Повторное регулирование веса после трансплантации печени с использованием глюкагонового пептида one агонисты желудочно-кишечного ингибитора полипептида.

Core Tip: While liver transplantation can be life-saving for end-stage liver diseases, it can exacerbate metabolic issues due to underlying pathology and immunosuppressive regimens. A thorough management plan is essential to prevent complications like metabolic dysfunction-associated steatotic liver disease, chronic renal dysfunction, and diabetes, ultimately improving prognosis and quality of life. glucagon-like peptide-1 (GLP-1) and GLP-1/glucose-dependent insulinotropic polypeptide receptor agonists have gained United States Food and Drug Administration approval for long-term weight management, but their long-term safety, optimal dosing, and effectiveness in transplant recipients remain underexplored. This review addresses the pathophysiology, risk factors, and burden of metabolic complications in liver transplant recipients while evaluating the potential role of GLP-1 and GLP-1/glucose-dependent insulinotropic polypeptide receptor agonists for managing these issues.

INTRODUCTION

Liver transplantation (LT) is often a life-saving intervention for candidates with end-stage liver disease, with increasingly promising survival rates and an average 15-year life span extension post-transplant[ 1 ]. However, many patients face post-transplant metabolic complications. Obesity is the most critical one, reducing the quality of life, graft and patient survival[ 1 - 3 ]. While global obesity rates have tripled since 1975[ 4 , 5 ], long-term metabolic complications are frequently observed after LT, encompassing conditions such as post-transplant diabetes mellitus (PTDM), hypertension, metabolic-associated steatotic liver disease (MASLD), dyslipidaemia and obesity, whether new onset or relapse, affect roughly half of the LT recipients[ 6 , 7 ].

The pathophysiological basis of these complications is multifactorial, including immunosuppressive therapy such as tacrolimus, a calcineurin inhibitors (CNI), which disrupt the gut microbiota and promote dysbiosis[ 8 ]. Also, the underlying condition of many recipients is MASLD[ 2 ]. Collectively, all these factors lead to extensive clinical impact, including a broad spectrum of non-communicable diseases such as metabolic syndrome (MetS), cardiovascular disease, type 2 diabetes, and several malignancies. Obesity contributes to the progression of de novo steatosis, osteoarthritis, and multiple respiratory disorders, including obstructive sleep apnoea, which can severely impair daily functioning and exacerbate perioperative risk[ 9 ]. The economic propositions must be taken into consideration, with obesity-related problems are causing a rising burden on healthcare facilities.

Conventionally, very low-calorie diets (VLCDs) and intensive lifestyle modifications were used to address the challenge of being overweight. While these approaches can be effective for particular patients, their success is usually dependent on adherence and sustainability, steering to variable outcomes[ 10 ]. Moreover, metabolic bariatric surgery is a well-established treatment for obesity, but following LT, this intervention carries higher technical difficulties due to anatomical and physiological alterations, expanding its overall complexity[ 11 , 12 ]. Conventional pharmacotherapies, such as former groups of anti-obesity drugs, have similarly been limited by restrained efficacy and substantial side effects, underscoring the unmet clinical need for safer and more effective alternatives[ 13 ]. Alternatively, novel pharmacological approaches, particularly glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) as well as GLP-1/glucose-dependent insulinotropic polypeptide (GIP) dual RA, have appeared as promising anti-obesity agents, offering the potential to improve long-term patient outcomes[ 14 ]. By accelerating post-operative weight reduction, these agents have the potential to improve the quality of life and prognosis of LT recipients. In this review, we aim to clarify the role of GLP-1 and GLP-1/GIP RA in mitigating the post LT complications. In addition, we seek to clarify various crucial knowledge gaps concerning the use of GLP1 and GLP1/GIP dual RA in this population such as the safety and effectiveness of these agents for weight loss after LT, the possible significant drug-drug interactions with immunosuppressive regimens and the availability of long-term regimens or therapeutic plans tailored to LT recipients.

PATHOPHYSIOLOGY, RISK FACTORS AND CLINICAL PRESENTATION OF METABOLIC COMPLICATIONS IN LT RECIPIENTS

Several factors have been consistently associated with the development of post-liver transplant MetS, including older age at transplantation, pre-existing diabetes mellitus, elevated post-transplant body mass index (BMI), smoking, and the underlying indication for transplantation, particularly hepatitis C infection or alcohol-related cirrhosis. In addition, the utilisation of cyclosporine as an immunosuppressive mediator and specific genetic polymorphisms have been identified as potential contributing risk factors[ 7 , 9 , 15 ].

