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| generic = Semaglutide
| generic = Semaglutide
| brand = Ozempic (T2DM SC), Wegovy (obesity SC), Rybelsus (oral T2DM)
| 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)
| 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>
| classes = [[GLP-1 receptor agonist]] · [[Antidiabetic medicines|Antidiabetic]] · [[Anti-obesity medicines|Anti-obesity]] · [[Cardiovascular risk reduction]] agent
| 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.
| 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>
| uses = [[Type 2 diabetes mellitus]] · [[Obesity]] · [[Cardiovascular risk reduction]] in obesity without diabetes · [[MASH]] with stage 2–3 fibrosis · [[Chronic kidney disease]] in T2DM
| 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 · Wegovy: 0.25 mg SC weekly × 4 wk · Rybelsus: 3 mg PO daily × 30 d
| 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>
| preparations = Pre-filled multi-dose pen (0.25 / 0.5 / 1 / 2 mg, Ozempic; 0.25 / 0.5 / 1 / 1.7 / 2.4 mg, Wegovy) · Oral tablet 3 / 7 / 14 mg co-formulated with SNAC absorption enhancer (Rybelsus)
| preparations = Pre-filled multi-dose pen (0.25 / 0.5 / 1 / 2 mg, Ozempic;<ref name="ozempic-label"/> 0.25 / 0.5 / 1 / 1.7 / 2.4 mg, Wegovy<ref name="wegovy-label"/>) · Oral tablet 3 / 7 / 14 mg co-formulated with SNAC absorption enhancer (Rybelsus)<ref name="rybelsus-label"/>
| fda_max = 2 mg/wk SC (Ozempic) · 2.4 mg/wk SC (Wegovy) · 14 mg PO daily (Rybelsus)
| fda_max = 2 mg/wk SC (Ozempic)<ref name="ozempic-label"/> · 2.4 mg/wk SC (Wegovy)<ref name="wegovy-label"/> · 14 mg PO daily (Rybelsus)<ref name="rybelsus-label"/>
| routes = Subcutaneous (abdomen, thigh, upper arm) · Oral (Rybelsus only, on empty stomach with ≤120 mL water, ≥30 min before any food/drink/other oral medicine)
| routes = Subcutaneous (abdomen, thigh, upper arm)<ref name="ozempic-label"/> · Oral (Rybelsus only, on empty stomach with ≤120 mL water, ≥30 min before any food/drink/other oral medicine)<ref name="rybelsus-label"/>
| onset = Glycemic effect within days; full weight effect over months
| onset = Glycemic effect within days;{{Citation needed}} full weight effect over months<ref name="step1">Wilding JPH et al. (2021). Once-weekly semaglutide in adults with overweight or obesity (STEP-1). ''NEJM'' 384:989. doi:10.1056/NEJMoa2032183</ref>
| duration = ~7 days (weekly SC dosing) · ~24 h (oral)
| duration = ~7 days (weekly SC dosing)<ref name="ozempic-label"/> · ~24 h (oral)<ref name="rybelsus-label"/>
| halflife = ~165 hours (~1 week) — among the longest of any GLP-1 RA
| halflife = ~165 hours (~1 week) — among the longest of any GLP-1 RA<ref name="lau2015"/>
| bioavailability = SC ~89% · Oral ~0.4–1% (SNAC-enhanced)
| bioavailability = SC ~89%{{Citation needed}} · Oral ~0.4–1% (SNAC-enhanced)<ref name="rybelsus-label"/>
| pregnancy = Avoid. Discontinue ≥2 months before planned pregnancy due to long half-life. Animal data show embryofetal harm. Not contraceptive — but rapid weight loss + improved ovulation may unmask fertility in [[PCOS]].
| pregnancy = Avoid. Discontinue ≥2 months before planned pregnancy due to long half-life. Animal data show embryofetal harm.<ref name="ozempic-label"/> Not contraceptive — but rapid weight loss + improved ovulation may unmask fertility in [[PCOS]].{{Citation needed}}
| legal = Rx-only · Schedule: none (not a controlled substance)
| legal = Rx-only;<ref name="ozempic-label"/> not a controlled substance
| intro = Semaglutide is a long-acting [[GLP-1 receptor agonist]] developed by [[Novo Nordisk]], marketed as '''[[Ozempic]]''' (weekly subcutaneous, for [[type 2 diabetes mellitus]]), '''[[Wegovy]]''' (weekly subcutaneous, for [[obesity]], [[cardiovascular risk reduction]] in obesity without diabetes, and [[MASH]] with fibrosis), and '''[[Rybelsus]]''' (daily oral tablet, for T2DM). It is, by revenue, the highest-grossing medicine on the planet as of 2024.
| intro = Semaglutide is a long-acting [[GLP-1 receptor agonist]] developed by [[Novo Nordisk]], marketed as '''[[Ozempic]]''' (weekly subcutaneous, for [[type 2 diabetes mellitus]]),<ref name="ozempic-label"/> '''[[Wegovy]]''' (weekly subcutaneous, for [[obesity]], [[cardiovascular risk reduction]] in obesity without diabetes, and [[MASH]] with fibrosis),<ref name="wegovy-label"/><ref name="select">Lincoff AM et al. (2023). Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT). ''NEJM'' 389:2221–32. doi:10.1056/NEJMoa2307563</ref><ref name="essence">Newsome PN et al. (2025). Semaglutide in MASH (ESSENCE). FDA approval basis. {{Citation needed}}</ref> and '''[[Rybelsus]]''' (daily oral tablet, for T2DM).<ref name="rybelsus-label"/> It is, by revenue, among the highest-grossing medicines on the planet as of 2024.{{Citation needed}}


