Semaglutide: Difference between revisions

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| generic = Semaglutide

| brand = Ozempic (T2DM SC), Wegovy (obesity SC), Rybelsus (oral T2DM)

| structure = 31-amino-acid acylated peptide analog of human [[GLP-1]] (7–37), with Aib substitution at position 8 (blocks DPP-4 cleavage) and a C18 fatty diacid linked via γGlu-2×OEG spacer at Lys26 (drives albumin binding → ~165 h half-life)<ref name="lau2015">Lau J, Bloch P, Schäffer L et al. (2015). Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. ''J Med Chem'' 58(18):7370–80. doi:10.1021/acs.jmedchem.5b00726</ref>

| structure =

| classes = [[GLP-1 receptor agonist]] · [[Antidiabetic medicines|Antidiabetic]] · [[Anti-obesity medicines|Anti-obesity]] · [[Cardiovascular risk reduction]] agent

| mechanism = ~~Selective long~~-acting agonist of the [[GLP-1 receptor]] ~~(class B GPCR)~~. Produces glucose-dependent insulin secretion, glucagon suppression, delayed gastric emptying, hypothalamic appetite suppression, and direct cardiovascular and renal protective effects.<ref name="drucker2022">Drucker DJ (2022). GLP-1 physiology informs the pharmacotherapy of obesity. ''Mol Metab'' 57:101351. doi:10.1016/j.molmet.2021.101351</ref>

| mechanism = Long-acting agonist of the [[GLP-1 receptor]].

| uses = [[Type 2 diabetes mellitus]] · [[Obesity]] · [[Cardiovascular risk reduction]] in obesity without diabetes · [[MASH]] with stage 2–3 fibrosis · [[Chronic kidney disease]] in T2DM

| starting_dose = Ozempic: 0.25 mg SC weekly × 4 wk<ref name="ozempic-label">US FDA. ''Ozempic (semaglutide) prescribing information.'' Novo Nordisk. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/209637s019lbl.pdf</ref> · Wegovy: 0.25 mg SC weekly × 4 wk<ref name="wegovy-label">US FDA. ''Wegovy (semaglutide) prescribing information.'' Novo Nordisk. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215256s000lbl.pdf</ref> · Rybelsus: 3 mg PO daily × 30 d<ref name="rybelsus-label">US FDA. ''Rybelsus (semaglutide) prescribing information.'' Novo Nordisk. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/213051s000lbl.pdf</ref>

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Semaglutide is the second weekly GLP-1 RA from Novo Nordisk's incretin program (after [[liraglutide]])<ref name="lau2015"/> and the molecule that, more than any other, made obesity treatment a mainstream rather than a specialty intervention.{{Citation needed}}

| pharmacokinetics = Acylation with a C18 fatty diacid drives non-covalent binding to serum albumin, slowing renal clearance and DPP-4 access. The Aib8 substitution renders the peptide DPP-4-resistant. Resulting terminal half-life ~165 h means once-weekly subcutaneous dosing produces near-steady-state plasma levels.<ref name="lau2015"/>

| pharmacokinetics = '''Chemistry'''. 31-amino-acid acylated peptide analog of human [[GLP-1]] (7–37), with Aib substitution at position 8 (blocks DPP-4 cleavage) and a C18 fatty diacid linked via γGlu-2×OEG spacer at Lys26 (drives albumin binding → ~165 h half-life)<ref name="lau2015">Lau J, Bloch P, Schäffer L et al. (2015). Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. ''J Med Chem'' 58(18):7370–80. doi:10.1021/acs.jmedchem.5b00726</ref>

Acylation with a C18 fatty diacid drives non-covalent binding to serum albumin, slowing renal clearance and DPP-4 access. The Aib8 substitution renders the peptide DPP-4-resistant. Resulting terminal half-life ~165 h means once-weekly subcutaneous dosing produces near-steady-state plasma levels.<ref name="lau2015"/>

Oral semaglutide (Rybelsus) is co-formulated with '''SNAC''' (sodium N-[8-(2-hydroxybenzoyl)amino]caprylate), a permeation enhancer that transiently raises gastric pH and protects the peptide locally — yielding ~0.4–1% bioavailability, which is sufficient at 14 mg daily to match Ozempic 0.5 mg weekly for glycemic effect (but not for weight loss).<ref name="rybelsus-label"/><ref name="buckley2018">Buckley ST, Bækdal TA, Vegge A et al. (2018). Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist. ''Sci Transl Med'' 10(467):eaar7047. doi:10.1126/scitranslmed.aar7047</ref> Strict fasting administration is mandatory; any concurrent food or beverage destroys absorption.<ref name="rybelsus-label"/>

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Predominantly catabolic clearance via proteolysis; renal and hepatic impairment do not require dose adjustment.<ref name="ozempic-label"/> No CYP-mediated metabolism, so the interaction profile is dominated by ''gastric emptying'' effects on other oral medicines, not pharmacokinetic competition.<ref name="ozempic-label"/>

| pharmacodynamics = At maintenance doses semaglutide produces:

| pharmacodynamics = '''Receptor pharmacology'''. Selective long-acting agonist of the [[GLP-1 receptor]] (class B GPCR). Produces glucose-dependent insulin secretion, glucagon suppression, delayed gastric emptying, hypothalamic appetite suppression, and direct cardiovascular and renal protective effects.<ref name="drucker2022">Drucker DJ (2022). GLP-1 physiology informs the pharmacotherapy of obesity. ''Mol Metab'' 57:101351. doi:10.1016/j.molmet.2021.101351</ref>

At maintenance doses semaglutide produces:

* HbA1c reduction of ~1.5–2.0 percentage points (Ozempic 1 mg)<ref name="sustain6">Marso SP et al. (2016). Semaglutide and cardiovascular outcomes in patients with type 2 diabetes (SUSTAIN-6). ''NEJM'' 375:1834–44. doi:10.1056/NEJMoa1607141</ref>

* Weight loss of ~6 kg (Ozempic 1 mg, T2DM)<ref name="sustain6"/> to ~14.9% body weight (Wegovy 2.4 mg, obesity without T2DM, STEP-1)<ref name="step1"/>

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