MASLD is a hepatic manifestation of MetS, with marked racial differences in prevalence, highest among Hispanics, followed by Caucasians, and lowest among African Americans[ 16 ]. It includes a spectrum of pathologies ranging from hepatic steatosis (fatty liver) to the more aggressive form, non-alcoholic steatohepatitis (NASH), in which fatty deposition, inflammation and necrosis are present. Histopathologically, NASH is defined by macro-vesicular steatosis, hepatocellular ballooning with or without Mallory bodies, and lobular or portal inflammation, with or without fibrosis[ 17 ]. In the context of obesity, cirrhosis resulting from non-alcoholic fatty liver disease is swiftly rising as a top indication for LT. Studies indicate that approximately 10%-20% of patients with NASH develop progressive fibrosis over time, ultimately developing cryptogenic cirrhosis, a condition commonly occurring in the context of obesity, diabetes, and cardiovascular disease. Insulin resistance and hypertension have been identified as key clinical risk factors for fibrosis progression. Additional evidence supporting the association between NASH and cryptogenic cirrhosis is provided by post-transplant findings, as patients transplanted for cryptogenic cirrhosis frequently demonstrate recurrent non-alcoholic fatty liver disease and NASH in their liver allografts[ 18 - 20 ]. MASLD is also claimed to be a clear risk factor for hepatocellular carcinoma, which is one of the significant indications for LT[ 21 ].

One of the key encounters following LT in patients with obesity is the management of post-transplant metabolic challenges, including MetS and new-onset diabetes. Nearly 46% of patients developed MetS following LT. This risk is guided by multiple factors, involving pre-transplant BMI and post-transplant weight gain, with various studies suggesting pre-transplant obesity as the strongest predictor of undue weight gain after LT. Additionally, rigorous post-transplant obesity (BMI ≥ 35) is associated with an increased risk of post-transplant diabetes, which is the strongest predictor of mortality following LT[ 7 , 22 ].

These metabolic complications reveal a multifactorial process involving immunosuppressive therapy, pre-existing metabolic abnormalities, postoperative lifestyle factors, and post-transplant disruptions in metabolic homeostasis. Characterising these instruments provides a basis for exploring targeted interventions with GLP-1 RAs[ 7 , 23 ]. Table 1 includes key drivers of metabolic disorders after LT[ 24 - 45 ].

Table 1 Key drivers of metabolic disorders after liver transplantation: A mechanistic basis for glucagon-like peptide-1 therapy
Pathophysiology


Triger


Resultant metabolic disorder

Role of GLP-1, dual GLP-1/glucose-dependent insulinotropic polypeptide

β-cell toxicity, reduced insulin secretion, and peripheral insulin resistance[ 24 , 25 ] Immunosuppressant agents Post-transplant diabetes mellitus[ 24 , 25 ] Promotes and increases insulin secretion, reduces glucagon secretion, Improves β-cell function, and Improved insulin sensitivity[ 24 , 26 , 27 ] Altered lipid metabolism (increased very LDL production, decreased lipoprotein lipase activity and impaired lipid clearance)[ 28 ] Immunosuppressant agents. Post-transplant metabolic changes Dyslipidaemia[ 29 ] Reduces triglycerides, LDL cholesterol and very LDL production[ 30 , 31 ] Return of appetite, resolution of catabolic cirrhosis state and visceral fat accumulation[ 32 ] Postoperative lifestyle Weight gain (obesity) and adipose dysfunction[ 33 ] Act on hypothalamic satiety centres, slow gastric emptying, reduce caloric intake, reduces liver fat contents, improve hepatic lipid metabolism[ 34 , 35 ] Insulin resistance, increased free fatty acid flux, de novo lipogenesis Pre-existing metabolic disease Pre-existing metabolic risk factors (obesity, diabetes, fatty liver or metabolic-associated steatotic liver disease)[ 36 , 37 ] Decrease hepatic de-novo lipogenesis, reduce liver fat contents, increase fatty-acid oxidation and reduce free-fatty-acid release from adipose tissue[ 30 , 38 , 39 ] Combination of insulin resistance, visceral adiposity, dyslipidaemia Immunosuppressant agents[ 32 , 40 ] Metabolic syndrome In addition to the above mechanisms, they reduce systemic inflammation, improve adipokine profiles and decrease oxidative stress[ 31 , 32 , 41 , 42 ] Loss of renal magnesium which aggravates insulin resistance Immunosuppressant agents[ 43 , 44 ] Renal/electrolyte disturbances[ 43 , 44 ] Modulation of tubular sodium handling and improved metabolic regulation[ 45 ] GLP-1: Glucagon-like peptide-1; LDL: Low-density lipoproteins.

