ABSTRACT
Obesity and its related metabolic comorbidities, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, and cardiovascular disease, are increasingly recognized as heterogeneous and multisystemic disorders. Despite the significant benefits in glycemic control and weight loss exhibited by GLP-1 receptor agonists (GLP-1RAs), their limitations have initiated the development of engineered multi-agonist therapies targeting additional nutrient-stimulated hormonal (NUSH) pathways. Dual and triple peptide-based co-agonists combining glucagon-like peptide-1 (GLP-1) with glucose-dependent insulinotropic polypeptide (GIP), glucagon, amylin, or peptide YY have demonstrated superior metabolic efficacy in preclinical and clinical studies. Tirzepatide (GLP-1/GIP dual agonist), CagriSema (GLP-1/amylin dual agonist), and retatrutide (GLP-1/GIP/glucagon triple agonist) have achieved unprecedented levels of weight loss and glycemic improvement, with certain agents also demonstrating hepatic, cardiovascular, and inflammatory benefits. Non-peptidyl oral GLP-1 RAs such as orforglipron, offer novel formulation strategies to enhance treatment accessibility and adherence. Multi-agonist incretin-based therapies represent a paradigm shift in the management of obesity and metabolic diseases. These agents offer broad clinical utility beyond glucose lowering by mimicking the pleiotropic hormonal responses observed after bariatric surgery. These therapies are poised to emerge as key components of precision metabolic medicine. This review article explores the mechanistic basis, pharmacological characteristics, and clinical data supporting the use of engineered NUSH-based peptide therapies for obesity and its related metabolic disorders, with particular emphasis on recent progress in the development and clinical application of dual and triple agonists.
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Keywords: Nutrient-stimulated hormonal multi-agonist; Glucagon-like peptide-1 receptor agonist; Precision metabolic medicine; Obesity and metabolic disorders
INTRODUCTION
The increasing incidence of obesity and its metabolic sequelae, including type 2 diabetes (T2D), metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH), and cardiovascular disease (CVD), continues to exert a huge clinical and socioeconomic burden worldwide [
1,
2]. Despite the inclusion of foundational lifestyle and behavioral interventions, their long-term efficacy in sustained weight reduction remains modest. Encouragingly for both patients and healthcare providers, pharmacotherapy has evolved dramatically, particularly with the advent of gut-derived hormonal therapeutics, for obesity [
3].
Glucagon-like peptide-1 (GLP-1), initially discovered in the 1980s, has multifaceted functions in regulating glucose homeostasis, appetite, gastric emptying, and body weight [
4]. The clinical success of GLP-1 receptor agonists (GLP-1 RAs), such as liraglutide and semaglutide, has ushered in a new era of incretin-based therapies [
5,
6]. However, the therapeutic ceiling of GLP-1 monotherapy, along with the heterogeneous nature of obesity, has highlighted the significance of developing more potent agents, engaging multiple nutrient-stimulated hormone (NUSH) pathways [
7]. Advances in peptide engineering over the last decade have led to the design of multi-agonist molecules targeting combinations of GLP-1, glucose-dependent insulinotropic polypeptide (GIP), glucagon, amylin, and peptide YY (PYY) receptors. The current development pipeline includes dual (e.g., tirzepatide [
8], CagriSema [
9]) and triple (e.g., retatrutide [
10]) agonists with unprecedented efficacy in weight loss and glycemic control.
Figure 1 demonstrates a chronological overview of GLP-1 discovery [
10-
21].
MECHANISTIC BASIS AND FRAMEWORK OF NUTRIENT-STIMULATED HORMONAL MULTIAGONISTS
The NUSH secreted in response to food intake, including GLP-1, GIP, glucagon, amylin, and PYY, are crucial physiological regulators of energy balance, glucose homeostasis, and metabolic adaptation. These hormones function through spatially distinct yet functionally integrated receptors in the pancreas, brain, gastrointestinal (GI) tract, liver, adipose tissue, and other metabolic organs (
Fig. 2). NUSH-based multiagonists simultaneously target these endogenous axes to achieve synergistic metabolic effects while minimizing adverse events.
Engineered NUSH-based multi-agonists commonly employ several peptide-design platforms to optimize pharmacokinetics and multi-receptor engagement. These include stabilizing amino-acid substitutions that enhance proteolytic resistance and receptor-binding geometry [
22]; fatty-acid acylation to enable reversible albumin binding and prolong systemic half-life [
22]; PEGylation strategies that increase molecular size and reduce renal clearance [
22-
24], and antibody– peptide conjugate scaffolds that leverage Fc-mediated recycling to achieve ultra–long-acting exposure [
22-
24]. Collectively, these engineering approaches support half-life extension, receptor-affinity fine-tuning, and balanced activation of various NUSH receptors, thereby enabling the pharmacological precision required for multi-agonist therapeutics.
Although each NUSH hormone exerts a unique set of metabolic benefits, their combined activation through dual or triple agonists produces more potent and harmonized outcomes. For instance, a combination of GLP-1 and GIP improves glucose regulation and reduces appetite, whereas that of glucagon and amylin targets energy expenditure and satiety [
3]. This synergy causes clinical results with weight loss exceeding 20% and glycemic control superior to that obtained with single-agent therapies [
25,
26].
Figure 2 illustrates these hormonal interactions and receptor sites, mapping tissue-specific actions of engineered multi-agonists.
GLP-1, secreted from intestinal L-cells in response to nutrient intake, exerts its actions via GLP-1 receptors, which are abundantly expressed in pancreatic β-cells, the brainstem (notably nucleus tractus solitarius), and the GI tract. GLP-1 enhances glucose-stimulated insulin secretion, suppresses glucagon, delays gastric emptying, and promotes satiety through central appetite pathways [
27]. These properties contribute to the clinical efficacy of GLP-1 RAs in both glycemic control and weight reduction [
4].
Semaglutide: the latest single peptide targeting the GLP-1 receptor
Semaglutide, a long-acting GLP-1 RA, represents a pinnacle among single-peptide incretin-based therapeutics. It was structurally engineered through acylation and incorporation of a spacer with a C18 fatty diacid chain, rendering it the ability to bind albumin with an extended half-life suitable for once-weekly subcutaneous administration [
28]. Semaglutide binds to the GLP-1 receptor with high affinity, stimulating glucose-dependent insulin secretion, suppressing inappropriately elevated glucagon, delaying gastric emptying, and reducing appetite through central and peripheral mechanisms [
29]. Its pharmacokinetic profile allows for stable plasma levels over 7 days, facilitating adherence and minimizing peak–trough variability [
30].
The Semaglutide Treatment Effect in People with Obesity (STEP) program demonstrated consistent and clinically meaningful reductions in body weight across multiple populations. In STEP 1, 2.4 mg of semaglutide caused a mean weight loss of 14.9% at 68 weeks in adults without diabetes [
18]. STEP 2 extended these findings to individuals with T2D, achieving 9.6% weight reduction versus placebo [
31]. STEP 5 confirmed the durability of weight loss over 104 weeks, supporting long-term efficacy [
32]. These trials established semaglutide (2.4 mg) as the first GLP-1 RA approved for chronic weight management. Recently, the SELECT trial assessed the impact of semaglutide on cardiovascular outcomes in overweight and obese patients without diabetes but with established CVD. Over a median of 39.8 months, semaglutide (2.4 mg) reduced three-point major adverse cardiovascular events (MACE) by 20%, reflected as reduced cardiovascular death and nonfatal myocardial infarction [
33]. These results positioned semaglutide not only as an anti-obesity agent but as a cardiometabolic therapeutic with disease-modifying potential.
