Transforming obesity: The advancement of multi-receptor drugs

Obesity, characterized by excessive body fat, constitutes a major risk factor for the development of type 2 diabetes (T2D), dyslipidemia, cardiometabolic disease 1 , cancer 2 , and overall mortality 3 . It further enhances complications associated with infectious diseases, as exemplified by COVID-19 4 . Between 1975 and 2014, global obesity rates escalated from 105 to 641 million adults (4% to 13% of the total population, respectively) 5 . It is estimated that worldwide obesity will continue to rise to one billion adults by 2030 6 , irrespective of gender, geography, or rural and urban styles of living 7 . Lifestyle modifications, with increased physical exercise and/or reduced caloric intake, are hallmarks of any successful weight loss intervention 8 . However, despite appreciable weight loss of ~5-8% in the short term, such lifestyle interventions have only limited potential for sustained weight reduction, particularly when utilized as a stand-alone therapy 8 . This is exemplified by a recent meta-analysis showing that ~56% of body weight loss, as achieved through lifestyle intervention, is regained within two years, and ~79% is regained after five years 9 . The major challenge in obesity management is the system’s intrinsic drive to preserve energy to defend the higher body weight. A reduction in caloric intake is therefore often accompanied by a decrease in energy expenditure, along with enhanced sensitivity to factors that stimulate food intake 10 . Combined, these responses hinder weight loss and promote weight regain. Until recently, bariatric surgery had been the most effective treatment for maintaining a reduction in body weight 11 , and as such, is the current benchmark for anti-obesity medications. The regulation of body weight is orchestrated primarily by the brain and adipose tissue ( Figure 1 ), which constantly integrate information related to the body’s energetic state to adjust food intake, satiety and energy balance 8 , 10 . Notable hormones implicated in this gut-brain-fat communication axis include, among many others, the adipokines leptin and adiponectin, the liver-secreted hormone fibroblast growth factor 21 (FGF21), the pancreatic α-cell-derived hormone glucagon, the gastrointestinal system peptides ghrelin, peptide YY (PYY) and cholecystokinin (CCK), in addition to the incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) 8 . Glucagon, traditionally known for its ability to counteract hypoglycemia, has been implicated in the pathogenesis of type 1 and type 2 diabetes 12 - 14 ( Textbox ). Glucagon acts through the glucagon receptor (GCGR), and alterations in GCGR signaling can have profound effects on glucose metabolism 12 . While lack of GCGR signaling can normalize glycemia under insulin-deficient conditions 15 , 16 , this effect is contingent on the presence of residual insulin 17 . Interestingly, glucagon has pleiotropic biology that extends beyond its role in glycemic control. In particular, preclinical studies have revealed that glucagon may be harnessed for metabolic benefits, such as body weight loss in the context of obesity 18 . Glucagon administration to rats was shown to promote a negative energy balance by increasing oxygen consumption 18 ; an effect later attributed to an increase in non-shivering thermogenesis 19 . Furthermore, enhanced GCGR signaling was reported to effectively reduce body weight through inhibition of food intake 20 - 22 and stimulation of energy expenditure 19 , 22 - 24 , and further, modulate lipid metabolism by driving lipolysis and inhibiting lipogenesis 25 - 28 . Glucagon also has the ability to inhibit gastric motility 29 and promote renal glomerular filtration 30 , with notable effects evident on the cardiovascular system to increase heart rate, cardiac contractility and cardiac output 31 ( Figure 1 ). Collectively, this supports the prospect that GCGR agonism may be employed as a viable option for the treatment of metabolic diseases associated with obesity, particularly when used in adjunct to therapeutics that are capable of restraining glucagon’s acute glycemic and cardiovascular limitations. Gut-hormone