 |
|
|
| |
Ursodeoxychic Acid Improved NASH, Not So Sure About Rosiglitazone
|
| |
| |
44th EASL April 2326 2009 Copenhagen Denmark
Reported by Jules Levin
A MULTICENTRIC, DOUBLE-BLIND, RANDOMISED-CONTROLLED TRIAL (RCT) OF HIGH DOSE URSODEOXYCHOLIC ACID IN PATIENTS WITH NON-ALCOHOLIC STEATOHEPATITIS (NASH)
"This RCT demonstrated a significant and marked biochemical response to HD-UDCA in NASH patients and suggested symptomatic improvement of asthenia and RUQP, without any significant safety concerns."
V. Ratziu1, V. De Ledinghen2, F. Oberti3, P. Mathurin4, C. Wartelle-Bladou5, C. Renou6, J. Spenard7,8
1Service d'Hepato-Gastroenterologie, Hopital Pitie-Salpêtrière Hospital, Paris, 2Service d'Hepato-Gastroenterologie, Hopital du Haut-Levêque, Pessac, 3Service d'Hepato-Gastroenterologie, CHU d'Angers, Angers, 4Service des Maladies de l'Appareil Digestif, Hopital Huriez, Lille, 5Service d'Hepato-Gastroenterologie, CHG du Pays d'Aix, Aix en Provence, 6Unite d'Hepato-Gastroenterologie, CH d'Hyères, Hyeres, France, 7Axcan Pharma, Mont St-Hilaire, 8Departement de Pharmacologie, Faculte de Medecine, Universite de Montreal, Montreal, QC, Canada
Aims: To date, there is no proven effective therapy for NASH. Hepatoprotectants directly targeting liver inflammation and/or fibrosis could be a useful treatment approach. We evaluated the efficacy and safety of high dose ursodeoxycholic acid (HD-UDCA) in patients with NASH in a double-blind RCT.
Methods: Patients with histologically proven NASH and ALT > 50 IU/L recruited in 18 centers were randomized to receive HD-UDCA (30 mg/kg/day) or placebo for 12 months. The primary efficacy endpoint was the change from baseline at 12 months in serum ALT. All biochemical measurements were centralized.
Results:
A total of 126 patients (64 placebo and 62 HD-UDCA) were enrolled (intent-to-treat population). There were 75% males, mean (± SD) age was 49.7 (±11.5) years, and BMI 30.9 (± 5.1) kg/m2. Metabolic syndrome, hypertension, and type-2 diabetes were present in 40%, 32%, and 35% of patients respectively.
After 12 months, ALT decreased by (mean ± SD) -28 ± 55% under HD-UDCA compared to -2 ± 35% under placebo (p < 0.001). ALT levels normalized (≥ 35 IU/L) in 25% and 5% of patients on HD-UDCA and placebo, respectively (p = 0.003).
Mean (± SD) decreases in serum AST and GGT levels were -8 ± 59% and -51 ± 28% respectively on HD-UDCA compared to placebo where they increased by +9 ± 37% (p< 0.001) and +19 ± 48 % (p< 0.001) respectively.
All results were confirmed in the per protocol population.
Asthenia and right upper quadrant pain (RUQP) were reported more frequently at baseline in the HD-UDCA group than in the placebo group; this difference disappeared early during treatment (3 months).
Changes in serum markers of insulin resistance, fibrosis, inflammation and apoptosis will be reported.
The HD-UDCA group experienced more mild diarrhea, abdominal pain, and gastrointestinal motility disorders than the placebo group.
Conclusions: This RCT demonstrated a significant and marked biochemical response to HD-UDCA in NASH patients and suggested symptomatic improvement of asthenia and RUQP, without any significant safety concerns. This is the largest RCT to support the biochemical efficacy of HD-UDCA in NASH and provides the rationale for further studies with histological endpoints. On behalf of the French Study Group for Urso in NASH (FRESGUN), 18 Hospital Centers, France.
LONG-TERM EFFICACY OF ROSIGLITAZONE IN NONALCOHOLIC STEATOHEPATITIS (NASH): RESULTS OF THE EXTENSION PHASE OF THE FLIRT-2 TRIAL
"Rosiglitazone has a substantial anti-steatogenic effect in the first year of treatment but without additional benefit with longer therapy. Long-term treatment does not improve other features of liver injury, including fibrosis, despite a maintained beneficial effect on insulin sensitivity and transaminase levels. This suggest that improving insulin sensitivity might not be sufficient for improving liver injury in NASH and that additional targets for therapy should be explored."
V. Ratziu, F. Charlotte, C. Bernhardt, L. Serfaty, P. Podevin, J. Moussalli, T. Poynard
Universite Pierre et Marie Curie (Paris 6), Paris, France
Background/ aim: Short term trials of glitazones in NASH had controversial histological results. We hypothesized that longer treatment duration results in continued histological improvement.
Methods: Four months after completing the one-year randomized phase of the FLIRT trial (Rosiglitazone, RSG vs. Placebo, PLB), 53 patients (33M, 20F) were enrolled in an open-label extension phase of RSG, 8 mg/d for two additional years. 44 completed the extension phase and 40 of those had a third liver biopsy. Of these, 22 received PLB in the randomized phase (PLB-RSG), and 18 RSG (RSG-RSG).
Results:
14/53 pts had diabetes. Throughout the 2 year extension phase, fasting insulin and HOMA decreased by 26% and 30% respectively and ALT by 24% without breakthrough.
In the PLB-RSG group steatosis significantly decreased after 2 years of RSG (median decrease by 15%); in the RSG-RSG group after an initial decline in the first year of 20%, two additional years of RSG did not result in further improvement.
The mean NAS score did not change: 3.8 (sd. 2.11) at M12 vs. 3.68 (sd. 1.8) at M40 neither did the mean ballooning score.
The mean fibrosis score did not change (1.76±1.18 at M12 vs. 1.85 ±1.19 at M40), neither did the perisinusoidal component of fibrosis.
This was confirmed by the micromorphometric analysis of the area of fibrosis: 4.43%± 0.68 at M12 to 5.54%±0.68 at M40 (p=0.25).
In the RSG-RSG group two additional years of rosiglitazone did not result in any additional improvement in the NAS score : 3.89 vs. 3.94, ballooning : 0.89 vs. 1.22, intralobular inflammation (1 vs. 1.11), or fibrosis stage (1.61 vs. 1.75), perisinusoidal fibrosis (1.17 vs. 1.28) or area of fibrosis by micromorphometry (3.74% vs. 5.33%) between M12 and M40, respectively.
Conclusion: Rosiglitazone has a substantial anti-steatogenic effect in the first year of treatment but without additional benefit with longer therapy. Long-term treatment does not improve other features of liver injury, including fibrosis, despite a maintained beneficial effect on insulin sensitivity and transaminase levels. This suggest that improving insulin sensitivity might not be sufficient for improving liver injury in NASH and that additional targets for therapy should be explored.
For the Lido Study Group, Universite Pierre et Marie Curie (Paris 6), Paris, France
|
| |
|
|
|
|
|
