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

Abstract

Obesity has emerged as a global health crisis, necessitating effective therapeutic options. The “GLORY-1” study evaluated the efficacy and safety of mazdutide, a dual receptor agonist targeting glucagon (GCG) and GCG-like peptide-1 (GLP-1). As the first GLP-1/GCG dual-receptor agonist to successfully complete phase 3 trials, this drug marks a significant advancement in innovative drug discovery for endocrine and metabolic diseases in China. Unlike conventional GLP-1 receptor (GLP-1R) single-target drugs, mazdutide activates both GCG receptor (GCGR) and GLP-1R simultaneously, enhancing fat oxidation and offering substantial benefits for weight reduction and comprehensive metabolic regulation. In terms of safety, mazdutide exhibits an overall safety profile comparable to existing GLP-1R agonists, with adverse events primarily involving mild to moderate gastrointestinal disturbances. Notably, GLP-1R inhibitors exhibit significantly fewer side effects than agonists, suggesting potential for long-term safety in mazdutide combination therapies. In conclusion, the GLORY-1 study underscores mazdutide’s promise as an effective obesity treatment. This review systematically investigates the therapeutic potential of mazdutide by examining its pharmacological mechanisms, clinical trial design, and safety considerations. Furthermore, it offers an initial evaluation of the prospects for combining mazdutide with GLP-1R inhibitors. These insights present new avenues for personalized obesity treatment and aim to enhance its clinical application.

Key Words: Obesity; Glucagon receptor; Glucagon-like peptide-1 receptor; Mazdutide; GLORY-1 study

Core Tip: Mazdutide has breakthrough value in terms of weight loss and metabolic regulation. Future research needs to further investigate its specific mechanisms to promote clinical translation.

INTRODUCTION

In the 21^st century, obesity has emerged as a worldwide epidemic, posing a significant health challenge to a growing portion of the population. This stems not only from its link to body image anxiety, discrimination, and various social issues, but also from its capacity to impose heavy physiological burdens and precipitate other serious illnesses[1]. Research indicates that individuals with obesity have a 57% likelihood of developing diabetes, 17% for hypertension, 30% for cholecystitis, and 14% for osteoarticular disorders, with these risks rising in tandem with further weight gain[2]. According to the 2023 report by the World Health Organization, the number of obese people worldwide has nearly tripled over the past three decades. By 2022, the global overweight and obese population had reached approximately 2 billion and 650 million, respectively, and it is estimated that by 2035, more than 4 billion people will be overweight or obese[3].

As the world’s most populous country, China exhibits obesity characteristics that differ markedly from global patterns. Although the average body mass index (BMI) among the Chinese population is lower than that in Europe and North America, the prevalence of metabolic syndrome is notably higher—approximately 40% of overweight individuals have visceral fat accumulation–dominant “hidden obesity”[4], most commonly accompanied by metabolic dysfunction–associated fatty liver disease (MAFLD), dyslipidemia, hypertension, and prediabetes[5]. Recent data show a trend toward younger onset of obesity in China, with rising obesity rates among children and adolescents, and a 27% increase over the past decade in the prevalence of abdominal obesity among individuals aged 20-40 years. This pattern of “younger onset, lower BMI, and higher metabolic risk” places greater demands on the precision of therapeutic interventions.

Limitations of current drug treatments

Presently, the main strategies for managing obesity emphasize a healthy, low-calorie diet, enhanced physical activity, and effective execution of intervention plans. According to Chinese obesity management guidelines, if lifestyle interventions cannot achieve adequate weight control, pharmacotherapy should be promptly initiated. Existing pharmacological agents for weight loss primarily include benaglutide, liraglutide, semaglutide, and tirzepatide[6], which achieve weight reduction by decreasing appetite or modifying caloric absorption.

Glucagon (GCG)-like peptide-1 receptor (GLP-1R) agonists, potent pharmacological agents for weight reduction, exert their effects by regulating intestinal hormone levels, thereby influencing body weight and metabolic processes[7,8]. It is worth noting that within the domain of GLP-1R targeted drugs, although the weight-reducing efficacy of GLP-1R agonists has been firmly established, current research on GLP-1R inhibitors [such as exendin (9-39)] remains predominantly focused on mechanistic studies in glucose and lipid metabolism, without revealing any tangible therapeutic benefits for obesity management[9]. These findings highlight the intricate nature of GLP-1R mediated pathways, indicating that drug development should transcend single-target, linear strategies and advance toward comprehensive, multidimensional mechanistic investigations.

The rise of multi-target agonists

Oxyntomodulin, an intrinsic cleavage derivative of proglucagon, has the ability to co-activate both GLP-1R and the glucagon receptor (GCGR)[10]. Mazdutide (IBI362 or LY3305677), structurally modeled on mammalian oxyntomodulin, has demonstrated clinical efficacy in weight reduction that surpasses that of existing agents such as semaglutide and may even approximate the outcomes of bariatric surgery. As an emerging obesity treatment, mazdutide offers distinctive therapeutic potential and long-term safety advantages, yet the adverse effect profile of this dual agonist remains insufficiently characterized, creating obstacles to its widespread clinical use[11,12].

In this review, we systematically examine the mechanisms of weight reduction and adverse events associated with mazdutide, contrasting them with those of current GLP-1R single-target drugs, to inform clinical decision-making and promote continued progress in this area.