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


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 enough at 14 mg daily to match Ozempic 0.5 mg weekly for glycemic effect (but not for weight loss). Strict fasting administration is mandatory; any concurrent food or beverage destroys absorption.
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"/>


Predominantly catabolic clearance via proteolysis; renal and hepatic impairment do not require dose adjustment. No CYP-mediated metabolism, so the interaction profile is dominated by ''gastric emptying'' effects on other oral medicines, not pharmacokinetic competition.
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 = At maintenance doses semaglutide produces:
* HbA1c reduction of ~1.5–2.0 percentage points (Ozempic 1 mg)
* 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) to ~15% body weight (Wegovy 2.4 mg, obesity without T2DM, STEP-1)
* 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"/>
* Systolic BP reduction of ~5 mmHg
* Systolic BP reduction of ~5 mmHg<ref name="select"/>
* Modest LDL-C reduction, larger triglyceride reduction
* Modest LDL-C reduction, larger triglyceride reduction{{Citation needed}}
* 20% relative risk reduction in MACE in obesity without T2DM (SELECT)
* 20% relative risk reduction in MACE in obesity without T2DM (SELECT)<ref name="select"/>
* 24% relative risk reduction in kidney + CV composite in T2DM + CKD (FLOW)
* 24% relative risk reduction in kidney + CV composite in T2DM + CKD (FLOW)<ref name="flow">Perkovic V et al. (2024). Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes (FLOW). ''NEJM'' 391:109. doi:10.1056/NEJMoa2403347</ref>


| indications = <indication ref="diabetes-type-2" author="MDElliottMD"/>
| indications = <indication ref="diabetes-type-2" author="MDElliottMD"/>
Line 44: Line 44:
→ 0.5 mg SC weekly × ≥4 weeks
→ 0.5 mg SC weekly × ≥4 weeks
→ 1 mg SC weekly × ≥4 weeks if further glycemic control needed
→ 1 mg SC weekly × ≥4 weeks if further glycemic control needed
→ 2 mg SC weekly (max) if needed
→ 2 mg SC weekly (max) if needed<ref name="ozempic-label"/>


Slower titration is reasonable in any patient with significant GI symptoms — holding at a tolerated dose for 8–12 weeks before advancing is standard practice.
Slower titration is reasonable in any patient with significant GI symptoms — holding at a tolerated dose for 8–12 weeks before advancing is standard practice.
Line 54: Line 54:
→ 1 mg × 4 weeks
→ 1 mg × 4 weeks
→ 1.7 mg × 4 weeks
→ 1.7 mg × 4 weeks
→ 2.4 mg weekly (maintenance)
→ 2.4 mg weekly (maintenance)<ref name="wegovy-label"/>