Key drivers of metabolic disorders after liver transplantation: A mechanistic basis for glucagon-like peptide-1 therapy

GLP-1: Glucagon-like peptide-1; LDL: Low-density lipoproteins.

All the factors of the MetS are linked to cardiovascular threats. The increased prevalence of MetS in LT recipients is associated with a higher incidence of cardiovascular events, reaching approximately 3% at three years post-transplant[ 46 , 47 ].

LT recipients frequently develop cardiometabolic risk factors that eventually predispose to major adverse cardiovascular events (MACE), containing stroke, myocardial infarction, and cardiovascular mortality[ 15 ]. Cardiovascular disease represents a leading cause of both short and long-term mortality following LT, caused by an unfavourable metabolic profile, immunosuppressive drug effects, and high prevalence of traditional risk factors such as diabetes, hypertension, and dyslipidaemia[ 48 ]. Essentially, MetS after LT is increasingly documented, with a ample section of recipients developing insulin resistance, visceral adiposity, and dyslipidaemia during follow-up, thereby increasing cardiovascular risk[ 15 , 48 ]. Post-transplant MetS promotes a pro-atherogenic and pro-inflammatory condition categorised by endothelial dysfunction, persistent insulin resistance, and adipokine dysregulation[ 48 , 49 ]. These pathophysiological mechanisms, combined with continuous exposure to CNI and corticosteroids, contribute not only to new metabolic imbalances but also to accelerated atherosclerotic processes, reflected in significantly increased rates of non-fatal and fatal MACE among long-term liver transplant survivors[ 49 ].

Moreover, MetS in liver transplant recipients is associated with a high incidence of renal dysfunction. Reduced glomerular filtration rate and microalbuminuria related to hypertension and diabetes, along with consequent structural renal damage, may be further exacerbated by the nephrotoxic effects of immunosuppressive therapies. Collectively, these factors contribute to the increased risk of chronic kidney disease among transplant recipients with MetS[ 50 , 51 ].

Clinical presentation of post-LT metabolic complications include: (1) Obesity: Patients who are overweight or obese ahead of the transplant stay overweight or obese following the transplant[ 15 ]. While 15% of candidates who are of normal weight on transplant time develop obesity within one year, and over 25% within 3 years[ 15 ]; (2) Arterial hypertension: The incidence of post-LT hypertension is remarkably high, the onset occurs at an average of 9 ± 6.98 months[ 48 ]. The prevalence significantly increases in liver transplant recipients, ranging from 21% to 56%[ 49 , 52 - 54 ]; (3) Diabetes: The prevalence of post-liver transplant diabetes has been reported to range between 14%-61%[ 53 ]; and (4) Dyslipidaemia/hyperlipidaemia: The prevalence of which ranges between 40%-71%[ 53 - 56 ].

GLP-1 and GLP-1/GIP RA

In non-transplant populations, large cardiovascular outcome trials and meta-analyses have demonstrated that GLP-1 RAs and dual GLP-1/GIP agonists significantly reduce MACE (a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) and mortality, with consistent evidence of cardioprotective effects across diverse high-risk cohorts[ 57 , 58 ]. These benefits have been attributed to weight reduction, improved glycaemic control, blood pressure lowering, anti-inflammatory effects, and favourable effects on lipids and endothelial function[ 57 , 58 ].

Although transplant-specific cardiovascular outcome data remain limited, emerging observational studies in solid organ transplant recipients suggest that GLP-1-based therapies can improve cardiometabolic parameters ( e.g. , body weight, glycated hemoglobin, and lipid profile) and may be associated with reduced cardiovascular events and mortality[ 6 , 59 ]. However, the absence of large randomised controlled trials in liver transplant populations necessitates cautious interpretation; current evidence should be viewed as extrapolative rather than definitive.

