Clinical review of the efficacy and safety of oral semaglutide in patients with type 2 diabetes compared with other oral antihyperglycemic agents and placebo

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ABSTRACT

Oral semaglutide is a tablet formulation of a glucagon-like peptide-1 receptor agonist (GLP-1RA), recently approved in the USA and other countries. This paper reviews data from clinical trials (PIONEER 1, 2, 3, and 7) comparing oral semaglutide (once-daily doses of 3, 7, or 14 mg) with either once-daily placebo, empagliflozin 25 mg, or sitagliptin 100 mg. After 26 weeks in PIONEER 1, patients randomized to 3, 7, or 14 mg doses of oral semaglutide monotherapy had statistically significant reductions in glycated hemoglobin (HbA_1c) of 0.9%, 1.2%, and 1.4%, respectively, versus 0.3% with placebo. In the active-comparator studies, oral semaglutide 14 mg provided better glycemic control than empagliflozin or sitagliptin after 26 weeks, with durable effects. Body weight reductions were significantly greater with oral semaglutide than with placebo and sitagliptin. However, body weight reductions with oral semaglutide 14 mg versus empagliflozin 25 mg were not significantly different. Gastrointestinal adverse events (AEs) with oral semaglutide were mostly mild-to-moderate, occurred early in the course of treatment, and abated over time. Across these trials, 5–13% and 15–20% of patients experienced nausea with oral semaglutide 7 and 14 mg, respectively, and 2.3–3.4% and 5.1–8.0%, respectively, discontinued treatment due to gastrointestinal AEs. Severe or blood glucose-confirmed symptomatic hypoglycemia occurred infrequently with oral semaglutide and was seen most often in patients taking concomitant sulfonylureas. Findings from these trials indicate that the addition of oral semaglutide reduces HbA_1c and body weight and is associated with a low risk of hypoglycemia. Oral semaglutide represents an additional option for treating people with type 2 diabetes in primary care, with the potential to expand the numbers of patients benefiting from GLP-1RAs beyond that currently seen with injectable formulations.

KEYWORDS:

• Oral semaglutide
• sitagliptin
• empagliflozin
• comparative studies
• treatment intensification
• type 2 diabetes

Acknowledgments

Under the direction of the authors, medical writing and editorial support were provided by Nicola Beadle of Axis, a division of Spirit Medical Communications Group Ltd. (funded by Novo Nordisk Inc.). The authors were involved with drafting the outline and critically editing all drafts during the development of the article, and all authors provided their final approval for submission.

Declaration of interest

F.L. serves on a speakers’ bureau for Janssen Pharmaceuticals.

L.B. has received: consultant fees from AstraZeneca, Gilead Sciences Inc., Janssen Pharmaceuticals, Merck, Novo Nordisk, and Sanofi; speaker honoraria from Janssen Pharmaceuticals, Novo Nordisk, and Sanofi; and research grant support from Novo Nordisk and Sanofi.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This peer reviewed article was supported by Novo Nordisk Inc.; the company was provided with the opportunity to perform a medical accuracy review.