Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial

Abstract

Importance: Glucagon-like peptide-1 (GLP-1) receptor agonists are effective therapies for the treatment of type 2 diabetes and are all currently available as an injection.

Objectives: To compare the effects of oral semaglutide with placebo (primary) and open-label subcutaneous semaglutide (secondary) on glycemic control in patients with type 2 diabetes.

Design, setting, and patients: Phase 2, randomized, parallel-group, dosage-finding, 26-week trial with 5-week follow-up at 100 sites (hospital clinics, general practices, and clinical research centers) in 14 countries conducted between December 2013 and December 2014. Of 1106 participants assessed, 632 with type 2 diabetes and insufficient glycemic control using diet and exercise alone or a stable dose of metformin were randomized. Randomization was stratified by metformin use.

Interventions: Once-daily oral semaglutide of 2.5 mg (n = 70), 5 mg (n = 70), 10 mg (n = 70), 20 mg (n = 70), 40-mg 4-week dose escalation (standard escalation; n = 71), 40-mg 8-week dose escalation (slow escalation; n = 70), 40-mg 2-week dose escalation (fast escalation, n = 70), oral placebo (n = 71; double-blind) or once-weekly subcutaneous semaglutide of 1.0 mg (n = 70) for 26 weeks.

Main outcomes and measures: The primary end point was change in hemoglobin A1c (HbA1c) from baseline to week 26. Secondary end points included change from baseline in body weight and adverse events.

Results: Baseline characteristics were comparable across treatment groups. Of the 632 randomized patients (mean age, 57.1 years [SD, 10.6]; men, 395 (62.7%); diabetes duration, 6.3 years [SD, 5.2]; body weight, 92.3 kg [SD, 16.8]; BMI, 31.7 [SD, 4.3]), 583 (92%) completed the trial. Mean change in HbA1c level from baseline to week 26 decreased with oral semaglutide (dosage-dependent range, -0.7% to -1.9%) and subcutaneous semaglutide (-1.9%) and placebo (-0.3%); oral semaglutide reductions were significant vs placebo (dosage-dependent estimated treatment difference [ETD] range for oral semaglutide vs placebo, -0.4% to -1.6%; P = .01 for 2.5 mg, <.001 for all other dosages). Reductions in body weight were greater with oral semaglutide (dosage-dependent range, -2.1 kg to -6.9 kg) and subcutaneous semaglutide (-6.4 kg) vs placebo (-1.2 kg), and significant for oral semaglutide dosages of 10 mg or more vs placebo (dosage-dependent ETD range, -0.9 to -5.7 kg; P < .001). Adverse events were reported by 63% to 86% (371 of 490 patients) in the oral semaglutide groups, 81% (56 of 69 patients) in the subcutaneous semaglutide group, and 68% (48 of 71 patients) in the placebo group; mild to moderate gastrointestinal events were most common.

Conclusions and relevance: Among patients with type 2 diabetes, oral semaglutide resulted in better glycemic control than placebo over 26 weeks. These findings support phase 3 studies to assess longer-term and clinical outcomes, as well as safety.

