Incretin-based therapies for cardio-kidney-liver-metabolic disease: the role of the liver in the modern era of chronic disease management

Abstract

Steatotic liver disease (SLD) is a leading cause of disease globally and demands new therapeutic approaches to mitigate underlying metabolic dysregulation. Incretin-based therapies are emerging as a viable prospect to fulfil this unmet niche. A literature review to inform the evidence base for incretin focussed pharmacology in the metabolic liver diseases space and an informed commentary on unmet areas of need. Incretin-based therapeutics demonstrate multifarious benefits across the chronic metabolic disease spectrum with promising data across the continuum of pathology.

INTRODUCTION

The trappings of modern society with its predilection towards sedentary lifestyles and an abundance of poor nutritional choices are fertile ground for excess adiposity, metabolic dysregulation and the ensuing systemic inflammation that results in the emergence of a cabal of chronic diseases that operationally define the metabolic syndrome. Of interest to the practising clinician is the burgeoning problem of metabolic dysfunction associated fatty liver disease (metabolic dysfunction-associated fatty liver disease [MAFLD], also known as metabolic dysfunction-associated steatotic liver disease [MASLD], “steatotic”), and its progressive subtype, metabolic dysfunction associated steatohepatitis (MASH). The fatty liver diseases are poised to be a leading cause of ill health globally, with their associated complications of cirrhosis, liver decompensation, hepatocellular carcinoma, cardiovascular disease and extra-hepatic malignancy [1]. Despite the established role of lifestyle interventions spanning healthy eating patterns, regular physical activity and sleep quality in disease mitigation, excess visceral adiposity and its related states of disordered metabolism are complex biopsychosocial maladaptations of an evolutionary propensity towards energy conservation. These biologically conserved mechanisms often resist broad-based recalibration strategies especially at the severe end of the disease spectrum. Herein lies the pressing need to evolve novel therapeutic approaches to augment the role of lifestyle changes to alter disease biology and slow disease progression [2].

Insights into the molecular topography of energy homeostasis have been accompanied by a growing appreciation of the incretin signalling axis as a lynchpin of metabolic regulation. Consequently, a once nascent field of weight loss pharmacotherapies has been transformed by the development of a cornucopia of incretin-based drugs with potent weight loss benefits. Fascinatingly, these agents are also associated with a readily expanding repertoire of end-organ benefits, including in the fatty liver diseases space where there has been a dearth of treatment options to date. The emerging evidence for this class of agents is compelling, heralding the promise of a physiologic regulator of metabolic health that has the potential to fulfil an unmet need as backbone pharmacotherapy in modern chronic disease management.

THE BIOLOGIC BASIS FOR USING INCRETIN THERAPIES IN MASH

Fundamentally, MAFLD/MASLD can be conceptualised as the hepatic manifestation of systemic metabolic dysregulation (aka the metabolic syndrome), a state of energy surplus and excess adiposity that foments insulin resistance and creates a milieu of intracellular steatosis, lipo-toxicity and inflammation in the liver and may potentially be organ agnostic. Hence, it follows that pharmacological recapitulation of the incretin effect which refers to glucagon- like peptide 1 (GLP-1) and gastrointestinal polypeptide (GIP) mediated potentiation of insulin release and attenuation of glucagon secretion by the pancreas in response to nutrient sensing by intestinal L cells would obviate a key driver of pathologic lipid accumulation. Hypothalamic modulation of glucose metabolism through GLP-1 agonism also potently suppresses appetite pathways and slows gastric emptying, creating an anorectic phenotype characterised by net negative energy balance and optimised metabolism which facilitates the robust weight loss observed in clinical trials.

