Semaglutide: Difference between revisions

| 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)

| 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.

| 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

| 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)

| fda_max = 2 mg/wk SC (Ozempic) · 2.4 mg/wk SC (Wegovy) · 14 mg PO daily (Rybelsus)

| 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)

| onset = Glycemic effect within days; full weight effect over months

| duration = ~7 days (weekly SC dosing) · ~24 h (oral)

| halflife = ~165 hours (~1 week) — among the longest of any GLP-1 RA

| bioavailability = SC ~89% · Oral ~0.4–1% (SNAC-enhanced)

| 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]].

| legal = Rx-only · Schedule: none (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.

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.

| 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.

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.

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.

| pharmacodynamics = At maintenance doses semaglutide produces:

* HbA1c reduction of ~1.5–2.0 percentage points (Ozempic 1 mg)

* Weight loss of ~6 kg (Ozempic 1 mg, T2DM) to ~15% body weight (Wegovy 2.4 mg, obesity without T2DM, STEP-1)

* Systolic BP reduction of ~5 mmHg

* Modest LDL-C reduction, larger triglyceride reduction

* 20% relative risk reduction in MACE in obesity without T2DM (SELECT)

* 24% relative risk reduction in kidney + CV composite in T2DM + CKD (FLOW)

| indications = <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"/>

| dosing = <titration slug="ozempic-standard" author="MDElliottMD" title="Ozempic — standard T2DM titration">

→ 2 mg SC weekly (max) if needed

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.

<titration slug="wegovy-standard" author="MDElliottMD" title="Wegovy — standard obesity titration">

→ 2.4 mg weekly (maintenance)

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.

<titration slug="rybelsus-standard" author="MDElliottMD" title="Rybelsus — standard oral T2DM titration">

→ 14 mg PO daily (max)

'''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.

* '''Early satiety''' — meals feel "complete" at a fraction of prior intake

* '''Food noise quieting''' — the most commonly volunteered subjective change. Patients report that intrusive food-related thoughts simply stop.

* '''Reduced alcohol craving''' — corroborated by observational and small RCT data; mechanism likely shared with food reward circuitry

* '''Nausea''' — dose-dependent, worst in first 1–2 weeks of any new dose level

* '''Constipation or diarrhea''' (variable, can alternate)

* '''Sulfurous eructation''' (a small but very real subgroup)

* '''Reduced taste preference for fatty / sweet foods''' in many users

| 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'''.

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

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.

| 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

* '''Pre-procedure''': hold weekly dose ≥7 days before any planned anesthesia (per [[ASA 2024 guidance]]) due to delayed gastric emptying / aspiration risk

* Inject SC in abdomen, thigh, or upper arm; rotate sites. Pen is single-patient, multi-dose.

* GI side effects almost always peak in first 2–4 weeks of any new dose level, then attenuate.

* 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).

* Resistance training during weight loss protects lean mass and is strongly encouraged.

* If a weekly dose is missed: take within 5 days; if >5 days, skip and resume on the next regular day.

* '''Pregnancy planning''': stop ≥2 months before trying to conceive.

* '''Surgery''': tell every anesthesiologist and surgeon you are on a weekly GLP-1 RA. Hold dose 7 days pre-op.

| references = <ref name="step1">Wilding JPH et al. (2021). Once-weekly semaglutide in adults with overweight or obesity (STEP-1). ''NEJM'' 384:989.</ref>

<ref name="kindel2024">Kindel TL et al. (2024). Perioperative GLP-1 RA safety guidance. ''Surg Obes Relat Dis'' 20(12):1183.</ref>