Tirzepatide: Mechanism of Action

1. Primary Receptor Targets — Dual GIP/GLP-1 Agonism

Tirzepatide is a first-in-class unimolecular dual agonist that simultaneously targets the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor. [1] It functions as an imbalanced agonist: binding affinity for the GIP receptor equals that of native GIP, while GLP-1 receptor affinity is approximately 5- to 13-fold weaker than native GLP-1. [6] Cryo-electron microscopy confirms the N-terminus of tirzepatide (Tyr1) forms hydrogen bonds with GLP-1R residues (e.g., Gln234), while Glu3 forms ionic bonds with Arg190, with analogous interactions at the GIPR. [8]

2. Biased Agonism — cAMP Over β-Arrestin

Unlike native GLP-1 which recruits both G-proteins and β-arrestin, tirzepatide exhibits biased agonism at the GLP-1 receptor: it preferentially activates cyclic adenosine monophosphate (cAMP) generation while inducing significantly lower β-arrestin recruitment. [9] This reduces receptor internalization and desensitization, maintaining GLP-1R availability at the cell surface for prolonged signaling. At the GIP receptor, tirzepatide mimics the signaling profile of native GIP. [10]

3. Downstream Signaling — cAMP/PKA, PI3K/AKT, AMPK, NF-κB

Binding to GIP/GLP-1 receptors initiates several key intracellular cascades: [11]

• cAMP/PKA Pathway: Upregulated intracellular cAMP activates Protein Kinase A, stimulating glucose-dependent insulin secretion from pancreatic β-cells.
• PI3K/AKT Pathway: Enhances mitochondrial function, reduces neuroinflammation, and promotes cell survival.
• AMPK Pathway: Activated in CNS and peripheral tissues, linked to metabolic regulation and energy homeostasis.
• NF-κB Inhibition: Suppresses the TLR4/NF-κB/NLRP3 inflammasome pathway, reducing pro-inflammatory cytokines (TNF-α, IL-6). [12]
• CREB/BDNF Pathway: In neuronal cells, activates pAkt/CREB/BDNF signaling to promote neuronal growth and survival. [13]

4. Tissue-Level Effects

Pancreas: Enhances both first- and second-phase insulin secretion in a glucose-dependent manner. Reduces fasting and postprandial glucagon secretion during hyperglycemia while preserving glucagonotropic function during hypoglycemia. [14]

Adipose Tissue: GIP receptor agonism improves insulin sensitivity in adipose tissue, increases adiponectin levels by 16–26%, and enhances lipid buffering via increased lipoprotein lipase (LPL) activity. [15]

CNS: Acts on the hypothalamus to regulate appetite and satiety. Animal research (Bossi et al., 2025) indicates tirzepatide temporarily increases energy expenditure shortly after dosing, unlike semaglutide which initially reduces it. [16]

Liver: Reduces liver fat content and stiffness; in the SYNERGY-NASH trial, resolved MASH without worsening fibrosis in up to 62% of participants. [17]

5. Pharmacokinetics — Once-Weekly Dosing

The C20 fatty diacid enables 99% albumin binding, yielding a half-life of ~5 days (116.7 hours), bioavailability of ~80% SC, T_max of 8–72 hours, and V_d of ~10.3 L. [3] Metabolism occurs via proteolytic cleavage, β-oxidation of the fatty diacid moiety, and amide hydrolysis. Metabolites are excreted via urine and feces. [18]

6. Dose-Response Relationships

Clinical trials demonstrate clear dose-dependent efficacy across all indications: [19]

• HbA1c (SURPASS-1): −1.87% (5 mg), −1.89% (10 mg), −2.07% (15 mg)
• Weight loss (SURMOUNT-1): −15.0% (5 mg), −19.5% (10 mg), −20.9% (15 mg)
• MASH resolution (SYNERGY-NASH): 44% (5 mg), 56% (10 mg), 62% (15 mg)