Mazdutide: An emerging glucagon/GCG-like peptide-1 dual receptor agonist for obesity—a comparison of therapeutic effects and potential side effects with GCG-like peptide-1 inhibitors

Table 1 Comparison of glucagon-like peptide-1 receptor/glucagon receptor dual-target agonist’s characteristics

Characteristic	Cotadutide	BI 456906	Mazdutide
Mechanism of action	GLP-1R and GCGR dual agonist	GLP-1R and GCGR dual agonist	GLP-1R and GCGR dual agonist (“dual metabolic engine” with appetite suppression + energy expenditure)
Primary target indications	Obesity, T2DM	Obesity, T2DM, and non-alcoholic fatty liver disease	Obesity, T2DM, MAFLD, NASH
Pharmacokinetics	Acylated for extended half-life, once-daily subcutaneous dosing	Acylated for extended half-life, once-weekly subcutaneous dosing	Lipidation-modified peptide, once-weekly subcutaneous dosing
Body weight reduction	Up to 12.37% placebo-corrected weight loss in clinical trials	Up to 13.8% placebo-corrected weight loss	Up to 14%-15% placebo-corrected (phase 3 GLORY-1 trial, 48 weeks)
Dose formulation	Daily subcutaneous injections	Weekly subcutaneous injections	Weekly injections (3-9 mg tested; 6 mg effective)
Efficacy on glucose control	Reduces glucose, HbA1c levels with dual receptor activation	Significant reduction in glucose AUC and improvement in oral glucose tolerance	Significant HbA1c reduction (up to -2.2%), enhanced insulin secretion, reduced glucagon
Gastric emptying effects	Delayed gastric emptying in the early phase of treatment	Modest effect on gastric emptying, dose-dependent	Delays gastric emptying + appetite suppression (stronger than GLP-1 mono-agonists)
Effect on lipid profile	Modest improvements in plasma lipids (cholesterol, triglycerides)	Significant reductions in liver triglycerides and plasma cholesterol	Significant reduction in liver fat (-80% in GLORY-1), lower TG, LDL-C, uric acid
Cardiovascular effects	No significant cardiovascular effects noted	Mild increase in pulse rate, no serious cardiovascular effects	Improves cardiac risk factors; transient tachycardia in some patients
Target receptor engagement	Balanced GLP-1R and GCGR engagement for weight loss and metabolic control	Balanced GLP-1R and GCGR engagement, more potent on GCGR	Balanced GLP-1R/GCGR; biased agonism favors fat oxidation
Clinical trial results	Positive results in T2D patients and obese patients with improved glycemic control	Proven superior weight loss compared to semaglutide in preclinical trials	Phase 3 GLORY-1 (China): -14% weight, 49.5% ≥ 15% weight loss, robust safety profile

GLP-1R: Glucagon-like peptide-1 receptor; GCGR: Glucagon receptor; T2DM: Type 2 diabetes mellitus; T2D: Type 2 diabetes; MAFLD: Metabolic dysfunction-associated fatty liver disease; NASH: Non-alcoholic steatohepatitis; HbA1c: Glycated hemoglobin A1c; AUC: Area under the curve; TG: Triglycerides; LDL-C: Low-density lipoprotein cholesterol; GLORY-1: Phase 3 clinical trial of mazdutide in patients with obesity; GLP-1: Glucagon-like peptide-1.