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The broad treatment armamentarium for type 2 diabetes (T2D) allows for a patient-centered approach to achieving and maintaining glycemic control. Following metformin and lifestyle modifications, there are a variety of second-line treatment options available [ADA 2019]. Selection of a second-line agent is based on a combination of patient-specific factors, including presence of comorbid conditions, weight, hypoglycemia risk, cost, and patient preference.1 Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are one such treatment option that have a wealth of data supporting their glucose-lowering efficacy, favorable safety profile, and in the case of some agents, improvement in CV outcomes.2–4
A limitation to the use of currently available GLP-1 RAs is that they are administered via subcutaneous injection in order to avoid enzymatic and pH degradation of the peptide in the gastrointestinal (GI) tract. Patients with T2D often have difficulty with adherence to and persistence with injectable medications, with “injection concerns” being one of the most frequently cited barriers.5–7 In order to overcome this barrier, an oral formulation of the GLP-1 RA semaglutide has been developed through co-formulation with an absorption enhancer. Oral semaglutide was studied in the PIONEER clinical trial program and was recently approved by the Food and Drug Administration (FDA) under the brand name Rybelsus® for the treatment of adults with T2D (Fig. 1).8 Oral semaglutide is available in 3 mg (starting dose), 7 mg, and 14 mg tablets. This review discusses the pharmacology, efficacy, safety, and place in therapy of the first oral GLP-1 RA, oral semaglutide.
2 Data sourcesA MEDLINE search (1995–October 2019) was conducted using the search terms oral semaglutide, semaglutide, PIONEER, and a combination of those terms. Review of the references listed in the articles identified was also performed. The oral semaglutide prescribing information was reviewed, as well as abstracts from scientific meetings and ongoing clinical trial data.
3 PharmacologySemaglutide is a 31-amino acid peptide that mimics native GLP-1 with two key structural modifications: substitution of alanine at position 8 with α-aminoisobutyric acid and addition of a spacer to conjugate the C18 fatty diacid to the position 26 lysine. These modifications allow for resistance of drug degradation by dipeptidyl peptidase-4 (DPP-4) and reduced renal clearance of the drug respectively, resulting in prolonged plasma...