Semaglutide has demonstrated therapeutic potential for MASLD/NASH and heart failure with preserved ejection fraction (HFpEF). Semaglutide (2.4 mg) significantly reduces hepatic steatosis and ALT and was studied in NASH resolution trials (e.g., ESSENCE) [
34]. The STEP-HFpEF and STEP-HFpEF-DM trials reported clinically meaningful improvements in the quality of life, exercise tolerance, and NTproBNP reduction [
35,
36]. Furthermore, exploratory studies are currently investigating its effects in Alzheimer’s disease, binge eating, and food addiction [
37-
39].
Figure 3 illustrates the results of semaglutide treatment in obesity and cardiometabolic disease, including its impact on glycemic control, appetite regulation, liver fat, and cardiovascular endpoints.
Semaglutide as a bridge to next-generation multireceptor agonists
The success of semaglutide has transformed the therapeutic landscape for obesity and T2D, providing a conceptual foundation for developing next-generation incretin coagonists. By achieving unprecedented efficacy in weight loss, glycemic control, and cardiovascular outcomes, semaglutide demonstrated the full potential of GLP-1 receptor activation while highlighting the limitations of monoreceptor therapy—namely, variable interindividual response, plateauing efficacy, and dose-related GI intolerance. These insights catalyzed the rational design of multi-receptor peptide agonists that build upon the GLP-1 paradigm by engaging complementary nutrient-stimulated hormonal pathways, such as GIP, glucagon, and amylin. The emergence of dual and triple agonists represents a natural and scientifically grounded evolution beyond semaglutide, aiming to amplify metabolic efficacy and broaden organ-specific benefits through integrated multi-hormonal modulation.
GIP: a potentiator of insulin action with emerging anti-obesity effects
GIP is released from K-cells in the proximal small intestine; it binds to GIP receptors (GIPR) expressed in pancreatic β-cells, adipose tissue, and selective central nervous system (CNS) nuclei. Although once considered ineffective in T2D, GIP agonism has been re-evaluated with the development of dual GLP-1/GIP agonists, where GIP contributes to improved insulin sensitivity and enhances adipocyte nutrient buffering [
40]. Preclinical models demonstrate that GIPR activation in the hypothalamus may contribute to reduced food intake and improved energy balance [
41,
42].
Recent mechanistic studies have provided further insight into how receptor-level interactions influence the pharmacological balance and tolerability of multi-agonists. For example, tirzepatide, the first dual GIP/GLP-1 receptor agonist approved for clinical use, demonstrates an imbalanced and biased pharmacology, exhibiting approximately fivefold greater affinity for the GIPR than for the GLP-1 receptor [
43]. This results in a higher predicted receptor occupancy for GIPR (≈40%) than for GLP-1R (≈10%) at therapeutic concentrations. In addition, tirzepatide shows signaling bias at the GLP-1 receptor, preferentially activating cAMP generation while weakly recruiting β-arrestin, thereby reducing receptor internalization and desensitization. This GIP-dominant yet GLP-1-biased profile likely underlies its superior metabolic efficacy and improved GI tolerability. These findings emphasize that optimizing receptor binding ratios and intracellular signaling patterns is not merely empirical but a critical determinant of therapeutic precision. Going forward, a quantitative systems pharmacology (QSP) framework integrating receptor occupancy, signaling bias, and tissue-specific receptor expression will be essential to guide the rational design of next-generation dual and triple incretin agonists.
GLP-1/GIP agonist: enhancing incretin synergy
Among dual peptide therapeutics, GLP-1/GIP co-agonists have demonstrated the most rapid clinical translation. Tirzepatide, a single-molecule agonist of both GLP-1 and GIPR, demonstrated remarkable efficacy in the SURPASS and SURMOUNT clinical trial programs. Recently, treatment with tirzepatide was superior to treatment with semaglutide with respect to reduction in body weight and waist circumference at week 72 among participants with obesity but without diabetes in SURMOUNT-5 trial [
26]. Furthermore, GIP enhances glucose-dependent insulin secretion and may offset the GI intolerance of GLP-1R agonism, possibly via action on hypothalamic circuits [
44]. This mechanistic hypothesis is supported by clinical data from the SURMOUNT-5 trial, which showed that GI adverse events led to treatment discontinuation less frequently with tirzepatide—a dual GIP/GLP-1—than with semaglutide, a selective GLP-1RA. Specifically, treatment discontinuation due to GI events occurred in 5.6% of participants receiving semaglutide versus only 2.7% of those receiving tirzepatide [
26]. These findings suggest that the addition of GIPR agonism may improve GI tolerability, enhancing the clinical applicability of incretinbased multi-agonists. Tirzepatide is now U.S. Food and Drug Administration (FDA)-approved for both T2D and obesity under the trade names Mounjaro and Zepbound, respectively, and is under investigation in MASLD.
GLP-1/GIP antagonist: reversing GIP signaling
Historically, GIPR antagonism emerged as an early experimental strategy to counteract obesity, based on preclinical findings that GIPR blockade could prevent diet-induced weight gain and improve insulin sensitivity, particularly when combined with GLP-1 agonism [
45]. This approach preceded the recognition of GIP benefits when used as a coagonist. For example, investigational conjugates, such as AMG-133, which combine GLP-1 agonism with GIPR antagonism, demonstrated notable weight loss (~14% at 12 weeks) with preserved glycemic control and favorable tolerability in early-phase trials [
46]. These findings underscore that GIP agonism and antagonism represent two distinct, context-dependent strategies—the former enhancing insulin secretion and metabolic flexibility under physiological stimulation, and the latter mitigating GIPR overstimulation in obesity-associated insulin resistance [
42,
47]. These results reflect the evolving understanding of GIP biology rather than a conceptual contradiction within incretin-based therapy development.
Glucagon functions through glucagon receptors (GCGRs) expressed predominantly in the liver, where it promotes glycogenolysis and fatty acid oxidation [
48]. Its co-activation with GLP-1Rs exerts catabolic effects contributing to weight loss without hyperglycemia [
49]. Survodutide, a GLP-1/glucagon dual agonist, demonstrated approximately 15% weight loss while maintaining euglycemia in a phase II clinical trial [
20]. In addition, GCGR activation in the adipose tissue, and possibly brown fat, increases thermogenesis and resting energy expenditure [
50,
51].
GLP-1/glucagon agonist: targeting energy expenditure
GLP-1 and glucagon dual agonists can leverage the glucoregulatory benefits of GLP-1 with the lipolytic and thermogenic effects of glucagon. Glucagon enhances hepatic lipid oxidation, increases energy expenditure by activating brown adipose tissue (BAT), and promotes body weight reduction [
52-
54]. Survodutide, developed as a GLP-1/glucagon co-agonist, achieved a 14.9% weight loss over 46 weeks in a recent phase 2 trial in individuals with obesity while maintaining acceptable glycemic profiles [
20]. The balance of glucagon-induced hyperglycemia is effectively counteracted by the insulinotropic action of GLP-1. Additional candidates, such as mazdutide and efinopegdutide, are in development [
55,
56].
Amylin, co-secreted with insulin from β-cells, delays gastric emptying, reduces postprandial glucagon, and acts on the area postrema in the brain to enhance satiety [
57]. A combination of semaglutide and cagrilintide, a long-acting amylin analog, exerts additive weight-lowering effects, possibly owing to complementary actions on gastric and hypothalamic targets [
9]. This combination offers reduced GI intolerance compared to a high-dose GLP-1 RA alone.
