PIONEER 2: Oral semaglutide trumps empagliflozin in HbA1c lowering

Oral form of the GLP-1* analogue semaglutide was superior to the SGLT-2i** empagliflozin in reducing HbA1c in patients with type 2 diabetes (T2D) uncontrolled on metformin, according to the head-to-head PIONEER 2*** trial.

“This trial provides a comparison of two increasingly used drug classes that are commonly added to metformin when glycaemic control is not achieved,” the researchers stated.

Previous studies have shown that oral semaglutide was more effective than the DPP-4^# inhibitor sitagliptin and noninferior to another GLP-1 analogue liraglutide in reducing HbA1c. The current study helps provide answers on the comparative efficacy and tolerability of a GLP-1 agonist vs SGLT-2i.

At 26 weeks, oral semaglutide lowered HbA1c significantly more than empagliflozin, regardless of whether the analysis was performed using the treatment policy estimand (-1.3 percent vs -0.9 percent; p<0.0001) or the trial product estimand (-1.4 percent vs -0.9 percent; p<0.0001) — meeting both the noninferiority and superiority criteria for the primary efficacy endpoint. [Diabetes Care 2019;42:2272-2281]

The between-group difference in HbA1c reductions remained significant at 52 weeks for both estimands (-1.3 percent vs -0.9 percent; p<0.0001 for the trial product estimand and -1.3 percent vs -0.8 percent; p<0.0001 for the trial product estimand), in favour of oral semaglutide.    

The treatment policy estimand included data for all randomized patients, regardless of treatment discontinuation or rescue medication use — which according to the authors, reflects intention-to-treat principle. On the other hand, the trial product estimand analysed data after excluding patients who discontinued treatment or used rescue medication — to compare the effects between treatments without potential confounding from rescue medication.

A total of 822 patients with T2D (mean age 58 years, 49.5 percent female) were randomized 1:1 to once-daily oral semaglutide 14 mg or empagliflozin 25 mg for 52 weeks in the multinational, open-label phase IIIa trial.

While superior weight loss was not demonstrated at week 26 for oral semaglutide vs empagliflozin, the difference became significant at week 52 in favour of semaglutide (-4.7 vs -3.8 kg; p=0.01140) based on the trial product estimand.

Reductions in postprandial glucose increments and the mean 7-point SMBG profiles were also greater with oral semaglutide than empagliflozin. Although both treatments reduced fasting plasma glucose, the extent of reduction was similar between the two groups. 

“Reductions in fasting plasma glucose were similar in both groups, suggesting differences in glycaemic control may be mostly driven by the greater reduction in postprandial glucose with oral semaglutide,” observed the researchers. 

In terms of safety, the rates of adverse events (AEs) were similar between the oral semaglutide and empagliflozin groups (70.5 percent vs 69.2 percent) whereas serious AEs were reported more frequently in the empagliflozin arm (6.6 percent vs 9.0 percent).

However, more patients in the oral semaglutide arm discontinued treatment due to AEs than the empagliflozin arm (10.7 percent vs 4.4 percent). The difference was mainly due to gastrointestinal (GI) AEs such as nausea, diarrhoea, and vomiting which were more common with oral semaglutide than empagliflozin. Nonetheless, the GI-related AEs, according to the researchers, were consistent with previous trials on oral semaglutide.

“Oral semaglutide was well tolerated, with a safety profile consistent with that of GLP-1RAs,” the researchers concluded.