GLP1 (semaglutide / Ozempic): research background
What Semaglutide Is
Semaglutide is a modified human glucagon-like peptide-1 (GLP-1) analogue developed using a proprietary protein-acylation technology (PMID 29363040). It is also known as Ozempic® and Wegovy® (PMID 29363040, PMID 34706925). Compared to human GLP-1, semaglutide has two amino acid substitutions (Aib(8), Arg(34)) and is derivatized at lysine 26 (PMID 26308095). Semaglutide is designed for once-weekly administration (PMID 26308095).
How It Is Thought to Work
Semaglutide functions as a GLP-1 receptor (GLP-1R) agonist (PMID 32213703, PMID 31031702). GLP-1R is expressed in various tissues, including the pancreas, gastrointestinal tract, heart, lungs, kidneys, and brain (PMID 31031702). Its design focuses on increasing affinity for serum albumin, which prolongs its exposure and action in the body, allowing for once-weekly dosing (PMID 26308095, PMID 31031702). The plasma half-life of semaglutide was observed to be 46.1 hours in mini-pigs after intravenous administration (PMID 26308095). It lowers blood glucose by stimulating insulin release (PMID 29363040) and mediates its effects on glycemic control and body weight through GLP-1Rs in the pancreas and brain, respectively (PMID 31031702).
Mechanistic studies in rodents suggest that semaglutide induces weight loss by modulating food preference, reducing food intake, and affecting neural pathways without decreasing energy expenditure (PMID 32213703). Semaglutide interacts with the brain via circumventricular organs and specific sites near the ventricles, rather than by directly crossing the blood-brain barrier (PMID 32213703). It induces c-Fos activation in ten brain areas in rodents, including hindbrain regions directly targeted and secondary areas like the lateral parabrachial nucleus, suggesting involvement in meal termination (PMID 32213703). Transcriptomic analysis in semaglutide-treated rats showed increased prolactin-releasing hormone and tyrosine hydroxylase in the area postrema (PMID 32213703).
Laboratory and Animal Studies Report
In mini-pigs, semaglutide showed a plasma half-life of 46.1 hours after intravenous administration, and a mean residence time (MRT) of 63.6 hours after subcutaneous dosing (PMID 26308095). Its GLP-1R affinity was measured at 0.38 ± 0.06 nM, which was three-fold decreased compared to liraglutide, while its albumin affinity was increased (PMID 26308095).
Preclinical studies in rodents indicate that semaglutide lowers body weight by directly interacting with GLP-1R populations and influencing neural pathways related to food intake, reward, and energy expenditure (PMID 32213703). In C57/BL6J mice, semaglutide significantly ameliorated doxorubicin-induced cardiac dysfunction (PMID 38574433). In vitro experiments showed that semaglutide, via the PI3K/AKT pathway, reduced BNIP3 expression in mitochondria, improving mitochondrial function (PMID 38574433).
Human Evidence So Far
Clinical trials, including SUSTAIN, PIONEER, and STEP, have demonstrated that semaglutide (both injected and oral formulations) has superior efficacy compared to placebo and other antidiabetic medications in reducing weight in individuals with type 2 diabetes or obesity (PMID 34706925). Semaglutide also lowers glucose levels and reduces cardiovascular risk in patients with diabetes (PMID 32213703). It has been approved in the US, Puerto Rico, Canada, and received a positive opinion in the EU for treating type 2 diabetes mellitus (PMID 29363040). The medication Wegovy (semaglutide) received FDA approval for chronic weight management based on these trial results (PMID 34706925).
Observational data on GLP-1 receptor agonists, including semaglutide, have suggested a reduction in alcohol use in humans. A review of three randomized controlled trials showed that semaglutide reduced alcohol use, while dulaglutide lowered alcohol intake in current drinkers. Exenatide, another GLP-1RA, showed no significant effect on heavy drinking days (PMID 41273789).
Open Questions and Limitations
The precise mechanism by which semaglutide positively affects cardiovascular outcomes in individuals with type 2 diabetes is still being explored (PMID 31031702). Ongoing investigations for semaglutide include its use for non-alcoholic fatty liver disease (NASH) (PMID 31031702) and further studies on its oral formulation (PMID 31031702). For alcohol use disorder, large randomized controlled trials are needed to further substantiate the role of GLP-1 receptor agonists (PMID 41273789).
Studies cited in this section
Summarised from the PubMed abstracts listed above. Educational reference only — not medical advice or instructions.
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