GLP-1/amylin agonist: dual appetite and gastric modulation
CagriSema, the fixed-ratio combination of semaglutide and cagrilintide, the long-acting amylin analog, produced 15.6% weight loss in 32 weeks—superior to semaglutide monotherapy in phase II trial [
9]. This combination could be especially beneficial in patients intolerant to higher GLP-1 RA doses or those requiring enhanced satiety signaling. Phase 3 REDEFINE 1 and 2 trials have confirmed clinically significant weight-reducing effects in adults with obesity, both with and without T2D [
58,
59].
Recently, a first-in-class unimolecular GLP-1 and amylin receptor agonist, Amycretin, was evaluated in a randomised, placebo-controlled phase 1b/2a trial in adults with overweight or obesity [
60]. Once-weekly subcutaneous amycretin at doses up to 60 mg achieved dose-dependent weight reductions up to 24% at 36 weeks, compared to –1% reduction with placebo, without new safety signals. GI adverse events—primarily nausea, vomiting, and decreased appetite—were the most common, but were generally mild to moderate, consistent with early-phase GLP-1 or amylin agonist studies. The drug showed additional favorable trends in fasting glucose and HbA1c reduction despite normoglycemic baseline levels, suggesting broader metabolic effects. These findings establish amycretin as the first unimolecular dual GLP-1/amylin agonist capable of achieving semaglutide- or tirzepatide-comparable efficacy over a shorter treatment duration, with a safety profile aligned with existing incretin-based therapies. Further phase 2 and 3 studies are ongoing to confirm its long-term efficacy and safety in obesity and T2D.
PYY is secreted from L-cells in the distal gut and reduces food intake via Y2 receptor-mediated inhibition of hypothalamic NPY/AgRP neurons [
61]. Preclinical studies in DIO mice demonstrated that GLP-1/PYY co-agonism caused greater weight loss and reduced food intake compared to GLP-1 monotherapy, without additional GI side effects [
62]. The current work focuses on optimizing the half-life and CNS penetration to translate these findings into viable clinical candidates [
62].
Mechanistic rationale for triple agonist
Triple agonists simultaneously activating the receptors for GLP-1, GIP, and glucagon represent a sophisticated pharmacological approach designed to address the multifaceted pathophysiology of obesity and its metabolic complications. The activation of GLP-1 receptor promotes glucosedependent insulin secretion, suppresses glucagon, delays gastric emptying, and reduces appetite through central and peripheral mechanisms [
63]. GIP, once believed to be metabolically redundant in individuals with T2D, has been demonstrated to augment insulin secretion, improve insulin sensitivity in adipocytes, and modulate reward and satiety pathways within the CNS [
64]. Glucagon exerts potent lipolytic and thermogenic effects by stimulating hepatic fatty acid oxidation and BAT activity, although its hyperglycemic potential necessitates co-activation with GLP-1 to ensure net euglycemia [
54].
These complementary hormonal actions converge to provide a multi-pronged attack on energy intake, energy expenditure, and nutrient partitioning. Preclinical studies and early clinical trials suggest that a balanced tri-receptor agonist may achieve metabolic benefits that mimic or surpass those observed following metabolic surgery [
65]. The success of this approach depends on the precise engineering of receptor selectivity, potency ratios, and pharmacokinetics to maximize efficacy while minimizing adverse events.
Retatrutide: the first triple agonist in phase II trials
Retatrutide (LY3437943) is the first triple incretin agonist to demonstrate clinical efficacy in humans [
66]. It produced a mean body weight reduction of 24.2% over 48 weeks at a 12 mg dose in a phase II trial involving 338 adults with obesity, with more than half of the participants achieving at least 20% weight loss [
10]. This extent of weight loss exceeds that reported with GLP-1/GIP dual agonists. The magnitude of weight reduction achieved with retatrutide has narrowed the gap between pharmacologic and surgical outcomes, marking a potential paradigm shift toward metabolic disease remission through non-surgical means. Beyond its quantitative efficacy, retatrutide’s ability to improve hepatic steatosis, glycemic control, and inflammatory markers suggests that next-generation triple agonists may provide surgery-comparable, yet less invasive, pathways to durable metabolic restoration. Hemoglobin A1c level was reduced by up to 2.02% in participants with T2D, confirming its glycemic efficacy [
10]. Furthermore, liver fat content measured using magnetic resonance imaging proton density fat fraction (MRI-PDFF) decreased by 84.2%, underscoring its potential role in MASLD treatment [
10]. The safety profile of retatrutide is consistent with that of other GLP-1-based agents. Most adverse events were found to be mild-to-moderate GI symptoms, including nausea and diarrhea, with no reported severe hypoglycemia or cardiovascular complications [
10]. Weight loss continued through week 48 without plateauing, suggesting ongoing efficacy with prolonged treatment duration [
10].
Considering its effects on both adiposity and hepatic lipid metabolism, retatrutide is currently being investigated in metabolic indications beyond obesity and T2D. The TRIUMPH clinical development program includes trials evaluating retatrutide in MASLD, MASH, HFpEF, and other cardiometabolic diseases.
Comparative insights across multi-receptor agonists
Recent clinical data enable a comparative understanding of how distinct receptor profiles shape metabolic outcomes. Dual GLP-1/GIP agonists, such as tirzepatide, primarily enhance glycemic control and insulin sensitivity through synergistic incretin and β-cell effects, producing the most pronounced HbA1c reductions among all classes. In contrast, GLP-1/glucagon co-agonists, such as cotadutide and survodutide, preferentially enhance lipid oxidation, energy expenditure, and hepatic fat clearance, conferring stronger effects on steatosis resolution relative to GIP-based combinations. Triple agonists, such as retatrutide, integrate both pathways, combining the potent weight and glycemic effects of tirzepatide with the hepatocellular lipid oxidation and thermogenic properties of glucagon agonism.
From a vertical perspective, these mechanistic differences correspond to specific outcome domains: incretin-dominant agents optimize glycemic endpoints, glucagon-dominant agents improve hepatic and energy balance parameters, and balanced tri-agonists bridge both dimensions. Contradictory findings—such as variable effects on lean body mass or GI tolerability—are likely explained by differences in receptor engagement ratios, pharmacokinetics, and dosing strategies. These comparisons illustrate that the diversity of receptor profiles offers an expanding therapeutic spectrum, allowing clinicians to match pharmacologic profiles to metabolic phenotypes and treatment priorities.
CLINICAL APPLICATIONS OF ENGINEERED NUTRIENT-STIMULATED HORMONAL MULTIAGONISTS
The development of nutrient-stimulated hormonal multiagonists has catalyzed a paradigm shift in the treatment of chronic metabolic diseases. Although originally designed for glycemic control in T2D, GLP-1 RAs and their advanced multi-agonist derivatives are now being applied in cardiometabolic and even neurodegenerative conditions.
Tables 1 and
2 summarize the major clinical applications supported by evidence from randomized controlled trials and ongoing phase III trials.
