GLP-1 y su papel en el tratamiento del hígado graso
Desde el lanzamiento de la exenatida en 2005, que inauguró la era de los agonistas del péptido 1 similar al glucagón (GLP-1), se ha despertado un gran interés por el uso de agonistas de la incretina no sólo para controlar los niveles de azúcar en sangre en la diabetes de tipo 2, sino también para tratar otras afecciones asociadas, como la obesidad, las enfermedades cardiovasculares, la nefropatía diabética y, más recientemente, la esteatohepatitis asociada a disfunción metabólica (MASH).
With regards to MASH, much initial data focussed on the correlation between GLP-1-induced weight loss and any downstream indirect effects on hepatic steatosis and associated inflammation. With the advent of dual and triple agonists which also target the glucagon receptor and the glucose-dependent insulinotropic peptide (GIP) receptor, there is renewed interest in whether these combination agents can exert synergistic effects and potentially directly affect hepatocyte metabolism. In this review, we examine the evolving evidence on the role of GLP-1 agonists, either alone or as part of combination therapies, in delaying or reversing MASH progression.
Incretins (GLP-1 receptor agonists and dual/triple agonists) and the liver
The principle pathological drivers of metabolic dysfunction-associated steatohepatitis (MASH) are obesity and associated insulin resistance, rendering them key therapeutic targets. As glucagon-like peptide 1 receptor agonists (GLP-1RAs) have been licensed for the treatment of diabetes and obesity, they were one of the first drug types to be evaluated in patients with MASH, and successful phase IIa and IIb studies have resulted in progression to phase III clinical trials. Alongside GLP-1RAs, newer combinations with glucagon agonists and/or glucose-dependent insulinotropic peptide (GIP) agonists have been explored in related patient groups, with evidence of improvements in weight, insulin resistance and non-invasive liver parameters. Whether GLP-1RAs have direct, independent effects on MASH or whether they impact on pathophysiology through improvements in weight, insulin resistance and glycaemic control remains a matter of debate. Combinations are being explored, although the potential improvement in efficacy will need to be weighed against the cumulative side-effect burden, potential drug-drug interactions and costs. There is also uncertainty regarding the optimal ratio of glucagon and GIP agonism to GLP-1 agonism in combination agents, and as to whether GIP agonism or antagonism is the optimal approach. Finally, there are also multiple hypothetical permutations combining gut hormone agonists with other emerging assets in the field. Given that the likely dominant mode of action of gut hormone agonists is upstream on weight, initial combinations might focus on agents which have been shown to have a more direct effect on fibrosis, which would include FGF21 and pan-PPAR agonists.
The principle pathological drivers of metabolic dysfunction-associated steatohepatitis (MASH) are obesity and associated insulin resistance, rendering them key therapeutic targets.
Increased glucose-dependent insulin release and reduced glucagon levels in response to GLP-1 (glucagon-like peptide 1) agonist therapy are associated with a reduction in liver fat fraction, improvements in glucose control and a reduction in liver injury in patients with MASH.
Glucagon agonist administration drives increased gluconeogenesis and glycogenolysis, reduced hepatic lipid accumulation, increased mitochondrial turnover, improved mitochondrial function, and reduced oxidative stress.
- GIP receptors are expressed within the central nervous system and modulation of these receptors is thought to regulate body weight and food intake, although whether GIP antagonism or agonism is the appropriate way to target these receptors is the subject of debate.
- •Combinations of incretins offer the potential for greater weight loss, as well as acting via synergistic mechanisms to enhance beneficial effects on liver injury.
- •The efficacy of combination therapy needs to be considered alongside the increased risk of side effects, drug-drug interactions and costs.
Sobrepeso
Mecanismos de acción
Agonistas duales y triples
Retos:
Adherencia y seguridad a largo plazo
Combinados con algo más? Agonistas FGF-21 y PPARs?
Administración oral?
No hay comentarios:
Publicar un comentario