Question: What is the effect of oral semaglutide on glycemic control in patients with type 2 diabetes?
Results: In this randomized clinical trial of 632 patients with type 2 diabetes followed up for 31 weeks, oral semaglutide statistically-significantly reduced hemoglobin A1c level by up to 1.9% vs placebo (0.3%).
Meaning: Oral semaglutide resulted in better glycemic control than placebo over 26 weeks. Phase 3 studies are warranted to assess longer-term and clinical outcomes, as well as safety.
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, & 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 1,106 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.
[So for the oral formulation of semaglutide, “Rybelsus”, with a bioavailability of ~1%, it takes almost 300× (40/0.14) more to achieve similar results as the injection. And then doctors don’t even prescribe Rybelsus at 40mg/day doses—the prescribing info tops out at 14mg.]
Main Outcomes & 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 statistically-significant vs placebo (dosage-dependent estimated treatment difference [ETD] range for oral semaglutide vs placebo, −0.4% to −1.6%; p = 0.01 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 statistically-significant for oral semaglutide dosages of 10 mg or more vs placebo (dosage-dependent ETD range, −0.9 to −5.7 kg; p < 0.001). Adverse events were reported by 63% to 86% (1⁄2 patients) in the oral semaglutide groups, 81% (1⁄2 patients) in the subcutaneous semaglutide group, and 68% (1⁄2 patients) in the placebo group; mild to moderate gastrointestinal events were most common.
Conclusions & 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.