Glucagon-like peptide-1 agonists usage to widen the living donor pool for liver transplantation: A novel metabolic strategy

Abstract

Glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide receptor agonists’ use as a weight loss tool is gradually expanding. They can be used as bridging therapies to reduce weight in potential living donors for liver transplantation and improve graft quality. A living donor with high body mass index is likely to be declined in most living donor programs due to concerns about donor safety and graft function. Reducing weight before surgical procedures can improve outcomes and lower the incidence of morbidity and mortality. Growing clinical evidence supports the advantage of GLP-1 receptor agonists as well as GLP-1/glucose-dependent insulinotropic polypeptide receptor agonists as bridging therapies to minimize perioperative complications. However, these agents should be used with caution due to concerns about side effects, particularly delayed gastric emptying and the risk of aspiration. This article summarizes the available evidence about the promising use of new weight-reducing agents to expand graft pool by including higher body mass index donors after weight optimization.

Key Words: Liver transplantation; Obesity; Graft pool; Steatosis; Donor

Core Tip: The use of glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptor agonists for weight loss is expanding, particularly as bridging therapies for living donors in liver transplantation. High body mass index donors are often declined due to safety concerns, but weight reduction can improve surgical outcomes and reduce morbidity and mortality. There is growing clinical evidence supporting these agents to minimize perioperative complications. However, they should be used cautiously due to potential side effects like delayed gastric emptying and aspiration risks.

INTRODUCTION

Liver transplantation is the ultimate solution for decompensated cirrhosis, acute liver failure, and selected primary and secondary liver malignancies; however, demand for grafts exceeds supply in most regions[1]. Metabolically-dysfunctional steatosic liver disease (MASLD), previously termed non-alcoholic fatty liver disease, has become a leading indication for transplantation in Western countries, driven by universal epidemics of type 2 diabetes (T2DM), obesity, and metabolic syndrome[1,2].

The prevalence of MASLD is roughly one quarter of the adult population worldwide, with a substantial subset progressing to metabolic dysfunction associated steatohepatitis and advanced fibrosis, which in turn increases the need for transplantation[2,3]. Obesity and insulin resistance increase the incidence of advanced liver disease among recipients, and they shape the metabolic profile of potential living donors, shrinking the pool of individuals who can donate safely[3]. Living donor liver transplantation is an essential strategy to mitigate organ shortage in many high-volume centres, particularly in Asia and parts of Europe, although wider adoption is limited by stringent safety thresholds for donors and graft quality[3].

In this article, we outline current donor thresholds, summarise existing optimization strategies, examine the emerging role of incretin therapy, and propose a pragmatic pathway for potential donors.

EFFECT OF HIGH BMI ON GRAFT QUALITY

High donor body mass index (BMI) is closely linked to hepatic steatosis. In living donor liver transplantation series, donors with BMI above 30 kg/m² are significantly more likely to have macrovesicular steatosis on biopsy, and steatosis severity tends to increase with BMI[4,5]. Steatotic grafts are more susceptible to ischaemia reperfusion injury, exhibit poorer microcirculatory flow, and are associated with higher rates of early allograft dysfunction and primary non-function, particularly when cold-ischaemia times are prolonged or graft volume is marginal[6].

Beyond steatosis, donor obesity may increase peri-operative risk, including wound infection and postoperative ileus, and some series suggest a greater incidence of venous thromboembolism[6]. These risks must be balanced against recipient benefit. Many programmes therefore apply a dual threshold, excluding donors with both high BMI and significant steatosis, while being more permissive when BMI is elevated but steatosis is minimal[6].

Consequently, any intervention that predictably lowers BMI and, more importantly, reverses hepatic steatosis within a realistic timeframe could convert marginal donors into safe donors, provided those interventions are acceptable and safe for healthy volunteers.

DEFINING DONOR INELIGIBILITY AND WHY LIVING DONOR POOLS ARE RESTRICTED (BMI, STEATOSIS THRESHOLDS, RISK TO DONOR AND GRAFT)

Briefly quantify the problem

Donor selection criteria are intentionally conservative, as healthy individuals are exposed to major hepatectomy purely for altruistic reasons. Many United Kingdom programmes use 35 kg/m² as a pragmatic ceiling for BMI, with individualized assessment for BMI 30 kg/m² to 35 kg/m², particularly when other metabolic risk factors coexist.

