Oral semaglutide monotherapy was superior to placebo for improving glycated hemoglobin (HbA1c) levels at all doses tested in adults with type 2 diabetes who had been previously insufficiently managed with diet and exercise, according to findings from a global, randomized trial.
The drug also showed dose-dependent weight loss, with a statistically significant effect on body weight, compared with placebo, at higher doses.
To date, the glucagon-like peptide–1 receptor agonist has been available as weekly subcutaneous shots for patients with type 2 diabetes, and in that form they have been shown to be effective in reducing HbA1c, inducing weight loss, and lowering the risk of cardiovascular events in patients with cardiovascular disease or those who are at high risk for it, wrote Vanita R. Aroda, MD, of Brigham and Women’s Hospital, Boston, and colleagues. The report is in Diabetes Care.
The novel oral semaglutide tablet is designed to enhance medication absorption, and the pharmacokinetics and dosage were established in phase 2 studies, they noted.
In the phase 3 Peptide Innovation for Early Diabetes Treatment 1 (PIONEER 1) study, Dr. Aroda and colleagues randomized 703 adults with type 2 diabetes to receive either 3 mg, 7 mg, or 14 mg of oral semaglutide daily, or placebo. The average age of the patients was 55 years, about half were women, and the average baseline HbA1c was 8.0% (64 mmol/mol). The primary endpoint was change in HbA1c level from baseline to week 26, and the secondary endpoint was change in body weight over the same period.
After 26 weeks of once-daily treatment, patients in semaglutide group showed significant reductions in HbA1c from baseline with all three doses: –0.6% (3 mg), –0.9% (7 mg), and –1.1% (14 mg), with P less than .001 for all, based on an intention-to-treat analysis. Similar results occurred using an on-treatment analysis, with differences of –0.7%, –1.2%, and –1.4%, respectively, for the three doses.
In addition, patients in all dose groups achieved the secondary endpoint of reduction in body weight, compared with placebo, from baseline to 26 weeks based on both types of analyses. “Significantly more patients achieved body weight loss of at least 5% with oral semaglutide at 7 mg and 14 mg, compared with placebo,” Dr. Aroda and colleagues wrote (intention-to-treat: –0.1 for 3 mg daily [P = .87], –0.9 for 7 mg [P = .09], –2.3 for 14 mg [P less than .001]; and on-treatment: –0.2 for 3 mg [P = .71], –1.0 for 7 mg [P = .01], –2.6 for 14 mg [P less than .001]).
The overall incidence of adverse events and serious adverse events was similar in the treatment and placebo groups, with the most frequent being nausea and diarrhea. No deaths occurred among patients on the medication.
The findings were limited by several factors, including a patient population that had a relatively short duration of diabetes (mean, 3.5 years) and that the oral semaglutide was used as first-line monotherapy, without first using metformin, the researchers noted. However, oral semaglutide “achieved clinically meaningful and superior glucose lowering,” compared with placebo, at all three doses, they wrote.
“Ongoing additional studies in the PIONEER program will further define the effect when used in combination with other glucose-lowering therapies and in other populations of interest, such as those with high cardiovascular risk or renal impairment,” they emphasized
Novo Nordisk funded the study. The lead author disclosed relationships with Novo Nordisk, and several coauthors disclosed relationships with or employment by the company.
SOURCE: Aroda VR et al. Diabetes Care. 2019 Jul. doi: 10.2337/dc19-0749.