Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With Sulfonylurea

Abstract

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 (HbA 1c), 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 HbA 1c (noninferiority margin, 0.3%) prior to testing for superiority of HbA 1c and body weight. RESULTS Among 1864 patients randomized (mean age, 58 [SD, 10] years; mean baseline HbA 1c , 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 HbA 1c (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 HbA 1c 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 HbA 1c 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.

Oral semaglutide for type 2 diabetes: A systematic review and meta‐analysis

“…The characteristics of trials included in the meta‐analysis and participants' baseline characteristics are summarized in Table . Oral semaglutide, either as monotherapy or as add‐on treatment, was compared with placebo in six trials, and with other glucose‐lowering agents (liraglutide, semaglutide weekly, sitagliptin and empagliflozin) in five trials . Notably, from a phase 2 dose‐finding trial, we extracted data for safety outcomes from the 2.5, 5 and 10 mg arms, while for two trials initially identified as conference abstracts, we used additional data from subsequently published full text reports .…”

“…Notably, from a phase 2 dose‐finding trial, we extracted data for safety outcomes from the 2.5, 5 and 10 mg arms, while for two trials initially identified as conference abstracts, we used additional data from subsequently published full text reports . All of the studies had a parallel group design and seven of them were double‐blind . Study duration ranged from 12 to 72 weeks.…”

“…Oral semaglutide, either as monotherapy or as add-on treatment, was compared with placebo in six trials, [24][25][26][27][28][29] and with other glucose-lowering agents (liraglutide, semaglutide weekly, sitagliptin and empagliflozin) in five trials. 27,[29][30][31][32] Notably, from a phase 2 dose-finding trial, we extracted data for safety outcomes from the 2.5, 5 and 10 mg arms, 29 while for two trials initially identified as conference abstracts, we used additional data from subsequently published full text reports. 28,30 All of the studies had a parallel group design and seven of them were doubleblind.…”

Incorporating and interpreting regulatory guidance on estimands in diabetes clinical trials: The PIONEER 1 randomized clinical trial as an example

“…In the PIONEER 3 trial, compared with sitagliptin, the 7 mg and 14 mg doses of oral semaglutide resulted in superior reductions in HbA1c and body weight. 10 While the two estimands used in the PIONEER 1 and results for both estimands are dependent on the frequency of intercurrent events and will be similar if these are very low. The PIONEER 1 trial had a very high completion rate (92% to 97%), and 85% to 87% of patients across the four treatment arms completed the trial and continued with trial product without use of rescue medication, 9 thus providing a high degree of concordance between the results of the two estimands.…”

“…In the PIONEER 1 trial, all dose levels of oral semaglutide were superior to placebo in reducing HbA1c and superior reductions in body weight were observed for the 14 mg dose compared with placebo (Figure ). In the PIONEER 3 trial, compared with sitagliptin, the 7 mg and 14 mg doses of oral semaglutide resulted in superior reductions in HbA1c and body weight . While the two estimands used in the PIONEER 1 and PIONEER 3 trials addressed two different scientific questions of interest, both contribute to the full clinical picture.…”