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Figure 3.Therapeutic targets of PPAR-δ in the metabolic syndrome. Reproduced from Barish et al.
[32] with permission.
GFT505 is a dual PPAR α and δ agonist that undergoes extensive enterohepatic cycling and is liver
targeted [36]. Human studies performed in abdominally obese, insulin resistant patients, with or without
diabetes have shown that GFT505 improves hepatic and peripheral IS, dyslipidemia, inflammatory
markers and liver function tests [37, 38]. Animal data confirmed the hepatoprotective effects of GFT505
in dietary models of NASH or fibrosis with, in particular, reduction in steatosis, hepatic inflammation
and pro-inflammatory genes [36]. Because genetically engineered mice lacking PPAR-α were also
rescued from this phenotype, the effects carried by GFT505 were at least partly due to its PPAR-δ
agonistic properties. Importantly, this compound exhibited antifibrotic properties in fibrosis models
that were independent of metabolic and IR abnormalities [36], thereby suggesting universal antifibrotic
potency in rodents. Based on these promising results, a large, phase IIb, randomized controlled trial is
now underway in NASH patients. Earlier phase IIa studies suggest a good safety profile, in particular
from the lack of evidence of PPAR-γ agonistic activity.
Conclusion
Insulin sensitizers are logical drug candidates for the treatment of NASH. Existing studies provide proof
of concept that improving insulin resistance results in metabolic but also histological improvement
across the whole spectrum of steatohepatitis.There are numerous regulators of insulin signalling as well
as defective pathways that drive IR and also ectopic fat deposits and lipotoxic intermediates that alter
insulin signalling, which can all be targeted in an effort to alleviate IR. It remains to be seen whether
anti-inflammatory compounds acting at the adipose tissue level or at the hepatic level might also
contribute to an improvement in insulin signalling either locally or systemically. Given the complexity
of mechanisms involved in the progression of NASH, simply correcting IR may not be enough for a
majority of patients. Combining insulin-sensitising agents with hepatoprotective or anti-inflammatory/
anti-fibrotic drugs could be an attractive option for future therapeutic strategies.
74 Postgraduate Course Syllabus • Metabolic Liver Disease
[32] with permission.
GFT505 is a dual PPAR α and δ agonist that undergoes extensive enterohepatic cycling and is liver
targeted [36]. Human studies performed in abdominally obese, insulin resistant patients, with or without
diabetes have shown that GFT505 improves hepatic and peripheral IS, dyslipidemia, inflammatory
markers and liver function tests [37, 38]. Animal data confirmed the hepatoprotective effects of GFT505
in dietary models of NASH or fibrosis with, in particular, reduction in steatosis, hepatic inflammation
and pro-inflammatory genes [36]. Because genetically engineered mice lacking PPAR-α were also
rescued from this phenotype, the effects carried by GFT505 were at least partly due to its PPAR-δ
agonistic properties. Importantly, this compound exhibited antifibrotic properties in fibrosis models
that were independent of metabolic and IR abnormalities [36], thereby suggesting universal antifibrotic
potency in rodents. Based on these promising results, a large, phase IIb, randomized controlled trial is
now underway in NASH patients. Earlier phase IIa studies suggest a good safety profile, in particular
from the lack of evidence of PPAR-γ agonistic activity.
Conclusion
Insulin sensitizers are logical drug candidates for the treatment of NASH. Existing studies provide proof
of concept that improving insulin resistance results in metabolic but also histological improvement
across the whole spectrum of steatohepatitis.There are numerous regulators of insulin signalling as well
as defective pathways that drive IR and also ectopic fat deposits and lipotoxic intermediates that alter
insulin signalling, which can all be targeted in an effort to alleviate IR. It remains to be seen whether
anti-inflammatory compounds acting at the adipose tissue level or at the hepatic level might also
contribute to an improvement in insulin signalling either locally or systemically. Given the complexity
of mechanisms involved in the progression of NASH, simply correcting IR may not be enough for a
majority of patients. Combining insulin-sensitising agents with hepatoprotective or anti-inflammatory/
anti-fibrotic drugs could be an attractive option for future therapeutic strategies.
74 Postgraduate Course Syllabus • Metabolic Liver Disease
