Long-term efficacy and safety of oral semaglutide and the effect of switching from sitagliptin to oral semaglutide in patients with type 2 diabetes: a 52-week, randomized, open-label extension of the PIONEER 7 trial

Abstract

Introduction: The PIONEER 7 trial demonstrated superior glycemic control and weight loss with once-daily oral semaglutide with flexible dose adjustment versus sitagliptin 100 mg in type 2 diabetes. This 52-week extension evaluated long-term oral semaglutide treatment and switching from sitagliptin to oral semaglutide.

Research design and methods: A 52-week, open-label extension commenced after the 52-week main phase. Patients on oral semaglutide in the main phase continued treatment (n=184; durability part); those on sitagliptin were rerandomized to continued sitagliptin (n=98) or oral semaglutide (n=100; initiated at 3 mg) (switch part). Oral semaglutide was dose-adjusted (3, 7, or 14 mg) every 8 weeks based on glycated hemoglobin (HbA1c) (target <7.0% (<53 mmol/mol)) and tolerability. Secondary endpoints (no primary) included changes in HbA1c and body weight.

Results: In the durability part, mean (SD) changes in HbA1c and body weight from week 0 were -1.5% (0.8) and -1.3% (1.0) and -2.8 kg (3.8) and -3.7 kg (5.2) at weeks 52 and 104, respectively. In the switch part, mean changes in HbA1c from week 52 to week 104 were -0.2% for oral semaglutide and 0.1% for sitagliptin (difference -0.3% (95% CI -0.6 to 0.0); p=0.0791 (superiority not confirmed)). More patients achieved HbA1c <7.0% with oral semaglutide (52.6%) than sitagliptin (28.6%; p=0.0011) and fewer received rescue medication (9% vs 23.5%). Respective mean changes in body weight were -2.4 kg and -0.9 kg (difference -1.5 kg (95% CI -2.8 to -0.1); p=0.0321). Gastrointestinal adverse events were the most commonly reported with oral semaglutide.

Conclusions: Long-term oral semaglutide with flexible dose adjustment maintained HbA1c reductions, with additional body weight reductions, and was well tolerated. Switching from sitagliptin to flexibly dosed oral semaglutide maintained HbA1c reductions, helped more patients achieve HbA1c targets with less use of additional glucose-lowering medication, and offers the potential for additional reductions in body weight.

Trial registration number: NCT02849080.

Keywords: dipeptidyl peptidase 4; glucagon-like peptide 1; treatment outcome.

Conflict of interest statement

Competing interests: JBB reports contracted consulting fees paid to the University of North Carolina (Chapel Hill, North Carolina, USA) from Adocia, AstraZeneca, Dance Biopharm, Dexcom, Elcelyx Therapeutics, Eli Lilly, Fractyl, GI Dynamics, Intarcia Therapeutics, Lexicon, MannKind, Metavention, NovaTarg, Novo Nordisk, Orexigen, PhaseBio, Sanofi, Senseonics, Shenzhen HighTide, Takeda, vTv Therapeutics, and Zafgen; grant support from AstraZeneca, Eli Lilly, GI Dynamics, GlaxoSmithKline, Intarcia Therapeutics, Johnson & Johnson, Lexicon, Medtronic, Novo Nordisk, Orexigen, Sanofi, Scion NeuroStim, Takeda, Theracos, and vTv Therapeutics; personal fees from Neurimmune AG and Fortress Biotech; and holds stock options in Mellitus Health, PhaseBio, and Stability Health. BWB reports personal fees from Adocia, AstraZeneca, Boehringer Ingelheim, Intarcia, Janssen, Lilly, MannKind, Medtronic, Novo Nordisk, Sanofi, and Senseonics; grant support from Boehringer Ingelheim, Dexcom, Diasome, Janssen, Lilly, MannKind, Medtronic, Novo Nordisk, Sanofi, and Senseonics; and holds shares in Aseko. AM reports board membership and consultancy fees paid to KU Leuven (Leuven, Belgium) from AstraZeneca, Merck Sharp & Dohme, Novo Nordisk, and Sanofi; and payment for lectures from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Novo Nordisk, and Sanofi. YMC reports grants from AstraZeneca, LG, and Sanofi; and consulting fees from Hanmi. EC, CLH, and MAN are employees of and hold shares in Novo Nordisk. TRP reports board membership and personal fees from Adocia, Arecor, AstraZeneca, Novo Nordisk, and Sanofi; and payment for lectures from Novo Nordisk.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Glycemic control-related efficacy endpoints. (A) Observed mean change from baseline in HbA1c over the entire trial for the durability part; (B) observed HbA1c at weeks 0 and 104 by current dose at week 104 for the durability part; (C) observed mean change from baseline in HbA1c from week 52 by week for the switch part; (D) estimated change from week 52 in HbA1c at week 104 for the switch part; (E) observed HbA1c at weeks 52 and 104 by current dose at week 104 for the switch part. The durability part includes all patients randomized to oral semaglutide at baseline (week 0). The switch part includes all patients previously randomized to sitagliptin at baseline (week 0) and rerandomized to either oral semaglutide or sitagliptin at the start of the extension phase (week 52). n: number of patients contributing to the mean. Error bars (A and B) represent SEM. ETD, estimated treatment difference; flex, flexible dosing; HbA1c, glycated hemoglobin.

Figure 2

Body weight-related efficacy endpoints. (A) Observed mean change from baseline in body weight over the entire trial for the durability part; (B) observed mean change from baseline in body weight from week 52 by week for the switch part; (C) estimated change from week 52 in body weight at week 104 for the switch part. The durability part includes all patients randomized to oral semaglutide at baseline (week 0). The switch part includes all patients previously randomized to sitagliptin at baseline (week 0) and rerandomized to either oral semaglutide or sitagliptin at the start of the extension phase (week 52). Error bars (A and B) represent SEM. ETD, estimated treatment difference; flex, flexible dosing; n, number of patients contributing to the mean.