Page 69 - EASL POSTGRADUATE COURSE
P. 69
Thiazolidinediones
Of all the tested drugs, glitazones are those with the best evidence-based data and also with the strongest
pathogenesis-based rationale for treatment of NASH. Of major importance is the ability of glitazones to
promote differentiation of insulin resistant large pre-adipocytes into small, proliferative, insulin sensitive
adipocytes. Upon induction of lipoprotein lipase and of a large set of lipogenic genes, glitazones enhance
fatty acid uptake and synthesis in the adipose tissue, which diverts the non-esterified FFA load towards
adipocytes instead of other organs such as the liver and muscle. Ultimately, inappropriate fat storage
in the latter organs is reduced, with subsequent improvement in IS despite the expansion in fat mass.
Another important mechanism of action is the ability to up-regulate production of adiponectin, an
insulin sensitising and antisteatogenic adipokine that increases fatty acid beta-oxidation in liver and
muscle. Other actions that contribute to the reduction of IR are increased expression of AMP-activated
protein kinase and up-regulation of the glucose transporter GLUT4 in muscle and adipose tissue.
Finally, studies in rodents have shown that glitazones may have anti-inflammatory actions, resulting
in decreased hepatic fibrogenesis in response to repetitive liver injury. Of particular interest to human
disease, these studies have shown a reduction in PPARγ nuclear expression upon activation and trans-
differentiation of stellate cells into fibrogenic myofibroblasts. Treatment with PPARγ agonists restored
PPARγ expression and significantly alleviated the hepatic scar-forming response. PPARγ agonists also
exert anti-inflammatory effects on Kupffer cells which might be indicative of direct hepatoprotective
effects.
Table 1 shows the randomized controlled trials of glitazones in NASH.These trials are very heterogeneous
in terms of drugs studied, dosage, treatment duration, population included, non-pharmacological
associated measures and study design. The two most robust and reproducible hepatic findings are
reduction of ALT and of steatosis. Maximum ALT reduction occurred by month 6 [8, 9].The reduction
in ALT levels was around 38-52% from baseline, significantly higher than for placebo (10-34%) [10,
11]. Reduction in steatosis has been documented in about one-half to two-thirds of treated patients,
significantly more than with placebo in all but one trial where some patients only had minimal steatosis
(5-25%) at baseline [12].The magnitude of reduction in steatosis is usually not reported; however, with
rosiglitazone the median reduction was 20%, ranging from 30-60% in the 47% of participants who were
labelled responders [11]. A reduction of this magnitude is sufficient for improving hepatic and systemic
insulin resistance.
The International Liver Congress™ 2015 • Vienna, Austria • April 22–23, 2015 69
Of all the tested drugs, glitazones are those with the best evidence-based data and also with the strongest
pathogenesis-based rationale for treatment of NASH. Of major importance is the ability of glitazones to
promote differentiation of insulin resistant large pre-adipocytes into small, proliferative, insulin sensitive
adipocytes. Upon induction of lipoprotein lipase and of a large set of lipogenic genes, glitazones enhance
fatty acid uptake and synthesis in the adipose tissue, which diverts the non-esterified FFA load towards
adipocytes instead of other organs such as the liver and muscle. Ultimately, inappropriate fat storage
in the latter organs is reduced, with subsequent improvement in IS despite the expansion in fat mass.
Another important mechanism of action is the ability to up-regulate production of adiponectin, an
insulin sensitising and antisteatogenic adipokine that increases fatty acid beta-oxidation in liver and
muscle. Other actions that contribute to the reduction of IR are increased expression of AMP-activated
protein kinase and up-regulation of the glucose transporter GLUT4 in muscle and adipose tissue.
Finally, studies in rodents have shown that glitazones may have anti-inflammatory actions, resulting
in decreased hepatic fibrogenesis in response to repetitive liver injury. Of particular interest to human
disease, these studies have shown a reduction in PPARγ nuclear expression upon activation and trans-
differentiation of stellate cells into fibrogenic myofibroblasts. Treatment with PPARγ agonists restored
PPARγ expression and significantly alleviated the hepatic scar-forming response. PPARγ agonists also
exert anti-inflammatory effects on Kupffer cells which might be indicative of direct hepatoprotective
effects.
Table 1 shows the randomized controlled trials of glitazones in NASH.These trials are very heterogeneous
in terms of drugs studied, dosage, treatment duration, population included, non-pharmacological
associated measures and study design. The two most robust and reproducible hepatic findings are
reduction of ALT and of steatosis. Maximum ALT reduction occurred by month 6 [8, 9].The reduction
in ALT levels was around 38-52% from baseline, significantly higher than for placebo (10-34%) [10,
11]. Reduction in steatosis has been documented in about one-half to two-thirds of treated patients,
significantly more than with placebo in all but one trial where some patients only had minimal steatosis
(5-25%) at baseline [12].The magnitude of reduction in steatosis is usually not reported; however, with
rosiglitazone the median reduction was 20%, ranging from 30-60% in the 47% of participants who were
labelled responders [11]. A reduction of this magnitude is sufficient for improving hepatic and systemic
insulin resistance.
The International Liver Congress™ 2015 • Vienna, Austria • April 22–23, 2015 69