If a dose escalation is not tolerated, hold at the prior dose for an extra 4 weeks before advancing. Discontinue if patient cannot tolerate 1.7 mg after extended titration.
If a dose escalation is not tolerated, hold at the prior dose for an extra 4 weeks before advancing. Discontinue if patient cannot tolerate 1.7 mg after extended titration.<ref name="wegovy-label"/>
</titration>
</titration>


Line 62: Line 62:
3 mg PO daily × 30 days (non-therapeutic ramp)
3 mg PO daily × 30 days (non-therapeutic ramp)
→ 7 mg PO daily × ≥30 days
→ 7 mg PO daily × ≥30 days
→ 14 mg PO daily (max)
→ 14 mg PO daily (max)<ref name="rybelsus-label"/>


'''Critical patient instruction''': swallow whole, with no more than 120 mL (4 oz) of plain water, on an empty stomach, ≥30 minutes before the first food, drink, or any other oral medicine of the day.
'''Critical patient instruction''': swallow whole, with no more than 120 mL (4 oz) of plain water, on an empty stomach, ≥30 minutes before the first food, drink, or any other oral medicine of the day.<ref name="rybelsus-label"/>
</titration>
</titration>


| effects = Subjective effects vary considerably with dose and titration speed but reliably include:
| effects = Subjective effects vary considerably with dose and titration speed but reliably include:
* '''Early satiety''' — meals feel "complete" at a fraction of prior intake
* '''Early satiety''' — meals feel "complete" at a fraction of prior intake<ref name="step1"/>
* '''Food noise quieting''' — the most commonly volunteered subjective change. Patients report that intrusive food-related thoughts simply stop.
* '''Food noise quieting''' — the most commonly volunteered subjective change. Patients report that intrusive food-related thoughts simply stop.{{Citation needed}}
* '''Reduced alcohol craving''' — corroborated by observational and small RCT data; mechanism likely shared with food reward circuitry
* '''Reduced alcohol craving''' — corroborated by observational and small RCT data; mechanism likely shared with food reward circuitry<ref name="wang2024">Wang W, Volkow ND, Berger NA et al. (2024). Associations of semaglutide with incidence and recurrence of alcohol use disorder in real-world population. ''Nat Commun'' 15:4548. doi:10.1038/s41467-024-48780-6</ref>
* '''Nausea''' — dose-dependent, worst in first 1–2 weeks of any new dose level
* '''Nausea''' — dose-dependent, worst in first 1–2 weeks of any new dose level<ref name="ozempic-label"/>
* '''Constipation or diarrhea''' (variable, can alternate)
* '''Constipation or diarrhea''' (variable, can alternate)<ref name="ozempic-label"/>
* '''Sulfurous eructation''' (a small but very real subgroup)
* '''Sulfurous eructation''' (a small but very real subgroup){{Citation needed}}
* '''Reduced taste preference for fatty / sweet foods''' in many users
* '''Reduced taste preference for fatty / sweet foods''' in many users{{Citation needed}}


| interactions = <pharmaInteractions/>
| interactions = <pharmaInteractions/>


| pregnancy_details = Category formerly X-equivalent; current FDA labeling: avoid in pregnancy. Animal embryofetal toxicity is well-documented. Because the half-life is ~1 week, current guidance is to '''discontinue at least 2 months before any planned conception'''.
| pregnancy_details = Category formerly X-equivalent; current FDA labeling: avoid in pregnancy.<ref name="ozempic-label"/> Animal embryofetal toxicity is well-documented.<ref name="ozempic-label"/> Because the half-life is ~1 week, current guidance is to '''discontinue at least 2 months before any planned conception'''.<ref name="ozempic-label"/>


Postpartum: not recommended during breastfeeding pending more data; small molecule transfer to milk is unlikely given peptide structure but not formally characterized.
Postpartum: not recommended during breastfeeding pending more data; small molecule transfer to milk is unlikely given peptide structure but not formally characterized.{{Citation needed}}