ELECTRONIC LITERATURE

The electronic literature was searched in international electronic databases including PubMed and Web of Science, from their inception to August 2025. The search employed a combination of core terms and free words, including: (“mazdutide” OR “IBI362” OR “LY3305677” OR “GLP-1R + GCGR” OR “GLP-1R/GCGR” OR “Dual-target” OR “Bifunctional” OR “Dual-receptor” OR “Combined targeting” OR “GLP-1RA+”) AND (“Obesity” OR “Overweight” OR “Weight loss” OR “Body weight reduction” OR “Adiposity” OR “Body mass index”). The inclusion criteria were: (1) Literature type was limited to original research (including animal studies and clinical trials), systematic reviews, meta-analyses, randomized controlled trials (RCTs), and cohort studies; (2) The research topic focuses on exploring the regulatory effects of weight loss and metabolism by GCGR/GLP-1R agonists and inhibitors; and (3) Only English-language literature was included. Regarding the exclusion criteria, duplicate entries and articles that lacked relevance to the subject matter were first eliminated. Articles that were not published in English or lacked critical data were further excluded based on a full-text evaluation. A total of 116 articles were included, and representative content was selected for discussion (Figure 1).

Figure 1 The screening process. GCGR: Glucagon receptor; GLP-1R: Glucagon-like peptide-1 receptor.

PHYSIOLOGY OF GLP-1 AND GCG

Discovery of GLP-1 and GCG

The identification of GLP-1 was facilitated by the development of recombinant DNA technology in the early 1970s. This technological advance enabled the decoding of nucleotide sequences from cloned cDNA corresponding to messenger RNA, which in turn allowed researchers to predict the amino acid sequences of proteins. In the early 1980s, scientists discovered two GCG-related peptides, GLP-1 and GCG-like peptide-2 (GLP-2), within the proglucagon sequences in a variety of species, including rats, hamsters, cows, and humans. The fact that the GLP-1 amino acid sequences are identical across these four mammalian species suggests that GLP-1 plays a vital and evolutionarily conserved role in biological processes.

The discovery of GCG followed the identification of insulin by Banting et al[13] in 1921, who noted that pancreatic extracts and crude insulin preparations caused transient hyperglycemic episodes before blood glucose levels returned to normal. Subsequent studies led to the isolation of a pancreatic substance that raised blood glucose in rabbits and dogs, counteracting insulin's glucose-lowering effects. This substance was named “GCG”[14].

Molecular physiology of GLP-1 and GCG

Molecular physiology of GLP-1: The signal transduction of GLP-1 primarily depends on the cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) pathways, with certain effects involving downstream molecules such as MAPK and PI3K[15]. These pathways generate diverse physiological effects. First, GLP-1 activates the cAMP/PKA and Epac signaling pathways in β-cells in a glucose-dependent manner, enhancing calcium influx and insulin granule exocytosis to promote glucose-dependent insulin secretion. Concurrently, it suppresses GCG secretion from α-cells (particularly under hyperglycemic conditions) and reduces endogenous glucose production, while enhancing peripheral glucose utilization to regulate glucose homeostasis[16,17]. In addition, GLP-1 acts on the central nervous system (e.g., nucleus tractus solitarius and arcuate nucleus) to activate pro-opiomelanocortin/cocaine amphetamine regulated transcript neurons and inhibit NPY/AgRP neurons, reducing food intake and enhancing satiety, thereby lowering body weight. Intestinal enteroendocrine L-cells are the primary endogenous source of GLP-1 peptides, and their effects on gastrointestinal motility—particularly delayed gastric emptying—are widely regarded as a key mechanism underlying their metabolic actions[18]. Studies have shown that by delaying gastric emptying and inhibiting intestinal motility, GLP-1 significantly reduces postprandial blood glucose fluctuations, exerting beneficial effects on patients with diabetes and obesity. Additionally, GLP-1 plays a crucial role in vasodilation, improving proteinuria, and slowing renal function decline, which may be achieved through activation of ATP-sensitive potassium channels and the central sympathetic-adrenal axis. Notably, GLP-1 may regulate energy metabolism by influencing brown adipose tissue (BAT) activity and reducing hepatic fat accumulation. However, this has so far been demonstrated only in rodents[19], and its effects in humans remain unclear (Figure 2).

Figure 2 Physiological effects of glucagon-like peptide-1. The physiological effects of glucagon-like peptide-1 (GLP-1) are extensive. GLP-1: Glucagon-like peptide-1; POMC: Pro-opiomelanocortin; CART: Cocaine amphetamine regulated transcript; NPY: Neuropeptide Y; AgRP: Agouti-related peptide.

Molecular physiology of GCG: GCG is a 29-amino-acid peptide hormone secreted by pancreatic α-cells and serves as a key regulator of hepatic glucose production, functioning in tandem with insulin. In contrast to the larger volume of insulin secreted by pancreatic β-cells, the secretion of GCG is relatively low. GCG acts through its receptor, GCGR, a G protein-coupled receptor primarily found in pancreatic β-cells and hepatocytes. Upon binding to GCG, GCGR stimulates hepatic glycogenolysis and elevates blood glucose levels[20]. Its tissue distribution is extensive, including the liver, kidneys (primarily in nephrons, renal tubules, and collecting ducts, especially distal tubules), pancreas (α, β, δ cells), intestinal smooth muscle, brain, adipose tissue, heart, and preadipocytes, among others[21].

