Oral semaglutide led to greater reductions in HbA1c, body weight than sitagliptin

The industry-funded PIONEER 3 trial randomized adults whose type 2 diabetes was uncontrolled with metformin, with or without sulfonylurea, to receive either oral sitagliptin (100 mg/d) or oral semaglutide (3, 7, or 14 mg/d).


Compared to oral sitagliptin at 100 mg/d, oral semaglutide at 7 or 14 mg/d, but not 3 mg/d, led to greater reductions in HbA1c at 26 weeks in patients whose type 2 diabetes was uncontrolled with metformin, with or without a sulfonylurea, a study found.

For the PIONEER 3 trial, researchers randomized 1,864 adults (mean age, 58 years; 47.2% women) in 14 countries to receive either once-daily oral sitagliptin (100 mg, n=467) or semaglutide (3 mg, n=466; 7 mg, n=466; or 14 mg, n=465) for 78 weeks. The latter drug, a glucagon-like peptide-1 (GLP-1) receptor agonist, was initiated at 3 mg/d and escalated every four weeks until the randomized dosage was achieved. Patients were excluded if they received any medication for diabetes or obesity other than metformin, sulfonylurea, or short-term insulin (≤14 days in total) within 90 days of screening; had a history of pancreatitis; had renal impairment; or had proliferative retinopathy or maculopathy requiring acute treatment.

The participants' mean baseline HbA1c level was 8.3%, and their mean body mass index was 32.5 kg/m2. The primary endpoint was change in HbA1c (noninferiority margin, 0.3%), and the main secondary endpoint was change in body weight, both measured from baseline to week 26. Both outcomes were assessed at weeks 52 and 78 as additional secondary endpoints. Results of the industry-funded trial were published online on March 23 by JAMA.

A total of 1,758 (94.3%) patients completed the trial. Compared with sitagliptin, 7 and 14 mg/d of semaglutide significantly reduced HbA1c (differences, −0.3% and −0.5%, respectively; P<0.001 for both) and body weight (differences, −1.6 kg and −2.5 kg, respectively; P<0.001 for both) from baseline to week 26. At 3 mg/d, semaglutide did not demonstrate noninferiority to sitagliptin with respect to HbA1c (difference, 0.2%; P=0.09); therefore, superiority with respect to body weight was not tested for this dose. At week 78, reductions in both endpoints were significantly greater with semaglutide at 7 and 14 mg/d versus sitagliptin, with no significant differences found with semaglutide at 3 mg/d. The proportions of patients who experienced at least one adverse event while receiving treatment were similar across groups (about 80%, mostly of mild severity).

The study authors noted limitations, such as the relatively high discontinuation rate and the fact that they did not formally measure adherence to treatment. They added that sitagliptin may not be the best comparator to semaglutide because dipeptidyl peptidase-4 inhibitors have modest glucose-lowering effects and minimal effects on body weight compared with GLP-1 receptor agonists.

While the trial results represent another advance for GLP-1 receptor agonists, the highest dosage of semaglutide (14 mg/d) was associated with high rates of gastrointestinal adverse events, an accompanying editorial noted. “There is evidence that adverse events with drugs like semaglutide wane over time while taking the treatment and can be mitigated with a slower escalation of dosage, although adverse gastrointestinal symptoms remain an important limiting factor with GLP-1 [receptor agonists],” the editorialist noted, adding that cost is another likely limitation to widespread use of oral semaglutide.