Research Profile
Tirzepatide (LY3298176) is a dual GIP/GLP-1 receptor agonist developed by Eli Lilly. It is acylated with a C20 fatty diacid enabling albumin binding for once-weekly dosing. Its pharmacology is "imbalanced" — GIPR affinity equivalent to native GIP, but GLP-1R affinity fivefold lower than native GLP-1, with bias favouring cAMP over β-arrestin recruitment, reducing receptor desensitisation.
In SURMOUNT-1, tirzepatide 15 mg produced 22.5% mean body weight reduction at 72 weeks. SURMOUNT-5 confirmed 47% greater relative weight reduction versus semaglutide 2.4 mg. FDA-approved as Mounjaro (diabetes) and Zepbound (obesity).
Obesity — SURMOUNT 1–5 programme. Superior to all prior monotherapy agents. SURMOUNT-OSA: first GLP-1 class drug approved for obstructive sleep apnoea.
Type 2 diabetes — SURPASS 1–5: HbA1c reductions of 1.24–2.58% at 40 weeks; most efficacious single injectable agent in diabetes care.
MASH/NAFLD — significant hepatic steatosis and inflammation reduction in early trials. Phase 3 ongoing.
Cardiovascular outcomes — SURPASS-CVOT evaluating MACE reduction via weight loss, BP, and lipid improvement.
PCOS and insulin resistance — dual incretin mechanism improves insulin sensitivity independently of weight loss.
Post-bariatric weight regain — compelling data for weight regain prevention post-surgical weight loss.
Escalation: 2.5 → 5 → 7.5 → 10 → 12.5 → 15 mg in 4-week steps. Resting HR elevation mild vs retatrutide. Cardiovascular monitoring advisable in relevant populations.