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PIONEER 3 outcomes

Oral semaglutide vs sitagliptin has superior reductions in HbA1c and weight

. Oral semaglutide is an investigational once-daily glucagon-like peptide-1 (GLP-1) analogue in a pill

Oral semaglutide 7mg and 14mg demonstrated superior HbA1c and body weight reductions compared to Januvia (sitagliptin 100mg), although non-inferiority for oral semaglutide 3mg for HbA1c reductions at 26 weeks was not confirmed. The data, presented at the Endocrine Society Annual Meeting in New Orleans, LA, with simultaneous publication in the Journal of the American Medical Association (JAMA), from PIONEER 3 was a phase 3a trial investigating the efficacy and long-term safety of oral semaglutide 3mg, 7mg and 14mg compared with sitagliptin 100mg in adults with type 2 diabetes inadequately controlled with metformin, with or without sulfonylurea, over 78 weeks. Oral semaglutide is an investigational once-daily glucagon-like peptide-1 (GLP-1) analogue in a pill.

“Many people living with type 2 diabetes do not meet their blood glucose targets despite many available oral antidiabetic therapies,” said Dr Dale Allison, PIONEER 3 investigator and director of medical research at the Hillcrest Family Health Center, Waco, Texas. “The PIONEER 3 findings are encouraging, as oral semaglutide demonstrated a clinically significant improvement in HbA1c and this investigational therapy has the potential to become the first oral GLP-1 receptor agonist for those living with type 2 diabetes.”

In PIONEER 3, the primary endpoints of HbA1c and confirmatory secondary endpoint of change in body weight were assessed after 26 weeks of treatment. When applying the primary statistical approach, oral semaglutide 7mg and 14mg demonstrated superior HbA1c reductions of 1.0% and 1.3% at 26 weeks, compared to a 0.8% reduction with sitagliptin (both p<0.001). Oral semaglutide 3mg demonstrated a reduction in HbA1c of 0.6%; non-inferiority vs. sitagliptin was not confirmed (p=0.09). Furthermore, at 26 weeks, oral semaglutide 7mg and 14mg demonstrated superior body weight reductions of 2.2kg and 3.1kg, both vs. a 0.6kg reduction for sitagliptin (p<0.01).

When applying the secondary statistical approach at week 26, oral semaglutide 7mg and 14mg demonstrated statistically significant reductions in HbA1c of 1.1% and 1.4%, respectively, vs. a 0.8% reduction with sitagliptin (both p<0.001). Reductions in HbA1c seen with oral semaglutide 3mg were 0.5% and compared to the reductions seen with sitagliptin, the difference is statistically significant in favour of sitagliptin. Reductions in body weight from baseline were statistically significant in favour of all three oral semaglutide doses.

In a supportive secondary endpoint at week 78, oral semaglutide 14mg demonstrated statistically significant reductions in HbA1c vs. sitagliptin for both statistical approaches (1.1% vs 0.7%; p<0.001a; 1.1% vs 0.4%; p<0.001b). There was no statistically significant difference with oral semaglutide 3mg (both estimands) or 7mg (TPol estimand) vs sitagliptin.

Reductions in body weight from baseline, which was dose dependent, were statistically significant with oral semaglutide 3mg, 7mg and 14mg at week 78 with reductions of 1.8kg, 2.7kg and 3.2kg, respectively, compared to a 1.0 kg reduction with sitagliptin (all p<0.05a) and 1.9kg, 2.7kg and 3.5kg, respectively, vs. a 1.1kg reduction with sitagliptin (all p<0.05b).

In this 78-week trial, the most common adverse event for oral semaglutide was nausea, which was dose dependent, affecting 7.3% to 15.1%. The nausea rate for sitagliptin was 6.9%. People taking oral semaglutide 3mg, 7mg and 14mg reported serious adverse events at a rate of 13.7%, 10.1% and 9.5%, respectively, vs. a rate of 12.4% of those taking sitagliptin. The proportion of people who discontinued treatment due to adverse events was 5.6%, 5.8% and 11.6% for people treated with oral semaglutide 3mg, 7mg and 14mg, respectively, vs. 5.2% with sitagliptin.

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