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Extrahepatic complications of liver fat
CURRENT AND FUTURE INSULIN SENSITIZERS IN
THE TREATMENT OF NASH
Vlad Ratziu
Institute of Cardiometabolism and Nutrition (ICAN),
Université Pierre et Marie Curie, Paris, France
E-mail: vlad.ratziu@upmc.fr
Take home messages
• IR is an almost universal finding in primary NASH. Existing studies provide proof of concept that
improving IR results in both metabolic and histological improvement across the whole spectrum of
steatohepatitis.
• Initial data suggested that metformin might be an ideal treatment for NAFLD but later small studies
gave inconsistent results.
• Current guidelines recommend the use of pioglitazone for the treatment of steatohepatitis in patients
with biopsy-proven NASH. However, the long-term safety and benefit is unknown.
• Obeticholic acid, a selective FXR agonist, has demonstrated encouraging histological results that
deserve confirmation.
• The dual PPAR α and δ agonist GFT505 improves hepatic and peripheral IS, dyslipidemia,
inflammatory markers and liver function tests in abdominally obese, IR patients.
• Combining insulin-sensitising agents with hepatoprotective or anti-inflammatory/ anti-fibrotic drugs
could be an attractive option for future therapeutic strategies.
Introduction
NASH is associated with a significant increase in liver-related mortality as well as cardiovascular
mortality. The recommended first-line therapy is non-pharmacological: weight reduction through
diet, changes in lifestyle, physical exercise and limiting sedentarity. Additionally, concurrent metabolic
disorders such as T2DM, hyperlipidemia, or arterial hypertension, when present, should be well
controlled but their specific impact in improving the hepatic disease has not yet been determined.
Occasionally, these measures result in a 7-10% weight loss, a threshold that is possibly associated with
histological improvement. In patients who failed these measures or in those with advanced disease
(NASH with significant fibrosis), pharmacological treatments specifically directed at improving hepatic
inflammation, fibrosis and/or clearing steatohepatitis might be necessary [1]. Here we will provide an
overview of data obtained so far with pharmacological agents in NASH. Most uncontrolled studies
and those without histological documentation of NASH will not be mentioned. The therapeutic area in
NASH is still in its infancy; therefore an urgent need exists for well-conducted, randomized controlled
trials with relevant therapeutic endpoints [2].
Rationale for the use of insulin sensitizers
Insulin resistance is an almost universal finding in primary NASH. It is the main driving force behind
excessive fat accumulation in the liver but may also play a role in the initiation and perpetuation of
steatohepatitis and fibrosis progression. Moreover hepatic steatosis and insulin resistance potentiate
The International Liver Congress™ 2015 • Vienna, Austria • April 22–23, 2015 67
CURRENT AND FUTURE INSULIN SENSITIZERS IN
THE TREATMENT OF NASH
Vlad Ratziu
Institute of Cardiometabolism and Nutrition (ICAN),
Université Pierre et Marie Curie, Paris, France
E-mail: vlad.ratziu@upmc.fr
Take home messages
• IR is an almost universal finding in primary NASH. Existing studies provide proof of concept that
improving IR results in both metabolic and histological improvement across the whole spectrum of
steatohepatitis.
• Initial data suggested that metformin might be an ideal treatment for NAFLD but later small studies
gave inconsistent results.
• Current guidelines recommend the use of pioglitazone for the treatment of steatohepatitis in patients
with biopsy-proven NASH. However, the long-term safety and benefit is unknown.
• Obeticholic acid, a selective FXR agonist, has demonstrated encouraging histological results that
deserve confirmation.
• The dual PPAR α and δ agonist GFT505 improves hepatic and peripheral IS, dyslipidemia,
inflammatory markers and liver function tests in abdominally obese, IR patients.
• Combining insulin-sensitising agents with hepatoprotective or anti-inflammatory/ anti-fibrotic drugs
could be an attractive option for future therapeutic strategies.
Introduction
NASH is associated with a significant increase in liver-related mortality as well as cardiovascular
mortality. The recommended first-line therapy is non-pharmacological: weight reduction through
diet, changes in lifestyle, physical exercise and limiting sedentarity. Additionally, concurrent metabolic
disorders such as T2DM, hyperlipidemia, or arterial hypertension, when present, should be well
controlled but their specific impact in improving the hepatic disease has not yet been determined.
Occasionally, these measures result in a 7-10% weight loss, a threshold that is possibly associated with
histological improvement. In patients who failed these measures or in those with advanced disease
(NASH with significant fibrosis), pharmacological treatments specifically directed at improving hepatic
inflammation, fibrosis and/or clearing steatohepatitis might be necessary [1]. Here we will provide an
overview of data obtained so far with pharmacological agents in NASH. Most uncontrolled studies
and those without histological documentation of NASH will not be mentioned. The therapeutic area in
NASH is still in its infancy; therefore an urgent need exists for well-conducted, randomized controlled
trials with relevant therapeutic endpoints [2].
Rationale for the use of insulin sensitizers
Insulin resistance is an almost universal finding in primary NASH. It is the main driving force behind
excessive fat accumulation in the liver but may also play a role in the initiation and perpetuation of
steatohepatitis and fibrosis progression. Moreover hepatic steatosis and insulin resistance potentiate
The International Liver Congress™ 2015 • Vienna, Austria • April 22–23, 2015 67
