SAT-139 Clinical Impact of Oral Semaglutide Compared with Sitagliptin in T2D on Metformin ± Sulfonylurea: The Pioneer 3 Trial

Abstract

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&nbsp;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&nbsp;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&nbsp;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&nbsp;kg [–3.1, –2.1] for 3, 7 and 14&nbsp;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...

Evaluation of the Cost Per Patient Achieving Treatment Targets with Oral Semaglutide: A Short-Term Cost-Effectiveness Analysis in the United States

“…There is significant evidence that people with type 2 diabetes in the US, UK and worldwide do not intensify treatment, despite not achieving glycemic control targets, with concerns around potential side effects of therapies (such as weight gain and hypoglycemia) and fear of injection often cited as reasons for therapeutic inertia [18–22]. The oral formulation of semaglutide allows people with type 2 diabetes to receive the benefits of treatment with a GLP-1 receptor agonist, such as improved glycemic control without weight gain and a low risk of hypoglycemia, without the requirement for daily or weekly injections [9–11]. The present analysis demonstrated that oral semaglutide is efficacious and cost-effective in varying patient populations versus comparators for patients with type 2 diabetes receiving differing background therapies, indicating it is a viable treatment option for a variety of patients, irrespective of prior treatment.…”

The development of oral semaglutide, an oral GLP-1 analog, for the treatment of type 2 diabetes

“…There were fewer serious adverse events with oral semaglutide than empagliflozin. PIONEER 3 was a 78-week, multinational, randomized, double-blind trial that compared the long-term efficacy, safety, and tolerability of oral semaglutide 3, 7, or 14 mg with the dipeptidyl peptidase-4 inhibitor, sitagliptin, in 1864 patients (including 207 patients from Japan) with type 2 diabetes uncontrolled on metformin with or without a sulfonylurea [47]. Oral semaglutide 7 and 14 mg resulted in superior HbA 1c reductions vs. sitagliptin at week 26 (estimated treatment differences of − 0.3% and − 0.5%, respectively), with this effect maintained to week 78 for the 14 mg dose (Fig.…”

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“…In the background medication subgroups, 3 -17% of patients experienced serious adverse events, and up to 17% of patients quit their prescribed medicine permanently [57]. In case of oral semaglutide 3, 7 or 14 mg the number of subjects who experienced gastrointestinal adverse events (mostly during dose escalation in the first 8 -16 weeks) and the number of subjects who discontinued the trial due to these symptoms, appeared to rise with the dose [3,6,63,79]. Accordingly, to these observations, a dosage-escalation strategy is suggested, beginning with a low dose (3 mg) to prevent gastrointestinal adverse effects [67].…”

“…Accordingly, to these observations, a dosage-escalation strategy is suggested, beginning with a low dose (3 mg) to prevent gastrointestinal adverse effects [67]. Despite patients receiving background basal/bolus insulin treatment in PIONEER 8 trial [79], oral semaglutide patients had a low frequency of symptomatic, blood glucose-confirmed hypoglycaemia, and its incidence did not surpass 8% in any treatment group [6,10,42,[55][56][57][58][59][60][61][62][63]69]. As for special patient populations, individuals with an e-GFR lower than 60 mL/min/1.73 m 2 had a greater proportion of severe gastrointestinal adverse effects than those with e-GFR > 60 mL/min/1.73 m 2 , although significant hypoglycaemic episodes were rare [42].…”