Physicians' Academy for Cardiovascular Education

Higher doses of oral GLP-1RA superior to approved dose in adults with T2D

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

Literature - Aroda VR, Alberle J, Bardtrum L, et al. - Lancet. 2023 Jun 23;S0140-6736(23)01127-3. [Online ahead of print]. doi: 10.1016/S0140-6736(23)01127-3

Introduction and methods


Glycemic control and weight management are considered important targets for patients with T2D, alongside cardiorenal protection and CV risk reduction [1]. To achieve a reduction in bodyweight as well as improved glycemic control, GLP-1RA such as semaglutide can be used in the treatment of T2D, next to diet and exercise [2-4]. The PIONEER clinical trials demonstrated that once-daily oral semaglutide at a dose of 7 mg and 14 mg lowered HbA1c levels and bodyweight in patients with T2D [5-11]. Intensification of treatment with higher doses of semaglutide may provide additional benefits to patients.

Aim of the study

The authors evaluated the efficacy, safety, and tolerability of once-daily oral semaglutide at higher doses (25 mg and 50 mg) and compared with the highest approved dose (14 mg) in adults with T2D.



The PIONEER PLUS trial was an active-controlled, multinational, double-blind, phase 3b trial in which 1606 adults with T2D were randomized (1:1:1) to once-daily oral semaglutide 14 mg, 25 mg, or 50 mg for 68 weeks. Adults were eligible for enrollment if they had HbA1c of 8.0−10.5% (64-91 mmol/mol), a BMI of 25.0 kg/m² or greater, and received stable daily doses of one to three oral glucose-lowering drugs (metformin, sulfonylurea, SGLT2 inhibitor, or DPP-4 inhibitor). Participants who were on a DPP-4 inhibitor at inclusion were asked to discontinue this treatment at randomization.

Dose escalation was done as following: all participants started at once-daily oral semaglutide treatment at 3 mg, then escalated to 7 mg at week 4, and to 14 mg at week 8. Participants who were assigned to 25 mg received their maintenance dose at week 12. Participants who were assigned to 50 mg escalated to 25 mg at week 12, and received their maintenance dose of 50 mg at week 16.


The primary outcome was the percentage change in HbA1c from baseline to week 52. The confirmatory secondary outcome was change in body weight (kg) from baseline to week 52. Supportive secondary outcomes were proportion of participants who reached HbA1c target (<7.0%; 53 mmol/mol) or 5%/10% weight loss. Supportive safety outcomes were the number of (serious) adverse events.

Main results

HbA1c and bodyweight

Safety and tolerability


Oral semaglutide at a dose of 25 mg and 50 mg were superior in reducing HbA1c and bodyweight at week 52 compared with the approved dose of 14 mg in adults with inadequately controlled T2D. The safety profile of the higher formulation of oral semaglutide were similar to previous trials with GLP1-RA and previous PIONEER trials.


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Find this article online at The Lancet

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