Importantly: semaglutide is '''not a contraceptive''', and the medicine may '''restore ovulation''' in patients with [[PCOS]] or [[obesity]]-associated anovulation. Patients of childbearing potential should be counseled about contraception ''before'' starting.
Importantly: semaglutide is '''not a contraceptive''', and the medicine may '''restore ovulation''' in patients with [[PCOS]] or [[obesity]]-associated anovulation.{{Citation needed}} Patients of childbearing potential should be counseled about contraception ''before'' starting.


| monitoring = * Baseline: HbA1c, weight, BP, renal function, lipid panel, [[ALT]]/AST (especially for MASH indication)
| monitoring = * Baseline: HbA1c, weight, BP, renal function, lipid panel, [[ALT]]/AST (especially for MASH indication)
* Personal or family history of MTC or [[MEN2]] — '''contraindicated''', do not start
* Personal or family history of MTC or [[MEN2]] — '''contraindicated''', do not start<ref name="ozempic-label"/>
* Every 3 months for first year: HbA1c, weight, GI tolerability, signs of [[pancreatitis]] or [[gallbladder disease]]
* Every 3 months for first year: HbA1c, weight, GI tolerability, signs of [[pancreatitis]] or [[gallbladder disease]]
* Annual: renal function, lipids
* Annual: renal function, lipids
* '''Pre-procedure''': hold weekly dose ≥7 days before any planned anesthesia (per [[ASA 2024 guidance]]) due to delayed gastric emptying / aspiration risk
* '''Pre-procedure''': hold weekly dose ≥7 days before any planned anesthesia (per [[American Society of Anesthesiologists|ASA]] 2024 guidance) due to delayed gastric emptying / aspiration risk<ref name="kindel2024">Kindel TL et al. (2024). Perioperative GLP-1 receptor agonist safety guidance. ''Surg Obes Relat Dis'' 20(12):1183–8.</ref>


| counseling = * '''Slow titration is non-negotiable''' for tolerability. Patients who insist on faster ramps usually quit from GI side effects.
| counseling = * '''Slow titration is non-negotiable''' for tolerability. Patients who insist on faster ramps usually quit from GI side effects.
* Inject SC in abdomen, thigh, or upper arm; rotate sites. Pen is single-patient, multi-dose.
* Inject SC in abdomen, thigh, or upper arm; rotate sites. Pen is single-patient, multi-dose.<ref name="ozempic-label"/>
* GI side effects almost always peak in first 2–4 weeks of any new dose level, then attenuate.
* GI side effects almost always peak in first 2–4 weeks of any new dose level, then attenuate.<ref name="ozempic-label"/>
* Eat smaller portions earlier in the day. Plate sizes will feel comically large after a few weeks — that is the medicine working, not a problem to fix.
* Eat smaller portions earlier in the day. Plate sizes will feel comically large after a few weeks — that is the medicine working, not a problem to fix.
* Hydrate aggressively (volume depletion → AKI is a real risk).
* Hydrate aggressively (volume depletion → AKI is a real risk).<ref name="ozempic-label"/>
* Resistance training during weight loss protects lean mass and is strongly encouraged.
* Resistance training during weight loss protects lean mass and is strongly encouraged.{{Citation needed}}
* If a weekly dose is missed: take within 5 days; if >5 days, skip and resume on the next regular day.
* If a weekly dose is missed: take within 5 days; if >5 days, skip and resume on the next regular day.<ref name="ozempic-label"/>
* Avoid alcohol during titration weeks (compounds nausea).
* Avoid alcohol during titration weeks (compounds nausea).
* '''Pregnancy planning''': stop ≥2 months before trying to conceive.
* '''Pregnancy planning''': stop ≥2 months before trying to conceive.<ref name="ozempic-label"/>
* '''Surgery''': tell every anesthesiologist and surgeon you are on a weekly GLP-1 RA. Hold dose 7 days pre-op.
* '''Surgery''': tell every anesthesiologist and surgeon you are on a weekly GLP-1 RA. Hold dose 7 days pre-op.<ref name="kindel2024"/>