Microbiome reconstruction as a mechanism of hepatoprotection

Dysbiosis is a widely cited phenomenon that is proposed to overlay significantly in the metabolic dysfunction phenotype [3]. The gut microbial metabolome acts as a rich reservoir of bioactive determinants of liver physiology, but the field is still in its infancy, and the exact nature and mechanisms that underpin this relationship have been difficult to elucidate. It would be reasonable to conjecture that altered gut transit mechanics associated with pharmacologic incretin manipulation and the dietary changes that accompany modulation of the brain’s reward and appetite circuitry would change dietary proclivities, redefine microbial ecology and have consequent impacts on the natural history of fatty liver disease. Preclinical models implicate GLP-1 receptor agonism with alterations in microbial taxa associated with positive metabolic effects such as enhanced short chain fatty acid production and fortified intestinal epithelial barrier function with consequent attenuation of endotoxin mediated systemic inflammation [4]. Whilst intriguing observations, methodological refinements with longitudinally appraised human cohort studies that incorporate standardised microbial profiling, include rigorous adjustment for confounders which is a challenging proposition in this space, utilise multi-omic approaches incorporating both metagenomic and metabolomic signatures and correlate findings with clinically significant outcomes will be necessary to add credence to these mechanistic speculations.

Pharmacodynamic considerations with incretin drugs

The incorporation of glucagon receptor (GCGR) agonism may seem counterintuitive by virtue of the hormone’s glycemia inducing properties, but this effect appears to be neutralised by concurrent GLP-1 action as observed with the newer combination drug approaches that variously titrate the relative incretin and glucagon receptor effects. Indeed, the relative ratio of receptor engagement seems to be a crucial determinant of drug efficacy and may be specific to organ and/or disease state. Pemvidutide which has an in vitro GLP-1 to glucagon receptor affinity of 1:1 is thrice as potent as cotadutide which has a receptor affinity ratio of 5:1 at reducing hepatic fat content at the expense of increased hyperglycaemia risk [5]. Furthermore, the incretin drugs can also function as receptor antagonists as observed with Tirzepatide which is suggested to function as a partial GIP receptor agonist [6]. This dual action pharmacodynamic property may account for part of its beneficial metabolic effect. Glucagon agonism also stimulates thermogenesis and caloric expenditure through browning of adipose tissue. Finally, iatrogenic chronic glucagon receptor agonism as opposed to native physiological pulsatile action also potently suppresses appetite pathways and activates GIP receptors contributing additional catabolic and lipolytic benefits [5,7]. The apparent superior weight loss kinetics of the tri-receptor agonist Retatrutide [8] compared with other permutations of therapy supports the logic of a multi-target approach to address metabolic diseases. Nevertheless, there is clear nuance in the structural chemistry and consequent pharmacodynamic properties of these classes of drugs that requires further study to define the optimal permutation of receptor affinity to apply in specific organ and/or clinical situations.

In summary, body recomposition, insulin sensitisation, hormesis (referring to the biological phenomenon where low dose physiological stress functions as a beneficial adaptogen in an organism) from caloric restriction, and possibly microbiome reconstitution likely explains the essence of how these agents work in effecting hepatoprotection in a steatotic liver (Fig. 1). Jara et el. [9], identified 72 independent protein signatures associated with semaglutide treatment and MASH resolution highlighting the diversity of bariatric and more intriguingly, weight agnostic mechanisms underpinning the therapeutic effect. Assertions around direct hepatic anti-inflammatory or anti-fibrotic effects are difficult to justify in the absence of GLP-1 and GIP receptor expression on hepatocytes, arguing for mainly indirect mechanisms [9,10]. Even with respect to glucagon receptors which are abundantly expressed in the liver, it has been difficult to establish putative mechanisms linking receptor agonism with direct modulation of hepatic stellate cell or macrophage activity. The alleged anti-fibrotic benefits ascribed to additional glucagon receptor action may therefore be a function of superior hepatic metabolic regulation with joint therapy. Indeed, the dual GLP-1/GCGR agonist, efinopegdutide, demonstrated greater liver fat lowering efficacy than semaglutide (GLP-1 agonist) for the same degree of total body weight loss achieved [11]. This phenomenon is akin to the viral hepatitides, where anti-viral agents with no direct antifibrotic or anti-inflammatory effects can reverse disease. Similarly, the incretin drugs have also demonstrated significant benefits in other organs within the CKLM spectrum, through both direct and indirect effects. This highlights the importance of shared biology in the pathophysiology of end organ phenotypes.

Figure 1.

Whole-system metabolic efficiency, the underlying premise on which Incretin analogues are suggested to benefit liver health. Created with Biorender.com.