derived GIP, secreted from enteroendocrine K-cells in the upper intestine in the duodenum and jejunum mucosae 32 , was initially discovered to play an integral role in the body’s response to glucose intake 33 , 34 ( Textbox ). GIP exerts a significant role in adipose tissue blood flow 35 , and under conditions of hyperinsulinemia, promotes lipid deposition in adipocytes by stimulating lipoprotein lipase 36 , 37 . The gut-hormone also potentiates insulin-induced glucose uptake, which leads to an increase in lipid conversion from glucose 38 - 40 . However, in vivo , GIP was shown to promote lipolysis under conditions of normo- or hypoinsulinemia, and mice overexpressing GIP exhibit lower fat mass when fed a high-fat diet 41 . Preclinical studies further revealed that chemogenetic activation of GIPR neu

Unimolecular multi-receptor agonists that employ several independent signaling pathways are emerging as the best-in-class drugs for glycemic control and weight loss. The pleiotropic nature of glucagon’s biology 30 , together with a rekindled interest in the pharmacology of GIP, has ignited much interest in exploring their therapeutic use in unimolecular formulations with GLP-1R agonism to treat obesity and diabetes. The objective has been to increase the magnitude of weight loss possible in a broad community of individuals with obesity, without imposing safety limitations that naturally reside in GLP-1R agonism. Particularly in subjects with obesity and persistent T2D, GLP-1R-driven weight loss still plateaus in the single digit range 69 , and as such, enhanced efficacy from supplemental pharmacology to further accelerate weight loss, while ideally simultaneously addressing obesity-linked co-morbidities, remains the primary goal. Multiple gut-hormone combinations have been explored preclinically, with an appreciable number having advanced to clinical studies, with unimolecular peptides possessing varying degrees of GLP-1R, GIPR and GCGR activity, constituting the clinically most matured set of drug candidates. Here, we will discuss the preclinical and clinical studies in receptor co-agonism of GLP-1 with GIP or glucagon, as well as the fully integrated triagonists. GLP-1R/GCGR co-agonists In recent years, there has emerged a deeper appreciation for the non-pancreatic biology of glucagon, specifically anchored on its role as a weight-regulatory hormone in energy balance and satiety 30 , 70 , 71 . In diet-induced obese rodents, GCGR agonist administration drives weight loss through a reduction in food intake, an induction of lipid utilization via brown fat thermogenesis, along with an increase in whole-body energy expenditure; the latter effect in part attributed to the stimulation of liver-secreted FGF21, and transcriptional upregulation of the hepatic bile acid-activated nuclear receptor, famesoid X receptor 19 , 30 , 72 , 73 . This partial regulation in energy expenditure suggests that there could be room for additional factors and mechanisms by which enhanced GCGR signaling mediates energy balance. Interestingly, treatment of diet-induced obese mice with a GCGR agonist revealed that glucagon-stimulated energy expenditure and weight loss can also be driven by hepatic amino acid catabolism, and thus a systemic response to hypoaminoacidemia 74 In addition to the liver, preclinical studies further suggest a role for GCGR agonism in the kidney 75 . The GCGR is potently downregulated during chronic kidney disease, and the lack of glucagon signaling in the kidney renders the tissue susceptible to fibrosis, inflammation, oxidative stress and lipid accumulation 75 . This indicates that some of the cardiorenal benefits observed for co-agonists may exert their beneficial effects directly through a kidney-GCGR signaling axis. Together with an appreciable (~50%) sequence homology with the incretin hormones 76 , the non-glycemic effects of glucagon thus render the peptide an attractive candidate for a unimolecular liaison with GLP-1 and GIP. Importantly, the benefits of such polypharmacotherapy are not only tethered on the assumption that these agents would bolster weight loss efficacy through complementary pharmacology at each target receptor, but