Semaglutide

Mechanism (as reported)

A study describing discovery/research design reports that semaglutide was selected for once-weekly GLP-1 analogue development by increasing albumin affinity and securing stability against metabolic degradation, with semaglutide having amino-acid substitutions versus human GLP-1 and being derivatized (PMID 26308095).

Key findings (each cites a source)

• A phase 3 trial in patients with type 2 diabetes reported that semaglutide (once weekly) was associated with an estimated mean change in glycated hemoglobin from baseline to 40 weeks of -1.86 percentage points (in the trial comparing tirzepatide versus semaglutide). [PMID 34170647]
• In the same type 2 diabetes phase 3 trial (tirzepatide vs semaglutide), gastrointestinal adverse events were reported as the most common adverse events, and the study described them as primarily mild to moderate in severity. [PMID 34170647]
• A preclinical/biophysical design study reported semaglutide was selected as an optimal once-weekly candidate for a GLP-1 analogue by increasing albumin affinity and ensuring stability against metabolic degradation, and it reports semaglutide has two amino acid substitutions versus human GLP-1 plus derivatization at lysine 26. [PMID 26308095]
• The semaglutide discovery/PK design study reported semaglutide plasma half-life of 46.1 h in mini-pigs after i.v. administration and that semaglutide had an MRT of 63.6 h after s.c. dosing to mini-pigs. [PMID 26308095]
• A review of semaglutide safety reported that semaglutide induces mostly mild-to-moderate and transient gastrointestinal disturbances and increases the risk of biliary disease (cholelithiasis), and stated no unexpected safety issues had arisen to date in the context described. [PMID 34305810]
• The safety review also reported that definitive conclusions for pancreatic and thyroid cancer could not be drawn at the time due to low incidence of these conditions, and it discussed monitoring considerations for diabetic retinopathy complications in contexts where patients are at risk. [PMID 34305810]
• A phase 3b head-to-head trial (SUSTAIN 7) reported that semaglutide improved glycemic control and reduced bodyweight versus dulaglutide, with gastrointestinal disorders being the most frequently reported adverse event. [PMID 29915923]
• A cohort study (EHR linked to dispensing) comparing on-treatment weight outcomes in adults with overweight or obesity reported that tirzepatide was associated with significantly greater weight loss than semaglutide, and it reported gastrointestinal AE rates were similar between groups. [PMID 38976257]
• A phase 3a trial of a semaglutide+cagrilintide combination (REDEFINE 1) reported gastrointestinal adverse events were mainly transient and mild-to-moderate in severity. [PMID 40544433]