INCRETIN-BASED THERAPIES IN MASH: CLINICAL EVIDENCE OF UTILITY

ESSENCE: The first phase 3 randomised trial of incretin therapies in MASH

Given the potent weight loss and insulinotropic properties of this new class of agents, it was inevitable that positive hepatic metabolic signals would become evident with observed decrements in radiologic liver fat content and amelioration of inflammatory biochemistry in secondary analyses of major diabetes and weight loss intervention trials. These findings were subsequently recapitulated in dedicated MASH populations, with the strength of evidence consolidated in large cohort studies and meta-analyses on the topic [12,13]. Given the uncertainties associated with the non-invasive grading of MASH, late-stage trials have emphasised histologic endpoints, with the final arbiter being reductions in adverse liver-related clinical outcomes. ESSENCE is the first phase 3, double-blinded placebo-controlled trial in adults with MASH. The efficacy analysis (which included the first 800 patients) demonstrated that once weekly subcutaneous semaglutide (a GLP-1 receptor agonist) 2.4 mg was superior to placebo in steatohepatitis resolution without worsening of fibrosis (62.9% vs. 34.1%, estimated difference in responder proportions (EDP) 28.9% [95% confidence interval [CI] 21.3; 36.5], P<0.001) and fibrosis improvement by ≥1 stage without worsening of steatohepatitis (37% vs. 22.5%, EDP 14.4% [95% CI 7.5; 21.4], P<0.001) at the 72-week time point. Significantly more patients with MASH and F2/3 fibrosis treated with semaglutide achieved resolution of steatohepatitis and improvement in fibrosis compared to placebo (32.8% vs. 16.2%, EDP 16.6% [95% CI 10.2; 22.9], P<0.001) [14]. Whilst the histologic outcomes are impressive, whether this phenomenon translates into discernible improvements in adverse liver outcomes (i.e., progression to cirrhosis, hepatic decompensation, transplant free survival, overall survival, etc.) remains to be elucidated. Results of the phase 2 of the ESSENCE study which looks at hard clinical endpoints (due in 2027), are therefore, much anticipated.

Clinical evidence of combination-based approaches

Combination agonism approaches also demonstrate promise with both Tirzepatide (a GLP-1 and GIP receptor dual agonist - SYNERGY-MASH) and Survodutide (a GLP-1 and Glucagon receptor dual agonist - NCT 1404-0043) demonstrating superiority to placebo in remitting steatohepatitis without worsening of liver fibrosis and fibrosis regression by at least 1 stage without worsening of inflammation in landmark phase 2 trials [15,16]. After 52 weeks on therapy, approximately 52% of patients on 5 mg of tirzepatide had an absence of MASH with no worsening of fibrosis, compared to 13% in the placebo group. The observed benefit escalated in a dose-response manner to 63% of patients administered 10 mg and 73% in those taking 15 mg of Tirzepatide respectively. More than 50% of patients in each cohort experienced a 1-stage or greater improvement in fibrosis without worsening of MASH, a key secondary endpoint, compared to 33% in the placebo group [16]. Similarly, in the NCT 1404-0043 trial, improvements in MASH without worsening of fibrosis occurred in 47% of the participants in the Survodutide 2.4 mg group, 62% of those in the 4.8 mg group, and 43% of those in the 6.0 mg group, as compared with 14% of those in the placebo group. Up to 52% of adults treated with survodutide achieved an improvement in fibrosis stage compared with 26% in the placebo group [15]. Phase 3 randomised trials (e.g., LIVERAGE - NCT06632444) to consolidate the strength of evidence for this class of combination agents are currently underway. Table 1 summarises the key results.

Table 1.

Primary outcome data from major Phase 2 and 3 trials of incretin drugs in MASH

Agent	MASH resolution without worsening of fibrosis (%)	EDP (%) (95% CI)	With ≥1 grade improvement in fibrosis without worsened steatohepatitis (%)	EDP (%) (95% CI)
Semaglutide subcutaneous once weekly (ESSENCE) (72 weeks for phase 1) (n=800) (P<0.001 for all comparisons)
2.4 mg	62.9 vs. 34.1	28.9 (21.3; 36.5)	32.8 vs. 16.2	16.6 (10.2; 22.9)
Tirzepatide subcutaneous once weekly (SYNERGY-NASH) (52 weeks) (n=190) (P<0.001 for all comparisons)
5 mg	44 vs. 10	34 (17; 50)	55 vs. 30	25 (5; 46)
10 mg	56 vs. 10	46 (29; 62)	51 vs. 30	22 (1; 42)
15 mg	62 vs. 10	53 (36; 69)	51 vs. 30	21 (1; 42)
Survodutide subcutaneous once weekly (NCT 1404-0043) (48 weeks) (n=293) (P<0.001 for all comparisons)
2.4 mg	47 vs. 14	-	34 vs. 22	-
4.8 mg	62 vs. 14	-	36 vs. 22	-
6.0 mg	43 vs. 14	-	34 vs. 22	-