Macrovesicular steatosis is a key determinant of graft suitability. Many programmes avoid grafts with more than 30% macrovesicular steatosis, since higher steatosis is associated with increased risks of primary non-function, early allograft dysfunction, and biliary complications[4,5]. In practice, several living donor liver transplantation series and a systematic review of weight-loss interventions report that donors with more than 10% macrovesicular steatosis are often considered marginal and may be declined unless steatosis can be reversed before donation[5].

The burden is substantial. Contemporary cohorts suggest that a sizeable fraction of otherwise acceptable candidates have hepatic steatosis that would preclude donation under standard thresholds, and a similar fraction have BMI above conventional cut-offs for donation[3-5].

These exclusions translate into fewer living-donor grafts, longer waiting times, and higher wait-list mortality for recipients with advanced liver disease[1,3].

THE NEW BARRIER, METABOLIC SYNDROME AND THE MARGINAL DONOR

Historically, donor exclusion was driven by anatomical constraints, inadequate remnant liver volume, or transmissible conditions. As MASLD has become more common, metabolic health has emerged as an equally important barrier. Metabolic syndrome clusters central obesity, dyslipidaemia, hypertension, and insulin resistance, each of which increases peri-operative risk for donors while promoting hepatic steatosis and steatohepatitis in donors and recipients[2,3].

Large observational series indicate that donors with obesity or metabolic syndrome are more likely to have significant hepatic steatosis on biopsy, longer operative times, and higher blood loss during donor hepatectomy[3,5,6]. Although careful selection and peri-operative management can maintain low major complication rates, the combination of metabolic comorbidity and steatosis has made many centres cautious, which further constrains the donor pool[6-8].

QUANTIFYING THE RISK: THE DEBATE ON USING OBESE AND STEATOTIC DONORS

There is continuing debate regarding acceptable steatosis in living donors. Some retrospective studies suggest that grafts with mild steatosis, typically less than 30%, can achieve acceptable short and long-term outcomes in carefully selected recipients, provided the graft-to-recipient weight ratio and remnant liver volume are adequate[6]. However, moderate or severe steatosis is consistently associated with increased risk of early allograft dysfunction, higher peak transaminases, and longer intensive care stay for recipients[4,6].

Similarly, the effect of donor obesity alone is nuanced. Obesity associates strongly with steatosis, but when steatosis is minimal and comorbidities are controlled, some series report comparable donor and recipient outcomes to those with non-obese donors, whereas other data indicate higher wound complications and a possible increase in biliary problems in recipients[6]. Many centres therefore apply a pragmatic approach, accepting elevated BMI with low steatosis in selected cases, usually avoiding steatosis above 30%, and considering intermediate cases as marginal[4-6,8].

IMPACT OF WEIGHT REDUCTION OF LIVING DONORS ON OUTCOMES OF LIVER TRANSPLANTATION

A potential strategy to alleviate the current shortage of organ donors is to consider the utilization of marginal living donors, explicitly those with hepatic steatosis. Hepatic steatosis, characterized by the accumulation of fat in liver cells, proposes several confronts in the context of liver donation and transplantation. Research has established that grafts from steatotic donors are associated with a heightened risk of complications, specifically significant ischemic damage, which can lead to primary dysfunction or, in severe cases, primary non-function of the graft. These complications can manifest as biliary strictures, which can further complicate postoperative recovery and necessitate additional medical interventions. Moreover, the presence of hepatic steatosis has been correlated with decreased one-year graft survival rates, raising concerns about the long-term viability of these grafts and the need for careful selection and management of donors within this category[9-11].

Chung et al[12] demonstrated that weight reduction significantly improved steatosis, with results showing 40.71 ± 14.56 compared to 7.867 ± 2.67 (P = 0.000). In the weight reduction group, both body weight and BMI decreased, measuring 85.40 ± 8.254 kg vs 76.27 ± 7.556 kg (P = 0.052) and 28.89 ± 2.303 kg/m² as opposed to 26.16 ± 1.629 kg/m² (P = 0.025), correspondingly. The grafts received by recipients and the liver remnants of donors exhibited preserved liver function, with similar liver function tests showed in reduction and control groups. Additionally, no substantial alteration in graft survival was noted.

The implementation of targeted short-term weight loss interventions for living liver donors represents a valuable strategy for transforming marginal donors into low-risk candidates, thereby significantly broadening the donor pool. These interventions not only demonstrate feasibility but also maintain a strong safety profile, yielding outcomes for donors, grafts, and recipients that are comparable to those observed in non-obese donors. By employing evidence-based approaches tailored to encourage sustainable weight loss, healthcare providers can enhance the eligibility of potential donors while ensuring that the overall quality of care and safety remains intact. This proactive strategy not only addresses the pressing need for liver transplants but also promotes the well-being of the donors involved[4].

