Mazdutide — Research, Dosing & Price Guide

Mazdutide (LY3305677/IBI362) is a novel dual GLP-1/glucagon receptor agonist developed by Eli Lilly (licensed to Innovent Biologics for China). Unlike tirzepatide (which targets GLP-1/GIP), mazdutide adds glucagon receptor agonism to enhance energy expenditure and fat oxidation alongside appetite suppression. It represents the next frontier in metabolic peptide therapeutics.

Mazdutide activates both the GLP-1 receptor and the glucagon receptor through a single engineered peptide. GLP-1 receptor activation produces appetite suppression via hypothalamic satiety signaling, slowed gastric emptying, and enhanced glucose-dependent insulin secretion from pancreatic beta cells — mechanisms shared with semaglutide and tirzepatide. The glucagon receptor agonism component is the differentiator: glucagon activates hepatic glycogenolysis and gluconeogenesis, but more importantly for obesity treatment, it potently stimulates energy expenditure through brown adipose tissue activation, hepatic fatty acid oxidation, and thermogenesis. The combination means mazdutide reduces caloric intake (via GLP-1) while simultaneously increasing caloric expenditure (via glucagon) — a dual mechanism that theoretically produces greater weight loss than GLP-1 agonism alone. The GLP-1 component also counterbalances glucagon's hyperglycemic effects, maintaining glucose homeostasis.

• Phase IIb trial (GLORY-1) in Chinese adults with obesity showed mazdutide 6 mg produced 14.4% mean body weight loss over 24 weeks vs. 0.3% for placebo
• The 9 mg dose achieved approximately 17% weight loss at 24 weeks in the same trial population
• Phase III GLORY-2 trial confirmed significant HbA1c reduction in type 2 diabetes patients alongside weight loss
• Mazdutide received approval in China from the NMPA for chronic weight management (2024) and type 2 diabetes
• Head-to-head positioning suggests mazdutide may offer advantages in energy expenditure over pure GLP-1 agonists due to glucagon-mediated thermogenesis
• Studies show favorable effects on liver fat reduction, likely related to glucagon's hepatic fat oxidation effects

• Clinical trial doses: 3 mg, 4.5 mg, 6 mg, and 9 mg subcutaneous injection once weekly
• Dose escalation: start at 3 mg weekly for 4 weeks, then increase by 1.5–3 mg every 4 weeks to target dose
• Maintenance dose: 6–9 mg weekly based on tolerability and response
• Inject subcutaneously in abdomen, thigh, or upper arm — rotate sites weekly
• Not yet FDA-approved — currently in Phase III clinical trials
• Approved in China (2024) for type 2 diabetes and obesity
• Dose escalation is critical to minimize GI side effects — do not skip titration steps

Known Side Effects

• Nausea: the most common side effect (40–50% of trial participants), usually mild-moderate and improves with dose stabilization
• Vomiting (15–25% incidence), primarily during dose escalation phases
• Diarrhea and constipation (GI motility effects)
• Decreased appetite (intended therapeutic effect, but can be excessive in some patients)
• Injection site reactions
• Potential for hypoglycemia when combined with insulin or sulfonylureas
• Elevated heart rate (2–5 bpm increase, class effect of GLP-1 agonists)
• Theoretical concerns: pancreatitis, gallbladder disease, thyroid C-cell tumors (GLP-1 class warnings)

Safety Profile

Mazdutide's safety profile is still being established through ongoing Phase III trials. The GLP-1 receptor agonist class has well-characterized safety concerns: GI side effects (nausea, vomiting, diarrhea), pancreatitis risk, gallbladder disease, and a theoretical risk of medullary thyroid carcinoma based on rodent studies (boxed warning applies to all GLP-1 RAs). The glucagon receptor component raises unique considerations: potential for hepatic glycogen depletion, transient hyperglycemia (offset by GLP-1's insulin-stimulating effects), and increased heart rate. Contraindications include personal or family history of medullary thyroid carcinoma, multiple endocrine neoplasia syndrome type 2, history of pancreatitis, and pregnancy. Not FDA-approved as of 2025 — available only through clinical trials or Chinese market. Those interested should discuss with their physician and monitor developments in the regulatory pipeline.

Weeks 1–4 (3 mg): Appetite suppression begins. Nausea is common but typically manageable. Weight loss of 2–4% may occur during initial titration. Weeks 5–8 (escalating dose): Appetite suppression intensifies. GI side effects may transiently worsen with each dose increase, then improve. Weight loss accelerates. Weeks 9–16 (target dose): Steady weight loss of 1–2% per month. Energy expenditure may be noticeably increased (feeling warmer). Blood glucose and HbA1c improve in diabetic patients. Weeks 17–24+: Approaching maximum weight loss for the treatment period. Clinical trials show 14–17% total body weight loss at 24 weeks at higher doses. Metabolic parameters (lipids, liver enzymes, blood pressure) typically improve substantially. Weight regain is expected after discontinuation, as with all GLP-1 class medications.

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