A patient with T2DM is considered for tirzepatide therapy. Tirzepatide's superior glycemic and weight-lowering efficacy compared to semaglutide is attributed to its dual agonism at:

• A GLP-1 and GIP receptors, with GIP agonism enhancing insulinotropic effect and centrallymediated appetite suppression ✓
• B GLP-1 and glucagon receptors, with glucagon agonism increasing energy expenditure and hepatic glucose production
• C GLP-1 and PYY receptors in the gut, synergistically delaying gastric emptying and ileal nutrient sensing
• D GLP-1 and leptin receptors, restoring hypothalamic leptin sensitivity lost in obesity

Explanation

Tirzepatide is a dual GIP/GLP-1 receptor agonist (a 'twincretin'). Both GIP and GLP-1 are incretin hormones released postprandially. GIP agonism augments insulin secretion in a glucose-dependent fashion and may also reduce glucagon secretion in hyperglycemia while paradoxically increasing it during euglycemia to prevent hypoglycemia. GIP receptors in adipose tissue and CNS are implicated in the enhanced weight loss. SURPASS clinical trials showed tirzepatide achieves greater HbA1c reductions and weight loss than semaglutide at equivalent doses. Glucagon receptor agonism would worsen hyperglycemia and is seen in non-selective agonists used experimentally for obesity.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.