Trial registration: clinicaltrials.gov Identifier: NCT01923181.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Davies reported board membership and consultancy fees from Novo Nordisk; sanofi-aventis; Lilly; Merck, Sharp & Dohme; Boehringer Ingelheim; AstraZeneca; Servier; and Janssen; institutional grants from Novo Nordisk, sanofi-aventis, Lilly, Boehringer Ingelheim, and Janssen; and payment for lectures or speakers bureaus from Novo Nordisk; sanofi-aventis; Lilly; Merck, Sharp & Dohme; Boehringer Ingelheim; AstraZeneca; Janssen; Mitsubishi Tanabe Pharma; and Takeda Pharmaceuticals International. Dr Pieber reported board membership and consulting fees for AstraZeneca, Novo Nordisk, Roche Diabetes Care, and Eli Lilly; institutional grants from AstraZeneca and Novo Nordisk; and payment for lectures or speakers bureaus from Novo Nordisk. Dr Hartoft-Nielsen reported holding shares in Novo Nordisk. Mr Hansen reported holding shares in Novo Nordisk and a pending patent for semaglutide methods. Dr Jabbour reported board membership of the Endocrine Society; consultancy fees from AstraZeneca, Eli Lilly, and Janssen; institutional grants from AstraZeneca, Novo Nordisk, Eli Lilly, Merck, and Janssen; and payment for lectures or speakers bureaus from AstraZeneca, Eli Lilly, and Janssen. Dr Rosenstock reported research support from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Hanmi, Intarcia, Janssen, Lexicon, Merck, Novo Nordisk, Sanofi, and Pfizer; serving on advisory boards of and receiving consulting honoraria from Boehringer Ingelheim, Daiichi Sankyo, Intarcia, Janssen, Novo Nordisk, Sanofi, and Eli Lilly.

Figures

Figure 1.. Trial Design

The trial was conducted among 632 patients with type 2 diabetes who were 18 years or older receiving stable treatment with diet and exercise or stable treatment with metformin for 30 days prior to screening. Patients had a hemoglobin A1c level of 7.0% to 9.5% and an estimated glomerular filtration rate of 60 mL/min/1.73 m2 or more. There was no dose escalation in the oral semaglutide 2.5-mg and placebo groups. In the other oral semaglutide groups, the dose was doubled from a starting dose of 2.5 mg or 5 mg every 4 weeks until the trial maintenance dose of the group (5-40 mg) was achieved (blue shades). The subcutaneous semaglutide dose was doubled every 4 weeks from a starting dose of 0.25 mg until a 1 mg trial maintenance dose was achieved. In addition, a slow dose escalation (purple) to 40 mg of oral semaglutide at 8-week intervals and a fast dose escalation (green) to 40 mg of oral semaglutide at 2-week intervals were included. Subcutaneous semaglutide was supplied as a 1.34-mg/mL solution in a 1.5-mL prefilled PDS290 pen injector (FlexTouch, Novo Nordisk A/S), and was administered in the abdomen, thigh, or upper arm on the same day of the week.

Figure 2.. Flow of Patients Through the Trial of Semaglutide in Type 2 Diabetes

BMI indicates body mass index (calculated as weight in kilograms divided by height in meters squared); eGFR, estimated glomerular filtration rate; HbA1c, hemoglobin A1c. “Completed treatment” refers to those patients who did not discontinue treatment prematurely (with or without the addition of rescue medication). aParticipants included in the primary analysis had completed the week 26 assessment. bDiscontinued treatment less than 1 week prior to week 26. The assessment at week 26 was still considered to be valid for the primary analysis due to the long half-life of semaglutide.

Figure 3.. Hemoglobin A1c (HbA1c) Efficacy Parameters From Baseline to Week 26 Among Patients With Type 2 Diabetes and Insufficient Glycemic Control

RMM indicates repeated measures model; SC, subcutaneous. A, Data are estimated means from RMM with treatment, stratum, country, and baseline value all nested within visit. Error bars indicate 95% CIs. B, The proportion of patients achieving an HbA1c level of less than 7.0% after 26 weeks of treatment was significant for the oral semaglutide 2.5-mg group vs placebo (P = .01) and for all other oral semaglutide dosages and SC semaglutide (P < .001). Missing HbA1c values are imputed from RMM analysis before calculating the proportions of patients reaching the target. aNo. of patients with an assessment (panel A) and imputed value (panel B).

Figure 4.. Fasting Plasma Glucose (FPG) Level and Body Weight Efficacy Parameters From Baseline to Week 26 Among Patients With Type 2 Diabetes and Insufficient Glycemic Control

RMM indicates repeated measures model; SC, subcutaneous. Data are estimated means from the RMM with treatment, stratum, country, and baseline value all nested within visit. Error bars are 95% CIs. aNo. of patients with an assessment.