The activation mechanism of GCGR involves triggering the cAMP/PKA/p-Creb signaling pathway upon binding to GCG. It mainly activates Gαs protein, stimulates adenylate cyclase to generate cAMP, and thereby activates PKA. In addition, it can activate phospholipase C through Gq protein, producing inositol trisphosphate and calcium ion (Ca²⁺) signals that participate in downstream regulation[22]. The regulatory mechanisms of GCG vary across different organs: (1) In the liver, activation of GCGR stimulates glycogen phosphorylase kinase and upregulates key enzymes such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, thereby promoting glycogenolysis and gluconeogenesis, which increases blood glucose levels. Research by Nason et al[23] has shown that hepatic GCGR signaling enhances circulating levels of fibroblast growth factor 21, which is a regulatory factor for the weight-loss effect of GCG and plays an important role in energy homeostasis. A review by Kleinert et al[24] specifically highlights the catabolic effects of GCG and the subsequent anabolic counter-regulatory responses aimed at restoring metabolite levels, which may result in a “futile cycle” that increases energy expenditure; (2) In the kidneys, GCGR plays a vital role in maintaining water and electrolyte balance, regulating blood pressure, and preserving redox homeostasis. Dysfunction in GCGR may contribute to the development and progression of chronic kidney disease by inducing insulin resistance and lowering the glomerular filtration rate, among other mechanisms[25,26]; (3) In the central nervous system, GCGR signaling can be transmitted to the hypothalamus via hepatic vagal afferents, directly influencing GCGR within the arcuate nucleus of the hypothalamus. GCG promotes satiety and enhances energy expenditure in both rodents and humans through the liver-vagus nerve-hypothalamus axis. Additionally, GCG increases circulating cortisol levels in humans and exerts effects on the sympathetic nervous system via the hypothalamic-pituitary-adrenal axis, thereby influencing energy expenditure[27]. A review by Müller et al[22] notes that GCG can cross the blood-brain barrier, with its immunoreactivity detected in several brain regions associated with metabolic regulation, including the hypothalamus, hippocampus, and amygdala. Furthermore, GCGR is expressed in the anterior pituitary, and GCG may be associated with pituitary secretion of arginine vasopressin/copeptin, growth hormone, and adrenocorticotropic hormone. However, experiments by Stangerup et al[28] indicate that GCG may not directly stimulate the secretion of these hormones, but it may interact with anterior pituitary cells, and its specific role remains unclear; (4) In the pancreas, studies have shown that GCGR knockout mice exhibit α-cell hyperplasia due to a lack of GCGR signaling[29,30], indicating that GCG affects α-cell proliferation and insulin secretion; (5) In the heart, research by Mukharji et al[31] using radiotelemetry on GCGR-deficient mice found that the chronotropic effects of oxyntomodulin (OXM) and GCG on the heart are both dependent on GCGR. Among gastrointestinal hormones that can increase intrinsic heart rate, their relative potency is ranked as follows: GCG > OXM > cholecystokinin; and (6) Moreover, GCGR is expressed in BAT and white adipose tissue (WAT). A review by Conceição-Furber et al[32] clarifies that activation of GCGR can enhance the thermogenic activity of BAT. It is also suggested that GCG might increase metabolic rate by promoting the browning of WAT and inducing uncoupling protein 1-independent metabolic futile cycles (Figure 3).

Figure 3 Physiological effects of glucagon. The physiological effects of glucagon are extensive. A: In the liver, glucagon activation stimulates glycogen phosphorylase kinase, increases circulating fibroblast growth factor 21, upregulates the expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, promotes glycogenolysis and gluconeogenesis, and thus increases blood glucose; B: In the kidney, glucagon is crucial for maintaining water and electrolyte balance, blood pressure, and redox homeostasis; C: In adipose tissue, glucagon can act on brown adipose tissue and white adipose tissue and augment the metabolic rate; D: In the pancreas, glucagon activation may cause the proliferation of α cells; E: In the central nervous system, glucagon can influence energy expenditure; F: In the heart, glucagon participates in the enhancement of intrinsic heart rate. BP: Blood pressure; BAT: Brown adipose tissue; WAT: White adipose tissue; FGF21: Fibroblast growth factor 21; IHR: Intrinsic heart rate.

Interaction between GLP-1 and GCG

GCG and GLP-1 are both derived from the same biosynthetic precursor, proglucagon, and play key roles in regulating lipid and bile acid metabolism. Previous studies have established the structural basis of GCGR and GLP-1R, comprising both shared and peptide-specific structural features. Moreover, the N-terminal and central regions of the peptides exhibit pronounced conformational flexibility, allowing dual agonism when appropriate amino acids are incorporated at these positions[33]. Notably, GCG itself is a dual agonist capable of activating both GLP-1R and GCGR, but with up to 100-fold higher selectivity for GCGR[34]. This suggests that dual agonists should possess comparable activity at both receptors, or potentially greater selectivity for GLP-1R. Because GCG and GLP-1 exert opposite effects on glycemic regulation, combining their bioactivities could promote weight loss through multiple mechanisms. However, the maximal activation potential of each receptor remains undefined, resulting in the emergence of various GLP-1R/GCGR dual-target agonists.

PHARMACOLOGICAL BASIS OF MAZDUTIDE

Drug overview and molecular structural characteristics

Mazdutide is a novel peptide-based metabolic modulator, structurally derived from the GLP-1 scaffold and modified by lipidation to extend its plasma half-life, thereby enabling a once-weekly subcutaneous dosing regimen[35]. Mazdutide integrates functional domains that activate both GLP-1R and GCGR, conferring multiple pharmacological activities including appetite suppression, glycemic control, and enhanced energy expenditure[36].

Mechanism of action of GLP-1R agonists

GLP-1R agonists are now widely used in the treatment of obesity and type 2 diabetes mellitus (T2DM), with classical mechanisms including: Activation of hypothalamic GLP-1R in the central nervous system to suppress appetite center activity and delay gastric emptying, thereby reducing energy intake, and, in peripheral tissues, enhancement of pancreatic β-cell insulin secretion and suppression of α-cell GCG secretion, thereby lowering both fasting and postprandial glucose levels[37,38]. These mechanisms have been well validated in multiple clinical studies of agents such as liraglutide and semaglutide[39].