CURRENT OPTIMISATION OPTIONS (DIET/VERY LOW CALORIE DIET, BARIATRIC SURGERY) AND THEIR LIMITS

Because steatosis is at least partially reversible, several strategies are used to convert marginal donors into acceptable donors, including lifestyle modification, supervised diets, very low-calorie diets, pharmacotherapy such as orlistat, and bariatric surgery in selected cases[4,5,13-15].

A systematic review and meta-analysis of living-donor interventions found that short-term intensive programmes, often combining 800 kcal to 1200 kcal per day with supervised exercise for two to twelve weeks, reduced hepatic steatosis and enabled a proportion of previously excluded donors to proceed to donation without apparent compromise in outcomes[4].

Very low-calorie diets are well studied in bariatric and general abdominal surgery. Reviews show that pre-operative very low calorie diets can reduce liver volume, decrease steatosis, and modestly shorten operative time, although adherence can be challenging and side effects such as fatigue, gallstones, and micronutrient deficiencies require monitoring when diets are prolonged[14,15].

Bariatric surgery is highly effective for sustained weight loss and can improve or resolve MASLD, and in transplant pathways has been used for recipients before, during, or after transplantation[8]. In small donor and candidate series, bariatric surgery appears to improve eligibility and metabolic measures, although it carries operative risk and can delay donation by months[13].

Thus, while lifestyle change, very low calorie diets, and bariatric surgery can reduce steatosis and make some marginal donors eligible, these approaches require a high degree of adherence and often extended time frames, and they may not be acceptable or feasible for all potential donors[4,13-15].

THE REMAINING GAP: ADHERENCE AND THE NEED FOR ADJUNCTS

Real-world adherence to intensive programmes is limited, particularly in individuals with longstanding obesity and metabolic syndrome[13]. In the transplant context, donors are healthy volunteers who may be juggling employment and caring responsibilities, which can limit engagement with restrictive diets and frequent supervised exercise.

Many potential donors therefore remain ineligible despite strong motivation, because lifestyle and standard dietary interventions are insufficient to achieve target BMI and steatosis thresholds within acceptable timelines[4,13]. In this setting, pharmacological agents that produce reliable weight loss and rapid reductions in liver fat represent an attractive adjunct to standard donor optimization pathways. Glucagon-like peptide-1 (GLP-1) agonists as well as dual GLP-1/glucose-dependent insulinotropic polypeptide receptor agonists are the most promising current candidates[16-20].

METABOLIC EFFECTS OF GLP-1 RECEPTOR AGONISTS

GLP-1 is a hormone formed of 30 amino acids whose action is intermediated by a certain receptor. GLP-1 receptors are positioned within the central nervous system, bowel (distal ileum and colon), in the alpha as well as the beta cells of the pancreas[21].

GLP-1 mediates its effect by augmenting insulin production from beta-cells as a reaction to hyperglycaemia and the suppression of glucagon secretion via alpha cells. Additionally, GLP-1 decelerates gastric emptying and gastrointestinal transit to lessen glucose absorption, permitting the regulation of post-prandial glucose and triglycerides excursions. Besides its influence on intestinal motility, GLP-1 induces satiety via direct action on CNS receptors and regulating mechanisms[22].

Using the above-mentioned influence on different body systems, GLP-1 receptor agonists (exenatide, lixisenatide, liraglutide, dulaglutide, albiglutide, semaglutide) toughen the physiological impact of endogenous GLP-1. Generally, these drugs are capable of decreasing glucose (primarily postprandial) and blood levels of glycosylated haemoglobin, concurrently endorsing weight reduction[23].

WEIGHT REDUCTION EFFECT OF GLP-1/GIP RECEPTOR AGONISTS

One of the new dual GLP-1/GIP receptor agonist is tirzepatide, it is also the foremost medication engineered as a solitary molecule to bind GIP as well as GLP-1 receptors simultaneously[18].

After utilization for 72 weeks, tirzepatide provoked substantial weight loss extending from 5% to 20.9% through diverse trials in a dose-dependent fashion[24]. Multiple studies have illustrated the metabolic effects of tirzepatide. SURMOUNT trials, are clinical trial programs investigated the efficacy and safety of tirzepatide. They are focusing mainly on bodyweight reduction effect[18,19].

