A Pharmacological and Clinical Overview of Oral Semaglutide for the Treatment of Type 2 Diabetes

Abstract

Oral semaglutide (Rybelsus^®) is a glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) with 94% homology to human GLP-1. It is the first GLP-1RA developed for oral administration, and it comprises a co-formulation of the peptide semaglutide with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, which overcomes the challenges of peptide absorption in the acidic conditions of the stomach. Oral semaglutide is indicated for use as an add-on combination therapy (with other glucose-lowering agents, including insulin) or as a monotherapy (in patients who are intolerant to metformin) for type 2 diabetes when diet and exercise do not provide adequate glycemic control. In an extensive phase III clinical program including patients from across the disease spectrum, treatment with oral semaglutide resulted in effective glycemic control, reductions in body weight, and decreases in systolic blood pressure when used as monotherapy or in combination with other glucose-lowering therapies. Studies showed that oral semaglutide was well tolerated, with a safety profile consistent with the GLP-1RA drug class. The risk of hypoglycemia was low, and the most common adverse events were gastrointestinal, with nausea and diarrhea generally being the most frequently reported manifestations. Cardiovascular (CV) safety was shown to be noninferior to placebo and observations suggest that the CV profile of oral semaglutide is likely to be similar to that of subcutaneous semaglutide. The evolution of the GLP-1RA class to include an oral agent could facilitate the use of these agents earlier in the diabetes treatment cascade owing to wider acceptance from patients and healthcare professionals.

Fig. 1

Structure of semaglutide and SNAC (a) and the mechanism of SNAC on semaglutide absorption (b). DPP-4 dipeptidyl peptidase-4, GLP-1 glucagon-like peptide-1, GLP-1RA glucagon-like peptide-1 receptor agonist, SNAC sodium N-(8-[2-hydroxybenzoyl] amino) caprylate

Fig. 2

Reductions in HbA_1c with oral semaglutide in the PIONEER program. *p < 0.05, **p < 0.01, ***p < 0.001 favoring oral semaglutide vs. placebo. ^†p < 0.05, ^††p < 0.01, ^†††p < 0.001 favoring oral semaglutide vs. active comparator. ^§p < 0.05, ^§§p < 0.01, ^§§§p < 0.001 favoring active comparator vs. oral semaglutide. Data are for the treatment policy estimand (regardless of premature treatment discontinuation or rescue medication use). BL baseline, HbA_1c glycated hemoglobin, ins insulin, met metformin, MRI moderate renal impairment, OAD oral antidiabetes drug, SGLT2i sodium-glucose co-transporter-2 inhibitor, SU sulfonylurea, T2D type 2 diabetes

Fig. 3

Reductions in body weight with oral semaglutide in the PIONEER program. *p < 0.05, **p < 0.01, ***p < 0.001 favoring oral semaglutide vs. placebo. ^†p < 0.05, ^††p < 0.01, ^†††p < 0.001 favoring oral semaglutide vs. active comparator. ^§p < 0.05, ^§§p < 0.01, ^§§§p < 0.001 favoring active comparator vs. oral semaglutide. Data are for the treatment policy estimand (regardless of premature treatment discontinuation or rescue medication use). BL baseline, ins insulin, met metformin, MRI moderate renal impairment, OAD oral antidiabetes drug, SGLT2i sodium-glucose co-transporter-2 inhibitor, SU sulfonylurea, T2D type 2 diabetes