Although GLP-1 RAs have demonstrated substantial cardiometabolic benefits in large randomized trials involving non-transplanted populations, the extent to which these benefits translate to liver transplant recipients remains uncertain. Cardiovascular outcome trials have consistently shown that GLP-1 RAs significantly reduce MACE and mortality among individuals with type 2 diabetes and high cardiovascular risk[ 60 ]. However, evidence in transplant recipients remains limited and is largely derived from small observational studies and systematic reviews involving heterogeneous solid organ transplant populations[ 61 ]. Subsequently, extrapolation of these findings to liver transplant recipients should be handled with caution. One potential source of divergence linked to the metabolic effects of immunosuppression. CNI, especially tacrolimus, are strongly linked with insulin resistance, β-cell dysfunction, and PTDM, which may modify the metabolic response to incretin-based therapies[ 7 ]. In addition, evolving evidence specifies that tacrolimus can induce significant shifts in gut microbiota composition, contributing to dysbiosis and metabolic disturbances after transplantation[ 8 ]. Since incretin hormone signalling and GLP-1 secretion are partially affected by intestinal microbial metabolites and gut-liver axis exchanges, these microbiome modifications could theoretically influence the metabolic efficacy of GLP-1-based therapies in transplant recipients[ 8 , 62 ]. Cooperatively, these factors emphasize important doubts regarding the magnitude of benefit and safety profile of GLP-1 RAs in liver transplant populations. Prospective studies and randomized controlled trials are therefore required to explain their long-term cardiometabolic effects and potential interactions with immunosuppressive regimens in this matchless clinical setting.

Mechanism of action of GLP-1 and GIP agonists

The “incretin effect”, primarily illustrated in the early 20 th century, refers to the remark that oral glucose produces a larger insulin response than intravenous glucose load. This is facilitated predominantly by two gut hormones: (1) GLP-1; and (2) GIP. Secreted from enteroendocrine cells following nutrient intake, these hormones play fundamental roles in postprandial glucose homeostasis[ 63 ].

GLP-1: A multifaceted regulator

GLP-1 is secreted by intestinal L-cells, located primarily in the ileum and colon but also present in the jejunum. Nutrient intake, including carbohydrates, fats, and proteins, stimulates its release. Its physiological actions extend beyond glucose regulation. In the pancreas, GLP-1 boosts glucose-dependent insulin secretion from β-cells and simultaneously controls glucagon secretion from α-cells, thereby lowering blood glucose without increasing the risk of hypoglycemia. A major contributor to weight loss is its ability to slow gastric emptying, extending nutrient absorption, encouraging satiety, and reducing postprandial glucose. GLP-1 receptors are also conveyed in the hypothalamus and brainstem, where their activation increases satiety, decreases food intake, and reduces eating. Additionally, GLP-1 has cardiovascular benefits, including improvements in cardiac function and blood pressure, and explains potential neuroprotective assets[ 62 , 64 ].

GIP: A partner in metabolic regulation

GIP release is triggered by nutrient ingestion, especially fats and glucose. Like GLP-1, GIP stimulates glucose-dependent insulin secretion from pancreatic β-cells[ 65 ]. GIP receptors are expressed in adipose tissue, where the hormone promotes glucose uptake and lipid storage, linking it to metabolic regulation and energy balance. Although traditionally viewed as less effective for weight management, emerging evidence highlights GIP’s larger metabolic role. Importantly, in type 2 diabetes, GIP’s insulinotropic action is often reduced, whereas GLP-1 sensitivity is preserved, a differential response that informs therapeutic strategies[ 62 , 65 ].

Synergy of dual GLP-1/GIP agonism

Many anti-obesity therapies are currently awaiting approvals or in superior stages of clinical trials, such as the triple agonist Retatrutide; a GLP1/GIP/glucagon triple agonist[ 66 , 67 ], the oral non-peptide GLP-1 agonist, orforglipron[ 67 , 68 ], and cAMP signalling biased GLP-1 agonist ecnoglutide[ 69 ]. As a first in class unimolecular dual receptor agonist, terzipatide represents a advance in metabolic therapy. It is the sole dual-receptor agonist commercially available. Dual agonists activate both receptors, employing synergistic effects to achieve improved glucose control and more robust weight reduction compared to GLP-1 RAs alone. The enhanced efficacy is attributed to complementary mechanisms: GLP-1 slows gastric emptying and suppresses appetite centrally, while GIP may exert direct effects on adipose tissue metabolism and support β-cell function. Notably, the GIP component may attenuate gastrointestinal upsets linked to GLP-1 monotherapy, enhancing acceptability[ 65 , 70 , 71 ].

