Oral Semaglutide versus Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes

Oral Semaglutide versus Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes

By Aly Becraft, MS and Kevin C Maki, PhD


The PIONEER3 trial was designed to compare the efficacy, long-term adverse event profile, and tolerability of an orally administered formulation of the glucagon-like peptide 1 receptor agonist (GLP-1RA), semaglutide, with the widely-used dipeptidyl peptidase-4 (DPP-4) inhibitor, sitagliptin, as an add on to metformin, with or without sulfonylurea, in patients with type 2 diabetes (T2D).1,2 This 78-week, phase 3a, randomized, double-blind, active-controlled, parallel-group trial included a total of 1864 patients with T2D and glycated hemoglobin (HbA1c) levels of 7.0% to 10.5%. Patients were randomized to receive either 3 mg/d (n = 466), 7 mg/d (n = 466), or 14 mg/d (n = 465) of semaglutide, or 100-mg/d sitagliptin (n = 467). The primary endpoint was change in HbA1c from baseline to week 26. The key secondary endpoint was change in body weight from baseline to week 26. Additional secondary endpoints included changes in HbA1c and body weight from baseline to weeks 52 and 78. The analysis evaluated both intention-to-treat and per-protocol samples.

Semaglutide at doses of 7 and 14 mg/d was found to be superior to sitagliptin for reducing HbA1c and body weight (see table, intention-to-treat results at week 26). Neither superiority nor non-inferiority with 3-mg/d semaglutide was demonstrated.


Estimated mean changes from baseline and estimated mean

(95% confidence interval) differences

from sitagliptin at week 26





100 mg/d

3 mg/d

7 mg/d

14 mg/d

 HbA1c, %





 Difference from sitagliptin

0.2 (0.0, 0.3)

-0.3 (-0.4, -0.1)

-0.5 (-0.6, -0.4)

 Body Weight, kg





 Difference from sitagliptin

-0.6 (-1.1, -0.1)

-1.6 (-2.0, -1.1)

-2.5 (-3.0, -2.0)


At week 78, significantly (p<0.05) greater reductions in HbA1c were observed with the semaglutide dosage of 14 mg/d versus sitagliptin in both intention-to-treat and per protocol samples (-0.4% and -0.7%, respectively), but semaglutide 7 mg/d was greater only in the per protocol sample (-0.3%). Significantly (p<0.05) greater body weight reductions were observed with all three dosages of semaglutide versus sitagliptin at week 78 (estimated mean differences of -0.8, -1.7 and -2.1 kg for 3, 7 and 14 mg/d of semaglutide). In addition, significant reductions in fasting plasma glucose and mean self-measured whole-blood glucose were greatest in the the14-mg/d semaglutide group at weeks 26 and 78 compared with sitagliptin.

The overall proportions of patients with at least one adverse event were similar across all treatment groups. However, a greater incidence of discontinuation due to adverse events was reported with 14 mg/d of semaglutide (11.6%), while 3- and 7-mg/d dosages (5.6% and 5.8%, respectively) had comparable incidences of discontinuation to sitagliptin (5.2%).  The primary cause of discontinuation in all treatment groups was gastrointestinal adverse events; for a substantial proportion of patients in the 7- and 14-mg/d semaglutide groups, the onset of the event leading to discontinuation occurred during the dose escalation period.

Conclusion: Compared to sitagliptin, oral semaglutide at 7 and 14 mg/d further reduced HbA1c and body weight over 26 weeks.


  1. Rosenstock J, Allison D, Birkenfeld AL, et al. Effect of additional oral semaglutide vs sitagliptin on glycated hemoglobin in adults with type 2 diabetes uncontrolled with metformin alone or with sulfonylurea: The PIONEER 3 randomized clinical trial. JAMA. 2019; Epub ahead of print.
  2. Hirsch IB. The future of the GLP-1 receptor agonists. JAMA. 2019;321:1457-1458.


Photo by David Clode