Efficacy of Semaglutide in a Subcutaneous and an Oral Formulation

Abstract

Despite the benefits of early and effective glycemic control in the management of type 2 diabetes (T2D), achieving glycated hemoglobin (HbA1c) targets is challenging in some patients. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) provide effective reductions in HbA1c and body weight. Semaglutide is the only GLP-1RA that is available in both an injectable and oral formulation. The efficacy of once-weekly subcutaneous semaglutide and once-daily oral semaglutide has been investigated in the global SUSTAIN and PIONEER phase III clinical trial programs in a range of clinical settings, including early T2D managed with diet and exercise only, more established T2D uncontrolled on one to three oral antidiabetic drugs, and advanced disease treated with insulin. Across the SUSTAIN program, once-weekly subcutaneous semaglutide 1.0 mg reduced HbA1c by 1.5-1.8% after 30-56 weeks, which was significantly more than sitagliptin, liraglutide, exenatide extended release, dulaglutide, canagliflozin, or insulin glargine. Across the PIONEER program, once-daily oral semaglutide 14 mg reduced HbA1c by 1.0-1.4%, significantly more than sitagliptin or empagliflozin, and to a similar extent as liraglutide after 26 weeks. In addition, subcutaneous semaglutide reduced body weight significantly more than all active comparators tested, while oral semaglutide reduced body weight more than sitagliptin and liraglutide, and to a similar extent as empagliflozin. Neither formulation of semaglutide has been associated with an increased risk of hypoglycemia and both improve various measures of health-related quality of life. Semaglutide offers the benefits of a highly effective GLP-1RA in both injectable and oral formulations. Selection of the most appropriate formulation can be made on an individual basis to best suit the patient's preferences and needs.

Keywords: body weight; efficacy; glucagon-like peptide-1 receptor agonist (GLP-1RA); glycated hemoglobin (HbA1c); oral; semaglutide; subcutaneous; type 2 diabetes.

Conflict of interest statement

JJM has received lecture honoraria and consulting fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme (MSD), Novartis, Novo Nordisk, and Sanofi; has received reimbursement of congress participation fees and travel expenses from MSD, Novo Nordisk, and Sanofi; and has initiated projects supported by Boehringer Ingelheim, MSD, Novo Nordisk, and Sanofi. The author declares that this article received funding from Novo Nordisk. The funder had the following involvement in the article: medical writing support.

Copyright © 2021 Meier.

Figures

Figure 1

Reduction in HbA1c with semaglutide and comparators in global glycemic efficacy trials (–, –26, 31, 33). (A) Trials in early T2D (mean duration 3–4 years). (B) Trials in established T2D (mean duration 6–10 years) with incretin-based therapies as comparators. (C) Trials in established T2D (mean duration 6–10 years) with other comparators. (D) Trials in advanced T2D (mean duration 13–15 years). For the SUSTAIN trials shown, HbA1c reduction at study end (weeks 30, 40, 52, or 56) was the primary endpoint. Estimated mean changes from baseline in HbA1c included only data obtained before initiation of any rescue medication or before premature treatment discontinuation. For the PIONEER trials shown, HbA1c reduction at week 26 was the primary endpoint, except for PIONEER 7 where the primary endpoint was achievement of HbA1c <7.0% (53 mmol/mol) at week 52. Estimated mean changes from baseline in HbA1c are regardless of trial product discontinuation or rescue medication (treatment policy estimand). Oral semaglutide 3 mg daily was also tested in PIONEER 1, PIONEER 3, and PIONEER 8; however, this dose is not recommended as a maintenance dose [Rybelsus SPC] and data are not shown (except for in PIONEER 7 as part of a flexible dosing approach in which investigators could increase or decrease the dose of oral semaglutide between 3, 7 and 14 mg according to efficacy and tolerability criteria and clinical judgment). *p < 0.05 for the estimated treatment difference with semaglutide vs. comparator. Cana, canagliflozin; dula, dulaglutide; empa, empagliflozin; ER, extended release; exe, exenatide; HbA1c, glycated hemoglobin; IGlar, insulin glargine; lira, liraglutide; met, metformin; N, number of randomized patients; pbo, placebo; s.c., subcutaneous; sema, semaglutide; SGLT2i, sodium-glucose co-transporter-2 inhibitor; sita, sitagliptin; SU, sulfonylurea; T2D, type 2 diabetes; TZD, thiazolidinedione.

Figure 2

Reduction in body weight with semaglutide and comparators (–, –26, 31, 33). (A) Trials in early T2D (3–4 years). (B) Trials in established T2D (6–10 years) with incretin-based therapies as comparators. (C) Trials in established T2D (6–10 years) with other comparators. (D) Trials in advanced T2D (13–15 years). For the SUSTAIN trials shown, estimated mean changes from baseline in body weight included only data obtained before initiation of any rescue medication or before premature treatment discontinuation. For the PIONEER trials shown, estimated mean changes from baseline in body weight are regardless of trial product discontinuation or rescue medication (treatment policy estimand). Oral semaglutide 3 mg daily was also tested in PIONEER 1, PIONEER 3, and PIONEER 8; however, this dose is not recommended as a maintenance dose [Rybelsus SPC] and data are not shown (except for in PIONEER 7 as part of a flexible dosing approach in which investigators could increase or decrease the dose of oral semaglutide between 3, 7 and 14 mg according to efficacy and tolerability criteria and clinical judgment). *p < 0.05 for the estimated treatment difference with semaglutide vs. comparator. Cana, canagliflozin; dula, dulaglutide; empa, empagliflozin; ER, extended release; exe, exenatide; IGlar, insulin glargine; lira, liraglutide; met, metformin; pbo, placebo; s.c., subcutaneous; sema, semaglutide; SGLT2i, sodium-glucose co-transporter-2 inhibitor; sita, sitagliptin; SU, sulfonylurea; T2D, type 2 diabetes; TZD, thiazolidinedione.

Figure 3

Overview of considerations related to the use of subcutaneous and oral formulations of semaglutide. HbA1c, glycated hemoglobin.