| anecdotes = <vote slug="food-noise"/>
| anecdotes = <vote slug="food-noise"/>
Line 108: Line 108:
| seealso = [[GLP-1 receptor agonist]] · [[Tirzepatide]] · [[Liraglutide]] · [[Dulaglutide]] · [[Exenatide]] · [[Type 2 diabetes mellitus]] · [[Obesity]] · [[MASH]]
| seealso = [[GLP-1 receptor agonist]] · [[Tirzepatide]] · [[Liraglutide]] · [[Dulaglutide]] · [[Exenatide]] · [[Type 2 diabetes mellitus]] · [[Obesity]] · [[MASH]]


| references = <ref name="step1">Wilding JPH et al. (2021). Once-weekly semaglutide in adults with overweight or obesity (STEP-1). ''NEJM'' 384:989.</ref>
| references = <references/>
<ref name="sustain6">Marso SP et al. (2016). Semaglutide and cardiovascular outcomes in patients with type 2 diabetes (SUSTAIN-6). ''NEJM'' 375:1834–44.</ref>
<ref name="select">Lincoff AM et al. (2023). Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT). ''NEJM'' 389:2221–32.</ref>
<ref name="flow">Perkovic V et al. (2024). Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes (FLOW). ''NEJM'' 391:109.</ref>
<ref name="essence">Newsome PN et al. (2025). Semaglutide in MASH (ESSENCE). FDA approval basis.</ref>
<ref name="pioneer6">Husain M et al. (2019). Oral semaglutide and cardiovascular outcomes in patients with T2DM (PIONEER-6). ''NEJM'' 381:841.</ref>
<ref name="stephfpef">Kosiborod MN et al. (2023). Semaglutide in patients with HFpEF and obesity (STEP-HFpEF). ''NEJM'' 389:1069.</ref>
<ref name="drucker2022">Drucker DJ (2022). GLP-1 physiology informs the pharmacotherapy of obesity. ''Mol Metab'' 57:101351.</ref>
<ref name="kindel2024">Kindel TL et al. (2024). Perioperative GLP-1 RA safety guidance. ''Surg Obes Relat Dis'' 20(12):1183.</ref>
}}
}}


Revision as of 22:58, 16 May 2026

GLP-1 receptor agonist · Antidiabetic · Anti-obesity · Cardiovascular risk reduction agent
Semaglutide
Ozempic (T2DM SC), Wegovy (obesity SC), Rybelsus (oral T2DM)
Semaglutide is a long-acting GLP-1 receptor agonist developed by Novo Nordisk, marketed as Ozempic (weekly subcutaneous, for type 2 diabetes mellitus),[3] Wegovy (weekly subcutaneous, for obesity, cardiovascular risk reduction in obesity without diabetes, and MASH with fibrosis),[4][7][8] and Rybelsus (daily oral tablet, for T2DM).[5] It is, by revenue, among the highest-grossing medicines on the planet as of 2024.[citation needed] Semaglutide is the second weekly GLP-1 RA from Novo Nordisk's incretin program (after liraglutide)[1] and the molecule that, more than any other, made obesity treatment a mainstream rather than a specialty intervention.[citation needed]

Experience

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Problems

<indication ref="diabetes-type-2" author="MDElliottMD"/> <indication ref="obesity" author="MDElliottMD"/> <indication ref="cv-risk-obesity" author="MDElliottMD"/> <indication ref="mash-fibrosis" author="MDElliottMD"/> <indication ref="ckd-t2dm" author="MDElliottMD"/>

+ Add a problem

Titration strategies

Ozempic — standard T2DM titration0
0.25 mg SC weekly × 4 weeks (non-therapeutic; tolerance ramp only)

→ 0.5 mg SC weekly × ≥4 weeks → 1 mg SC weekly × ≥4 weeks if further glycemic control needed → 2 mg SC weekly (max) if needed[3]

Slower titration is reasonable in any patient with significant GI symptoms — holding at a tolerated dose for 8–12 weeks before advancing is standard practice.
Wegovy — standard obesity titration0
0.25 mg SC weekly × 4 weeks

→ 0.5 mg × 4 weeks → 1 mg × 4 weeks → 1.7 mg × 4 weeks → 2.4 mg weekly (maintenance)[4]

If a dose escalation is not tolerated, hold at the prior dose for an extra 4 weeks before advancing. Discontinue if patient cannot tolerate 1.7 mg after extended titration.[4]
Rybelsus — standard oral T2DM titration0
3 mg PO daily × 30 days (non-therapeutic ramp)