also that the positive glycemic and cardiovascular effects of the incretins would restrain any potentially detrimental effects that may, or may not, reside in GCGR agonism. Unimolecular peptides of GLP-1R and the GCGR were the first purposeful co-agonists to emerge, seeking to amalgamate the glucagon-mediated increase in energy expenditure, with the anorectic action of GLP-1R to promote weight loss, while employing the anti-diabetic action of GLP-1 to minimize the diabetogenic risk of unopposed glucagon receptor agonism 77 . Once proven that full potency at each of the two receptors could be chemically assembled into a single chimeric peptide of comparable size to each native hormone, studies in animal models of obesity, utilizing first-generation GLP-1R/GCGR co-agonists, resulted in superior weight loss, enhanced glucose-lowering efficacy, as well as a reduction in food intake, when compared with selective GLP-1R agonists 78 - 81 ( Figure 2 ). These initial preclinical reports thus promoted an avalanche of pharmaceutical interest that validated these initial observations to a point where numerous GLP-1R/GCGR peptides have now progressed from bench-to-clinical development, with the most characterized described below. The first GLP-1R/GCGR co-agonist to emerge The first preclinically evaluated GLP-1R/GCGR co-agonist was based on the glucagon sequence, in which amino acid residues from GLP-1 and GIP were stepwise introduced to achieve balanced activity at both target receptors 79 . The DPP-4-protected peptide carried a 40 kDa polyethylene glycol to delay renal clearance, and a

Cotadutide (also termed MEDI0382) is a synthetic peptide based on human OMX, which employs a palmitic acid side-chain 91 that enables albumin binding and thus extension of its duration of action. The peptide is notably more potent at GLP-1R, relative to GCGR, with a ratio of ~5:1 92 . Similar to other GLP-1R/GCGR co-agonists, cotadutide displays robust metabolic efficacy in rodents and healthy cynomolgus non-human primates, with superiority in weight loss and glucose control, when compared with the selective GLP-1R agonist liraglutide 92 . This enhanced body weight-lowering efficacy is again attributed to a GCGR agonist-driven increase in energy expenditure, associated with a GLP-1R agonist-mediated induction in satiety 92 . More recently, cotadutide was shown to alleviate hepatic steatosis, dampen liver fibrosis and improve mitochondrial function in murine models of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), far more effectively than liraglutide 93 . Of note, to raise disease awareness and prevent stigma, the terminology and diagnostic criteria of Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) was recently replaced with the nomenclature MASLD and Metabolic Dysfunction-Associated Steatohepatitis (MASH), respectively 94 . Taken together, cotadutide and similar co-agonists, are firmly positioned as viable prospects for the treatment of MASLD and MASH. Moreover, their metabolic benefits signal that enhanced glucagon agonism can promote hepatic de-lipidation, which should have vast medicinal advantages for the treatment of obesity, independent of the magnitude of weight loss. In clinical studies, cotadutide was indeed well tolerated 95 , 96 , and in Phase 2 clinical trials, the peptide displayed impressive weight loss efficacy, superior hepatic lipid-lowering capabilities and appetite suppression, along with a reduction in blood pressure and HbA 1c levels in individuals with obesity and T2D 91 , 95 , 97 . Following 32 days of daily treatment, cotadutide further improved postprandial glucose control and potentiated weight loss in subjects with T2D and chronic kidney disease, which was paralleled with a notable 51% reduction in the urinary albumin-to-creatinine ratio 98 . Cotadutide is currently being assessed in Phase 2b clinical trials in subjects with MASLD (PROXYMO-ADV, NCT05364931 ), with several additional Phase 2b studies completed in subjects with either 1) chronic kidney disease with T2D ( NCT04515849 ), 2) obesity and MASLD/MASH ( NCT04019561 ) and, 3) obesity with T2D ( NCT03555994 ), with results awaiting publication ( Figure 3 ).

