the 50-mg dose at week 16.
The primary and secondary endpoints were the percent change in HbA1c and change in body weight from baseline to week 52, respectively.
A total of 1606 patients were enrolled in the study (mean age, 58.2 years; 58.3% men; 78% White). The mean duration of diabetes was 9.3 years, mean HbA1c was 9.0%, mean body weight was 96.4 kg, and mean BMI was 33.8 kg/m2.
A total of 536 patients were assigned to receive 14 mg of oral semaglutide, 535 received 25 mg, and 535 received 50 mg. Among these, 446 (83%) patients in the 14-mg group, 420 (79%) in the 25-mg group, and 434 (81%) in the 50-mg group completed the treatment course.
At week 52, HbA1c was improved from baseline for all treatment groups. The mean change in HbA1c was -1.5 percentage points (standard error [SE], 0.05) for patients in the 14-mg group, -1.8 percentage points (SE, 0.06) in the 25-mg group, and -2.0 percentage points (SE, 0.06) in the 50-mg group.
Changes in HbA1c were greater among patients in the 25-mg group (estimated treatment difference [ETD], -0.27 percentage points; 95% CI, -0.42 to -0.12; P =.0006) and 50-mg group (ETD, -0.53 percentage points; 95% CI, -0.68 to -0.38; P <.0001).
While bodyweight loss was noted among all study groups from baseline to week 52, changes in body weight were significantly greater among the 25-mg (ETD, -2.32 kg; 95% CI, -3.11 to -1.53; P <.0001) and 50-mg (ETD, -3.63 kg; 95% CI, -4.42 to -2.84; P<.0001) groups compared with the 14-mg group.
Adverse events (AEs) were reported by 404 (76%) patients in the14-mg group, 422 (79%) in the 25-mg group, and 428 (80%) in the 50-mg group. The most frequently reported AEs were gastrointestinal symptoms, which were mild to moderate in severity; patients in the 25-mg and 50-mg groups reported these symptoms more frequently vs those in the 14-mg group (53% and 54% vs 42%, respectively).
Study limitations included potential inadequate duration of dose escalation periods, inability to reduce doses below 14 mg, and limited generalizability due to the predominantly White study cohort.
“The availability of a wider ranges of doses might allow individualized dose titration to the desired effect, and the ability to intensify treatment by increasing the dose of a single oral agent might help overcome therapeutic inertia. This might encourage improved management of type 2 diabetes earlier and in the primary care setting,” the study authors concluded.
Disclosure: This study was funded by Novo Nordisk. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Aroda VR, Aberle J, Bardtrum L, et al. Efficacy and safety of once-daily oral semaglutide 25 mg and 50 mg compared with 14 mg in adults with type 2 diabetes (PIONEER PLUS): a multicentre, randomised, phase 3b trial. Lancet. Published online June 26, 2023. doi:10.1016/S0140-6736(23)01127-3.
This article originally appeared on Endocrinology Advisor