Table 2 summarises the key characteristics of the most commonly used GLP-1 and dual GLP-1/GIP RA for weight management. The average weight loss percentages are based on data from major clinical trials[ 71 - 74 ].

Table 2 Key characteristics of commonly used glucagon-like peptide-1 and glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptor agonists for weight management
Medication class


Dosing frequency


Dosage form


Average weight loss


Key considerations

Liraglutide (Saxenda ® ) Once-daily SC Approximately 8% First GLP-1 RAs approved for weight management Semaglutide (Wegovy ® ) Once-weekly, once daily SC, tablet Approximately 15%-17% Highly effective for weight loss, available in oral and injectable forms Tirzepatide (Zepbound ® ) Once-weekly SC Approximately 20%-22% First-in-class dual agonist, demonstrates superior weight loss to GLP-1 RAs GLP-1: Glucagon-like peptide-1; RA: Receptor agonists; SC: Subcutaneous injection.

Key characteristics of commonly used glucagon-like peptide-1 and glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptor agonists for weight management

GLP-1: Glucagon-like peptide-1; RA: Receptor agonists; SC: Subcutaneous injection.

Clinical evidence: GLP-1/GIP agonists in transplant recipients

The utility of GLP-1 and dual GLP-1/GIP dual agonists is driven by robust efficacy in weight reduction, metabolic improvements, and perioperative risk mitigation. Their use to mitigate the consequences associated with post-transplant multiple sclerosis (MS) such as PTDM, cardiovascular and renal complication in addition to recurrent liver pathologies and increased mortality is supported by growing clinical evidence though still the data about the use of GLP-1 and GLP-1/GIP in liver transplant recipient is limited and yet to be studied for efficacy and safety for longer durations and in larger cohorts[ 1 , 27 , 75 ].

Efficacy in weight loss and metabolic optimisation

GLP-1 and dual GLP-1/GIP RA have transformed the therapeutic landscape of obesity and type 2 diabetes, demonstrating unprecedented efficacy in weight loss. Obesity recurs in 20%-40% of LT recipients, causing MS and central vein sign complications, the primary cause of mortality in liver transplant recipients[ 1 , 2 , 76 ]. GLP-1 agonist promote 5%-15% weight loss in transplant populations, reducing visceral adiposity and dyslipidemia, with observational data showing BMI decreases from 32 kg/m 2 to 28 kg/m 2 over 12 months[ 27 ]. If the primary liver pathology was MASLD, these agents prevent de novo obesity by suppressing appetite and delaying gastric emptying, regardless of baseline immunosuppression[ 2 ].

Emerging evidence suggests GLP-1/GIP dual agonist could amplify weight loss (up to 15%-20%) through GIP-mediated energy expenditure, potentially addressing steroid-induced weight gain[ 77 ]. Yet a comprehensive management plan including lifestyle modification led to superior results, lowering MS prevalence from 60% to 40%[ 1 ].

Safety, complications and current regimen

While GLP-1 and GLP-1/GIP RA provide substantial clinical benefits, their use in the postoperative setting requires careful consideration of safety concerns, particularly those linked to delayed gastric emptying and potential interactions with immunosuppressants.

Overall, GLP-1 RAs are well-tolerated after LT. The most frequent side effects are gastrointestinal nausea (20%-30%), which rarely causes discontinuation (5%), vomiting, diarrhoea, and constipation, typically mild to moderate, transient, and dose-dependent, with improvements seen with dose titration. Rare but considerable adverse events include acute pancreatitis, cholelithiasis, and acute kidney injury, mainly in patients with pre-existing renal disease or those experiencing severe dehydration secondary to gastrointestinal disturbance. A boxed warning for certain GLP-1 RAs regarding thyroid C-cell tumours (medullary thyroid carcinoma) necessitates the exclusion of patients with personal or family histories of such tumours or multiple endocrine neoplasia type 2. No increased risk of infection or malignancy rates is observed[ 2 , 27 , 78 , 79 ].

