Semaglutide

Category: peptide

Aliases: Ozempic, Wegovy, Rybelsus

Pharmacological Mechanism

GLP-1(7-37) analog with three modifications: Aib at position 2 (blocks DPP-4), Arg-34 (resists degradation), and C-18 fatty-acid acylation on Lys-26 via γGlu + 2 short PEGs → albumin binding → 7-day t½. Activates GLP-1R on pancreatic β-cells (insulin release), α-cells (glucagon suppression), hypothalamus (satiety), and gut (slowed emptying). STEP trials showed ~15% weight loss at 68 weeks (2.4 mg). SELECT showed MACE reduction in CV-risk population.

Half-Life (t½)

SC: 168h

Dosing Guidelines

SC: Typical 9.33 mg (Range: 7–14 mg)
PO: Typical 9.33 mg (Range: 7–14 mg)

Target Organ Systems

nervous
cardiovascular
endocrine
digestive

Interactions

Empagliflozin (synergistic): Complementary — GLP-1 targets β-cell + appetite; SGLT2i targets renal glucose reabsorption + CV/renal outcomes.
Sitagliptin (caution): Overlapping incretin mechanism — generally not combined (redundant PD + additive GI).

Pathways It Modulates

AMPK energy sensor (activator) — AMPK (incretin-driven)
Atherosclerosis plaque pathology (inhibitor) — GLP-1R → cardiometabolic risk ↓ (SELECT CV outcomes)
Bile acid (activator) — GLP-1R + indirect TGR5 stimulation
Brown adipose thermogenesis (activator) — indirect BAT activation via weight loss + central mechanisms
cAMP / PKA second-messenger signaling (activator) — GLP-1R (Gs)
FXR / TGR5 bile-acid receptor signaling (activator) — TGR5 indirect (GLP-1R axis intersects bile-acid signaling)
GLP-1 central appetite + reward-cue dampening (activator) — GLP-1 receptor
Insulin signaling + glucose homeostasis (activator) — GLP-1R (incretin mimetic)
NAFLD / MASH (activator) — GLP-1R → weight loss + ↓hepatic FFA flux + direct anti-steatotic
PI3K / AKT signaling (activator) — PI3K/AKT (via GLP-1R → improved insulin signaling + weight loss)

Chemical Identifiers

PubChem CID: 56843331
Formula: C187H291N45O59
Molecular weight: 4113.58 g/mol
InChIKey: DLSWIYLPEUIQAV-CCUURXOWSA-N
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