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Table 2. Outcomes of glitazone studies for inflammation, liver cell injury and fibrosis.
Author Drug Dose / Lobular inflammation Ballooning Fibrosis
duration
Intragroup Change vs. Intragroup Change vs. Intragroup Change vs.
comparator
change comparator change comparator change
Caldwell Troglita- 400 mg Improved NA NA NA No NA
2001 [14] zone /6 mo NA NA change
Improved NA NA
Neuscwander Rosiglita- 8 mg NA P=0.003 Improved
-Tetri, 2003 zone /12mo PSF NA
[15] Improved NA Improved NA
Pioglita- 45 mg P<0.001 P=0.001 Improved No
Promrat, zone /12 mo NA NA No P=0.04 change
2004 [16] Improved change No
Pioglita- 30 mg Improved Improved P=0.01 Improved No change
Sanyal, 2004 zone /6 mo P<0.001 P=0.008 P<0.02 change P=0.08
[13] Improved No
Pioglita- 45 mg P=0.001 Improved change
Belfort, zone /6 mo P=0.002 Improved
2006 [10] P=0.05
No
Ratziu, 2008 Rosiglita- 8 mg No No No No change No
[11] zone /12 mo change change change change change
Improved
Aithal, 2008 Pioglita- 30 mg Improved No No Improved P=0.006
[12] zone /12 mo P=0.04 change change P=0.005
P=0.09 No
Sanyal, 2010 Pioglita- 30 mg Improved Improved Improved change
[9] zone /2 years NA P=0.001 Improved P=0.01
NA
NA, statistical comparison not available; PSF, zone 3 perisinusoidal fibrosis
Improvement in necroinflammatory lesions was less consensual between studies. Ballooning improved in
32-54% of patients, more than placebo in three RCTs [9, 10, 12]. Intralobular inflammation improved
in most, but not all studies [11], whereas portal inflammation was either unchanged or worse in one
study with rosiglitazone [11]. Finally, no study has shown a convincing effect on fibrosis. Table 2 shows
the main histological effects of glitazones.
Needless to say, there is no consensus on the optimal duration of therapy. On one hand, a prolonged,
three-year therapy did not result in additional histological improvement beyond that obtained in the
first year [8]. On the other hand, glitazone-induced metabolic and hepatic effects seem to be short-lived
after treatment discontinuation. Both ALT and HOMA values return to baseline starting three months
after discontinuation and, in the few patients with one year follow-up biopsies, steatohepatitis recurred
despite on-treatment clearance [18].
The largest RCT that tested pioglitazone in NASH was a multicentre study of low-dose pioglitazone
(30 mg/day) vs. vitamin E (800 IU/day) vs. placebo in non-diabetic NASH patients over a two-year
period [9]. Pioglitazone failed to achieve a statistically significant improvement of a complex composite
primary end-point which included a 2-point reduction in the NAS (P=0.04, higher than a preset 0.025
significance level). However, secondary endpoints of elementary histological lesions, steatosis, lobular
inflammation and ballooning except fibrosis were significantly improved by pioglitazone. Importantly,
clearance of steatohepatitis, a major outcome with prognostic implications, occurred in 47% and 21%
The International Liver Congress™ 2015 • Vienna, Austria • April 22–23, 2015 71
Author Drug Dose / Lobular inflammation Ballooning Fibrosis
duration
Intragroup Change vs. Intragroup Change vs. Intragroup Change vs.
comparator
change comparator change comparator change
Caldwell Troglita- 400 mg Improved NA NA NA No NA
2001 [14] zone /6 mo NA NA change
Improved NA NA
Neuscwander Rosiglita- 8 mg NA P=0.003 Improved
-Tetri, 2003 zone /12mo PSF NA
[15] Improved NA Improved NA
Pioglita- 45 mg P<0.001 P=0.001 Improved No
Promrat, zone /12 mo NA NA No P=0.04 change
2004 [16] Improved change No
Pioglita- 30 mg Improved Improved P=0.01 Improved No change
Sanyal, 2004 zone /6 mo P<0.001 P=0.008 P<0.02 change P=0.08
[13] Improved No
Pioglita- 45 mg P=0.001 Improved change
Belfort, zone /6 mo P=0.002 Improved
2006 [10] P=0.05
No
Ratziu, 2008 Rosiglita- 8 mg No No No No change No
[11] zone /12 mo change change change change change
Improved
Aithal, 2008 Pioglita- 30 mg Improved No No Improved P=0.006
[12] zone /12 mo P=0.04 change change P=0.005
P=0.09 No
Sanyal, 2010 Pioglita- 30 mg Improved Improved Improved change
[9] zone /2 years NA P=0.001 Improved P=0.01
NA
NA, statistical comparison not available; PSF, zone 3 perisinusoidal fibrosis
Improvement in necroinflammatory lesions was less consensual between studies. Ballooning improved in
32-54% of patients, more than placebo in three RCTs [9, 10, 12]. Intralobular inflammation improved
in most, but not all studies [11], whereas portal inflammation was either unchanged or worse in one
study with rosiglitazone [11]. Finally, no study has shown a convincing effect on fibrosis. Table 2 shows
the main histological effects of glitazones.
Needless to say, there is no consensus on the optimal duration of therapy. On one hand, a prolonged,
three-year therapy did not result in additional histological improvement beyond that obtained in the
first year [8]. On the other hand, glitazone-induced metabolic and hepatic effects seem to be short-lived
after treatment discontinuation. Both ALT and HOMA values return to baseline starting three months
after discontinuation and, in the few patients with one year follow-up biopsies, steatohepatitis recurred
despite on-treatment clearance [18].
The largest RCT that tested pioglitazone in NASH was a multicentre study of low-dose pioglitazone
(30 mg/day) vs. vitamin E (800 IU/day) vs. placebo in non-diabetic NASH patients over a two-year
period [9]. Pioglitazone failed to achieve a statistically significant improvement of a complex composite
primary end-point which included a 2-point reduction in the NAS (P=0.04, higher than a preset 0.025
significance level). However, secondary endpoints of elementary histological lesions, steatosis, lobular
inflammation and ballooning except fibrosis were significantly improved by pioglitazone. Importantly,
clearance of steatohepatitis, a major outcome with prognostic implications, occurred in 47% and 21%
The International Liver Congress™ 2015 • Vienna, Austria • April 22–23, 2015 71
