Oral semaglutide achieves outcomes similar to those of subcutaneous semaglutide

Oral semaglutide can achieve levels of glycemic control and weight loss similar to those of subcutaneous semaglutide, according to a phase 2, placebo-controlled trial published in the Oct. 17 edition of JAMA.

In a parallel-group, dosage-finding 26-week trial, 632 patients with type 2 diabetes and poor glycemic control were randomized to either 2.5 mg, 5 mg, 10 mg, 20 mg, or 40 mg of once-daily oral semaglutide escalated over 4 weeks (standard escalation); 40 mg escalated over 8 weeks; 40 mg escalated over 2 weeks; once-weekly subcutaneous semaglutide (1 mg) for 26 weeks, or oral placebo.

The study found that all patients who had received oral or subcutaneous semaglutide showed significantly reduced mean hemoglobin A_1c levels compared with placebo. Almost all patients treated with semaglutide – both oral and subcutaneous – showed a reduction in HbA_1c levels while only 74% of patients in the placebo group did (JAMA 2017 Oct 17;318[15]:1460-70. doi: 10.1001/jama.2017.14752).

The estimated treatment difference compared with placebo at week 26 ranged from –0.4% for the 2.5-mg group to –1.6% for the 40-mg-over-4-weeks group, and –1.6% for the subcutaneous group.

Dr. Melanie Davies

Researchers also saw a dose-dependent decrease in mean body weight from baseline to 26 weeks, ranging from –0.9 kg in the 2.5-mg group to –5.7 kg in the 40-mg standard escalation group, compared with –1.2 kg in the placebo group. The difference between treatment and placebo was significant only for doses at or above 10 mg.

The most common adverse events reported were mild to moderate gastrointestinal problems, mostly associated with oral and subcutaneous semaglutide, which are a known side effect of GLP-1 receptor agonists. There was also a higher rate of premature discontinuation of treatment due to gastrointestinal effects in the semaglutide-treated patients.

However, the overall rate of hypoglycemic episodes was low, and was similar in both semaglutide groups and the placebo group.

There were three cases of acute pancreatitis in patients treated with semaglutide, and the treatment was also associated with a significant increase in heart rate, compared with placebo.

“A longer study duration may have demonstrated the maximum HbA_1c level and weight reductions in the groups administered the higher doses of the medication,” wrote Melanie Davies, MD, professor of diabetes medicine at the University of Leicester, England, and her coauthors. “Future trials should assess the efficacy of oral semaglutide in patients with a high baseline HbA_1c level to explore its potential in patients who are less well controlled, and in combination with other glucose-lowering agents.”

Semaglutide manufacturer Novo Nordisk provided editorial support. Three authors declared board membership and consultancy fees from the company, as well as institutional grants, lecture fees, and other funding from other pharmaceutical companies. Two authors declared shares in Novo Nordisk. One author declared a patent relating to semaglutide, and two authors declared funding from pharmaceutical companies including Novo Nordisk.