While transplant-specific regimens are not yet standardised, clinical practice involves a gradual dose-escalation protocol to mitigate gastrointestinal side effects, which can theoretically interfere with the absorption of narrow-therapeutic-index immunosuppressants like tacrolimus. Recent data indicate that GLP-1-based therapies are generally beneficial in LT recipients, effectively reducing glycated hemoglobin, body weight, and insulin requirements without increasing graft rejection or significantly altering immunosuppressive drug levels. Yet, the long-term impact of these drugs on graft function and survival is infrequently reported, making it hard to generalise their benefits. More specific studies are imperative to synthesise clear evidence and guidelines for the optimal regimen and dosing titration for specific populations such as paediatric/MAFDL LT[ 2 , 80 ].

Also, the available guidelines lack discontinuation regimens or plans. Upon drug cessation, the obesity patients face recurrence, with an average of weight regain at a rate of 0.4 kg/month, resulting in the loss of any metabolic benefit after 1.7 years. These findings suggest little to no benefit of short-term use of GLP-1 and GLP-1/GIP agonists, and uncover a critical research gap into cost-effective long-term management plans[ 81 ]. Table 3 includes published evidence and graded strength of evidence on the potential benefit of GLP-1/GIP RA on metabolic complications in liver transplant recipients[ 59 , 60 , 75 , 82 , 83 ].

Table 3 Published evidence and graded strength of evidence on the potential benefit of glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptor agonists on metabolic complications in liver transplant recipients
Metabolic complication


Associated cardiovascular/clinical risk


Potential benefit of glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptor agonist

Evidence level (grade)


Ref.

Post-transplant insulin resistance/type 2 diabetes mellitus Increased: Risk of MACE, myocardial infarction, stroke, and cardiovascular mortality Improved glycaemic control, weight reduction, and reduced insulin resistance Moderate (extrapolated from large RCTs in non-transplant populations) Kristensen et al [ 60 ], Grancini et al [ 75 ], Lin et al [ 82 ] Dyslipidaemia Increased: Atherogenesis, MACE, accelerated atherosclerosis Improved lipid profile, reduced triglycerides and low-density lipoproteins, and improved endothelial function Low-moderate (observational in LT, high-quality in non-LT) Kristensen et al [ 60 ], Lin et al [ 82 ], Dotan et al [ 83 ] Visceral adiposity/obesity Increased: Insulin resistance, blood pressure, MACE Weight reduction, improved body composition, anti-inflammatory effects Moderate (non-LT RCTs, LT observational) Kristensen et al [ 60 ], Grancini et al [ 75 ], Lin et al [ 82 ], Dotan et al [ 83 ] Metabolic syndrome (cluster of risk factors) Increased: Combined cardiovascular risk, long-term mortality Multifactorial improvement: Weight, glycaemia, blood pressure, lipids, inflammation Low (transplant-specific RCTs lacking, evidence extrapolated) Yakubu et al [ 59 ], Kristensen et al [ 60 ], Grancini et al [ 75 ], Lin et al [ 82 ], Dotan et al [ 83 ] Pro-inflammatory state/endothelial dysfunction Increased: Atherosclerosis progression, MACE Anti-inflammatory effects, improved endothelial function, potential reduction in cardiovascular events Low (mechanistic, limited clinical transplant data) Kristensen et al [ 60 ], Grancini et al [ 75 ], Lin et al [ 82 ] LT: Liver transplantation; MACE: Major adverse cardiovascular events; RCTs: Randomized controlled trials.

Published evidence and graded strength of evidence on the potential benefit of glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptor agonists on metabolic complications in liver transplant recipients

LT: Liver transplantation; MACE: Major adverse cardiovascular events; RCTs: Randomized controlled trials.

Comparison of GLP-1/GIP RA with other obesity management strategies

GLP-1/GIP RA offer significant advantages compared with traditional obesity management interventions, though relative effectiveness and patient-specific considerations remain important.

VLCDs: Historically the cornerstone of preoperative weight loss, VLCDs achieve rapid reductions in body weight and liver size but suffer from poor long-term adherence, nutritional deficiencies, and muscle mass loss[ 84 ].

