Redefining weight management after liver transplantation with glucagon-like peptide one and gastric inhibitory polypeptide receptor agonists

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.

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.

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.