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Clinical Trial
. 2023 Aug 26;402(10403):693-704.
doi: 10.1016/S0140-6736(23)01127-3. Epub 2023 Jun 26.

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

Vanita R Aroda  1 , Jens Aberle  2 , Lars Bardtrum  3 , Erik Christiansen  3 , Filip K Knop  4 , Sanaz Gabery  3 , Sue D Pedersen  5 , John B Buse  6
Affiliations
Clinical Trial

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

Vanita R Aroda et al. Lancet. .

Abstract

Background: Once-daily oral semaglutide is an effective type 2 diabetes treatment. We aimed to investigate a new formulation of oral semaglutide at higher investigational doses versus the approved 14 mg dose in adults with inadequately controlled type 2 diabetes.

Methods: This global, multicentre, randomised, double-blind, phase 3b trial, carried out at 177 sites in 14 countries, enrolled adults with type 2 diabetes, glycated haemoglobin (HbA1c) 8·0-10·5% (64-91 mmol/mol), a BMI of 25·0 kg/m2 or greater, receiving stable daily doses of one to three oral glucose-lowering drugs. Participants were randomly assigned (1:1:1), by means of an interactive web response system, to once-daily oral semaglutide 14 mg, 25 mg, or 50 mg for 68 weeks. Investigators, site personnel, trial participants, and trial sponsor staff were masked to dose assignment throughout the trial. The primary endpoint was change in HbA1c from baseline to week 52, evaluated with a treatment policy estimand in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of trial drug. This trial is registered with ClinicalTrials.gov, NCT04707469, and the European Clinical Trials register, EudraCT 2020-000299-39, and is complete.

Findings: Between Jan 15 and Sept 29, 2021, of 2294 people screened, 1606 (n=936 [58·3%] male; n=670 [41·7%] female; mean [SD] age 58·2 [10·8] years) received oral semaglutide 14 mg (n=536), 25 mg (n=535), or 50 mg (n=535). At baseline, mean (SD) HbA1c was 9·0% (0·8; 74·4 mmol/L [SD 8·3]) and mean bodyweight was 96·4 kg (21·6). Mean changes (SE) in HbA1c at week 52 were -1·5 percentage points (SE 0·05) with oral semaglutide 14 mg, -1·8 percentage points (0·06) with 25 mg (estimated treatment difference [ETD] -0·27, 95% CI -0·42 to -0·12; p=0·0006), and -2·0 percentage points (0·06) with 50 mg (ETD -0·53, -0·68 to -0·38; p<0·0001). Adverse events were reported by 404 (76%) participants in the oral semaglutide 14 mg group, 422 (79%) in the 25 mg group, and 428 (80%) in the 50 mg group. Gastrointestinal disorders, which were mostly mild to moderate, occurred more frequently with oral semaglutide 25 mg and 50 mg than with 14 mg. Ten deaths occurred during the trial; none were judged to be treatment related.

Interpretation: Oral semaglutide 25 mg and 50 mg were superior to 14 mg in reducing HbA1c and bodyweight in adults with inadequately controlled type 2 diabetes. No new safety concerns were identified.

Funding: Novo Nordisk.

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Conflict of interest statement

Declaration of interests VRA reports receiving consultancy fees from Applied Therapeutics, Fractyl, Novo Nordisk, Pfizer, and Sanofi, and research grant support (to their institution) from Applied Therapeutics, Eli Lilly, Fractyl, Novo Nordisk, and Sanofi. LB, EC, and SG are employees and shareholders in Novo Nordisk. JA reports consulting fees or speaking honoraria from Astra Zeneca, Boehringer Ingelheim, Lilly, and Novo Nordisk. FKK reports participating in scientific advisory panels or speakers' bureaus for, consulting fees, or receiving research support from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, Gubra, Lupin, MedImmune, MSD–Merck, Mundipharma, Norgine, Novo Nordisk, Pharmacosmos, Sanofi, ShouTi, Zealand Pharma, and Zucara; is a minority shareholder in Antag Therapeutics, and co-owner of the weight loss clinic Medicinsk Vægttabsbehandling ApS. SDP reports consulting fees or speaking honoraria from Abbott, AstraZeneca, Bausch, Bayer, Boehringer Ingelheim, Dexcom, HLS, Janssen, Lilly, Merck, Novo Nordisk, Pfizer, and Sanofi; and research studies for AstraZeneca, Boehringer Ingelheim, Lilly, Medpace, and Novo Nordisk. JBB contracted consulting fees and travel support for contracted activities that are paid to the University of North Carolina by Novo Nordisk and vTv Therapeutics; has received grant support from Dexcom, NovaTarg, Novo Nordisk, Sanofi, Tolerion, and vTv Therapeutics; has received personal compensation for consultation from Alkahest, Altimmune, Anji, AstraZeneca, Bayer, Boehringer Ingelheim, Carmot Therapeutics, CeQur, Cirius Therapeutics, Corcept Therapeutics, Dasman Diabetes Institute (Kuwait), Eli Lilly, Fortress Biotech, GentiBio, Glycadia, Glyscend, Janssen, Mellitus Health, Moderna, Pendulum Therapeutics, Praetego, Sanofi, Stability Health, Terns, and Valo; has received payment for expert testimony from Medtronic; and in lieu of payment for consultation he has received stock or options in Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio, Praetego, and Stability Health.

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