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.

Background: Escherichia coli causes over one third of the bacteraemia cases in England each year, and the incidence of these infections is increasing.

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Long-term effects, safety and tolerability of oral semaglutide (SEMA; a GLP-1 receptor agonist [GLP-1RA]) vs sitagliptin (SITA) as add-on to metformin ± sulfonylurea was investigated in patients (pts) with T2D in a 78-week, double-blind, double-dummy trial. Pts were randomized to once daily oral SEMA 3 mg (N=466), 7 mg (N=466) or 14 mg (N=465), or SITA 100 mg (N=467). Primary endpoint was change in HbA 1c , confirmatory secondary endpoint was change in body weight, both from baseline to week 26. Two estimands were defined (‘treatment policy [TPol] estimand’: treatment effect regardless of trial product discontinuation and rescue medication use; ‘trial product estimand’: treatment effect assuming on trial product without rescue medication use) in all randomized pts. Confirmatory testing was based on the TPol estimand; within each dose level, non-inferiority for the primary endpoint (non-inferiority margin: 0.3%) had to be confirmed before testing superiority for the primary and confirmatory secondary endpoints. Estimated week 26 HbA 1c reductions with 7 and 14 mg were –1.0% and –1.3%, vs –0.8% with SITA, and were superior (TPol estimand; estimated treatment difference vs SITA [ETD; 95% CI]: –0.3% [–0.4, –0.1]; –0.5% [–0.6, –0.4]; both P<0.001). Non-inferiority of 3 mg vs SITA was not confirmed (ETD: 0.2% [0.1, 0.3]; P=0.09); HbA 1c reductions favored SITA (P=0.008). Similar results were obtained with the trial product estimand at week 26 (ETD: –0.3% [–0.4, –0.2]; –0.6% [–0.7, –0.5] for 7 and 14 mg; both P<0.001 favoring oral SEMA; 0.2% [0.1, 0.4] for 3 mg; P<0.001 favoring SITA). At week 78, HbA 1c reductions with 14 mg were statistically significantly greater vs SITA for both estimands; there was no statistically significant difference with 3 mg (both estimands) or 7 mg (TPol estimand). All oral SEMA doses significantly lowered body weight vs SITA at week 26 for the TPol estimand (ETD: –0.6 kg [–1.1, –0.1]; –1.6 kg [–2.0, –1.1]; –2.5 kg [–3.0, –2.0] for 3, 7 and 14 mg; all P<0.02), confirming superiority of 7 and 14 mg (3 mg superiority not tested), and the trial product estimand (ETD: –0.5 kg [–1.0, –0.1]; –1.5 kg [–2.0, –1.1]; –2.6 kg [–3.1, –2.1] for 3, 7 and 14 mg; all P<0.03). Week 78 body weight reductions were also statistically significant, favoring oral SEMA (all doses, both estimands). Adverse events (AEs) occurred similarly across treatment arms. The most common AE with oral SEMA was transient mild/moderate nausea, affecting 7.5–15.7% of pts. Serious AEs were reported by 13.7%, 10.1% and 9.5% of pts for 3, 7 and 14 mg, and 12.4% for SITA. AEs led to premature trial product discontinuation in 5.6%, 5.8% and 11.6% of pts for 3, 7 and 14 mg, and 5.2% for SITA, mainly due to gastrointestinal AEs. In conclusion, oral semaglutide 7 and 14 mg provided statistically superior HbA 1c and body weight reductions at week 26 compared with SITA 100 mg (T...