Mechanism of action of GLP-1R inhibitors

Exendin is a functional mimetic of GLP-1, while its variant exendin (9-39) lacks the N-terminal segment required for receptor activation and internalization, thereby functioning as a GLP-1R inhibitor. As a classical inhibitor, exendin (9-39) does not induce rapid receptor activation or internalization and is widely used in animal studies for mechanistic investigations. Studies have shown that blocking GLP-1 signaling markedly reduces insulin secretion, diminishes appetite suppression, and attenuates metabolic improvement, further confirming the central role of the GLP-1 pathway in metabolic interventions. In terms of secretion mechanisms, GLP-1 release is finely regulated by multiple ion channels and signaling pathways. Existing studies have demonstrated that the synergistic interaction between intestinal TRPV4 channels and the sodium–calcium exchanger NCX1 can trigger glucose-dependent GLP-1 secretion via the Ca²⁺/PKCα signaling axis. This mechanism not only aids in understanding the dynamic release process of GLP-1 but also provides a theoretical basis for developing novel targets to regulate its secretion. However, it is important to note that non-specific modulation of calcium channels may pose risks such as hypoglycemia. Thus, GLP-1 signaling interventions must balance metabolic benefits against potential side effects, offering a key direction for GLP-1R inhibitor development.

Mechanism of action of GLP-1R/GCGR dual-target agonists

The core innovation of mazdutide lies in its dual activation of both GLP-1R and GCGR, establishing a "dual-pathway" model of metabolic modulation. Through the GLP-1R pathway, mazdutide exerts effects akin to GLP-1R agonists, promoting glucose homeostasis. Additionally, the activation of GCGR provides a distinct advantage in metabolic regulation. GCGR is abundantly expressed in the liver and other tissues, and mazdutide stimulates the hepatic cAMP-PKA signaling pathway, which enhances fatty acid oxidation and mitochondrial thermogenesis, leading to an increase in basal metabolic rate and significant elevation in energy expenditure[40]. This action offsets the limitation of the GLP-1 pathway in suppressing energy intake, enabling a bidirectional regulation of both energy intake (via central appetite suppression and delayed gastric emptying) and energy expenditure. Based on these mechanisms, the "dual metabolic engine" theory has been proposed, suggesting that mazdutide facilitates weight loss by concurrently regulating intake and expenditure. This dual action may offer superior synergistic effects compared to GLP-1R single-target therapies[41].

It is worth noting that, beyond stimulating lipid metabolism and energy use, GCGR activation in the liver can increase gluconeogenesis, potentially diminishing the net glucose-lowering capacity of mazdutide[42]. Nonetheless, evidence from clinical and preclinical studies indicates no substantial hyperglycemia risk with mazdutide, implying that GLP-1–driven increases in insulin release and reductions in GCG secretion may dynamically counterbalance gluconeogenesis. Additionally, concurrent GLP-1R and GCGR activation can avert hyperglycemia caused by GCGR stimulation. Mazdutide may achieve this by regulating GCGR expression levels, prolonging signaling activity, or engaging in biased agonism to favor lipid metabolism pathways while restraining overactivation of gluconeogenesis, a proposition meriting further investigation via receptor pharmacodynamics and molecular analyses (Figure 4).

Figure 4 Pharmacological effects of mazdutide. Mazdutide binds to both glucagon-like peptide-1 receptor and glucagon receptor on cell membranes, triggering cyclic adenosine monophosphate–protein kinase A signaling. Glucagon-like peptide-1 receptor activation delays gastric emptying and stimulates central appetite suppression, while glucagon receptor activation enhances hepatic fatty acid oxidation, thermogenesis, and uncoupling protein 1-mediated heat production in adipose tissue. Together, these effects contribute to weight loss, improved glycemic control, reduced hepatic fat deposits, and increased basal metabolic rate. PKA: Protein kinase A; cAMP: Cyclic adenosine monophosphate; GCGR: Glucagon receptor; GLP-1R: Glucagon-like peptide-1 receptor; UCP1: Uncoupling protein 1.

The GLP-1/GCG dual-receptor agonists offer innovative approaches for the treatment of obesity and metabolic disorders. BI 456906 has demonstrated promising results in preclinical and clinical studies, with its dual receptor agonism shown to synergistically enhance anti-obesity efficacy. Zimmermann et al[43] provided a comprehensive pharmacological profile, confirming its potential as a therapeutic agent for metabolic diseases. Additionally, Yazawa et al[44] confirmed the agent's safety and efficacy in a Japanese cohort, noting significant body weight reduction and improved metabolic parameters. As ongoing research continues to elucidate its pharmacological mechanisms, BI 456906 is poised to become a key player in the management of obesity and related metabolic conditions[45,46]. Similarly, Cotadutide, by targeting both the GLP-1R and GCGR, promotes glycemic control, weight loss, and liver health. Studies have demonstrated Cotadutide’s effectiveness in reducing hepatic steatosis and fibrosis, making it a promising treatment for non-alcoholic steatohepatitis (NASH) as well as obesity[47-49]. Pharmacokinetic and safety evaluations confirm the drug's promising efficacy and tolerability profile, further supported by mechanistic models like the 4GI model, which demonstrate how Cotadutide’s dual agonism orchestrates these metabolic effects[50,51]. In comparison to BI 456906 and cotadutide, mazdutide presents a distinct advantage due to its unique mechanism of action, which provides more targeted metabolic regulation. This targeted approach positions mazdutide as a particularly strong contender in the treatment of metabolic disorders such as obesity, diabetes, and NASH. Given its focused regulatory effects on metabolic pathways, mazdutide holds significant promise to become one of the leading therapeutic agents in the future (Table 1).

