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.

Table 2 Comparison of the different effects produced by mazdutide and glucagon-like peptide-1 receptor agonists

Therapeutic efficacy	Mazdutide	GLP-1R agonists
Appetite suppression	GLP-1R activation → slows gastric emptying and increases satiety, while GCGR activation also suppresses appetite. The dual mechanism enhances the appetite-suppressing effect	GLP-1R activation → same effect, mainly through slowing gastric emptying and increasing satiety to suppress appetite
Energy expenditure	GCGR activation → increases basal metabolic rate and energy expenditure, promotes fat oxidation, and aids in weight loss	No such effect; mainly affects energy intake through mechanisms such as slowing gastric emptying, with no direct effect on energy expenditure
Liver fat metabolism	GCGR activation → promotes fatty acid oxidation, inhibits lipid synthesis, reduces liver fat accumulation, and improves liver metabolism	Indirect effect (through weight loss), mainly improves liver fat metabolism by reducing body weight, with minimal direct impact on liver fat
Glucose metabolism regulation	Dual synergistic effect → reduces hepatic glucose output and increases insulin sensitivity, through activation of GLP-1R and GCGR, jointly regulating glucose metabolism with more pronounced effects	Primarily dependent on insulin secretion promotion, through activation of GLP-1R to promote insulin secretion and inhibit glucagon secretion, thereby regulating blood glucose levels

GCGR: Glucagon receptor; GLP-1R: Glucagon-like peptide-1 receptor.

Table 3 Summary of the hypoglycemic and weight loss effects of mazdutide at different doses

Ref.	Dose (mg)	HbA1c reduction (%)	Weight loss (%)	Achieving HbA1c < 7.0%	Adverse effects
Zhang et al[36], 2024	3	-1.41	-7.1	54%	Diarrhea (36%), nausea (23%)
	4.5	-1.35	-5.3	67%	Decreased appetite (29%)
	6	-1.67	-7.1	73%	Vomiting (14%), hypoglycemia (10%)
Ji et al[62], 2022	6, 9	N/A	6 mg: -6.1; 9 mg: -11.7	N/A	Nausea (23%), diarrhea (36%) (6 mg); nausea (28%), diarrhea (32%) (9 mg)
Ji et al[63], 2023	3, 4, 6	N/A	3 mg: -6.7; 4 mg: -10.4; 6 mg: -11.3	N/A	Diarrhea (36%), nausea (29%), vomiting (14%) (3 mg); diarrhea (38%), nausea (31%), vomiting (16%) (4 mg); diarrhea (36%), nausea (29%), vomiting (14%) (6 mg)
Ji et al[42], 2025	4, 6	N/A	4 mg: 11.0; 6 mg: -14.01	N/A	Nausea (25%), diarrhea (22%), transient tachycardia (4 mg); nausea (28%), diarrhea (25%), transient tachycardia (6 mg)
Dong et al[64], 2025	3	N/A	-14.8	N/A	Mild GI (vomiting, nausea)

N/A: Not applicable; HbA1c: Glycated hemoglobin A1c; GI: Gastrointestinal.

Table 4 Comparison of clinical efficacy between mazdutide and glucagon-like peptide-1 receptor single-target drugs

Classification	Drug	Mechanism of action	Test method	Body weight	Metabolism	Glucose	Cardiovascular	Central nervous system	Ref.
GLP-1R agonist	Liraglutide	GLP-1R	Controlled clinical trials		Decreased MAlb/creatinine; reduced C-reactive protein by 0.8-0.2; decreased IL-6; CD34+, CD133+, and other circulating progenitor cells and endothelial progenitor cell concentrations were elevated in the liraglutide-treated group	Significant difference in TcPO2 at 18 months in liraglutide group	Higher increase in vascular endothelial growth factor A		[52]
	Semaglutide	GLP-1R	Clinical controlled trial	Body weight -13.7% and waist circumference least squares mean -13.0 cm in semaglutide group at week 72			Smaller decrease in mean annual eGFR slope; reduced BNIP3 expression in mitochondria via PI3K/AKT pathway	Trial of effects on AD biomarkers and neuroinflammation will provide data on potential disease-modifying effects of semaglutide	[65-68]
	Tirzepatide	GLP-1R	Clinical controlled trials, basic animal studies	Percentage of least squares mean of body weight in tirzepatide group -20.2%, least squares mean of waist circumference -18.4 cm		Regulates Aβ-induced reactive oxygen species production and mitochondrial membrane potential; reduces mitochondrial function, ATP levels in astrocytes via GLP-1R	Reduces blood glucose level and increases mRNA expression of GLP-1R, SACF1, etc. in the hypothalamus of APP/PS1 mice	Decrease the expression level of GLP-1R and GFAP proteins in the cortex; Decrease Aβ-induced neuronal apoptosis; Increase mRNA expression of Glut1, CAS, etc. in the cortex	[65,69]
GLP-1R inhibitors	SGLT-2 inhibitor	Decreases glucose reabsorption in proximal tubules	Meta-analysis		Improved HRQoL parameters of KCCQ-CSS scores, KCCQ-OSS scores and exercise capacity 6MWTD		SGLT2i significantly reduced AF risk; SGLT2i was associated with a borderline reduced risk of SCD; SGLT-2 was detected in epithelial cells of proximal tubules, and ETA, SGLT-2 receptor in cardiomyocytes		[70-72]
GLP-1R/GCGR dual-target agonist	Mazdutide	GLP-1R/GCGR	Clinical controlled trials, basic animal studies	Substantial reduction in body weight, BMI	Regulates the expression level of GCGR, Slc22a7 and other genes, regulates glucose and lipid metabolism, purine metabolism, bile secretion, to achieve the effect of lowering uric acid	Reduces the precursors of uric acid production and regulates glucose and lipid metabolism	Up-regulate the expression level of GCGR, Aqp2 and other genes, and down-regulates the expression level of Dnmt3a, Rest, and other genes	Improves cognitive performance in db/db mice; Enhancement of neural structure and brain tissue integrity	[42,64,73]

GLP-1R: Glucagon-like peptide-1 receptor; GCGR: Glucagon receptor; MAlb: Microalbumin; IL-6: Interleukin-6; CD34: Cluster of differentiation 34; CD133: Cluster of differentiation 133; TcPO₂: Transcutaneous partial pressure of oxygen; eGFR: Estimated glomerular filtration rate; BNIP3: BCL2/adenovirus E1B 19 kDa-interacting protein 3; ATP: Adenosine triphosphate; GI: Gastrointestinal; SGLT-2: Sodium-glucose co-transporter-2; BMI: Body mass index.