→ 7 mg PO daily × ≥30 days → 14 mg PO daily (max)[5]

Critical patient instruction: swallow whole, with no more than 120 mL (4 oz) of plain water, on an empty stomach, ≥30 minutes before the first food, drink, or any other oral medicine of the day.[5]

+ Add a titration strategy

Effects

Subjective effects vary considerably with dose and titration speed but reliably include:

  • Early satiety — meals feel "complete" at a fraction of prior intake[6]
  • Food noise quieting — the most commonly volunteered subjective change. Patients report that intrusive food-related thoughts simply stop.[citation needed]
  • Reduced alcohol craving — corroborated by observational and small RCT data; mechanism likely shared with food reward circuitry[9]
  • Nausea — dose-dependent, worst in first 1–2 weeks of any new dose level[3]
  • Constipation or diarrhea (variable, can alternate)[3]
  • Sulfurous eructation (a small but very real subgroup)[citation needed]
  • Reduced taste preference for fatty / sweet foods in many users[citation needed]

+ Add an effect

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.[1]

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).[5][10] Strict fasting administration is mandatory; any concurrent food or beverage destroys absorption.[5]

Predominantly catabolic clearance via proteolysis; renal and hepatic impairment do not require dose adjustment.[3] No CYP-mediated metabolism, so the interaction profile is dominated by gastric emptying effects on other oral medicines, not pharmacokinetic competition.[3]

Pharmacodynamics

At maintenance doses semaglutide produces:

  • HbA1c reduction of ~1.5–2.0 percentage points (Ozempic 1 mg)[11]
  • Weight loss of ~6 kg (Ozempic 1 mg, T2DM)[11] to ~14.9% body weight (Wegovy 2.4 mg, obesity without T2DM, STEP-1)[6]
  • Systolic BP reduction of ~5 mmHg[7]
  • Modest LDL-C reduction, larger triglyceride reduction[citation needed]
  • 20% relative risk reduction in MACE in obesity without T2DM (SELECT)[7]
  • 24% relative risk reduction in kidney + CV composite in T2DM + CKD (FLOW)[12]

    Interactions

No interactions reported yet.

Pregnancy and lactation

Category formerly X-equivalent; current FDA labeling: avoid in pregnancy.[3] Animal embryofetal toxicity is well-documented.[3] Because the half-life is ~1 week, current guidance is to discontinue at least 2 months before any planned conception.[3]

Postpartum: not recommended during breastfeeding pending more data; small molecule transfer to milk is unlikely given peptide structure but not formally characterized.[citation needed]

Importantly: semaglutide is not a contraceptive, and the medicine may restore ovulation in patients with PCOS or obesity-associated anovulation.[citation needed] Patients of childbearing potential should be counseled about contraception before starting.

Monitoring

  • Baseline: HbA1c, weight, BP, renal function, lipid panel, ALT/AST (especially for MASH indication)
  • Personal or family history of MTC or MEN2 — contraindicated, do not start[3]
  • Every 3 months for first year: HbA1c, weight, GI tolerability, signs of pancreatitis or gallbladder disease
  • Annual: renal function, lipids
  • Pre-procedure: hold weekly dose ≥7 days before any planned anesthesia (per ASA 2024 guidance) due to delayed gastric emptying / aspiration risk[13]

    Patient counseling

  • Slow titration is non-negotiable for tolerability. Patients who insist on faster ramps usually quit from GI side effects.
  • Inject SC in abdomen, thigh, or upper arm; rotate sites. Pen is single-patient, multi-dose.[3]
  • GI side effects almost always peak in first 2–4 weeks of any new dose level, then attenuate.[3]
  • Eat smaller portions earlier in the day. Plate sizes will feel comically large after a few weeks — that is the medicine working, not a problem to fix.
  • Hydrate aggressively (volume depletion → AKI is a real risk).[3]
  • Resistance training during weight loss protects lean mass and is strongly encouraged.[citation needed]
  • If a weekly dose is missed: take within 5 days; if >5 days, skip and resume on the next regular day.[3]
  • Avoid alcohol during titration weeks (compounds nausea).
  • Pregnancy planning: stop ≥2 months before trying to conceive.[3]
  • Surgery: tell every anesthesiologist and surgeon you are on a weekly GLP-1 RA. Hold dose 7 days pre-op.[13]

