Oral Semaglutide versus Empagliflozin in Patients with Type 2 Diabetes Uncontrolled on Metformin: The PIONEER 2 Trial

Rodbard HW, Rosenstock J, Canani LH et al.,

Diabetes Care 2019 Sep; dc190883. https://doi.org/10.2337/dc19-0883

Efficacy, Safety and Tolerability of Oral Semaglutide Versus Placebo Added to Insulin ± Metformin in Patients with Type 2 Diabetes: the PIONEER 8 Trial

Zinman B, Aroda VR, Buse JB et al.,

Diabetes Care 2019 Sep; dc190898. https://doi.org/10.2337/dc19-0898

Introduction and methods

For many patients with type 2 diabetes (T2DM), metformin monotherapy is not sufficient to maintain adequate glycemic control. Injectable GLP-1 receptor agonists (GLP-1RAs) and oral SGLT2 inhibitors (SGLT2i) are now recommended as second-line therapy because they can lower glucose levels without increasing hypoglycemia risk, induce weight loss and are associated with CV benefits [1,2].

Semaglutide is a human GLP-1 analogue that is already available as a once-weekly injection, which is associated with reduced HbA1c, weight loss and fewer CV events in T2DM [3-9]. An oral version has also been developed, optimized to facilitate absorption across the gastric mucosa. This oral semaglutide was shown to give significantly greater reductions in HbA1c and body weight compared with placebo in patients with T2DM uncontrolled with diet and exercise or oral antidiabetic medication, including patients with moderate renal impairment [11-14]. CV safety of oral semaglutide has been confirmed [15].

Two studies evaluating oral semaglutide have recently been published in Diabetes Care.

• PIONEER 2 is a randomized, open-label phase 3 trial that compared oral semaglutide with the SGLT2i empagliflozin, in T2DM uncontrolled on metformin monotherapy. 822 Patients were 1:1 randomized to once-daily oral semaglutide 14 mg (initiated at 3 mg, escalated to 7 mg at week 4 and to 14 mg after week 8) or empagliflozin 25 mg for 52 weeks.
• PIONEER 8 is a randomized, double-blind placebo-controlled trial that investigated the efficacy and tolerability of oral semaglutide added-on to insulin with or without metformin, in patients with uncontrolled T2DM. Randomization (n=731) was done as 1:1:1:1 to once-daily oral semaglutide 3, 7 or 14 mg or placebo, for 52 weeks.

Key endpoints of both studies were change in %HbA1c from week 1 to week 26, and change in body weight. Both studies used two estimands to address two aspects of the efficacy objective:

• Treatment policy: evaluates the treatment effect for all randomized patients, regardless of trial product discontinuation or use of rescue medication (reflects intention-to-treat principle).
• Trial product: evaluates the treatment effect for all randomized patients under the assumption that all patients remained on trial product for the entire planned duration of the trial, without use of rescue medication.

Main results

PIONEER 2 | Oral semaglutide vs. empagliflozin, on top of metformin monotherapy

• Up to week 26, 4.1% of patients (7) in the semaglutide group initiated additional anti-diabetic medication, of whom 8 (1.9%) used it as rescue medication. In the empagliflozin group, 3.2% (13) initiated additional medication, which was rescue medication in 5 (1.2%). Up to week 52, the respective percentages were 12.7% and 7.5% in the semaglutide group and 13.7% and 10.7% in the empagliflozin group.
• Oral semaglutide gave greater HbA1c reduction compared with empagliflozin at week 26 according to the treatment policy estimand (-1.3% vs. 0.9%, estimated treatment difference (ETD): -0.4%, 95%CI: -0.6 to -0.3), P<0.0001 for non-inferiority and superiority).
• When estimating by the trial product estimand, oral semaglutide gave a greater HbA1c reduction at week 26 than empagliflozin (-1.4% vs. -0.9%, ETD: -0.5%, 95%CI: -0.7 to -0.4, P<0.0001).
• HbA1c reductions, according to both estimands, were also greater with semaglutide at week 52.
• Semaglutide was not superior over empagliflozin in the reduction of body weight (treatment policy: ETD: -0.1, 95%CI: -0.7 to 0.5, P=0.76, trial product: ETD: -0.4, 95%CI: -1.0 to 0.1, P=0.14). The trial product estimand at 52 weeks showed a greater reduction in body weight with semaglutide (ETD: -0.9, P=0.00114), while the treatment policy estimand did not (ETD: -0.2, P-.62).

PIONEER 8 | Oral semaglutide vs. placebo, on top of insulin with or without metformin

• By week 26, 2.7% had initiated rescue medication for semaglutide 3 mg, 1.1% for 7 mg, 2.2% for 14 mg and 4.9% for placebo. At week 52, the percentages were 29.3%, 18.1%, 17.1% and 36.4%, respectively. The latter increase reflects that insulin was freely adjustable in weeks 26-52.
• 67.2% Of patients used background metformin.
• Compared with placebo, HbA1c reductions based on the treatment policy estimand were superior for all doses of oral semaglutide, with significant ETDs of -0.5% (95%CI: -0.7 to -0.3) for 3 mg, -0.9% (95%CI:-1.1 to -0.7) for 7 mg and -1.2% (95%CI: -1.4 to -1.0).
• The trial product estimand also showed significantly greater HbA1c reductions with oral semaglutide vs. placebo at week 26.
• Both estimands were also statistically significantly in favor of semaglutide at week 52.
• At week 26, total daily insulin dosage was reduced from baseline in all treatment groups. At week 52 the total daily dose was reduced in the groups receiving 7 and 14 mg, and increased in the 3 mg and placebo group.
• For the treatment policy estimand, all doses of semaglutide showed superior weight reductions compared with placebo (ETD for 3 mg: -0.9, 95%CI: -1.8 to 0.0, for 7 mg: -2.0, 95%CI: -3.0 to -1.0, and for 14 mg: -3.3, 95%CI: -4.2 to -2.3). The trial product estimand also gave greater weight reductions with semaglutide.
• At week 52, both estimands showed greater weight reductions with oral semaglutide vs. placebo.

Conclusion

References

Find the article by Rodbard et al. at Diabetes CareFind the article by Zinman et al. at Diabetes Care