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Original Investigation
March 23, 2019

Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With Sulfonylurea: The PIONEER 3 Randomized Clinical Trial

Author Affiliations
  • 1Dallas Diabetes Research Center at Medical City, Dallas, Texas
  • 2Hillcrest Family Health Center, Waco, Texas
  • 3Department of Medicine III, Carl Gustav Carus University Hospital, Technische Universität Dresden, Dresden, Germany
  • 4Paul Langerhans Institute Dresden, Helmholtz Center Munich at Technische Universität Dresden, Dresden, Germany
  • 5Novo Nordisk A/S, Søborg, Denmark
  • 6Endocrinology, Diabetology and Nutrition, Clinique Portes du Sud, Venissieux, France
  • 7Departamento Endocrinología, Instituto Mexicano del Seguro Social, Ciudad Madero, Mexico
  • 8Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
  • 9Diabetes Research Centre, University of Leicester, Leicester, England
JAMA. 2019;321(15):1466-1480. doi:10.1001/jama.2019.2942
Key Points

Question  What is the efficacy of oral semaglutide (3, 7, or 14 mg/d) compared with sitagliptin, 100 mg/d, when added to metformin with or without sulfonylurea in patients with uncontrolled type 2 diabetes?

Findings  In this randomized clinical trial that included 1864 adults, oral semaglutide, 7 mg/d and 14 mg/d, compared with sitagliptin resulted in statistically significantly greater reductions in glycated hemoglobin over 26 weeks (–1.0% and –1.3%, respectively, compared with –0.8%). There was no significant benefit with oral semaglutide, 3 mg/d, compared with sitagliptin.

Meaning  In this trial, oral semaglutide, 7 mg/d and 14 mg/d, when added to metformin with or without sulfonylurea, resulted in greater improvements in glycated hemoglobin than sitagliptin after 26 weeks.

Abstract

Importance  Phase 3 trials have not compared oral semaglutide, a glucagon-like peptide 1 receptor agonist, with other classes of glucose-lowering therapy.

Objective  To compare efficacy and assess long-term adverse event profiles of once-daily oral semaglutide vs sitagliptin, 100 mg added on to metformin with or without sulfonylurea, in patients with type 2 diabetes.

Design, Setting, and Participants  Randomized, double-blind, double-dummy, parallel-group, phase 3a trial conducted at 206 sites in 14 countries over 78 weeks from February 2016 to March 2018. Of 2463 patients screened, 1864 adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea were randomized.

Interventions  Patients were randomized to receive once-daily oral semaglutide, 3 mg (n = 466), 7 mg (n = 466), or 14 mg (n = 465), or sitagliptin, 100 mg (n = 467). Semaglutide was initiated at 3 mg/d and escalated every 4 weeks, first to 7 mg/d then to 14 mg/d, until the randomized dosage was achieved.

Main Outcomes and Measures  The primary end point was change in glycated hemoglobin (HbA1c), and the key secondary end point was change in body weight, both from baseline to week 26. Both were assessed at weeks 52 and 78 as additional secondary end points. End points were tested for noninferiority with respect to HbA1c (noninferiority margin, 0.3%) prior to testing for superiority of HbA1c and body weight.

Results  Among 1864 patients randomized (mean age, 58 [SD, 10] years; mean baseline HbA1c, 8.3% [SD, 0.9%]; mean body mass index, 32.5 [SD, 6.4]; n=879 [47.2%] women), 1758 (94.3%) completed the trial and 298 prematurely discontinued treatment (16.7% for semaglutide, 3 mg/d; 15.0% for semaglutide, 7 mg/d; 19.1% for semaglutide, 14 mg/d; and 13.1% for sitagliptin). Semaglutide, 7 and 14 mg/d, compared with sitagliptin, significantly reduced HbA1c (differences, –0.3% [95% CI, –0.4% to –0.1%] and –0.5% [95% CI, –0.6% to –0.4%], respectively; P < .001 for both) and body weight (differences, –1.6 kg [95% CI, –2.0 to –1.1 kg] and –2.5 kg [95% CI, –3.0 to –2.0 kg], respectively; P < .001 for both) from baseline to week 26. Noninferiority of semaglutide, 3 mg/d, with respect to HbA1c was not demonstrated. Week 78 reductions in both end points were statistically significantly greater with semaglutide, 14 mg/d, vs sitagliptin.

Conclusions and Relevance  Among adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea, oral semaglutide, 7 mg/d and 14 mg/d, compared with sitagliptin, resulted in significantly greater reductions in HbA1c over 26 weeks, but there was no significant benefit with the 3-mg/d dosage. Further research is needed to assess effectiveness in a clinical setting.

Trial Registration  ClinicalTrials.gov Identifier: NCT02607865

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