Tirzepatide is superior to semaglutide in weight reduction in clinical trials. Its pharmacological advantage is based on which dual mechanism?

• A GLP-1 agonism plus SGLT2 inhibition in a single molecule
• B Dual GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 receptor agonism, improving insulin secretion, glucagon suppression, and central appetite regulation with additive or synergistic effects ✓
• C GLP-1 agonism plus amylin receptor activation reducing gastric emptying
• D Dual GLP-1 and glucagon receptor agonism increasing metabolic rate

Explanation

Tirzepatide is a dual GIP/GLP-1 receptor agonist (a 'twincretin'). GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 are both incretin hormones released from the gut after meals. GLP-1 receptor agonism reduces appetite and gastric emptying, while GIP receptor agonism in adipose tissue promotes lipid uptake and metabolic flexibility. The combined activation of both receptors produces additive or synergistic effects on insulin secretion, glucagon suppression, weight loss (SURPASS trials: up to 22% body weight reduction), and glycemic control superior to semaglutide. Tirzepatide represents the first in the twincretin class.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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