Obesity is the primary indicator of modern incretin-based therapies, particularly because of their ability to target central appetite regulation, GI motility, and peripheral metabolic processes. GLP-1 RAs, such as semaglutide (2.4 mg weekly), have produced 14.9% mean weight loss in the STEP 1 trial [
18]. Dual agonists, most notably tirzepatide, have set new benchmarks, with weight losses exceeding 20% in the SURMOUNT-1 trial [
8]. Retatrutide, the first triple GLP-1/GIP/glucagon agonist to complete a phase II trial, reported an average of 24.2% weight loss over 48 weeks, approaching outcomes observed with bariatric surgery [
10]. Moreover, combinations, such as CagriSema (GLP-1/amylin) and Survodutide (GLP-1/glucagon), expand the therapeutic options for patients with poor GLP-1 monotherapy tolerability or insufficient weight loss response [
9,
20]. Recently, phase III trials of CagriSema in those with obesity not accompanied with T2D (REDEFINE1) and by T2D (REDEFINE 2) have been published, in which once-weekly coadministration of cagrilintide and semaglutide (2.4 mg each) led to substantial and clinically meaningful reductions in body weight compared to placebo—by 20.4% in REDEFINE 1 and 13.7% in REDEFINE 2 [
58,
59]. Furthermore, recent phase II trial of oncemonthly Maridebart cafraglutide (known as MariTide), a long-acting peptide–antibody conjugate that combines GLP-1 receptor agonism and GIPR antagonism, will give us the new opportunity of managing obesity with/without T2D in a monthly-based manner [
67].
GLP-1 RAs have long been established as second-line therapeutic agents for T2D. They have been recommended by the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) guidelines for their dual benefit in glycemic control and cardiovascular risk reduction [
68]. Semaglutide and liraglutide reduce HbA1c by approximately 1.5 to 1.8%, with a minimal risk of hypoglycemia and added weight loss benefit [
69]. Tirzepatide has redefined glycemic targets, achieving HbA1c reductions of up to 2.5% even in insulin-treated patients in the SURPASS trial [
70]. Retatrutide, although still under investigation, reduced HbA1c up to 2.02% in individuals with T2D, along with marked improvements in insulin sensitivity and betacell function [
71].
In parallel with the rapid advancement of peptide-based incretin agonists, the development of oral small-molecule incretin mimetics has emerged as a significant inflection point in the field [
72,
73]. Agents such as orforglipron, a first-inclass, non-peptidyl GLP-1 RA, demonstrate that small-molecule scaffolds can achieve clinically meaningful glycemic and weight-lowering efficacy with once-daily oral administration [
74]. Recently, orforglipron demonstrated a glycemic and weight-lowering efficacy superior to that of placebo in patients with early T2D, supporting its potential as a firstin-class oral agent for T2D [
75]. These compounds offer potential advantages in terms of manufacturing scalability, and improved patient accessibility, particularly for populations reluctant to initiate injectable therapies [
72,
73]. However, limitations remain, including dose-escalation–related GI intolerance, insufficient long-term safety, and currently unestablished relative potency compared with injectable GLP-1 RAs and multi-receptor peptide agonists [
76].
The liver is a principal metabolic target of incretin-based multi-agonists, integrating systemic and local hormonal signals that coordinate lipid oxidation, glucose flux, and inflammatory tone. Previous studies suggested potential GLP-1 receptor expression in hepatocytes; however, subsequent evidence indicates that most GLP-1–mediated hepatic effects are indirect, driven by reductions in caloric intake, body weight, and insulin resistance [
77]. Through secondary AMPK activation and suppression of SREBP-1c–dependent lipogenesis, GLP-1 RAs reduce hepatic de novo lipogenesis and gluconeogenic enzyme expression while improving glycogen storage [
78]. The pivotal phase III ESSENCE trial demonstrated that once-weekly semaglutide (2.4 mg) significantly improved liver histologic features in patients with MASH and moderate to advanced fibrosis. A greater proportion of patients receiving semaglutide achieved the primary endpoint of MASH resolution without worsening of fibrosis at 72 weeks, compared to placebo. In addition, semaglutide markedly reduced liver stiffness, Enhanced Liver Fibrosis (ELF) score, and key cardiometabolic risk factors. These findings provide the first phase III-level evidence that a GLP-1 RA can improve hepatic steatosis and alter the histopathologic trajectory of MASH, confirming the potential of semaglutide as a disease-modifying agent in MASLD/NASH [
34].
The metabolic actions of GIPR signaling in the liver are context-dependent and mechanistically complex. Under physiological conditions, GIP enhances adipose tissue insulin sensitivity and stimulates adiponectin secretion, thereby indirectly activating hepatic AMPK and FGF21 pathways that promote fatty-acid oxidation and improve metabolic flexibility. Conversely, under conditions of nutrient excess, GIP signaling may facilitate hepatic lipid uptake and contribute to steatosis, suggesting that the net hepatic outcome reflects a balance between GIP agonism and antagonism [
79]. Supporting this, GIP knockout mice exhibit reduced hepatic steatosis and lower IL-6 levels when fed a high-fat diet, implicating GIP in inflammatory signaling within the liver [
80]. Clinically, dual GIP and GLP-1 receptor agonism has demonstrated therapeutic potential in MASH; in the phase 2 SYNERGY-NASH trial, tirzepatide significantly reduced NAS scores and improved fibrosis stage in a substantial proportion of patients [
81]. In this trial, MASH resolution without worsening of fibrosis was achieved in 44–62% of participants receiving tirzepatide, compared with 10% in the placebo group, and fibrosis improvement of at least one stage without worsening of MASH occurred in up to 55% of tirzepatide-treated individuals versus only 30% with placebo [
81]. These quantitative outcomes underscore the substantial histologic efficacy of tirzepatide, reinforcing its therapeutic potential in the management of MASH.
In contrast, GCGR activation directly modulates hepatocellular energy metabolism. Engagement of the GCGR stimulates mitochondrial biogenesis and β-oxidation, increases FGF21 and PPARα signaling, and enhances autophagic lipid turnover [
53]. These mechanisms collectively accelerate lipid clearance, lower hepatic triglyceride content, and attenuate stellate-cell activation and oxidative stress. Therefore, dual GLP-1/glucagon co-agonists, such as survodutide [
82], cotadutide [
83] and pemvidutide [
84] yield greater improvements in hepatic steatosis and fibrosis biomarkers than GLP-1 monotherapy, reflecting additive modulation of mitochondrial and inflammatory pathways. For instance, survodutide achieved the improvement of MASH without worsening of fibrosis in up to 62% of participants versus 14% with placebo, and significantly reduced liver fat content measured by MRI-PDFF in the phase 2 trial in patients with MASH [
82], further reinforcing the therapeutic relevance of dual GLP-1/GCGR engagement in MASH.
When these hormonal axes are simultaneously engaged—as achieved with triple agonists such as retatrutide—hepatic metabolism shifts from lipid storage toward oxidative and anti-inflammatory states. In a phase 2 trial, retatrutide achieved an 82% reduction in liver fat content measured by MRI-PDFF, reinforcing its potential as a cornerstone therapy for MASLD [
85]. These findings highlight that concurrent activation of GLP-1, GIP, and GCGRs orchestrates a coordinated improvement in hepatic lipid handling, offering a multifaceted approach to reversing metabolic steatosis and inflammation.
Several GLP-1 RAs have demonstrated cardioprotective benefits, including reductions in MACE, heart failure hospitalizations, and progression of atherosclerosis. For instance, semaglutide (2.4 mg) reduced 3-point MACE by 20% in overweight and obese individuals without diabetes in the SELECT trial, indicating a cardiovascular benefit independent of glycemic control [
33]. In the STEP-HFpEF and STEP-HFpEF-DM trials, semaglutide also significantly improved symptoms, physical function, and NT-proBNP levels in patients with HFpEF, thereby expanding the therapeutic potential of GLP-1 RAs beyond atherosclerotic CVD [
35,
36].
