Tirzepatide is a dual GIP/GLP-1 receptor agonist approved for type 2 diabetes and obesity. Compared to selective GLP-1 agonists, the additional GIP receptor agonism contributes to greater weight loss through which mechanism?

• A GIP receptor activation in adipose tissue promotes lipolysis, releasing fatty acids for β-oxidation
• B GIP receptor signalling in the central nervous system amplifies hypothalamic satiety signalling, potentiating the anorectic effect of GLP-1 receptor co-stimulation ✓
• C GIP receptor activation stimulates glucagon secretion, which indirectly suppresses appetite
• D GIP receptor activation on gastric parietal cells reduces gastric acid secretion more than GLP-1 alone, slowing gastric emptying further

Explanation

GIP (glucose-dependent insulinotropic polypeptide) receptors are expressed in the hypothalamus and limbic areas, and their activation cooperates with GLP-1 receptor signalling to produce additive suppression of appetite and food intake. In adipose tissue, GIP receptor activation promotes fat storage at physiological levels, but when GIP and GLP-1 receptors are co-activated in the CNS as with tirzepatide, the net hypothalamic effect is greater anorexia and energy expenditure than with GLP-1 agonism alone. Clinical trials (SURPASS series) show tirzepatide achieves ~20–22% body weight reduction, surpassing semaglutide.

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

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