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.

Preclinical research evidence

Mazdutide’s dual receptor agonist properties enable it to exert a comprehensive regulatory effect, thereby achieving a more comprehensive therapeutic effect[52,53]. In diet-induced obesity models, it markedly reduces body weight by decreasing fat mass and increasing basal metabolic rate. Intra-islet GCG signaling through β-cell GCGR and GLP-1R restores first-phase glucose-stimulated insulin secretion, while mazdutide enhances insulin gene transcription and mRNA stability[54], improving glycemic control. It also delays gastric emptying more effectively than GLP-1 mono-target agents, suppressing hunger, increasing satiety, and supporting long-term weight management. Jungnik et al[55] found that GCGR in the liver utilizes alanine to synthesize urea and produce glucose, leading to a decrease in plasma alanine concentration. Parker et al[56] used 13C magnetic resonance spectroscopy to find that GCGR activity in the liver was positive, confirming the activity characteristics of GCGR in agonists. Therefore, GCGR can stimulate the liver to oxidize fatty acids and reduce fat production, and the combination of these two mechanisms may provide additional hepatoprotective potential for mazdutide. Studies have shown that mazdutide improves hepatic metabolic function, reducing triglycerides, total cholesterol, low-density lipoprotein cholesterol, and serum uric acid levels without elevating transaminases. Given the high prevalence of fatty liver disease and dyslipidemia among obese individuals in China, mazdutide’s significant effect in reducing liver fat accumulation and blood glucose levels has produced excellent results in this population[57]. Both GLP-1R/GCGR dual-target agonists can increase heart rate. The prevailing view is that the primary cause of increased heart rate is the result of drug interactions with the noradrenergic pathway, involving both the central and peripheral systems[58]. Interestingly, despite the increase in heart rate, multiple cardiovascular studies of GLP-1R agonists have shown that they can improve cardiac function and possess certain cardiovascular protective effects. Mazdutide also exhibits this effect. In an obese mouse model, mazdutide improved multiple cardiac metabolic risk factors in a dose-dependent manner, enhanced lipid metabolism markers, reduced waist circumference, blood pressure, and blood lipids, and produced beneficial effects on low-density lipoprotein cholesterol levels and high-sensitivity C-reactive protein. However, it is worth noting that experiments related to the pharmacology of mazdutide were primarily conducted in anesthetized mice rather than awake mice, and it remains unclear whether cardiovascular changes are indirectly influenced by the gastrointestinal tract. GLP-1R are widely distributed in the central nervous system and participate in regulating appetite and satiety[59]. By activating these receptors, mazdutide modulates appetite regulation pathways in the central nervous system, significantly reducing food intake and improving glucose tolerance and insulin secretion[60]. Finally, due to the effects of GLP-1R and GCGR on the kidneys, mazdutide effectively reduces urinary albumin levels. Through its indirect effects on blood glucose, blood pressure, and other parameters, it may exert potential renal protective effects. Overall, mazdutide integrates intake regulation and energy expenditure mechanisms through the synergistic activation of GLP-1R and GCGR, demonstrating clinical potential in weight management and metabolic improvement that surpasses that of GLP-1 monotherapy[61] (Figure 5 and Table 2).

Figure 5 Mechanistic pathways of mazdutide via dual glucagon-like peptide-1 receptor and glucagon receptor activation. Mazdutide plays an important role in the digestive system (stomach, pancreas, and liver), cardiovascular system, and central nervous system (brain), and it regulates weight, metabolism, blood glucose, and cardiovascular risk factors. TG: Triglycerides; GLP-1R: Glucagon-like peptide-1 receptor; GLP-1: Glucagon-like peptide-1; GCGR: Glucagon receptor; LDL-C: Low-density lipoprotein cholesterol; GLU: Glutamate; NTS: Nucleus of the solitary tract; RVLM: Rostral ventrolateral medulla.

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.

CLINICAL APPLICATION OF MAZDUTIDE AND GLP-1R SINGLE-TARGET DRUGS

Comparison of the efficacy

Mazdutide, the first dual-target agonist of GLP-1R/GCGR to complete phase 3 trials, has been approved for inclusion in weight management treatments for obese or overweight individuals in China. In phase 1 trials, mazdutide at a dosage of 10 mg was well tolerated, demonstrating a safety profile comparable to that of existing GLP-1 agonists. By week 12, participants receiving mazdutide at doses of 6 mg and 9 mg experienced average body weight reductions of 6.1% and 11.7%, respectively[62]. Phase 2 trials utilized a randomized, double-blind, placebo-controlled design, revealing mean percentage changes in body weight from baseline to week 24 of -6.7%, -10.4%, -11.3%, and 1.0% for the mazdutide 3 mg, 4 mg, and 6 mg groups, and the placebo group, respectively. These results confirmed the safety of mazdutide at doses up to 6 mg over a 24-week treatment period[63]. In phase 3 trials, by week 32, the mean percentage changes in body weight from baseline were -10.09%, -12.55%, and 0.45% for the mazdutide 4 mg, 6 mg, and placebo groups, respectively, with the majority of patients achieving at least a 5% weight loss. By week 48, the mean percentage changes in body weight from baseline were -11.00%, -14.01%, and 0.30% in the mazdutide 4 mg, 6 mg, and placebo groups, respectively, with many patients experiencing weight loss of at least 15%. These findings validate the clinically significant weight-loss effects of mazdutide over extended periods of use (Table 3)[36,42,62-64]. To systematically compare the clinical efficacy of mazdutide with GLP-1R single-target drugs from multiple perspectives, this review combines core data from the GLORY-1 trial with experimental evidence from GLP-1R single-target drugs, providing a more comprehensive reference for clinical drug selection (Table 4)[42,52,64-73].