CI, confidence interval; EDP, estimated difference in responder proportions; MASH, metabolic dysfunction associated steatohepatitis.

Tri-agonists (GLP-1, GIP, and glucagon receptor activators) are also in the investigational pipeline for MASH and results from dedicated phase 2 trials are anticipated. A sub analysis of the Retatrutide obesity trial suggested improvements in radiologic liver fat content and biomarkers of inflammation and fibrosis [17]. A summary of all the key clinical trials results in the MASH arena is highlighted in Table 2.

Table 2.

Results from key incretin drug trials in MASH

Trial identifier	Comparison	Population	Duration	MASH resolution without worsening of fibrosis (P-value)	Fibrosis regression (≥1 grade) without worsening of steatohepatitis? (P-value)
GLP-1 agonists
NCT01237119	Liraglutide (1.8 mg subcut OD) vs. placebo (2016) - phase 2 (LEAN)	MASH with F0–4 fibrosis (n=52)	48 weeks	Yes (0.019)	-
NCT02970942	Semaglutide (0.1, 0.2, and 0.4 mg subcut OD) vs. placebo (2021) - phase 2	MASH with F1–3 fibrosis (n=320)	72 weeks	Yes (<0.001)	No (0.48)
NCT03987451	Semaglutide (2.4 mg once weekly subcut) vs. placebo (2023) - phase 2	MASH cirrhosis (n=71)	48 weeks	No (0.29)	No (0.087)
NCT04822181	Semaglutide (2.4 mg once weekly subcut) vs. placebo (2025) - phase 3 (ESSENCE)	MASH with F2–3 fibrosis (n=1,197)	240 weeks	Yes (0.001)	Yes (0.001)
GLP-1/GIP dual agonists
NCT04166773	Tirzepatide (5, 10, and 15 mg once weekly subcut) vs. placebo (2025) - phase 2 (SYNERGY-NASH)	MASH with F2–3 fibrosis (n=190)	52 weeks	Yes (0.001)	Yes (0.001)
Glucagon/GLP-1 dual agonists
NCT04771273	Survodutide (2.4, 4.8, and 6 mg once weekly subcut) vs. placebo (2025) - phase 2	MASH with F1–3 fibrosis (n=293)	48 weeks	Yes (0.001)	Yes (0.001)
NCT05989711	Pemvidutide (1.2 and 1.8 mg once weekly subcut) vs. placebo (ongoing) -phase 2 (IMPACT)	MASH with F2–3 fibrosis (n=190)	24 weeks	Pending	Pending
NCT04944992	Efinopegdutide (10 mg once weekly subcut) vs. semaglutide (1 mg once weekly subcut) - phase 2a	MASLD as defined by LFC on MRI based PDFF	24 weeks	Efinopegdutide (72.7% [90% CI 66.8–78.7]) LFC relative reduction from baseline compared with semaglutide treatment (42.3% [90% CI 36.5–48.1]) - P<0.001
GLP-1/GIP/glucagon tri-agonists
NCT04505436	Efocipegtrutide (2, 4, and 6 mg once weekly subcut) vs. placebo (ongoing) - phase 2	MASH with F1–3 fibrosis (n=240)	52 weeks	Pending	Pending

CI, confidence interval; GIP, gastrointestinal polypeptide; GLP-1, glucagon-like peptide-1; LFC, liver fat content; MASH, metabolic dysfunction associated steatohepatitis; MASLD, metabolic dysfunction-associated steatotic liver disease; MRI-PDFF, magnetic resonance-based proton densitometry fat fraction.

