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of pioglitazone and placebo treated patients, respectively (P<0.001). Interestingly, when the analysis
was restricted to patients with well-defined steatohepatitis, pioglitazone reached the primary endpoint
[9]. Collectively, these data strongly suggest the efficacy of pioglitazone in NASH, thus confirming
converging information from earlier trials.
It has been suggested [19], but not confirmed [20], that glitazones strongly improve adipose tissue IR
which correlates with the reduction in steatosis and necroinflammation [19]. Whether this information
can be used to identify responders early on during therapy is unclear but it deserves future investigation.
Since most NASH patients treated with glitazones were non-diabetic, and the largest trial (PIVENS)
excluded diabetic patients, current guidelines recommend the use of pioglitazone in patients with NASH
but warn against the lack of substantial evidence-based data in diabetic patients. However, since these
drugs are indicated for treatment of T2DM, there is considerable experience of using them in these
patients.Whether their efficacy differs according to the degree of IR or the diabetic status of the patients
is, at this point, entirely speculative.
The main obstacle to the widespread use of glitazones is their safety profile. Weight gain that tends to
persist after discontinuation is mostly due to increased peripheral fat mass [21] and therefore seems
devoid of adverse metabolic consequences. A detailed discussion on the safety of glitazones goes beyond
the scope of this syllabus. Nevertheless, the use of glitazones has been severely restricted by black-box
warnings based on increased cardiovascular events [22], congestive heart failure [23], bone fractures in
women [24] and risk of bladder cancer for pioglitazone [25], which justified its market withdrawal in
France. Recent data collected in one million T2DM individuals from six cohorts around the world did
not confirm an increased risk of gall-bladder cancer [26].
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 and it should be used
with caution in diabetic patients and in those with impaired cardiac function [27].
Figure 2. Metabolic and hepatoprotective actions of FXR activation. Reproduced from Adorini et
al. [29] with permission.
72 Postgraduate Course Syllabus • Metabolic Liver Disease
was restricted to patients with well-defined steatohepatitis, pioglitazone reached the primary endpoint
[9]. Collectively, these data strongly suggest the efficacy of pioglitazone in NASH, thus confirming
converging information from earlier trials.
It has been suggested [19], but not confirmed [20], that glitazones strongly improve adipose tissue IR
which correlates with the reduction in steatosis and necroinflammation [19]. Whether this information
can be used to identify responders early on during therapy is unclear but it deserves future investigation.
Since most NASH patients treated with glitazones were non-diabetic, and the largest trial (PIVENS)
excluded diabetic patients, current guidelines recommend the use of pioglitazone in patients with NASH
but warn against the lack of substantial evidence-based data in diabetic patients. However, since these
drugs are indicated for treatment of T2DM, there is considerable experience of using them in these
patients.Whether their efficacy differs according to the degree of IR or the diabetic status of the patients
is, at this point, entirely speculative.
The main obstacle to the widespread use of glitazones is their safety profile. Weight gain that tends to
persist after discontinuation is mostly due to increased peripheral fat mass [21] and therefore seems
devoid of adverse metabolic consequences. A detailed discussion on the safety of glitazones goes beyond
the scope of this syllabus. Nevertheless, the use of glitazones has been severely restricted by black-box
warnings based on increased cardiovascular events [22], congestive heart failure [23], bone fractures in
women [24] and risk of bladder cancer for pioglitazone [25], which justified its market withdrawal in
France. Recent data collected in one million T2DM individuals from six cohorts around the world did
not confirm an increased risk of gall-bladder cancer [26].
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 and it should be used
with caution in diabetic patients and in those with impaired cardiac function [27].
Figure 2. Metabolic and hepatoprotective actions of FXR activation. Reproduced from Adorini et
al. [29] with permission.
72 Postgraduate Course Syllabus • Metabolic Liver Disease