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.

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Common adverse effects: Ji et al[63] conducted a comprehensive study on the safety profile of mazdutide, revealing that both the experimental and placebo groups experienced low to moderate adverse effects. Reported adverse effects included upper respiratory tract infections, diarrhea, decreased appetite, nausea, urinary tract infections, abdominal distention, and vomiting. The findings indicated that gastrointestinal side effects predominated, with an increased incidence correlating with higher mazdutide dosages. Additionally, a small number of patients developed serious conditions, including anal fistula, cholecystitis, obstructive pancreatitis, electrolyte imbalances, and lipometritis during treatment. However, these occurrences were primarily attributed to pre-existing underlying health issues rather than a direct consequence of mazdutide. Chen et al[74] have thoroughly summarized the adverse neurological effects of GLP-1R agonists, including dizziness, headache, fatigue, drowsiness, and brain fog. Furthermore, the treatment can also induce epileptic seizures, Wernicke encephalopathy with symptoms such as nystagmus, ophthalmoparesis, ataxia, and confusion, and even taste disturbances such as altered taste and dry mouth[75]. They provide references for the adverse neurological effects of mazdutide.

Long-term concerns: Low-dose mazdutide has been shown to clinically impact heart rate, with a peak effect observed during the dose-escalation phase. However, as the dose increases further, heart rate does not continue to rise. Most of the cardiac symptoms observed clinically to date are transient episodes of sinus tachycardia. Cardiovascular outcome trials (CVOTs) are crucial for evaluating the cardiovascular safety and benefits of drugs used to treat various conditions, including obesity[76,77]. Although mazdutide is currently considered to have potential cardiovascular side effects, its underlying mechanisms and key changes are still under investigation. Isolated cases of cardiovascular events, such as arrhythmias and atrial fibrillation, observed following the use of mazdutide have raised concerns about its long-term cardiac safety. The heart primarily relies on fatty acid oxidation and other metabolic pathways for energy to maintain normal rhythm and pumping function. The sustained activation of fatty acid oxidation by mazdutide may alter the heart's substrate utilization over time, disrupting energy metabolism homeostasis, and potentially impairing cardiac function, including myocardial cell damage, decreased cardiac performance, or arrhythmias. However, the available CVOT data associated with mazdutide does not yet support an assessment of its long-term safety. Therefore, future evaluation of its cardiovascular safety can be achieved by assessing its impact on three major adverse cardiovascular events in patients with high cardiovascular risk T2DM: Cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke.

Pancreatitis and thyroid C-cell carcinoma have been key concerns in monitoring the safety of GLP-1R agonists. A 2013 study indicated a potential association between GLP-1R drugs and an increased risk of pancreatitis and pancreatic cancer[78]. Basic research has demonstrated that medications such as liraglutide can elevate serum lipase and amylase levels in patients; however, these increases do not directly predict the onset of acute pancreatitis[79]. More recently, some researchers have identified that DPP-4 inhibitors, which work through GLP-1 pathways, may raise the risk of acute pancreatitis in individuals with T2DM[80]. Although definitive evidence linking GLP-1R agonists to pancreatic cancer is lacking, the hypothesis that GLP-1R are expressed in pancreatic ductal epithelial cells suggests that these drugs could lead to ductal hyperplasia and dilatation, indicating potential risks. Another significant concern is the association of GLP-1R agonists with the risk of thyroid C-cell carcinoma. Research indicates that these agonists may elevate the risk of various thyroid cancers, particularly medullary thyroid cancer, after 1-3 years of treatment[81]. Although studies have reported the targeting effects of GLP-1R agonists on thyroid C cells in rodent models[82], there is a notable lack of experimental evidence in human and primate subjects[83]. Additionally, GCG and GLP-1 exhibit both synergistic and antagonistic effects on regulating glucose and energy homeostasis. In clinical trials of mazdutide, no cases of pancreatitis and thyroid C-cell carcinoma were observed. However, further experimental investigation is required to determine whether mazdutide exerts any detrimental effects when considering the interplay of these mechanisms.

Mazdutide’s notable effects on weight control and metabolic improvement primarily stem from its sustained activation of fat oxidation. The liver plays a crucial role as a metabolic organ, overseeing a range of complex functions, including material synthesis, decomposition, and transformation[84]. The long-term impact of mazdutide on liver energy metabolism may involve the continuous regulation of various metabolic pathways and signaling cascades within the liver. However, whether these effects could result in adverse outcomes, such as disturbances in liver cell energy metabolism or abnormal accumulation of metabolic intermediates, remains to be confirmed in future clinical trials.

Adverse effects of GLP-1R inhibitors: Radiolabeled exendin significantly enhances GLP-1R molecular imaging[85]. In preclinical models, the uptake of radiolabeled exendin is correlated with β-cell mass[86], providing a crucial foundation for understanding the pathophysiology of related diseases[87]. In the research and application of drugs related to the GLP-1 signaling pathway, GLP-1R inhibitors, such as exendin (9-39), do not activate the receptor to cause internalization of the peptide-receptor complex compared to GLP-1R agonists, so its side effects are significantly fewer than agonists and it has strong tolerability[88]. However, current research on exendin (9-39) remains at a basic stage, and due to the lack of clinical data, its adverse effects have not been comprehensively evaluated[89].