The rationale for combining GLP-1R and GIPR agonism Anchored on the lingering observation that germline Gipr -deficient mice are protected from diet-induced obesity 103 , combined with the findings that show the insulinotropic action of GIP is largely dampened in subjects with T2D 104 , there is persistent debate as to whether the receptor should be activated or inhibited, to reach optimal metabolic merit 105 - 107 . For instance, pharmacological or genetic inhibition of the GIPR has been shown to alleviate intramuscular lipid accumulation in aged mice 108 . Furthermore, while some GIPR mutations are associated with a lower body mass index in humans 109 - 111 , certain GIPR antagonists reduce body weight and caloric intake in diet-induced obese mice and non-human primates, particularly when given in adjunct to GLP-1R agonism 112 , 113 . However, while protection from obesity is also observed in Glp1r -deficient mice 114 , 115 , near-normalization of hyperglycemia restores the insulinotropic effect of GIP in subjects with T2D 116 . In contrast, GIPR agonist treatment is equally effective in promoting weight loss in obese mice, and further, GIP-driven weight loss is also synergistically enhanced by adjunct GLP-1R agonism 47 - 49 , 117 . Importantly, in mice with loss of the Gipr in the CNS at large, the GIP-driven inhibition in food intake is completely diminished, while the GIP-induced weight loss is partially restored 45 . This indicates that GIP drives weight loss via central inhibition of food intake, and through non-CNS peripheral mechanisms unrelated to food intake. Additional evidence for the peripheral benefits of GIPR activation stem from recent observations showing that the anti-inflammatory effects of GLP-1R activation are mediated exclusively through the central actions of GLP-1R 118 . However, treatment of brain-specific Glp1r -deficient mice with a GLP-1R/GIPR co-agonist retains anti-inflammatory action, suggesting that peripheral GIPR activity in adipose tissue and immune cells, i.e. macrophages, can elicit positive systemic effects 118 . In light of this, we would postulate that peripheral activation of the GIPR in white adipocytes has the capacity to modulate energy balance and weight loss. To substantiate these claims, further work with a focus on adipose tissue is warranted in the future to better define the contributions that peripheral GIPR activation, specifically in the white adipocyte, elicits towards the overall metabolic benefits of these agonists. The rationale for engaging GIPR agonism in unimolecular liaison with GLP-1 was thus two-fold. First, combining GLP-1R and GIPR agonism could further improve glucose metabolism through additive insulinotropic and glucagonostatic action on the pancreas, and potentially even restore the impaired GIPR sensitivity characteristic of T2D 119 . Second, the physical combination of GLP-1 and GIP could synergize to outperform GLP-1-based mono-agonism, thus yielding greater weight loss with a further reduction in food intake 48 . While the question of the therapeutic value of GIP has been hampered by the ongoing debate as to whether GIPR should be activated or inhibited 105 - 107 , 120 , no GIPR antagonist has yet received regulatory approval, and the success of GLP-1R/GIPR co-agonism, as discussed below, has rehabilitated the opinion that GIPR agonism is a successful constituent of incretin-based therapies. There are two notable unimolecular GLP-1R/GIPR co-agonist peptides that have been preclinically and clinically most characterized to display enhanced glucose-lowering potential, superior weight loss and appetite suppression, when evaluated with comparable GLP-1R agonists. They are NN0090-2746 (also known as NN9709, MAR709, RG7697 or RO6811135) 45 , 48 , and tirzepatide (initially referred to as LY3298176) 47 , 121 - 123 ( Table 1 ). Preclinical studies focused on whether the addition of GIPR activation enhances, or provides unique metabolic benefits, through mechanisms distinct from GLP-1R mono-agonism.

The second important GLP-1R/GIPR co-agonist generated was LY3298176, also termed tirzepatide 47 . This peptide reflects the progression in the chemical optimization of GLP-1R agonists, with the application of a fatty-acylated diacid. This modification had prompted semaglutide to be a much longer-acting GLP-1R agonist of greater potency and efficacy than liraglutide. In an analogous fashion, tirzepatide represents a similar evolution in the co-agonist structure of MAR709, by employing a fatty diacid analogous to semaglutide at the same location in a GIP-based peptide that has been modified to include GLP-1 activity 47 . The clinical half-life of tirzepatide is approximately five days (~116.7 h), thus permitting once weekly dosing. A critical difference between tirzepatide and MAR709, is