Intragastric balloons: Intragastric balloons (IGBs) provide another non-surgical alternative. Comparative studies in super-obese patients found IGBs superior to liraglutide in short-term BMI reduction and in achieving higher %EWL and %EBWL at 6-12 months postoperatively[ 85 , 86 ]. However, liraglutide was better suited for patients with extreme BMI (> 70 kg/m 2 ) or those ineligible for IGB placement due to life-limiting comorbidities. Notably, liraglutide use was associated with lower rates of postoperative complications compared with IGBs, though differences were not statistically significant[ 85 ].

Metabolic bariatric surgery: Bariatric interventions pre-LT or post-LT may synergise, but GLP-1 RAs offer a less invasive alternative[ 2 ].

Other pharmacological options: Agents such as orlistat, phentermine/topiramate, and naltrexone/bupropion have been used preoperatively but generally achieve only modest weight loss compared to GLP-1/GIP agonists, with less favourable tolerability or contraindications that limit perioperative use[ 13 ].

Taken together, GLP-1 and dual GLP-1/GIP RA provide superior efficacy, broader metabolic benefits, and an improved safety profile compared with most alternative pharmacological or procedural strategies. Their role is particularly valuable for patients requiring substantial weight reduction and metabolic stabilisation after a solid organ transplant[ 61 ].

Patient-centred outcomes, expectations and experiences

The burden of obesity in LT patients has been reported in many studies[ 87 - 90 ], while patient-centred studies focusing on patients’ expectations and experiences are scarce. A cohort study merging 2 datasets, including electronic health records and claims, involved 10316 patients with MASH who initiated a GLP-1 receptor agonist in high dose [2043 constitute (19.8%)] and low dose [8273 constitute (80.2%)], evaluated treatment patterns, healthcare resource utilisation, and costs. Treatment pattern revealed that more than half of patients discontinued GLP-1 RAs therapy within a year. Examining the reasons for treatment discontinuation by an exploratory review of clinical notes clarified that more than one-third of patient discontinuations stem from adverse effects, while 9% are directly linked to cost or insurance constraints.

Another study examined the real-world evaluation of weekly subcutaneous treatment with semaglutide in a cohort of 285 Italian type 2 diabetic patients. Discontinuation data revealed that a total of 39 out of 258 patients (15.1%) receiving at least one dose of once weekly semaglutide withdrew from treatment. In 29 cases (11.2%) for gastrointestinal intolerance occurring within few weeks since therapy commencement (nausea and vomiting in 16, diarrhea or constipation in 7, abdominal cramps in 2 and malaise in 1 patient), while treatment was discontinued due to therapeutic inefficacy in 9 patients and pregnancy in 1 case[ 91 ].

Generally, patients’ expectations regarding weight loss medications, particularly GLP1/GIP RA, vary considerably. Many patients expect quick weight reduction with least effort, sometimes underestimating the importance of sustained lifestyle modifications such as dietary changes and physical activity. Donnan et al [ 92 ] reported distinguished variation in patients’ perceptions. While some patients set high and occasionally unrealistic goals, others focused on improving their quality of life. When questioned about specific weight loss targets, most patients indicated they would be dissatisfied with less than a 10% target. Past weight loss, patients also expressed high expectations for improvements in comorbidities as diabetes mellitus, hypertension, and dyslipidemia[ 92 ].

The main concern of most patients was the cost of medication. Most of the patients were worried that they may have to stop the medication due to the high cost, particularly patients without insurance coverage. The other concern was about side effects. Although most patients believed that GLP-1/GIP RA are generally safe, some patients were sceptical about GIT upset as well as long-term complications[ 92 , 93 ].

In conclusion, comprehensive patient education is obviously an indispensable component of the weight management plan to have realistic weight loss goals and assist clinicians in shared decision-making.

Health system impact and economic considerations

The integration of GLP-1/GIP RA into a comprehensive postoperative plan has the potential to reshape healthcare delivery for LT recipients with obesity, with or without other manifestations of MS. By facilitating weight loss and metabolic optimisation, these agents may reduce post-transplant metabolic complications[ 27 ].

The previously discussed cohort study involved 10316 patients with MASH who initiated a GLP-1 receptor agonist, has also examined the healthcare resource utilisation and costs among patients. Results revealed that treatment was associated with reasonable improvements in obesity – chiefly while using high doses – but also with significant discontinuation rates and high economic effect[ 94 ].