Previous studies have shown that exendin (9-39) significantly affects arterial blood pressure and heart rate at high concentrations, leading us to consider that its primary adverse effects may involve interference with cardiovascular regulation. For instance, one study found that exendin (9-39) could negate the effects of GLP-1R agonists on increasing renal sympathetic nerve activity and mean arterial pressure[90]. Wei et al[91] demonstrated that the combination of GLP-1 with a GLP-1R inhibitor resulted in a significantly lower reduction in microvascular permeability compared to GLP-1 alone. This indicates that GLP-1 may influence vascular permeability independently of the GLP-1R, offering insights into the adverse cardiovascular reactions associated with GLP-1R inhibitors. However, since exendin (9-39) stimulates the secretion of all L cell products, including GLP-1, it presents a complex profile of effects[92]. Additionally, exendin (9-39) lacks an internalization process, making its mechanism of action challenging to elucidate. These factors create significant hurdles for subsequent studies aiming to isolate GLP-1 for verification using exendin (9-39). Notably, cell-penetrating peptides (CPPs), which are generally 5 to 10 amino acids in length, can be internalized by cells without receptor activation[93,94]. Penetratin (Pen), derived from the antennapedia homeobox protein of Drosophila melanogaster, is one such CPP[95]. Studies have indicated that Pen can enhance the binding and internalization of exendin (9-39) in vitro, laying the groundwork for combining Pen with exendin variants for GLP-1R-directed approaches[96,97]. Future research could employ image-guided surgery and targeted photodynamic therapy to investigate the cellular internalization of GLP-1R inhibitors, further exploring their potential for weight loss treatment[98].

For safety reasons, glucose infusion needs to be monitored during exendin imaging to avoid severe hypoglycemia. This concern underscores the necessity for developing highly effective inhibitors. Calabria et al[99] demonstrated through experiments on mice and humans that short-term intravenous infusion of exendin (9-39) inhibits insulin secretion, resulting in significantly increased fasting blood glucose concentrations. This finding suggests that inhibiting GLP-1 signaling is an effective strategy for reversing GLP-1-induced hypoglycemia. Further research has revealed that GLP-1R inhibitors exert both pancreatic and extrapancreatic effects[100]. They contribute to increased blood glucose levels through several mechanisms. Under normal conditions, GLP-1 enhances insulin's ability to promote nutrient transport to peripheral tissues such as muscle cells. In contrast, GLP-1R inhibitors antagonize this synergistic effect, reducing glucose transport and leading to its retention in the bloodstream[101]. Studies have shown that GLP-1R agonists can enhance cellular glucose uptake by increasing the translocation of glucose transporter 4 (GLUT4) to the cell surface under insulin stimulation[102]. In contrast, GLP-1R inhibitors hinder GLUT4 translocation, decrease insulin sensitivity in peripheral tissues, and impair glucose uptake and utilization, ultimately diminishing blood glucose clearance efficiency. These inhibitors also reduce insulin extraction by the liver, which weakens the liver's inhibitory effect on endogenous glucose production. Consequently, more insulin enters peripheral circulation, but due to reduced sensitivity, it fails to exert a hypoglycemic effect, causing blood glucose levels to rise. For instance, Zheng et al[103] noted a 28% decrease in liver insulin extraction in children with ATP-sensitive potassium channel congenital hyperinsulinism during the mixed meal tolerance test. Moreover, studies have shown that during the infusion of exendin (9-39)[104], blocking GLP-1R significantly alters the body’s response to meals via a feedback mechanism. Currently, there is no insulin sensitivity index to quantify insulin sensitivity, highlighting the need for future experimental designs to focus on multiple-dose exendin (9-39) studies to evaluate its cellular effects and safety comprehensively.

COMBINED USE OF AGONISTS AND INHIBITORS

Antibody-drug conjugates use the targeting specificity of antibodies to recognize antigens and enter cells, undergo lysosomal degradation, and release the effective payload to exert its effects. This method of using antibodies to promote the delivery of small molecules to antigens allows a single molecule to simultaneously exert the effects of agonists and inhibitors on receptors. Glucose-dependent insulinotropic polypeptide (GIP), another incretin hormone, plays a critical role in regulating human metabolism, similar to GLP-1 and GCG. Recent studies have demonstrated that the combined use of GIP receptor (GIPR) inhibitors and GLP-1R agonists significantly enhances weight loss efficacy. AMG 133 (maridebart cafraglutide) exemplifies this, as phase 1 clinical trials indicated its potential by conjugating a monoclonal anti-human GIPR inhibitor antibody with two GLP-1 analog agonist peptides through amino acid linkages[105]. In experimental models involving obese mice, crab-eating macaques, and human subjects, this conjugate exhibited substantial weight loss effects, lasting up to 150 days post-treatment. Moreover, Killion et al[106] discovered that the combination of a mouse anti-mouse GIPR antibody (muGIPR-Ab) with the GLP-1R agonist liraglutide led to significant weight loss in DIO mice. Jensen et al[107] provided further validation through experiments showing that the peptide-based GIPR inhibitor AT-7687 combined with liraglutide was not only stable but also resulted in weight loss effects comparable to bariatric surgery. However, the underlying mechanisms of the combined drug approach remain largely unclear. Current studies have not defined the maximum weight loss effect associated with the highest doses of GLP-1R agonists used in combination, which hampers further exploration of the additive impact of receptor antagonism on weight loss within the maximally stimulated GLP-1 system. Additionally, disparities between animal and human obesity models complicate the interpretation of results, and the small sample sizes in clinical trials, predominantly involving liraglutide, limit the generalizability of the findings. Consequently, the pharmacological differences observed restrict the statistical significance of many outcomes, emphasizing the necessity for further investigation across broader datasets in future studies.