Considerations for use of incretin therapies in advanced fibrosis/cirrhosis

The safety signals associated with incretin therapies agents once full-fledged cirrhosis is established appear reassuring from early data but whether these drugs can also maintain their gamut of anti-inflammatory and anti-fibrotic properties and thus alter the natural history of advanced disease needs to be discerned. Once weekly subcutaneously administered semaglutide 2.4 mg did not appear to improve fibrosis or resolve MASH in a small phase 2 study [18]. The upcoming phase 3 LIVERAGE-Cirrhosis study (NCT06632457) which examines the effect of once weekly subcutaneous survodutide on all-cause mortality and liver-related events in compensated cirrhotic patients will be an important addition to the evidence base. Concerns around iatrogenic sarcopenia and its adverse impacts on the cirrhotic phenotype appear overstated especially when contemplating evidence that suggests that the observed diminutions in muscle mass associated with the use of incretin analogues are offset by positive body recomposition from visceral fat reduction, improved myocellular steatosis and optimised muscle energetics/efficiency [19]. Moreover, sarcopenia may also be mitigated by complementary anabolic strategies with an emphasis on resistance/weight-based exercise and possibly pharmacological modulation of androgen receptors and blockade of activin type 2 and myostatin. Topline results of the phase 2 EMBRAZE trial (NCT06445075) demonstrated the potential of apitegromab, an anti-myostatin antibody in helping to ameliorate Tirzepatide induced muscle loss providing early proof of concept of this therapeutic philosophy. Nevertheless, lean subjects with steatotic liver disease (i.e., the “Lean MAFLD” phenotype) may represent a distinct biologic category that may be harmed by such weight focused approaches to disease modification and where alternative organ directed mechanisms of therapy may be a more prudent strategy.

INCRETIN THERAPIES IN MODERN CLINICAL PRACTICE

Incretin therapies in extra-hepatic disease

The landscape of metabolic disease management is on the precipice of a transformative change with the advent of the incretin analogues and their purported slew of end-organ disease modifying benefits. Evidence supporting their use in attenuating addiction biology is already suggesting new niches for this class of drugs in curtailing hazardous patterns of alcohol use which functions as a major societal aetiological factor for liver disease [20,21]. Independent of their liver-tropic effects, the modern hepatologist is likely to encounter patients on these agents for a variety of alternate clinical indications. Indeed, dedicated large pharmaceutical research and development portfolios such as the STEP (Novo Nordisk) and the Surmount program (Lilly) have culminated in these drugs being sanctioned as international society guideline directed treatments for obesity and type 2 diabetes mellitus. Newer agents like retatrutide, a GLP-1/GIP/glucagon receptor tri-agonist continue to challenge assumptions around what is pharmacologically possible achieving impressive weight loss magnitudes exceeding 24% of body mass, with effect sizes approaching equivalence with bariatric surgical interventions [8]. Advances in peptide medicinal chemistry will likely continue to innovate novel iterations of multi-functional/targeting chimeras with nuanced receptor specificities specific to organ and/or disease state, and improved clinical efficacy and safety profiles.

Mechanistically, weight loss and insulin sensitisation mitigate formation of chronic hyperglycaemia-induced non-enzymatic glycation of proteins and lipids (advanced glycation end products, AGE). These AGE products interfere with native lipid metabolism, disrupt extracellular matrix integrity, induce phenotypic shifts in vascular smooth muscle cells towards an osteoblastic phenotype and initiate cascades of inflammation through signalling via cognate receptors (receptors for AGE or R-AGE). This AGE/R-AGE schematic provides the mechanistic basis of how the incretin analogues attenuate key pathophysiological processes such as atherosclerosis, and the excessive glomerular porosity and mesangial sclerosis pathognomonic of diabetic kidney disease (Fig. 2) [22]. Weight loss also contributes direct mechanical benefits in ameliorating the disease expression of osteoarthritis and obstructive sleep apnoea syndromes [23,24].

Figure 2.

Chronic hyperglycaemia induced activation of the AGE/R-AGE signalling axis induces a state of chronic inflammation and mechanistically underpins much of CKLM disease axis expression. AGE, advanced glycation end-products; MACE, major adverse cardiac outcomes. Created with BioRender.com.

