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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Rosenstock reported serving on scientific advisory boards and receiving honoraria or consulting fees from Eli Lilly, Novo Nordisk, Sanofi, Janssen, Boehringer Ingelheim, and Intarcia and receiving grants/research support from Merck, Pfizer, Sanofi, Novo Nordisk, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, AstraZeneca, Janssen, Genentech, Boehringer Ingelheim, Intarcia, and Lexicon. Dr Birkenfeld reported serving on advisory boards, participating in meetings, and acting as a research investigator for Novo Nordisk, Sanofi, Boehringer Ingelheim, and AstraZeneca. Drs Blicher and Deenadayalan and Mr Jacobsen reported that they are employees of Novo Nordisk. Dr Serusclat reported serving on advisory boards, participating in meetings, and acting as a research investigator for Novo Nordisk, Eli Lilly, Sanofi, Abbott, and Medtronic. Dr Violante reported acting as an advisory board member and speaker for Eli Lilly, AstraZeneca, Sanofi, Janssen, Novo Nordisk, Takeda Pharmaceuticals International Inc, and Boehringer Ingelheim and as a research investigator for Eli Lilly, AstraZeneca, Janssen, Novo Nordisk, Boehringer Ingelheim, and Merck Sharp & Dohme. Dr Watada reported acting as an advisory board member for Novo Nordisk and as a speaker for Astellas Pharma, Sanofi, Mitsubishi Tanabe Pharma, Novo Nordisk, Kowa Pharmaceutical, AstraZeneca, Takeda Pharmaceutical, Novartis, Nippon Boehringer Ingelheim, Merck Sharp & Dohme, Sumitomo Dainippon Pharma, Eli Lilly Japan, Sanwa Kagaku Kenkyusho, Ono Pharmaceutical, Kissei Pharmaceutical, and FUJIFILM Pharma and receiving grants from Astellas Pharma, Sanofi, Mitsubishi Tanabe Pharma, Novo Nordisk Pharma, AstraZeneca, Takeda Pharmaceutical, Novartis Pharma, Nippon Boehringer Ingelheim, Merck Sharp & Dohme, Sumitomo Dainippon Pharma, Eli Lilly Japan, Ono Pharmaceutical, Kyowa Hakko Kirin, Daiichi Sankyo, Terumo, Pfizer Japan, Mochida Pharmaceutical, Taisho Toyama Pharmaceutical, Johnson & Johnson, and Kowa. Dr Davies reported acting as a consultant, advisory board member, and speaker for Novo Nordisk, Sanofi-Aventis, and Lilly, as an advisory board member for Servier and Janssen, and as a speaker for Boehringer Ingelheim and Takeda Pharmaceuticals International Inc and receiving grants in support of investigator and investigator-initiated trials from Novo Nordisk, Sanofi-Aventis, Lilly, Boehringer Ingelheim, and Janssen. No other disclosures were reported.

Figures

Figure 1.. Participant Flow and Treatment Disposition Over Time

Dotted lines in treatment disposition graphs indicate time points at which escalation to randomized dosages was achieved (week 4 in 7-mg/d semaglutide group and week 8 in 14-mg/d semaglutide group). aOther reasons included patient withdrew consent and/or did not attend scheduled randomization visit (n = 58), study center–related issues (n = 8), incomplete screening data (n = 8), investigator unable to confirm patient eligibility (n = 1), and serious adverse event occurring between screening and randomization (n = 1). bNo assessments were performed. cReceived disallowed background medication (nateglinide). dDid not provide informed consent.

Figure 2.. Glycemic Control–Related Efficacy End Points

HbA1c indicates glycated hemoglobin. Data in panel A are observed absolute mean values (with 95% confidence intervals shown as error bars) for the “in-trial” period (ie, while participants remained in the trial regardless of trial product discontinuation or rescue medication use) and the “on-treatment without rescue observation” period (ie, while patients were receiving trial product without use of rescue medication), and data in panel B are estimated mean changes from baseline by the treatment policy estimand and the trial product estimand at weeks 26, 52 and 78. Unadjusted 2-sided P values are given for the test of no difference. Treatment policy estimand: analysis of covariance using data irrespective of discontinuation of trial product or initiation of rescue medication. Missing values were imputed by a pattern mixture model using multiple imputation. Pattern was defined by randomized trial product and treatment status (premature trial product discontinuation and/or initiation of rescue medication). Trial product estimand: mixed model for repeated measurements. Data collected after discontinuation of trial product or initiation of rescue medication were excluded. aFavored sitagliptin.

Figure 3.. Body Weight–Related Efficacy End Points

Data in panel A are observed mean change from baseline values (with 95% confidence intervals shown as error bars) for the “in-trial” period (ie, while participants remained in the trial regardless of trial product discontinuation or rescue medication use) and the “on-treatment without rescue observation” period (ie, while patients were receiving trial product without use of rescue medication), and data in panel B are estimated mean changes from baseline by the treatment policy estimand and the trial product estimand at weeks 26, 52 and 78. Unadjusted 2-sided P values are given for the test of no difference. Treatment policy estimand: analysis of covariance using data irrespective of discontinuation of trial product or initiation of rescue medication. Missing values were imputed by a pattern mixture model using multiple imputation. Pattern was defined by randomized trial product and treatment status (premature trial product discontinuation and/or initiation of rescue medication). Trial product estimand: mixed model for repeated measurements. Data collected after discontinuation of trial product or initiation of rescue medication were excluded.