The combined use of agonists and antagonists appears to present a paradox; however, studies in mice and non-human primates have demonstrated that this combination can yield superior weight loss results compared to single-drug treatments. As previously mentioned, the side effects associated with GLP-1R inhibitors are significantly less than those of agonists. Perhaps we can speculate that combining GLP-1R inhibitors with mazdutide could produce a synergistic effect, enhancing weight loss and metabolic improvement while minimizing adverse effects. For instance, AMG 133, influenced by incretin during administration, leads to only mild gastrointestinal side effects within 8-12 hours following the first dose. Importantly, the severity of these side effects does not increase with higher doses compared to a single agonist, providing evidence for the potential efficacy of combining agonists and inhibitors. Optimizing the balance between efficacy and side effects may be achievable through the combination of mazdutide with GLP-1R inhibitors. By leveraging the complementary effects of different drugs, this approach could lower the risk of side effects associated with high-dose monotherapy, thereby reducing patient discomfort and potentially decreasing treatment costs, contributing positively to obesity treatment within the healthcare system. Nevertheless, it is essential to highlight that while the stimulation of hepatic glucose production by GCG is transient, its long-term stimulation mechanisms remain unclear. Maintaining a balance between the activities of the two receptors continues to be a major research focus[108]. After combining with GLP-1R inhibitors, it will be crucial to balance receptor affinity and control variables to maximize the weight loss effect.

CONCLUSION

Compared to single-target drugs, mazdutide represents a significant improvement in both weight reduction and overall metabolic regulation. As a new weight-loss treatment, it shifts the focus from merely achieving weight loss to restoring metabolic homeostasis—encompassing holistic management of weight, metabolism, and complications. However, despite the promising potential of mazdutide, current research is limited by several factors.

A significant challenge in understanding mazdutide lies in the insufficient systematic investigation of its receptor binding characteristics and the mechanisms of multi-organ metabolic regulation in basic research. Clinical trials show that varying dosages and increments yield different outcomes in terms of weight loss efficacy and the management of complications. Once mazdutide binds to its receptor, it activates key downstream proteins, with signal transduction intensity displaying nonlinear changes depending on dose adjustments. As a structurally more complex dual agonist, it remains uncertain whether mazdutide poses risks of accumulation, whether its elimination half-life is extended, and what the safety margins are at various dosages. Future research should leverage advanced technologies such as molecular biology, metabolomics, and single-cell sequencing to further clarify the precise mechanisms and interplay of complementary pharmacological effects between GCGR and GLP-1R. Notably, obesity often coexists with various metabolic dysregulations, which makes it difficult for single-agent therapies to achieve optimal outcomes. Given the significant role of GLP-1R inhibitors in glycemic control, future studies could investigate the combined use of mazdutide with them[109]. This strategy should utilize a stepwise dose-escalation clinical trial design, incorporating patient-specific characteristics to establish optimal combination dosages and treatment durations based on dose-response analyses.

Beyond pharmacokinetics, pharmacodynamics is a crucial parameter in understanding treatment outcomes. Many individuals with a BMI exceeding 30 kg/m² require long-term medication to reach target weight and realize comprehensive cardiometabolic benefits. Natural fluctuations in hormone levels elicit distinctly different physiological responses in the body over short and long timeframes. However, a substantial number of patients discontinue treatment due to intolerable side effects. Current studies on mazdutide have primarily focused on short-term results, making it challenging to accurately assess its long-term efficacy and rare adverse reactions. Furthermore, most published studies on mazdutide have small sample sizes. Although available clinical data support mazdutide, current research has largely focused on standard populations at high risk for metabolic syndrome. Evidence on efficacy and safety remains limited for specific groups, including individuals with T2DM and obesity, cardiovascular failure, or renal insufficiency. While some patients with diabetes have been enrolled in current clinical trials, the primary focus has been on obese or metabolically abnormal populations. Whether mazdutide carries a dose-dependent risk of hyperglycemia in T2DM with obesity, and whether combination therapy with hypoglycemic agents is needed for blood glucose control, have yet to be examined. To date, no systematic analysis of the efficacy or safety of mazdutide has been conducted in adults aged 65 years and older. Common geriatric features, such as multiple comorbidities and slowed gastrointestinal motility, may affect the drug’s pharmacokinetics and tolerance of adverse reactions. Therefore, future studies should extend follow-up periods and collect and analyze safety data in real time during drug administration. Meanwhile, clinical trials should be conducted across diverse populations, with findings promptly fed back into basic research to foster a virtuous cycle of “basic research → clinical validation → mechanism re-exploration”. It is essential to note that studies on mazdutide have primarily centered on Chinese populations. China adopts lower BMI thresholds for overweight and obesity compared to those recommended by the World Health Organization, which may significantly restrict the generalizability of mazdutide’s therapeutic efficacy to individuals of different races and ethnicities. Therefore, while ensuring therapeutic efficacy, future research must also strengthen the evidence base regarding its applicability to specific populations and individual response variations to enhance the quality and effectiveness of its application in global weight management and metabolic disease treatment[110].

In comparison to previous studies, this review moves beyond a one-dimensional approach to efficacy assessment. We systematically explore multiple dimensions, including clinical trial design, potential challenges, and underlying mechanisms, thereby providing comprehensive and up-to-date resources for academic research in this area. By balancing the integrated effects of dual GLP-1R/GCGR dual-target agonist both in vivo and in vitro, mazdutide shows promising application potential. However, further research is essential to facilitate its clinical translation.