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.
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
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