ADA 2023. Results from PIONEER PLUS trial showed oral semaglutide 25 mg and 50 mg were superior than 14 mg in reducing HbA1c and body weight in adults with T2D.
Higher doses of once-daily oral semaglutide (25 mg and 50 mg) were associated with more effective glycemic control and greater loss of body weight than oral semaglutide 14 mg in a new clinical trial of adults with inadequately controlled type 2 diabetes (T2D).
Findings come from the PIONEER PLUS clinical trial and were presented at the 83rd Scientific Sessions of the American Diabetes Association® (ADA) in San Diego, CA, and simultaneously published in The Lancet.
“PIONEER PLUS is the first study to indicate that these higher doses might provide a highly effective oral option to improve both glycemic control and weight loss in type 2 diabetes,” wrote study authors.
In 2019, the US Food and Drug Administration (FDA) approved oral semaglutide (Rybelsus, Novo Nordisk) as the first oral GLP-1 receptor agonist for adults with T2D. In clinical trials leading to that approval, accompanying body weight reductions were observed. The approval was for a dose of up to 14 mg.
Investigators conducted the randomized, multicenter, double-blind, global phase 3b clinical trial to evaluate the efficacy, safety, and tolerability of once-daily oral semaglutide 25 mg and 50 mg compared with the FDA-approved 14 mg dose in adults with inadequately controlled T2D.
Researchers enrolled adults aged ≥18 years and older with T2D, an HbA1c between 8% and 10.5%, and a body mass index of ≥ 25 kg/m2 who were on a stable daily dose of 1 to 3 of the following oral glucose-lowering therapies: metformin, sulfonylurea, SGLT2 inhibitor, or DPP-4 inhibitor.
Participants were randomly assigned, 1:1:1, to oral semaglutide 14 mg, 25 mg, or 50 mg for 68 weeks. Adults continued their existing glucose-lowering medication, except for those receiving DPP-4 inhibitors, who were asked to discontinue the therapy, according to the study.
The primary endpoint was change in HbA1c from baseline to 52 weeks, which was evaluated with a treatment policy estimand in the intention-to-treat group. Researchers also analyzed the proportion of participants who achieved an HbA1c of <7% or ≤6.5% at 52 weeks, as well as the proportion of participants who had a weight loss of ≥5% or ≥10% at week 52. Investigators assessed safety in all participants who received at least 1 dose of the trial drug.
A total of 1606 participants (mean age, 58 years; 58.3% men) were enrolled in the study, of whom 536 received oral semaglutide 14 mg, 535 received 25 mg, and 535 received 50 mg. At baseline, mean HbA1c was 9% and mean body weight was 96.4 kg, according to researchers.
In the treatment-policy estimand, mean changes in HbA1c at week 52 were −1.5 percentage points (standard error [SE] 0.05) with oral semaglutide 14 mg, −1.8 percentage points (SE 0.06) with 25 mg, and −2.0 percentage points (SE 0.06) with 50 mg. Researchers observed that changes were significantly greater with oral semaglutide 25 mg and 50 mg compared with 14 mg, with estimated treatment differences (ETDs) of -0.27 percentage points (95% CI −0.42 to −0.12; P=.006) for 25 mg and −0.53 percentage points (95% CI −0.68 to −0.38; P<.001).
Results showed that an HbA1c of <7% was achieved by 63% of participants in the 50 mg group and 51% of those in the 25 mg group compared with 39% of those in the 14 mg group. The percentage of participants who achieved an HbA1c of ≤6.5% was 51% in the 50 mg group, 40% in the 25 mg group, and 26% in the 14 mg group.
Also, researchers noted that changes in body weight by week 52 were “significantly greater” in the oral semaglutide 25 mg and 50 mg groups compared with the 14 mg group. In treatment policy estimand, adults receiving 50 mg lost 8 kg of body weight and those receiving 25 mg lost 6.7 kg of weight compared with a 4.4 kg weight loss for adults receiving 14 mg (P<.001 for both).
The percentage of adults who lost ≥5% of their body weight at 52 weeks was 67% in the 50 mg group, 60% in the 25 mg group, and 41% in the 14 mg group. Moreover, a weight loss of ≥10% was achieved by 37% of adults in the 50 mg group, 29% of those in the 25 mg group, and 14% of those in the 14 mg group.
“The superior glycemic control and body weight loss with oral semaglutide 25 mg and 50 mg compared with the current highest approved dose of 14 mg observed in PIONEER PLUS suggest that these higher doses might support individually tailored treatment goals, based not only on glucose-lowering but also bodyweight and cardiovascular risk factor reduction targets,” wrote investigators.
Adverse events were reported by 76% of participants in the 14 mg group, 79% of those in the 25 mg group, and 80% of those in the 50 mg group. Gastrointestinal disorders, such as nausea, vomiting, and diarrhea, were the most frequently reported adverse events. “The majority of gastrointestinal disorders were mild to moderate in severity and occurred during dose escalation,” noted PIONEER PLUS authors.
Ten deaths occurred during the trial, however, none of them were judged to be related to oral semaglutide. Researchers also reported no new safety concerns with oral semaglutide 25 mg or 50 mg.
“The availability of a wider range 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,” concluded authors. “This might encourage improved management of type 2 diabetes earlier and in the primary care setting. Future real-world studies will be needed to investigate the clinical impact of the availability of higher doses of oral semaglutide.”
Reference: 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.