Systemic immune regulation and optimised endothelial health also combat oxidative stressors, fibrogenesis and neuro-inflammation, hallmark biologic signatures which define the degenerative phenotype synonymous with many modern-day chronic illnesses such as heart failure and the dementia syndromes. In line with recent pivots in research philosophy looking to expand indications for drug use and regulatory oversight that emphasise hard clinical outcome data over biochemical and/or radiological rationales, the last 5 years have lent empiric credence to many of these mechanistic speculations with several seminal trials showcasing benefits of the incretin drugs in disease modification and/or ameliorating symptom burden in various chronic disease states (Fig. 3).

Figure 3.

A pictorial representation of the major clinical trials elucidating the non-hepatic benefits of the incretin drugs. Weight loss and insulin sensitisation are suggested to contribute to the development of a systemic anti-inflammatory milieu that positively rebalances whole body health. Created with Biorender.com.

There is a theoretical precedent by which the incretin therapies may exert anti-neoplastic properties through attenuation of visceral adiposity and insulin resistance-mediated end-organ inflammation, and oncogenic transformation. However, real world data paints a more complex and heterogenous relationship with cancer subtype, genetic predilection, pharmacokinetic considerations and the potential for length and lead time biases to overlay significantly in tumour risk assessment [25]. Ultimately, given the relative nascency of utilising these drugs in clinical applications, further work spanning elucidation of the mechanistic underpinnings of incretin modulation on tumour biology, pooled post-hoc analyses of large-scale randomised trials and dedicated pharmacovigilance networks to appraise cancer incidence will be necessary to define clinical recommendations around cancer risk.

Reflecting the impending ubiquity of the incretin analogues in clinical practice, data to support how exposure to these drugs influences the natural history of liver disease will have important ramifications for how care pathways and surveillance strategies such as hepatocellular carcinoma (HCC) screening are defined. Retrospective data suggests that these agents are associated with reduced rates of hepatic decompensation, HCC and mortality [26,27]. The phase 2 results of the ESSENCE trial will provide a much-needed prospective precedent to nuance current management paradigms.

Non-invasive testing in therapeutic calibration: an unmet area of need

MASH resolution has historically required liver biopsy as the gold standard to define endpoints in clinical trials, but this approach is resource intensive and impractical to implement at a population level. Similarly, the use of magnetic resonance-based liver fat content or stiffness assessments used as an outcome measure in some trials contends with the same logistical limitations. A key challenge would then be to conceptualise cost effective and easily accessible non-invasive tools to approximate the histologic grading and more importantly, provide alternative, non-invasive surrogate endpoint measures of clinical outcomes. In this context, risk stratification for an extremely prevalent disease should ideally be blood/serum based and minimally complex in its derivation. Stefanakis et al. [28] provides an excellent overview on the current state and commentary on this issue. Several proprietary algorithms (e.g., enhanced liver fibrosis [ELF] score and ADAPT) have been developed that demonstrate superiority to indirect fibrotic assessments such as the FIB4 and NAFLD Fibrosis Score in capturing hepatic inflammation, fibrosis stage (especially in defining the clinically silent but therapeutically significant F2–F3 stages with high specificity and sensitivity) and more recently, in predicting liver related morbidity and mortality [29-31]. ELF has the largest evidence of use with validation cohorts across the spectrum of hepatic diseases and defined cut-off values for clinically significant fibrosis in fatty liver disease that are accepted across major society clinical practice guidelines [32-34]. However, cost and availability of testing are barriers to widespread uptake especially outside of major metropolitan centres. Democratising access to these bespoke non-invasive testing (NIT) is an important priority and is streamlined with innovations such as the Elecsys PRO-C3 assay which can be conducted on the widely utilised Roche COBAS platform. This allows for rapid derivation of the ADAPT score (which includes PRO-C3 levels, platelet count, age and diabetes status) and thus a clearer assessment of disease activity in routine clinical practice. As the next step, active incorporation of these biomarkers into trial designs is required to compare and finesse their use as firm drug response criteria for which there is limited evidence to date. Non-invasive monitoring algorithms proposed for the safe implementation of resmetirom [35], a liver-directed therapy in clinical practice, whilst useful, are difficult to wholly extrapolate into the incretin therapy space where there is also a multitude of systemic end-organ benefits to be accounted for. Grappling with the full gamut of benefits for this class of agents demands epistemological interrogations into the nature of whole-body metabolism and how it can be reproducibly quantified in clinical practice to better capture composite end organ outcomes. The field is perhaps ripe to consider novel and/or repurpose existing biomarkers (e.g., homeostatic model assessment for insulin resistance, high sensitivity C reactive protein, etc.) of dysmetabolism to attempt a holistic encapsulation of clinical efficacy. In this regard, artificial intelligence-based mining of large electronic population health data sets may also yield novel signatures and associations that could be incorporated into clinical decision making. Machine learning models constructed using aminotransferases, metabolic syndrome criteria, body mass index, 3-ureidopropionate and alpha-ketoglutarate outperformed existing NITS (e.g., Fib4 followed by elastography and fibro scan-AST) in predicting MASH with F2–3 fibrosis providing empirical data for this technology in guiding therapy calibration [36]. As an added consideration, training artificial intelligence models on electronic health records also allows for the appraisal of longitudinal trends in patients’ biochemical profiles which can enhance predictive abilities above and beyond snapshot clinical data.