Tirzepatide, a dual GIP and GLP-1 receptor agonist, is currently under investigation in cardiovascular outcome trials such as SURPASS-CVOT and SURMOUNT-MMO [
86]. Notably, the SUMMIT trial recently demonstrated that once-weekly tirzepatide significantly reduced the risk of cardiovascular death or worsening heart failure events in patients with HFpEF and obesity (hazard ratio, 0.62; 95% confidence interval [CI], 0.41–0.95) [
87]. Compared to placebo, tirzepatide also led to greater improvements in healthrelated quality of life, 6-minute walk distance, body weight, and markers of systemic inflammation [
87]. These findings align with and extend previous data from semaglutide studies, reinforcing the emerging role of dual agonists in the management of obesity-related HFpEF.
Emerging evidence supports a potential neuroprotective function for GLP-1 RAs in neurodegenerative diseases. GLP-1R is expressed in several brain regions, including the hippocampus and cortex, where it may influence synaptic plasticity, neuroinflammation, and cellular energy metabolism [
88,
89]. Preclinical studies and early-phase trials have demonstrated that semaglutide may reduce amyloid-beta accumulation, mitigate tau pathology, and improve cognitive performance in Alzheimer’s disease models [
90]. Although they have not yet been approved for neurological indications, this application reflects the expanding therapeutic landscape of incretin-based agents beyond classical metabolic targets.
As discussed in the preceding paragraph, substantial preclinical and clinical evidence support the neuroprotective benefits of NUSH-based therapies in neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Beyond their metabolic and neuroprotective actions, NUSH-based therapies may also exert favorable influences on mental health through integrated neuroendocrine and reward-regulatory pathways. Experimental and translational studies have shown that activation of GLP-1 receptors modulates dopaminergic signaling within the mesolimbic system and prefrontal cortex, attenuating stress-induced and reward-driven behaviors [
91]. These mechanisms provide a plausible biological basis for clinical observations linking GLP-1 RAs to improved mood, motivation, and hedonic control independent of weight reduction. Recent clinical evidence further supports these neurobehavioral benefits; for example, a phase 2 randomized trial demonstrated that once-weekly administration of semaglutide reduced alcohol craving and consumption in adults with alcohol use disorder [
92], and meta-analytic data suggest improvements in emotional well-being and quality of life among individuals receiving GLP-1-based therapy [
93]. Moreover, novel multiagonist peptides that combine GLP-1 with GIP, glucagon, or amylin activity may synergistically target central circuits governing appetite, cognition, and affect, thereby expanding the therapeutic spectrum of incretin-based agents [
91,
93]. These data are preliminary; however, accumulating evidence indicates that NUSH-based therapies could bridge metabolic and psychiatric care, providing a new paradigm for improving physical and mental health outcomes.
As incretin-based multi-agonists move toward routine clinical practice, tailoring their use to individual metabolic phenotypes is central to realizing precision medicine. Patients with hepatic steatosis, visceral adiposity, or reduced energy expenditure may particularly benefit from agents with GCGR activity (such as GLP-1/glucagon or triple GLP-1/GIP/glucagon agonists), which enhance lipid oxidation and thermogenesis. In contrast, those with marked hyperglycemia or insulin resistance may achieve superior glycemic and weight outcomes with dual GLP-1/GIP agonists, such as tirzepatide, which combine potent insulinotropic and insulin-sensitizing effects. For individuals with appetite dysregulation or poor GI tolerance to high-dose GLP-1 therapy, GLP-1/amylin co-agonists (such as CagriSema) provide additive satiety benefits with improved tolerability. The emergence of GIP antagonist conjugates (such as AMG-133 and Maridebart cafraglutide) further broadens the therapeutic landscape for patients with hyperphagic obesity or GLP-1 resistance. These mechanistically distinct strategies enable a phenotype-guided selection of multi-agonist therapy—bridging molecular design with individualized metabolic needs.
ADVERSE EFFECTS AND TOLERABILITY
With the clinical success of GLP-1-based multi-agonists, an urgent requirement to understand and monitor the safety and tolerability of these agents has emerged. Because their use extends beyond diabetes into obesity, MASLD, and potentially neurodegenerative disorders, characterizing both common and rare adverse effects across diverse populations and treatment durations is essential. GI symptoms remain the most frequently observed side effects; increasing attention is being paid to risks related to lean mass loss, neuropsychiatric effects, and long-term organ safety (
Table 3).
The most common side effects of GLP-1 RAs and their multi-agonist derivatives are GI adverse events. Symptoms such as nausea, vomiting, diarrhea, abdominal pain, and early satiety are frequently reported, particularly during the early weeks of therapy and dose escalation phases. Semaglutide (2.4 mg) caused nausea in 44.2% of participants in the STEP 1 trial, whereas vomiting and diarrhea were reported in 24.8% and 22.7%, respectively [
18]. Clinical strategies, such as slow dose titration, meal timing adjustment, and reassurance, can help improve tolerability and minimize treatment discontinuation [
94].
Emerging evidence suggests that GIPR co-activation may mitigate the GI adverse effects commonly observed with GLP-1 RAs. Preclinical and translational studies have demonstrated that GIPR agonism exerts antiemetic and anti-nausea effects by modulating inhibitory pathways in the hindbrain. In particular, GIPR-expressing GABAergic neurons in the area postrema and nucleus tractus solitarius form a local inhibitory network that suppresses GLP-1R– mediated emetic signaling [
95]. In rodent and primate models, activation of this pathway reduced GLP-1 agonist-induced nausea and emesis without diminishing metabolic efficacy. Consistently, Samms et al. [
96] have proposed that balanced GIP co-activation may buffer excessive GLP-1R stimulation within central emetic circuits, thereby improving therapeutic tolerability. These findings provide a plausible neurophysiological basis for the lower incidence of nausea and vomiting observed with dual GIP/GLP-1 receptor agonists, such as tirzepatide, although the detailed molecular mechanisms remain to be elucidated.
The risk of developing acute pancreatitis, gallbladder disease, and medullary thyroid carcinoma (MTC) has been scrutinized since the early development of GLP-1 RAs. Meta-analyses of large cardiovascular outcome trials, including LEADER, SUSTAIN-6, and REWIND, have not revealed a statistically significant increase in pancreatitis or pancreatic cancer compared to placebo [
97,
98].
Gallbladder-related adverse events, such as cholelithiasis and cholecystitis, could be related to rapid weight loss or altered bile composition, and their incidence appears slightly higher with agents such as liraglutide and semaglutide [
99]. In addition, rodent studies have demonstrated the risk of developing C-cell hyperplasia and MTC following chronic GLP-1 exposure [
100]; however, human data remain inconclusive. No increased MTC incidence has been confirmed in long-term human trials [
101].
Substantial weight loss achieved with GLP-1-based therapies has raised concerns regarding potential adverse effects on muscle mass and function. Clinical trial data on changes in lean mass remain heterogeneous; while some studies report that 40–60% of total weight loss is derived from lean tissue, others suggest a lower proportion, typically around 15% or less [
102]. In the SURMOUNT-1 trial, tirzepatide treatment resulted in favorable changes in body composition, with fat mass reduction approximately threefold greater than lean mass reduction. Consequently, the fat-to-lean mass ratio decreased significantly—from 0.93 to 0.70 with tirzepatide versus 0.95 to 0.88 with placebo—indicating an overall improvement in body composition [
8]. Nonetheless, in populations with advanced age or comorbidities, the potential risk of sarcopenia warrants individualized riskbenefit assessment when initiating pharmacologic weight loss interventions.
