PIONEER 3: Oral semaglutide proves worth against sitagliptin
medwireNews: Oral semaglutide offers greater efficacy for glucose control and weight loss when compared with sitagliptin for people with type 2 diabetes, although with more adverse events at the highest dose, show the PIONEER 3 findings.
“In reality, greater glucose lowering and weight loss compared with sitagliptin is not surprising given that this effect has been reported for other GLP-1RAs [glucagon-like peptide-1 receptor agonists], including subcutaneous semaglutide,” writes Irl Hirsch (University of Washington School of Medicine, Seattle, USA), author of an editorial accompanying the paper in JAMA.
“However, the comparable rates of adverse events and overall safety, at least with the 7-mg/d dosage, are notable because sitagliptin is one of the better-tolerated drugs available to treat diabetes.”
For the randomized PIONEER 3 trial, Melanie Davies (University of Leicester, UK) and co-investigators tested oral semaglutide at doses of 3, 7, and 14 mg/day against sitagliptin 100 mg/day for 78 weeks in 1864 people with type 2 diabetes, although the primary outcome was tested at 26 weeks.
At this point, the 7 and 14 mg semaglutide doses were significantly more efficacious than sitagliptin, producing average glycated hemoglobin (HbA1c) reductions of 1.0% and 1.3%, respectively, versus 0.8%. The 3 mg semaglutide dose produced a 0.6% reduction, which did not meet the criteria for noninferiority to sitagliptin.
The key secondary endpoint of bodyweight change was also in semaglutide’s favor, with participants taking the 7 and 14 mg doses losing a respective 2.2 and 3.1 kg, on average, compared with 0.6 kg for those taking sitagliptin.
The rate of adverse events leading to discontinuation was similar to that for sitagliptin with the 7 mg semaglutide dose, but was markedly higher with the 14 mg dose, at 5.2%, 5.8%, and 11.6%, respectively. Gastrointestinal complaints were the most frequently cited adverse events leading to discontinuation for all treatment groups.
Hirsch notes that this “illustrates the difficult balance between clinical effectiveness and tolerability that has been a challenge in the development of GLP-1RAs.”
He adds: “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-1RAs.”
The study participants were aged an average of 58.0 years, with an average diabetes duration of 8.6 years and HbA1c level of 8.3%. Their average BMI was 32.5 kg/m2. All participants were taking metformin and around half were also taking a sulfonylurea.
Severe or confirmed symptomatic hypoglycemia occurred at a similar or lower frequency with oral semaglutide as with sitagliptin, at rates of 5.2% and 7.7% in the 7 and 14 mg dose groups, respectively, versus 8.4%. Most instances occurred in people taking a sulfonylurea.
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