Some recent trials have examined the weight loss effects of weight loss agents. The SURMOUNT-1 trial evaluated the weight-loss capability of tirzepatide in obese cohort (BMI > 30 or > 27 with weight-linked problems) without T2DM. In the meantime, the SURMOUNT-2 trial was concerned with weight reduction in overweight candidates (BMI > 27) and concomitant T2DM. SURMOUNT-1 trial showed a drop in bodyweight of that reached 20.9% following 72 weeks of starting tirzepatide at a dose of 15 mg, while placebo showed a weight loss of only 3.1%. Similarly, in the SURMOUNT-2 trial placebo treatment experienced a weight loss of 3.2%, whereas participants in the 15 mg treatment dose experienced a weight reduction of 14.7% after 72 weeks. The SURMOUNT-3 clinical trial established the consequence of consuming tirzepatide following an effective rigorous lifestyle interference in overweight or obese adults and a minimum of one weight-related problem. The contributors acknowledged an 18.5% weight reduction following 72 weeks of tirzepatide utilization, whereas placebo had a 2.5% weight reduction (treatment difference of 20.8%; 95% confidence interval: -23.2% to -18.5%; P < 0.001). Moreover, the trial showed that 87.5 % of contributors lost more than 5% extra weight with tirzepatide though 16.5% of the contributors on placebo reached that threshold[18,19,25]. Comparison between different weight loss strategies were summerized in Table 1.

Table 1 Comparison between weight loss strategies for living liver donors.

Aspect	Strict lifestyle modification (diet + exercise)	GLP-1 receptor agonists (e.g., semaglutide, liraglutide)	Bariatric surgery (sleeve, bypass)
Primary goal in donors	Reduce BMI and hepatic steatosis safely	Pharmacologic weight and fat reduction	Major, durable weight loss
Typical components	Calorie restriction, low-fat or low-carb diet, aerobic + resistance exercise	Weekly injections + diet counselling	Surgical alteration of the stomach/intestine
Speed of weight loss	Moderate	Moderate-rapid	Rapid (after recovery)
Effect on liver fat (steatosis)	Very effective	Effective	Effective
Time to donor eligibility	4-12 weeks	2-6 months	6-12 + months
Reversibility	Fully reversible	Reversible (drug stopped)	Irreversible
Nutritional risk	Low if supervised	Moderate (reduced intake, nausea)	High (malabsorption, deficiencies)
Surgical risk added	None	None	Yes (major surgery)
Impact on donor safety	Safest approach	Uncertain perioperative effects	Increased risk
Transplant centre acceptance	Standard of care	Case-by-case	Uncommon practice
Ethical considerations	Acceptable	Debated	Generally unacceptable
Typical candidates	BMI mildly-moderately elevated, fatty liver	Obese donors failing lifestyle alone	Obesity is too severe for donation anyway

GLP-1: Glucagon-like peptide-1; BMI: Body mass index.

FUTURE RESEARCH AND UNANSWERED QUESTIONS

Carlessi et al[26] demonstrated that administering GLP-1 agonists to brain-dead rat model liver donors significantly reduced the levels of circulating aspartate aminotransferase and lactate dehydrogenase. This treatment also led to a notable decrease in hepatocyte apoptosis. In this model, brain death was linked to the upregulation of tumor necrosis factor and stress-related genes, which matches previous findings in both clinical and animal studies. In conclusion, treating brain-dead rats with GLP-1 agonists mitigated liver injury caused by brain death. Further research is vital to comprehend the molecular mechanisms underlying the observed liver protection. A randomized clinical trial, featuring GLP-1 analogues in organ donor management, may help improve organ quality, maximize organ donation, and potentially increase the success rates of liver transplantation.

It is not clear from currently available literature when to stop GLP-1 agonists following hepatectomy in living donors. GLP-1 agents were found to negatively influence hepatic regeneration in rodent models following partial hepatectomy[27]. Ammann et al[28] proposed that there is dynamic inverse regulation of GLP-1 and GLP-2 during liver regeneration, which is likely due to an increase in their expression and release rather than changes in their degradation capacity. This regulation may be linked to inflammatory responses. Additionally, the close relationship between these peptides and circulating markers of lipid metabolism, along with the observation of insufficient hepatic regeneration following liver surgery, suggests they play a crucial role in these processes in humans.

CONCLUSION

GLP-1 receptor agonists hold the promise of expanding the pool of living donors by enabling a greater number of potential donors to satisfy the BMI criteria essential for organ donation. This innovative approach could significantly enhance the availability of viable grafts, ultimately benefiting patients in need of transplants. However, further rigorous studies must be conducted to thoroughly assess both the safety and practicality of implementing this strategy in real-world scenarios.