Mazdutide: Complete Guide

Mazdutide is an Fc-fusion protein that activates both GLP-1 and glucagon receptors. The rationale for dual agonism is that each receptor system contributes complementary metabolic benefits:

• GLP-1 agonism: Appetite suppression, insulin secretion, glucose control
• Glucagon agonism: Hepatic fat oxidation, increased energy expenditure, amino acid metabolism

While glucagon is traditionally associated with raising blood glucose, controlled glucagon receptor activation within a GLP-1 agonist context can enhance weight loss and metabolic health without clinically significant hyperglycemia.

Mazdutide's dual mechanism combines:

• GLP-1R activation: Suppresses appetite through hypothalamic signaling, stimulates glucose-dependent insulin secretion, slows gastric emptying
• Glucagon receptor activation: Promotes hepatic lipid oxidation (reducing liver fat), increases resting energy expenditure by 100–200 kcal/day, stimulates amino acid catabolism

The net effect is weight loss through both reduced caloric intake (GLP-1) and increased caloric expenditure (glucagon) — a mechanistic advantage over GLP-1-only agonists.

Phase 3 trials used weekly subcutaneous doses of 3 mg, 4.5 mg, or 6 mg, with dose escalation over 8–12 weeks. Not yet commercially available; dosing is from clinical trial protocols.

• Nausea and vomiting: Most common, consistent with GLP-1 agonist class
• Diarrhea: Common GI effect
• Transient hyperglycemia: Possible from glucagon component, though generally offset by GLP-1 insulin effects
• Heart rate increase: Mild increases observed, consistent with glucagon effects
• Injection site reactions: Mild and transient

Mazdutide is one of several multi-target GLP-1-based compounds in development. For a full class overview, see the complete GLP-1 guide.

• Survodutide: The closest competitor — also a dual GLP-1/glucagon agonist, developed by Boehringer Ingelheim. Phase 2 data shows 18.7% weight loss and strong MASH histological improvement (Sanyal et al., NEJM 2024). Received FDA Breakthrough Therapy designation for MASH.
• Retatrutide: A triple GLP-1/GIP/glucagon agonist that adds GIP to the GLP-1/glucagon combination. Phase 2 showed up to 24.2% weight loss and 82% liver fat reduction (Jastreboff et al., NEJM 2023).
• Tirzepatide (Mounjaro/Zepbound): FDA-approved dual GLP-1/GIP agonist with up to 22.5% weight loss. Targets GIP instead of glucagon for its second receptor.
• Semaglutide (Ozempic/Wegovy): The benchmark GLP-1-only agonist with 14.9% weight loss and proven cardiovascular benefits.
• Liraglutide (Saxenda): First-generation daily GLP-1 agonist with the longest safety track record.
• Cagrilintide (CagriSema): Amylin analog combined with semaglutide for a different dual-pathway approach (22.7% weight loss in Phase 3).