that MAR709 displays balanced activity at both GLP-1R and GIPR 48 , 124 , whereas tirzepatide favors human GIPR over GLP-1R in a ratio of 5:1 47 . Notably, MAR709 and tirzepatide harbor important species-specific differences, with both molecules being fully active agonists at the human GIP receptor, however only MAR709 being fully active at the mouse GIP receptor. As a result, while MAR709 requires functional GIPR signaling in the CNS to outperform GLP-1R agonism to further reduce body weight and food intake 45 , 127 , tirzepatide does not lower body weight in Glp1r -deficient mice 121 . Moreover, while tirzepatide promotes insulin secretion in murine islets exclusively via the GLP-1R, the peptide stimulates insulin secretion in human islets predominantly via the GIPR 128 . However, consistent with unleashing its full activating potential at the human GIPR 47 , 128 , in vitro studies in human HEK293 cells revealed that tirzepatide activates both GIPR and GLP-1R signaling, and in isolated human pancreatic β-cells, the tirzepatide-induced insulin secretion was greater, relative to treatment with either GIP or GLP-1 alone 47 . In vivo studies demonstrated that in diet-induced obese mice, tirzepatide enhances glucose-dependent insulin secretion, improves glucose tolerance, stimulates appetite suppression and promotes remarkable weight loss; the latter a result of increased tissue lipid oxidation 47 ( Figure 2 ). More specifically, tirzepatide treatment was reported to drive a tissue-specific increase in glucose disposal, preferentially into epididymal white adipose tissue, brown adipose tissue (BAT) and skeletal muscle 121 ; an effect associated with transcriptional upregulation in genes associated with branched chain amino acid catabolism in BAT 123 , 129 . The peptide was further shown to induce a switch of macronutrient intake by selectively dampening palatable high-fat/sweet-taste preference to a low-fat chow diet preference 130 . On a similar note, studies in musk shrews and mice revealed that GIPR mono-agonist administration attenuated the emetic effect of GLP-1R agonism 44 , 131 ; a highly desirable property that may contribute to increased tolerability of the GIP-based drugs relative to GLP-1-based monotherapies at higher doses.

Based on the preclinical success of the GLP-1R/GCGR co-agonists 79 and GLP-1R/GIPR co-agonists 48 , it was naturally intuitive to assume that a single peptide that displays balanced activity at all three target receptors would further enhance glycemic control and accelerate weight loss, with the hope of surpassing what had already been achieved with bariatric surgery 8 , 76 . The chemical challenge, however, was to satisfy the structural requirements for agonism at three related but different receptors, where the native hormones GLP-1, GIP, and glucagon are highly specific in their interactions. Appreciably, the pharmacology of the first-generation of such unimolecular triagonists already proved superior to any best-in-class single, or co-agonist peptides at that time 150 - 154 ( Figure 2 ). Preclinical findings that launched unimolecular triagonism Informative preclinical studies that began much before the achievement of weight loss in humans, which now exceeds 20% with the best-in-class co-agonists, described the synthesis and characterization of several unimolecular GLP-1R/GIPR/GCGRtriagonists 150 - 153 , 155 . These preclinical findings elegantly set the stage for the ongoing clinicals trials in obesity and T2D using triagonist peptides. The first preclinically established unimolecular GLP-1R/GIPR/GCGR triagonist was MAR423. This peptide was shielded from DPP-4 recognition through an aminoisobuturic acid at position 2, while the lysine at position 10 was fatty-acylated with a palmitic acid through a γ-glutamic acid linker 150 . Distinct amino acid substitutions were introduced into the center of the peptide to restore balanced glucagon receptor activity, while the C-terminal end of exendin-4 was attached to display balanced full agonism at all three receptors 150 . In diet-induced obese mice, MAR423 displayed impressive dose-dependent body weight-lowering effects of 26.6% in 20 days, compared to 15.7% with GLP-1R/GIPR co-agonist treatment. The peptide further reduced food intake and fat mass, enhanced glycemic control, reduced hypercholesterolemia, and improved hepatic lipid metabolism, relative to GLP-1R agonism or balanced GLP-1R/GIPR co-agonism 150 ( Figure 2 ). Mice individually lacking each of the three receptors, or pharmacological antagonism of each receptor, confirmed the functional relevance of each of the three peptide entities 150 , which was further apparent with glucagon-induction of energy expenditure and lipid utilization 72 , 150 . MAR423 further improved dyslipidemia and ameliorated hepatic steatosis