Healthcare utilisation was largely similar between GLP-1 RAs users and non-users, yet the cost was markedly higher among GLP-1 cohort. Although GLP-1 RAs users had slightly fewer inpatient admissions than the comparator cohort in both baseline and followup periods, they required wide outpatient care – averaging 14-18 outpatient visits and 15-20 unique drug formulas per period – reflecting the complex clinical needs of patients with MASH. Mean costs in the GLP-1 RAs cohort rose from $20912 at baseline to $27586 during follow-up, with high-dose and low-dose subgroups showing similar costs. In contrast, costs in the non-GLP-1 RAs cohort increased, from $19019 to $24917. Pharmacy spending was a major driver of rising costs among GLP-1 RAs users, more than doubling from $4619 to $10700, while medical costs remained stable at approximately $16000 across periods. Outpatient services denoted the largest medical cost in both groups. Even after removing the top 1% of payers, cost increases persisted, underscoring that GLP-1 RAs initiation is consistently associated with higher healthcare costs. While clinical utilisation may not differ, the economic burden of GLP-1 RAs therapy in hepatosteatosis is substantial and driven largely by medicationrelated costs[ 94 ].

The economic problem of GLP-1/GIP RA is vital. Their high monthly cost (often > $1000 without health insurance) creates barriers to access and presents challenges for healthcare[ 95 ]. These concerns highlight the importance of cost-effectiveness analyses, policy initiatives, and payor strategies to ensure sustainability. Approaches such as value-based pricing, expanded insurance coverage, and tiered access according to clinical need may be required. Importantly, long-term modelling suggests that reductions in obesity-related complications, improvements in quality of life, and increased productivity may justify medication costs. Thorough economic studies are needed to evaluate their sustainability.

Navigating the new landscape of obesity management

The introduction of GLP-1 and dual GLP-1/GIP RA has been transformative. Traditional weight management strategies – ranging from dietary interventions to first-generation pharmacotherapies – have often resulted in limited long-term accomplishment. Bariatric surgery has remained the most effective intervention, but its invasive nature and associated risks, specifically in patients with extreme obesity and multiple comorbidities, need to be taken into consideration.

The ability of GLP-1/GIP RA to induce substantial and sustained weight loss, coupled with their favourable metabolic effects, has shifted this paradigm. These agents not only lower BMI but also optimise physiological parameters – including glycaemic control, blood pressure, and respiratory function – thereby improving the quality of life and prognosis of LT recipients.

However, this evolving therapeutic option leads to new challenges. The delayed gastric emptying stimulated by GLP-1 RAs, while central to their efficacy, demands caution. Although not highly possible, drug-drug interaction with immunosuppressants, especially CNI should be taken into consideration.

Economic obstacles further complicate widespread adoption. Despite their profound clinical benefits, the high cost of GLP-1/GIP RA raises questions of economic feasibilty. Advocacy for value-based pricing, expanded insurance coverage, and robust pharmacoeconomic analyses will be critical to ensure these therapies are accessible to patients.

The role of GLP-1 and dual GLP-1/GIP RA in obesity management will likely expand. Many patients will use these medications post-transplant and may rely on them for long-term weight management. Ongoing research is essential to refine dosing, evaluate the durability of effect, and investigate interactions with other therapeutic modalities. Clinicians must adopt these innovations responsibly, considering their benefits while carefully managing risks, always prioritising patient-centred outcomes.

CONCLUSION

GLP-1 and GLP-1/GIP RA are a major advancement in obesity treatment, offering an effective and relatively safe therapeutic option for liver transplant recipients with severe obesity and/or MS. Challenges like delayed gastric emptying and potential drug-drug interactions merit careful consideration. Beyond clinical concerns, these agents could reverse metabolic complications faced by this cohort of patients and improve their prognosis. Though their high cost raises questions about access, underscoring the need for ongoing policy evaluation. To maximise outcomes, patient education and shared decision-making are critical for setting realistic expectations and ensuring adherence. Eventually, these therapies expand the treatment options for severe obesity, but their integration into clinical practice guidelines must be guided by research-based evidence, multidisciplinary collaboration, and patient-centred care, with long-term trials essential to define their full role in MS control and obesity management among complex populations.