Steatotic liver disease as a mirror of whole-body metabolic control

On a related note, the field of metabolism also demands refinements in elucidating the multifarious mechanistic interactions (genetics, environmental, microbial factors, etc.) which account for the observed clustering of distinct end-organ dysfunctions or diseases (i.e., a conceptual “dysmetabolome”) (Fig. 4).

Figure 4.

The “dysmetabolome” as a framework to conceptualise how metabolic diseases are characterised by common risk predictors resulting in a tendency to cluster together. The hypothesis is that these risk modifiers also dictate which disease phenotypes tend to predominate in any given individual, creating reproducible patterns of disease expression that could be utilised to enable treatment according to comorbidities. BMI, body mass index; CKD, chronic kidney disease; CTCA, computer tomography based coronary angiogram; DEXA, dual energy X ray absorptiometry; GFR, glomerular filtration rate; HOMA-IR, homeostatic model assessment for insulin resistance; hsCRP, high sensitivity C reactive protein; NGAL, neutrophil gelatinase-associated lipocalin; NIT, non-invasive tests; T2DM, type 2 diabetes mellitus. Created with Biorender.com.

This work would have important ramifications with respect to risk prediction and potentially in the primary prevention of disease through pre-emptive surveillance and pharmacological modulation strategies. There is empiric precedence for this concept in the MAFLD/MASLD arena with polymorphisms in the PNPLA3 genotype attenuating the histologic response to Tirzepatide in a secondary analysis of the SYNERGY-NASH study [37]. Similarly, Ding et al. [38] have leveraged multiomic technologies to define intra-ethnic polymorphisms of MAFLD/MASLD expression in a Chinese cohort that may predict inflammatory burden and the development of clinically significant endpoints such as HCC and cirrhosis. As an extension, there needs to be emphasis on conceptualising randomised trials assessing head-to-head comparisons of different incretin analogues, pharmacokinetic experimentation (i.e., variable dosing, drug delivery models, etc.) and/or combination therapies with organ-directed (e.g., ACE inhibitors in renal disease, resmetirom in MAFLD/MASLD, SGLT2 and/or neprilysin inhibitors in heart failure, etc.) therapies to define the optimal permutation of receptor agonism to apply in different clinical contexts. Indeed, while the incretin analogues demonstrate significant promise in the fatty liver diseases space, there appear to be limits to monotherapy with only approximately a third of patients responding in clinical trials and arguing for combination therapies as the future standard of care [14,39]. There is a rapidly expanding research portfolio of organ directed therapies in the investigational pipeline (Fig. 5) and reconciling the potential myriad of options into clinical workflows (i.e., a proverbial “treat to target” philosophy) will be a priority in the coming years.

Figure 5.

Expanding research and development into several novel mediators targeting cardiometabolic disease across phase 1–3 clinical trials. AS-CVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; MASLD, metabolic dysfunction associated steatotic liver disease; GLP-1, glucagon-like peptide-1. Created with Biorender.com.