Preliminary data suggest minimal adverse effects on bone mineral density (BMD); A recent meta-analysis suggested that pharmacologic interventions including GLP-1-based therapies can induce weight loss without significantly compromising BMD, whereas bariatric surgery was consistently linked to decreased lumbar spine BMD [
103]. However, emerging evidence warrants cautious interpretation. A randomized, double-blind, placebo-controlled phase 2 trial in Denmark involving 64 adults at high fracture risk found that once-weekly subcutaneous semaglutide did not increase the bone formation marker P-PINP relative to placebo, but did increase bone resorption and led to reductions in lumbar spine and hip BMD, tibial cortical thickness, and body weight over 52 weeks [
104]. Longitudinal data using DXA and sarcopenia-specific functional endpoints are warranted to elucidate the long-term musculoskeletal safety of these agents [
105-
108].
Regulatory authorities have recently focused on potential neuropsychiatric adverse events—including suicidal ideation, depression, and anxiety—associated with GLP-1 RAs. Post-marketing reports of mood changes and suicidal thoughts among users of semaglutide and liraglutide prompted the FDA and the European Medicines Agency to initiate pharmacovigilance reviews in 2023. In clinical development programs, including the STEP and SURPASS trials, a higher incidence of psychiatric events was observed in the semaglutide arm of certain studies (STEP 2 and 6), although these were not prespecified endpoints, and posthoc analyses did not demonstrate a significant increase in suicidal behavior or psychiatric hospitalization [
31,
109,
110].
Large-scale randomized controlled trials such as SUSTAIN, SELECT, and SURPASS, as well as multiple realworld cohort studies, have consistently reported no significant increase in the risk of depression, suicidality, or psychiatric hospitalization compared with placebo or other anti-diabetic agents [
110-
112]. However, recent pharmacovigilance analyses from FAERS and VigiBase have produced mixed findings, with weak-to-moderate safety signals for depressive or suicide-related events observed for semaglutide but not for other GLP-1 RAs, such as liraglutide or tirzepatide [
113,
114].
To date, no causal relationship has been established between GLP-1RA therapy and suicidal ideation or mood disorders; however, given the high baseline prevalence of psychiatric conditions among individuals with obesity, continued vigilance, patient education, and careful screening for psychiatric history remain warranted. Ongoing post-marketing surveillance and long-term prospective studies will be crucial to further elucidate the neuropsychiatric safety profile of current and emerging incretin-based multi-agonists.
UNRESOLVED QUESTIONS
Despite their remarkable therapeutic potential, GLP-1-based multi-agonists raise several unresolved questions that must be addressed to ensure sustainable, equitable, and effective integration into long-term clinical care. These questions involve pharmacological duration, health system access, and real-world implementation.
Therapy duration and post-discontinuation weight regain
The optimal duration of GLP-1–based multi-agonist therapy remains to be established. Most pivotal clinical trials, including the STEP, SURMOUNT, REDEFINE, and TRIUMPH programs, have evaluated treatment durations ranging from 36 to 72 weeks, with no randomized evidence extending beyond two years. Increasing evidence now recognizes weight regain after treatment discontinuation as a clinically relevant and persistent challenge.
In the STEP 1 extension trial, participants previously treated with once-weekly semaglutide 2.4 mg achieved a mean weight reduction of 17.3% at week 68 but regained 11.6 percentage points of body weight within one year following treatment withdrawal, resulting in a net loss of only 5.6% from baseline [
115]. Similarly, in the STEP 4 withdrawal study, participants randomized to placebo after 20 weeks of semaglutide regained 6.9 percentage points of body weight compared with those who continued treatment [
116]. The SURMOUNT-4 trial further demonstrated that participants who discontinued tirzepatide experienced a 14.0% weight regain over a 52-week withdrawal phase, whereas continued therapy maintained an overall 25.3% reduction from baseline [
117]. A recent pooled analysis integrating data from these withdrawal trials (n=800) reported a mean absolute weight regain of 9.69 kg after discontinuation of semaglutide or tirzepatide [
118], underscoring the chronic and relapsing nature of obesity that necessitates long-term pharmacologic management. Although newer agents such as CagriSema and orforglipron have demonstrated robust weight-lowering efficacy, systematic data on post-discontinuation outcomes remain unavailable. Future investigations should determine optimal maintenance strategies—such as gradual dose tapering, intermittent continuation, or combination regimens—to prevent rebound weight gain and sustain metabolic benefits after cessation of incretinbased multi-agonist therapy.
Recent evidence suggests that while the efficacy of incretin-based therapies may attenuate modestly beyond two years, clinically meaningful benefits persist. A 2025 systematic review and network meta-analysis of 55 randomized trials (18,876 participants) demonstrated sustained improvements in HbA1c, fasting glucose, body weight, and systolic blood pressure with GLP-1 RAs for up to 104 weeks, although HbA1c and fasting glucose reductions declined slightly (–0.36% and –0.47 mmol/L, respectively) after two years [
119]. Weight loss generally plateaued between 68 and 78 weeks, indicating durable yet adaptive efficacy [
119]. Nevertheless, evidence regarding the long-term durability of newer multi-agonists such as tirzepatide remains scarce, highlighting the need for further confirmation from long-term and real-world studies.
It remains uncertain whether these long-term cardiorenal benefits can be replicated or further enhanced by multi-agonists. Cardiovascular outcome trials of tirzepatide—SURPASS-CVOT and SUMMIT—have shown encouraging signals, with SURPASS-CVOT meeting the prespecified criteria for non-inferiority for MACEs and a 16% reduction in all-cause mortality [
86]. In SYNERGY-NASH, tirzepatide also achieved higher rates of MASH resolution without fibrosis worsening versus placebo, suggesting hepatic benefits [
81]. However, whether longer use of multi-agonists can induce sustained improvements in hard outcomes—such as cardiovascular events, liver cirrhosis, or mortality—remains to be determined.
The remarkable clinical efficacy of GLP-1–based multiagonists has not yet translated into broad population-level benefits due to cost and access barriers. In most OECD countries—including Korea—these agents remain unreimbursed despite strong evidence for cardiovascular and metabolic benefits. In the United States, the list price of a 4-week supply of semaglutide or tirzepatide ranges from USD 900 to 1,350 [
120,
121], rendering them inaccessible for uninsured or underinsured patients. Such inequities disproportionately affect individuals from lower socioeconomic groups, who already carry a higher burden of obesity and diabetes [
120,
122-
124].
A recent lifetime cost-effectiveness analysis using the validated Diabetes-Obesity-Cardiovascular Disease Microsimulation (DOC-M) model projected the long-term health and economic impacts of tirzepatide and semaglutide in 126 million US adults [
125]. Both drugs substantially reduced lifetime incidences of obesity, diabetes, and CVD—preventing up to 45,609 obesity and 20,854 diabetes cases per 100,000 individuals—and yielded the largest incremental Quality-Adjusted Life Year (QALY) gains (0.35 for tirzepatide; 0.25 for semaglutide). However, their incremental cost-effectiveness ratios were USD 197,023/QALY and USD 467,676/QALY, respectively, indicating that price reductions of ~30% (tirzepatide) and ~82% (semaglutide) would be required to meet the conventional threshold of USD 100,000/QALY. These results were derived from USbased pricing, where drug acquisition costs are among the highest worldwide. Importantly, the United States not only faces higher medication prices but also bears markedly higher costs for diabetes, cardiovascular, and obesity-related care compared with other health systems. Therefore, cost-effectiveness should be interpreted within each country’s healthcare cost structure and willingness-to-pay threshold. Overall, the findings highlight that further price reductions and value-based reimbursement will be necessary for GLP-1-based therapies to achieve sustainable cost-effectiveness globally.
The global demand for GLP-1-based therapies has also outpaced manufacturing capacity, leading to intermittent shortages of semaglutide and tirzepatide since 2022 [
126]. Such disruptions prompted regulatory advisories and interrupted continuity of care. Coordinated strategies among manufacturers, payers, and regulators are urgently needed to expand production capacity and maintain supply stability.
