Research Topic

Reviews and Novel Clinical Perspectives on Semaglutide: A GLP-1 Receptor Agonist with Both Injectable and Oral Formulations

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About this Research Topic

This Research Topic will comprise five articles focusing on the development, efficacy, safety, and clinical implications of semaglutide, the first glucagon-like peptide-1 receptor agonist (GLP-1RA) available as both a subcutaneous (s.c.) and oral formulation.

GLP-1RAs act on multiple pathophysiological defects in type 2 diabetes (T2D) and are highly effective glucose-lowering agents, that reduce body weight and have a low risk of hypoglycaemia.
Although GLP-1RAs act via the same overall mechanism, they vary structurally and in their pharmacokinetic and clinical effects. Early GLP-1RAs needed to be administered once or twice daily. To reduce injection burden, molecules or formulations have been modified to produce GLP-1RAs with a prolonged duration of action and requiring less frequent administration. The latest marketed GLP-1RA, semaglutide, has close homology to native glucagon-like peptide-1 and a half-life of ~1 week permitting once-weekly s.c. administration.

An oral GLP-1RA formulation may be preferred by some patients. However, significant barriers exist for the oral delivery of peptides, such as rapid gastric degradation and poor absorption. To address these challenges, a tablet was developed in which semaglutide is co-formulated with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC), which protects semaglutide from proteolytic degradation and enhances absorption across the gastric mucosa via transcellular effects.
In the SUSTAIN phase 3 program, once-weekly s.c. semaglutide substantially reduced HbA1c and weight versus several comparable alternatives (e.g. sitagliptin, dulaglutide, extended-release exenatide and insulin glargine). Recently, in the PIONEER phase 3 program, the safety and efficacy of oral semaglutide once daily was assessed in a variety of patient populations across the spectrum of diabetes, and reductions in HbA1c of up to 1.5% and in body weight of up to 4.7 kg were observed.

Pharmacokinetic data from the phase 3a programs, SUSTAIN and PIONEER, have shown that the exposure-response is similar for both formulations of semaglutide with regards to both efficacy and tolerance.

In the SUSTAIN and PIONEER programs, s.c. and oral semaglutide were well tolerated, with a long-term safety profile consistent with other GLP-1RAs. As expected for the class, the most frequent adverse events were gastrointestinal effects, which were mostly mild-to-moderate in severity and transient. The cardiovascular safety of s.c and oral semaglutide have also been confirmed, with superior reductions in the risk of the 3-point major adverse cardiovascular events with once-weekly s.c. semaglutide. A large cardiovascular outcomes trial is ongoing with oral semaglutide to show cardiovascular benefit.

Despite being effective glucose-lowering therapies and their early use advocated by guidelines, GLP-1RAs are underutilized. The availability of an oral formulation of a GLP-1RA will expand treatment options for those patients and physicians who are wary initiating of inject-able therapy.

**The Topic Editors have or currently receive(d) Research Support from:
- Dr. Meier: Boehringer-Ingelheim, MSD, Novo Nordisk, Sanofi.
- Dr. Giorgino: Eli Lilly, Lifescan, and Takeda.
The Topic Editors declare no other Conflicts of Interest.


Keywords: GLP-1, type 2 diabetes, cardiovascular outcomes, glucose, insulin


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

This Research Topic will comprise five articles focusing on the development, efficacy, safety, and clinical implications of semaglutide, the first glucagon-like peptide-1 receptor agonist (GLP-1RA) available as both a subcutaneous (s.c.) and oral formulation.

GLP-1RAs act on multiple pathophysiological defects in type 2 diabetes (T2D) and are highly effective glucose-lowering agents, that reduce body weight and have a low risk of hypoglycaemia.
Although GLP-1RAs act via the same overall mechanism, they vary structurally and in their pharmacokinetic and clinical effects. Early GLP-1RAs needed to be administered once or twice daily. To reduce injection burden, molecules or formulations have been modified to produce GLP-1RAs with a prolonged duration of action and requiring less frequent administration. The latest marketed GLP-1RA, semaglutide, has close homology to native glucagon-like peptide-1 and a half-life of ~1 week permitting once-weekly s.c. administration.

An oral GLP-1RA formulation may be preferred by some patients. However, significant barriers exist for the oral delivery of peptides, such as rapid gastric degradation and poor absorption. To address these challenges, a tablet was developed in which semaglutide is co-formulated with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC), which protects semaglutide from proteolytic degradation and enhances absorption across the gastric mucosa via transcellular effects.
In the SUSTAIN phase 3 program, once-weekly s.c. semaglutide substantially reduced HbA1c and weight versus several comparable alternatives (e.g. sitagliptin, dulaglutide, extended-release exenatide and insulin glargine). Recently, in the PIONEER phase 3 program, the safety and efficacy of oral semaglutide once daily was assessed in a variety of patient populations across the spectrum of diabetes, and reductions in HbA1c of up to 1.5% and in body weight of up to 4.7 kg were observed.

Pharmacokinetic data from the phase 3a programs, SUSTAIN and PIONEER, have shown that the exposure-response is similar for both formulations of semaglutide with regards to both efficacy and tolerance.

In the SUSTAIN and PIONEER programs, s.c. and oral semaglutide were well tolerated, with a long-term safety profile consistent with other GLP-1RAs. As expected for the class, the most frequent adverse events were gastrointestinal effects, which were mostly mild-to-moderate in severity and transient. The cardiovascular safety of s.c and oral semaglutide have also been confirmed, with superior reductions in the risk of the 3-point major adverse cardiovascular events with once-weekly s.c. semaglutide. A large cardiovascular outcomes trial is ongoing with oral semaglutide to show cardiovascular benefit.

Despite being effective glucose-lowering therapies and their early use advocated by guidelines, GLP-1RAs are underutilized. The availability of an oral formulation of a GLP-1RA will expand treatment options for those patients and physicians who are wary initiating of inject-able therapy.

**The Topic Editors have or currently receive(d) Research Support from:
- Dr. Meier: Boehringer-Ingelheim, MSD, Novo Nordisk, Sanofi.
- Dr. Giorgino: Eli Lilly, Lifescan, and Takeda.
The Topic Editors declare no other Conflicts of Interest.


Keywords: GLP-1, type 2 diabetes, cardiovascular outcomes, glucose, insulin


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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