Semaglutide vs Tirzepatide

## Overview

Tirzepatide (Mounjaro/Zepbound) is a dual GIP/GLP-1 receptor agonist — the first in a new class that simultaneously activates both glucoseinsulinotropic polypeptide (GIP) and GLP-1 receptors. This dual agonism produces superior glycemic control and dramatically greater weight loss compared to semaglutide monotherapy.

## Mechanism of Action

Semaglutide: selective GLP-1 receptor agonist. Tirzepatide: dual GIP + GLP-1 receptor agonist. GIP receptor agonism acts synergistically with GLP-1 to enhance insulin secretion, reduce glucagon, and promote adipose tissue lipolysis. The combination may produce additive or synergistic weight loss vs. GLP-1 alone.

## Pharmacokinetics

Both are once-weekly SC injections. Tirzepatide: half-life ~5 days, peptide with C20 fatty diacid. Semaglutide: half-life ~7 days. Both are protein-bound.

## Efficacy

SURPASS-2 trial (head-to-head): tirzepatide 5/10/15 mg vs semaglutide 1 mg. Tirzepatide achieved HbA1c reductions of 2.0–2.3% vs semaglutide 1.8%. Weight loss 7.6–11.2 kg vs 5.7 kg. SURMOUNT-1 (tirzepatide 10/15 mg for obesity): ~20–22% body weight reduction — the greatest weight loss seen with any weekly injectable short of bariatric surgery. STEP trials (semaglutide 2.4 mg for obesity): ~15% weight reduction.

## Cardiovascular Evidence

SUSTAIN-6 (semaglutide): established MACE reduction. SURPASS-CVOT (tirzepatide): completed 2024, demonstrating non-inferior/superior CV protection. SELECT (semaglutide 2.4 mg): established CV benefit in obesity without T2DM.

## Key Takeaways

- Tirzepatide: dual GIP+GLP-1 agonist, ~20–22% weight loss (unprecedented for a weekly injectable)
- Semaglutide: established longer-term data, CV data including obesity without DM (SELECT)
- Tirzepatide now broadly preferred for T2DM and obesity when cost/access allows