From a policy perspective, recent health economics frameworks emphasize drug-economics-informed solutions to achieve affordable access [
124]. Key proposals include valuebased pricing tied to measurable clinical outcomes, risksharing or subscription-based payment models, and government-negotiated procurement mechanisms. Moreover, public–private partnerships and pooled purchasing strategies could reduce manufacturing costs and secure equitable global distribution. As discussed in recent economic analyses [
127], integrated approaches combining patent licensing for generic competition, tiered pricing across income regions, and federal reinvestment of public R&D subsidies may enhance affordability and sustainability of GLP-1-based obesity medications. Ultimately, translating the therapeutic potential of multi-agonists into population-wide cardiometabolic benefits will depend on both biomedical innovation and deliberate policy action to ensure equitable access and scalable implementation.
The use of NUSH-based therapies in special populations presents unique challenges and uncertainties that warrant careful evaluation. In adolescent obesity, evidence supporting the use of GLP-1–based therapies in adolescents is rapidly expanding. Liraglutide 3.0 mg was the first agent approved for adolescent obesity, and the STEP-TEENS trial demonstrated that once-weekly semaglutide reduced body mass index (BMI) by a mean −16.1 percentage points versus −0.6 with placebo in adolescents aged 12–18 years [
128]. A 2025 meta-analysis confirmed that GLP-1 RAs significantly reduced BMI z-score, waist circumference, and body weight in children and adolescents with obesity [
129]. Short-term tolerability was similar to that in adults, with GI symptoms being the most frequent adverse events [
129]. However, pediatric obesity differs substantially from adult obesity: ongoing growth, nutritional requirements, and psychosocial sensitivity raise concerns regarding potential effects on bone accretion, linear growth, and behavioral adaptation [
130]. Long-term safety and optimal treatment duration remain uncertain, necessitating cautious, multidisciplinary management.
GLP-1 RAs and dual agonists maintain metabolic efficacy in elderly populations. A 2024 meta-analysis demonstrated comparable HbA1c and weight-reduction effects in adults ≥65 years and younger groups, though discontinuation due to adverse events was slightly higher [
131]. Clinicians and researchers have recently emphasized the need to consider frailty and sarcopenic–obese phenotypes [
132]: frail individuals with high cardiometabolic risk may benefit, whereas anorexic or malnourished phenotypes are vulnerable to excessive weight loss or dehydration [
133]. Therefore, individualized initiation thresholds, gradual dose titration, and periodic assessment of muscle mass and bone density—an issue recently highlighted in relation to GLP-1 therapy [
104]— are critical when treating older or frail patients.
Data on hereditary or monogenic obesity remain limited but are emerging. A 2024 study reported attenuated efficacy of GLP-1 RAs in individuals with obesity associated with pathogenic mutations or type 1 diabetes [
134]. Conversely, a case series described meaningful weight loss (mean −5.7 kg/m² BMI) and improved satiety with liraglutide in adults with molecularly confirmed genetic obesity—including MC4R variants and 16p11.2 deletion syndrome—without major adverse events [
135]. In patients with Alström syndrome, treatment with semaglutide or exenatide reduced body weight by 5.4±1.7 kg (95% CI, 3.6–7.0), and improvements in metabolic parameters were comparable to those observed in polygenic obesity, irrespective of weight loss [
136]. A 2025 Nature Medicine analysis of the SURMOUNT-1 trial showed that tirzepatide achieved similar 72-week weight reduction in carriers of pathogenic MC4R mutations (−18.3%) and noncarriers (−19.9%), suggesting preserved responsiveness in the most common form of monogenic obesity [
137].
These findings indicate that NUSH-based therapies can provide meaningful benefits across age and genetic subgroups; however, in such specific populations, further discussion and investigation are clearly needed to determine the optimal timing, duration, and discontinuation strategies for GLP-1–based and multi-agonist treatments.
Challenges in predicting and optimizing multireceptor agonism
Predicting in vivo efficacy of multi-receptor agonists remains a major unresolved challenge, as the pharmacologic activity depends not only on receptor affinity but also on tissue-specific receptor density, distribution, and internalization kinetics. GLP-1R, GIPR, and GCGR exhibit distinct expression patterns across metabolic organs, and their occupancy levels in vivo may differ substantially from in vitro predictions. Recent cryo-electron microscopy (cryo-EM) studies revealed that retatrutide (LY3437943) engages these receptors through conserved and receptor-specific contact residues within the extracellular loops and transmembrane helices, allowing differential activation despite shared sequence motifs [
138]. These structural findings underscore that receptor activation is governed by intrinsic binding potency, conformational flexibility, and local receptor accessibility—factors that collectively influence efficacy and tolerability. Thus, in vitro affinity data alone cannot accurately predict therapeutic performance, highlighting the need for QSP models that integrate receptor kinetics, tissue expression, and signaling bias to better forecast clinical potency and safety.
This complexity is further magnified in GLP-1/GIP/glucagon triple agonists, where optimal receptor balance determines the trade-off between metabolic efficacy and glycemic safety. The preclinical study by Knerr et al. demonstrated that the design of unimolecular peptide triagonists was guided by empirically optimized receptor potency ratios, derived through iterative in vivo testing rather than theoretical modeling [
139]. Through systematic variation of receptor potency ratios, the authors identified compounds achieving maximal weight loss and glucose control in obese mice, confirming that receptor balance cannot yet be predicted in silico due to complex receptor crosstalk and feedback regulation.
Mechanistically, GCGR activation adds an energy-expending component by stimulating lipid oxidation and thermogenesis, while GLP-1R and GIPR co-activation counteracts glucagon-induced hyperglycemia. Consequently, most next-generation triagonists—including SAR441255, retatrutide, and NN1706—are designed with reduced glucagon potency (approximately one-tenth that of GLP-1R activity) to preserve euglycemia while maintaining thermogenic drive [
66,
139-
141]. However, this attenuation, although protective against hyperglycemia, constrains the maximal weight-loss potential of the glucagon component, which has a steep dose–response curve [
142,
143].
Therefore, identifying an optimized receptor potency ratio is crucial to harmonize efficacy and safety. Future advances should aim to replace empirical trial-and-error with structure-guided, model-based design strategies that integrate receptor kinetics, structural adaptability, and metabolic feedback. Such approaches may enable rational tuning of receptor engagement, expanding the therapeutic window for glucagon activity and maximizing the synergistic benefits of multi-receptor activation.
CONCLUSION
The emergence of engineered nutrient-stimulated hormonal multi-agonists has emerged as a transformative advancement in the treatment of obesity and its related metabolic disorders. These agents simultaneously target multiple hormonal pathways—GLP-1, GIP, glucagon, amylin, and others—to mimic the physiologic complexity of postprandial endocrine signaling, thereby offering a pharmacological surrogate for multisystemic benefits. The robust and durable efficacy of dual agonists, such as tirzepatide and CagriSema, and more recently, of the triple agonist retatrutide, has been validated clinically across diverse populations. These agents have consistently demonstrated double-digit weight loss, HbA1c reductions approaching or exceeding 2%, improvements in hepatic steatosis and inflammation, and in certain cases, meaningful cardiovascular and functional benefits. In addition, orally active smallmolecule agents, such as orforglipron, have expanded the accessibility and acceptability of GLP-1-based therapies, representing a complementary innovation in drug formulation and delivery.