in obese mice, notably even at doses where the drug only had marginal effects on body weight and satiety 152 . Following the publication of the first triagonist, a series of similar peptides emerged, but with notable differences in duration of action and activity at each target receptor 151 , 153 , 155 . Following 2 weeks of treatment, such a biochemically refined second-generation triagonist exhibited impressive weight loss of >30% in diet-induced obese rodents, with superior weight loss relative to the best-in-class GLP-1R/GIPR co-agonists 151 . This GLP-1R/GIPR/GCGR triagonist, LY3437943, is based on the GIP sequence, in which amino acid substitutions were stepwise introduced to achieve triple agonism 47 , 155 . The 39 amino acid peptide carries non-natural amino acids at positions 2, 13 and 20, which not only protect from DPP-4-mediated degradation, but also enhance the activity at the receptors for GIP and glucagon 155 . A C20 fatty-diacid was further anchored onto the lysine at position 17 to enhance bioavailability through albumin binding 155 . In contrast to the balanced triagonist MAR423 150 , 151 , LY3437943 displayed balanced activity for GCGR and GLP-1R, but enhanced potency at the GIPR. In diet-induced obese mice, LY3437943 very effectively lowered body weight by ~45%, which was largely preserved at thermoneutrality 155 . Weight loss was further accompanied by a reduction in fat mass, a transient suppression in food intake, along with marked improvements in glycemic control 155 . Notably, the LY3437943 triagonist peptide outperformed the GLP-1R/GIPR co-agonist tirzepatide to achieve a greater degree of weight loss 47 ; an observation attributed to an increase in energy expenditure, which remarkably accounted for ~30-35% of the weight lost in diet-induced obese mice, and was diminished upon antibody-based inhibition of GCGR 155 . SAR441255 is a synthetically balanced unimolecular GLP-1R/GIPR/GCGR triagonist, structurally based on the exendin-4 sequence with selected substitutions and palmitic acid acylation 153 . In lean cynomolgus non-human primates, positron emission tomography imaging revealed high receptor occupancy to GLP-1R and GCGR 153 . In diet-induced obese mice, SAR441255 was shown to alleviate hyperglycemia and reduce body weight by ~14.1%; moreover, when compared with a GLP-1R/GCGR co-agonist, this effect was primarily ascribed to an increase in energy expenditure

The medicinal objectives of the unimolecular triagonists were to harness three complementary signaling mechanisms in weight reduction to achieve unprecedented efficacy, which could rival, or even surpass bariatric surgery. One question in particular however, is how much of the three receptor activities exhibit independent or overlapping mechanisms in weight loss? Initially, the spectacular weight loss achieved with GLP-1R/GIPR co-agonism begged the question of how best to integrate GCGR agonism. The biological impasse that glucagon can induce hyperglycemia, is an immediate and obvious brake to the degree of GCGR agonism. Additionally, glucagon has vascular effects that must be successfully managed, or risk the full improvement in cardiovascular outcomes achieved with less aggressive forms of therapy. Nonetheless, the deepened appreciation for the role that glucagon has on energy expenditure has placed this hormone in a new light, and rekindled its consideration as a component that could provide additional weight loss when needed, or to sustain the weight loss that may otherwise wane through some form of supplementation 70 . A recent report also puts forth potent reno-protective effects that are exerted through the GCGR in the kidney 75 . The clinical results regarding tirzepatide appear to anchor GIPR activity as much as GLP-1 activity in the treatment of obesity. However, questions remain as to whether the GIPR is predominantly a metabolic booster to GLP-1 or, with sustained efficacy, increasingly emerging as a primary contributor to maintaining metabolic health. The importance of GIP in triple agonism may be doubly so, where these peptides appear to tolerate glucagon activity much more than GLP-1R/GCGR co-agonism. The role of GIPR activity within the triagonist may prove more complex, and albeit speculative at this stage, its function could include the stimulation of energy-wasting futile cycling pathways. Future genetic studies will no doubt shine light on the shadow of GIP function. But for now, the broader history of anti-obesity drug development instructs that we progress with due caution, as there have been other forms of pharmacology that have unsafely promoted weight loss. The task before us is to use these pharmacological tools and preclinical mechanistic observations in the most intelligent and informed manner in treatment of obese and T2D individuals.

