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 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.