The therapeutic implications of these agents are surpassing those of obesity and T2D. Ongoing studies suggest their meaningful clinical benefits in MASLD/MASH, HFpEF, atherosclerotic CVD, and potentially even neurodegenerative disorders. Altogether, GLP-1–based multi-agonist therapies have evolved from metabolic regulators to disease-modifying agents to address multiple organ systems involved in different chronic diseases.
FOOTNOTES
-
Authors’ contributions
C.H.J. conceptualized and supervised the study. Y.K.C. performed data collection and wrote the original draft. C.H.J. reviewed and finalized the manuscript.
-
Conflicts of Interest
The authors have no conflicts to disclose.
Figure 1.Timeline of GLP-1 discovery and clinical development of nutrient-stimulated hormonal multi-agonists. This figure was created using BioRender. GLP-1, glucagon-like peptide-1; RA, receptor agonist; T2D, type 2 diabetes.
Figure 2.Tissue-specific metabolic effects of nutrient-stimulated hormones targeted by multi-agonist therapies. GLP-1, GIP, glucagon, amylin, and PYY exert pleiotropic actions across multiple organ systems involved in energy homeostasis. GLP-1, GIP, amylin, and PYY primarily reduce appetite through central pathways and delay gastric emptying. GLP-1 and GIP stimulate insulin secretion, whereas glucagon increases energy expenditure and promotes lipolysis, despite also stimulating hepatic glucose production. Amylin and PYY enhance satiety and contribute to delayed gastric emptying. The co-activation of these hormonal axes using dual and triple agonists enables synergistic modulation of glycemic control, energy balance, and adipose tissue metabolism. This figure was created using BioRender. GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; PYY, peptide YY.
Figure 3.Pleiotropic metabolic and organ-specific benefits of semaglutide across multiple disease domains. This figure was created using BioRender. CI, confidence interval; HbA1c, glycated hemoglobin; HFpEF, heart failure with preserved ejection fraction; HR, hazard ratio; MACEs, major adverse cardiovascular events; MASH, metabolic dysfunction-associated steatohepatitis; MASLD, metabolic dysfunction-associated steatotic liver disease.
Table 1.Summary of major randomized controlled trials evaluating GLP-1 RAs, dual and triple hormonal co-agonists, and orforglipron for the treatment of obesity, T2D, and MASLD
Table 1.
|
Drug |
Agonist type |
Target indications |
HbA1c reduction (%) |
Weight loss (%) |
Additional clinical outcomes |
|
Semaglutide |
GLP-1 RA |
Obesity, T2D, MASLD |
1.8–2.0 in T2D; up to 1.5 in obesity without diabetes |
14.9% (STEP 1, 68 wk); 9.6% in T2D (STEP 2) |
↓ MACE by 20% (SELECT); ↓ hepatic steatosis and fibrosis (ESSENCE); improved HFpEF symptoms |
|
Tirzepatide |
Dual (GLP-1/GIP) |
Obesity, T2D, MASLD |
Up to 2.5 in insulin-treated T2D (SURPASS-5) |
20.9% (SURMOUNT-1, 72 wk); 15.7% in T2D (SURPASS-2) |
↓ liver fat; preserved lean mass; insulin sensitization in adipose tissue |
|
CagriSema |
Dual (GLP-1/ Amylin) |
Obesity, T2D |
2.2 in combination with semaglutide (REDEFINE-1) |
15.6% over 32 wk (REDEFINE-1) |
Improved GI tolerability; additive central and gastric satiety effects |
|
Survodutide |
Dual (GLP-1/ Glucagon) |
Obesity, MASLD |
1.7 in obesity without diabetes (Phase 2) |
14.9% over 46 wk (Loomba et al., 2024) |
Hepatoprotective; ↑ energy expenditure; maintained glycemic control |
|
Retatrutide |
Triple (GLP-1/GIP/ Glucagon) |
Obesity, T2D, MASLD |
Up to 2.02 in T2D (Phase 2) |
24.2% over 48 wk (Jastreboff et al., 2023) |
↓ liver fat by 84.2%; ↓ CRP and IL-6; weight loss continued beyond 48 wk |
|
Orforglipron |
Oral non-peptidyl GLP-1 RA |
Obesity, T2D |
1.48 in early T2D (ACHIEVE-1) |
14.7% over 36 wk (Rubino et al., 2023) |
Oral small molecule; comparable to injectable GLP-1 RA; favorable safety and adherence profile |
Table 2.Selected ongoing or recently completed clinical trials investigating GLP-1 receptor agonists, dual and triple peptides, and orforglipron in obesity, T2D, and MASLD
Table 2.
|
Drug |
Target indication |
Trial name |
Phase |
Primary endpoints |
Status |
Key reference |
|
Retatrutide |
Obesity, MASLD, HFpEF, T2D |
TRIUMPH (1–6) |
Phase 3 |
Body weight, hepatic fat reduction, NASH resolution, cardiovascular markers |
Recruiting |
Jastreboff et al., 2023 (NEJM) |
|
CagriSema |
Obesity+T2D |
REDEFINE 1/2/3 |
Phase 3 |
Body weight reduction, HbA1c change, safety and tolerability |
Ongoing |
Rosenstock et al., 2023 (Lancet) |
|
Orforglipron |
T2D, Obesity, MASLD |
ACHIEVE 1 |
Phase 3 |
Body weight, hepatic steatosis, HbA1c |
Ongoing |
Rubino et al., 2023 (NEJM) |
|
Tirzepatide |
MASLD with fibrosis (NASH) |
SYNERGY-NASH |
Phase 2 |
NASH resolution without fibrosis worsening |
Completed |
Neuschwander-Tetri et al., 2024 (JAMA) |
Table 3.Safety profile of GLP-1-based multi-agonists: common adverse events, frequency estimates, and clinical considerations
Table 3.
|
Category |
Common observations |
Estimated frequency |
Clinical implications |
|
Gastrointestinal adverse events |
Nausea, vomiting, diarrhea; typically dose-dependent; early-phase prevalence up to 44% (e.g., STEP 1) |
Common (30–45%) |
Often transient; mitigated with slow dose escalation, dietary counseling, and patient reassurance |
|
Serious and rare adverse events |
Acute pancreatitis (rare); gallbladder disease (e.g., cholelithiasis); theoretical risk of MTC (rodent data) |
Uncommon to rare (<2%) |
Contraindicated in patients with MEN2 or personal/family history of MTC; monitor gallbladder symptoms during rapid weight loss |
|
Muscle and bone health |
Lean mass loss accounting for 25–40% of total body weight reduction observed in trials (e.g., SURMOUNT-1) |
Moderate (25–40% of total WL) |
Recommend monitoring of appendicular lean mass, physical performance, and bone mineral density in older adults |
|
Neuropsychiatric safety |
Post-marketing reports of suicidal ideation or mood changes; no significant risk increase in RCTs |
Rare; under regulatory investigation |
Baseline screening for depression or psychiatric history advised; monitor high-risk patients closely |
|
Long-term safety |
Robust long-term data for semaglutide and liraglutide; limited data for retatrutide, CagriSema, orforglipron |
Unknown; to be determined |
Need for real-world pharmacovigilance and long-term extension trials for emerging agents |
Abbreviations
glucose-dependent insulinotropic polypeptide
heart failure with preserved ejection fraction
major adverse cardiovascular events
metabolic dysfunction-associated steatohepatitis
metabolic dysfunction-associated steatotic liver disease
magnetic resonance imaging proton density fat fraction
medullary thyroid carcinoma
nutrient-stimulated hormone
Quality-Adjusted Life Year
quantitative systems-pharmacology
Semaglutide Treatment Effect in People with Obesity
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