Real world considerations for public health

While the incretin drug class has broad clinical appeal, they are expensive and demand life-long adherence to therapy based on the current evidence. Discontinuation which can be due to various drivers such as cost, adverse effects and/or psychological factors (e.g., dislike of injections, adherence fatigue, etc.) is a notable phenomenon in the literature and is associated with significant and rapid weight re-gain, presumably in the same composition in which it was lost. The kinetics and clinical impact of this rebound physiology upon end-organ health remain unknown but require ongoing post-marketing surveillance to elucidate. The incretin analogue space is also becoming increasingly competitive with multiple agents entering the trial space with compelling data. As the evidence for their niche in clinical use and relative inter-changeability becomes evident, it would be expected to exert downward pressure on costs. Similarly, patent expiry, optimisation of supply chain logistics and creation of biosimilar products would facilitate more affordable access to these products. Refinements in disease risk stratification and appreciation of where in the disease spectrum these drugs are most beneficial (e.g., cirrhosis vs. F2 fibrosis) would also help to streamline the burden of care among health services with milder disease phenotypes potentially being managed in primary care settings. Nevertheless, an anticipated public health conundrum would be in ensuring equitable access to a potent therapy for chronic lifestyle diseases which are disproportionately over-represented among the most disenfranchised tiers of the socioeconomic spectrum. Reframing non-communicable chronic diseases as a national health priority is essential to shift fiscal strategy and democratise care delivery. Ultimately, from a societal point of view, managing lifestyle-related diseases early will likely be cost effective for curtailing health costs associated with end organ disease. Balancing limited health budgets against the expected monetary savings and productivity gains from an amelioration of chronic disease burden will be a looming economic challenge to reconcile in the coming decades.

Table 3 summarizes some key considerations requiring further study in the incretin therapy space.

Table 3.

Key areas of controversy/uncertainty in the use of the incretin drugs in MAFLD/MASLD

Area of controversy/uncertainty	Research required
Correlation of therapeutic use with clinical endpoints	Phase 3 RCTs with trial durations sufficient to capture important clinical outcomes. Phase 2 of the ESSENCE study (due 2027) will be the first of its kind.
Safety and efficacy in advanced fibrosis/cirrhosis	Dedicated randomised trials in cirrhotic/F4 patients (e.g., LIVERAGE-Cirrhosis) or pre-specified F4 fibrosis patient subgroup analyses included in conceptualised trials.
Are fears of iatrogenic sarcopenia clinically relevant? If so, how to risk mitigate?
	Concomitant use of anabolic agents and lifestyle interventions e.g., resistance exercise programs to circumvent sarcopenia.
Drug receptor affinity and permutations optimised for liver function/health	Head-to-head comparison trials of different incretin analogues in the MAFLD/ MASLD population.
How long do patients need to be on therapy? Is this disease specific?	Pharmacovigilance data that assesses patterns of use, effects of drug cessation on health outcomes. Ultimately, stop trials to define optimal therapeutic durations.
Elucidating effective and widely available NITs to approximate histology and allow monitoring in clinical practice	Routine incorporation of NITs in conjunction with biopsy in trial protocols to validate use.
	Retrospective analyses of biochemical data from trial participants to define and validate blood-based biomarkers (the most ideal form a population-based risk assessment tool)
How to reconcile and calibrate use considering whole body metabolic health benefits/effects i.e., specific agent for a pre-determined cluster of comorbidities (the “dysmetabolome”)	Wholistic trials that look at multi-outcome measures. Defining metabolic risk and how and why diseases tend to cluster in specific individuals. Can this be predicted?
Cost and ensuring equity of access	Economic analyses around cost savings from amelioration of chronic disease reconciled against cost of continued government funded drug coverage.
	Screening strategies to capture and enrol vulnerable patients into management pathways.

MAFLD, metabolic dysfunction-associated fatty liver disease; MASLD, metabolic dysfunction-associated steatotic liver disease; NIT, non-invasive testing.

CONCLUSIONS

The evolving conceptual framework of fatty liver disease as a manifestation of underlying systemic metabolic dysregulation demands holistic perspectives on treatment. The incretin drugs in many ways embody the empiric underpinnings of this philosophy and represent an exciting solution to the real-world limitations of supporting lasting lifestyle change. The field is nascent; questions remain, and practical considerations apply, but the early evidence across the metabolic disease spectrum is compelling, and it is very likely these agents will feature prominently and transform the practice of modern clinical hepatology.