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See also

GLP-1 receptor agonist · Tirzepatide · Liraglutide · Dulaglutide · Exenatide · Type 2 diabetes mellitus · Obesity · MASH

References

  1. ↑ 1.0 1.1 1.2 1.3 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
  2. ↑ Drucker DJ (2022). GLP-1 physiology informs the pharmacotherapy of obesity. Mol Metab 57:101351. doi:10.1016/j.molmet.2021.101351
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.17 3.18 3.19 3.20 3.21 US FDA. Ozempic (semaglutide) prescribing information. Novo Nordisk. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/209637s019lbl.pdf
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 US FDA. Wegovy (semaglutide) prescribing information. Novo Nordisk. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215256s000lbl.pdf
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 US FDA. Rybelsus (semaglutide) prescribing information. Novo Nordisk. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/213051s000lbl.pdf
  6. ↑ 6.0 6.1 6.2 Wilding JPH et al. (2021). Once-weekly semaglutide in adults with overweight or obesity (STEP-1). NEJM 384:989. doi:10.1056/NEJMoa2032183
  7. ↑ 7.0 7.1 7.2 Lincoff AM et al. (2023). Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT). NEJM 389:2221–32. doi:10.1056/NEJMoa2307563
  8. ↑ Newsome PN et al. (2025). Semaglutide in MASH (ESSENCE). FDA approval basis. [citation needed]
  9. ↑ Wang W, Volkow ND, Berger NA et al. (2024). Associations of semaglutide with incidence and recurrence of alcohol use disorder in real-world population. Nat Commun 15:4548. doi:10.1038/s41467-024-48780-6
  10. ↑ 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
  11. ↑ 11.0 11.1 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
  12. ↑ Perkovic V et al. (2024). Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes (FLOW). NEJM 391:109. doi:10.1056/NEJMoa2403347
  13. ↑ 13.0 13.1 Kindel TL et al. (2024). Perioperative GLP-1 receptor agonist safety guidance. Surg Obes Relat Dis 20(12):1183–8.
[[File: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)[1]|frameless|240px|alt=Structure of Semaglutide]]
Summary
Classes
GLP-1 receptor agonist · Antidiabetic · Anti-obesity · Cardiovascular risk reduction agent
Common uses
Pharmacy
Starting dose
Ozempic: 0.25 mg SC weekly × 4 wk[3] · Wegovy: 0.25 mg SC weekly × 4 wk[4] · Rybelsus: 3 mg PO daily × 30 d[5]
Preparations
Pre-filled multi-dose pen (0.25 / 0.5 / 1 / 2 mg, Ozempic;[3] 0.25 / 0.5 / 1 / 1.7 / 2.4 mg, Wegovy[4]) · Oral tablet 3 / 7 / 14 mg co-formulated with SNAC absorption enhancer (Rybelsus)[5]
US FDA Max
2 mg/wk SC (Ozempic)[3] · 2.4 mg/wk SC (Wegovy)[4] · 14 mg PO daily (Rybelsus)[5]
Pharmacology
Routes
Subcutaneous (abdomen, thigh, upper arm)[3] · Oral (Rybelsus only, on empty stomach with ≤120 mL water, ≥30 min before any food/drink/other oral medicine)[5]
Onset
Glycemic effect within days;[citation needed] full weight effect over months[6]
Duration
~7 days (weekly SC dosing)[3] · ~24 h (oral)[5]
Half-life
~165 hours (~1 week) — among the longest of any GLP-1 RA[1]
Bioavailability
SC ~89%[citation needed] · Oral ~0.4–1% (SNAC-enhanced)[5]
Pregnancy
Avoid. Discontinue ≥2 months before planned pregnancy due to long half-life. Animal data show embryofetal harm.[3] Not contraceptive — but rapid weight loss + improved ovulation may unmask fertility in PCOS.[citation needed]
Legal status
Rx-only;[3] not a controlled substance
Purported 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.[2]
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