The progress witnessed in the last decade in the management of obesity and its related diseases has been nothing short of stunning. Advances in metabolism over the last century were accelerated in the last few decades by collective biotechnologies to fulfill the incretin hypothesis. GLP-1 proved exceedingly effective in the management of T2D-associated hyperglycemia, without the risk of hypoglycemia commonly associated with insulin and sulfonylureas. Through state-of-the-art iterative enhancements in its pharmaceutical properties, highly effective selective GLP-1R peptide agonists emerged for the treatment of T2D. The therapeutic focus then transitioned to obesity, as preclinical and clinical observations revealed body weight-lowering as an adjunctive benefit in the management of T2D-associated obesity. The first forms of therapy proved comparably effective to the conventional non-peptide forms in providing a mid-single digit lowering in body weight, with reductions in adverse cardiovascular events. The serendipitous step forward emerged when semaglutide, a peptide designed for increased patient convenience in reducing injectable dosing from daily to once weekly, proved doubly efficacious in lowering body weight to beyond 10%, when compared with a daily dosing of the chemically related peptide, liraglutide. By clinically exceeding the anti-obesity efficacy of liraglutide, semaglutide transformed the vision of what was pharmaceutically possible, and thus launched the medicinal management of obesity, despite reaching only a fraction of what can be achieved through bariatric surgery. Shortly thereafter, the clinical performance of semaglutide in the treatment of T2D and/or obesity was substantially eclipsed by the integrated pharmacology of GIP and GLP-1, in tirzepatide. The peptide served to double the conviction for the prospect of body weight-lowering efficacy comparable to bariatric surgery; a goal that was within reach, for the first time, through the use of multi-mechanism pharmacology. While the clinical results validated this prospect, the short time interval in moving from semaglutide to tirzepatide is a manifestation that the seeds of invention had been planted more than a decade earlier, with preclinical observations that predicted this outcome, and an even greater performance with further iterations in mechanisms of action. With respect to GIPR agonism, while a definitive mechanism in how GIPR signaling impacts energy balance is yet to be reported, GIPR activation has been associated with improved adipose tissue health 41 , 106 , 123 , 171 . Considering the prominent role of adipose tissue in energy homeostasis 59 , 172 , it is plausible that GIPR agonism in fat could harness beneficial effects on metabolic homeostasis. The advance beyond selective GLP-1 agonism was also rooted in controversy. Beginning with glucagon agonism, which is counterintuitive to glucagon’s diabetogenic pharmacology, with decades of work in the literature that unsuccessfully pursued its antagonism for the treatment of diabetes. The deeper appreciation that glucagon, much like insulin, has a larger scope of pharmacology than just acute glucose management, coupled with the integration with GLP-1 and GIP, has enlightened the prospect of utilizing the hormone for constructive purposes. Nonetheless, it needs to be approached with great caution, particularly relating to its potential cardiovascular effects, which are more challenging to assess and potentially more difficult to reverse than its impact on glycemic control. The success with GLP-1, and the similar emerging success with GIP, should not lessen our concern in the management of glucagon, as the former are physiological incretins and more alike than the latter hormone. The integration of glucagon and GIP agonism into GLP-1 pharmacology represents the most advanced form of multimode therapy that is achieving extraordinary progress, currently advancing to the last stage of clinical development. Figure 3 highlights some of the next-generation therapeutics for the treatment of obesity and T2D, with the relative GLP-1, glucagon and GIP gut-hormone contributions in each agonist peptide, and the remarkable weight loss achieved for each. The ongoing observations that GIP agonism and antagonism can achieve similar preclinical outcomes in lowering body weight are perplexing. The physiological role of GIP in other endocrine functions, such as the maintenance of bone health, is one of appreciable importance 173 . For instance, GIPR agonism within multi-receptor agonists, improves bone metabolism 153 . As such, the unintended prospect that inhibiting GIP activity in a T2D patient population with reduced bone mineral density, could represent a chronic adverse risk that needs to be addressed. A recent study utilizing a GIPR-blocking antibody conjugated with a potent GLP-1R agonist in obese subjects, has reignited interest in such multi-mode therapy 174 . The sustained body weight-loweri