Rosiglitazone for Nonalcoholic Steatohepatitis: One-Year Results of the Randomized Placebo-Controlled Fatty Liver Improvement With Rosiglitazone Therapy (FLIRT) Trial

Ratziu, Vlad; Giral, Philippe; Jacqueminet, S.; Charlotte, Frédéric; Hartemann–Heurtier, Agnès; Serfaty, Lawrence; Podevin, Philippe; Lacorte, Jean‐Marc; Bernhardt, C.; Bruckert, Éric; Grimaldi, A.; Poynard, Thierry

doi:10.1053/j.gastro.2008.03.078

Cited by 556 publications

(575 citation statements)

References 49 publications

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“…In a 6-month study, 22 the score improved in 46% of pioglitazone-treated patients by 2 points versus 14% in the placebo group (P ¼ 0.02), although this could be due to steatosis reduction, which is part of the score. A 1-year study with rosiglitazone failed to show significant changes in the NAS score, 21 whereas a 2-year study with pioglitazone improved the NAS score significantly more often than placebo. 26 Fibrosis.…”

Section: Efficacy Outcomesmentioning

confidence: 88%

“…Glitazones robustly reduced aminotransferase levels by 30%-58%. 21,22 Interestingly, the reduction in the comparator arm was highly variable, 10%-34% for placebo 21,22 and 67% for vitamin E. 23 Normal end-of-treatment ALT was reported in 38%-100% of patients. Direct comparisons between studies can be misleading, as the magnitude of change might simply reflect variable baseline values, whereas the proportion of normal ALT depends on the reference range, which varies between laboratories.…”

Section: Efficacy Outcomesmentioning

confidence: 99%

“…However, individual response was variable with only 47%-65% of patients experiencing reduction in steatosis. 21,22,26,28 Importantly, the magnitude of reduction is usually not reported. With rosiglitazone it was 20%, ranging from 30%-60% in responders.…”

Section: Efficacy Outcomesmentioning

confidence: 99%

“…With rosiglitazone it was 20%, ranging from 30%-60% in responders. 21 How large a reduction is clinically relevant is unsettled. Sampling variability of liver biopsy for steatosis can be as high as 20% 29 ; hence, a one grade reduction (33%) could reasonably define improvement.…”

Section: Efficacy Outcomesmentioning

confidence: 99%

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Therapeutic trials in nonalcoholic steatohepatitis: Insulin sensitizers and related methodological issues

2010

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Insulin sensitizers are attractive candidate therapies for nonalcoholic steatohepatitis mainly because of the strong association between this disease and insulin resistance. This review provides a critical overview of the mechanisms of action, clinical trial results, and safety issues of metformin and glitazones in nonalcoholic steatohepatitis. It also highlights methodological challenges for trial design and proposes endpoints for future proof of principle, registrational, and postmarketing trials. (HEPATOLOGY 2010;52:2206-2215 N onalcoholic steatohepatitis (NASH) is emerging as the next big therapeutic challenge in hepatology. 1 Currently the top cause of newly identified chronic liver diseases, NASH has potential for fibrosis, cirrhosis decompensation, and hepatocellular carcinoma. Not all individuals with metabolic risk factors will experience these adverse outcomes and identifying those at risk is critical. Prognostic markers for progression have mostly been derived from histological studies. Compared to steatosis alone or to steatosis and minimal inflammation, the coexistence of inflammation, cell injury (ballooning), and steatosis, a pathological aggregate labeled steatohepatitis, is associated with a significant increase in overall mortality and in liver-related mortality. The degree of inflammation is the best predictor of fibrosis progression, 2 a widely accepted surrogate for hard endpoints such as cirrhosis, endstage liver disease, and possibly hepatocellular carcinoma.Insulin resistance (IR) is consistently found in patients with NASH in both cross-sectional and longitudinal studies. Moreover, there is a stepwise increase in the severity of IR and its phenotypic complications (clustered as elements of the metabolic syndrome) between normal liver, isolated steatosis, and steatohepatitis that has prompted speculation that IR might contribute to liver damage. Logically, most therapeutic trials focused on insulin sensitizers (IS) as candidate therapies.The aim of this report is to critically review the results of trials of metformin and glitazones for NASH. We highlight methodological challenges for trial design and propose endpoints for future proof of principle, registrational, and postmarketing trials.

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Section: Efficacy Outcomesmentioning

confidence: 88%

Section: Efficacy Outcomesmentioning

confidence: 99%

Section: Efficacy Outcomesmentioning

confidence: 99%

Section: Efficacy Outcomesmentioning

confidence: 99%

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Therapeutic trials in nonalcoholic steatohepatitis: Insulin sensitizers and related methodological issues

2010

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“…Clinical studies of the approved doses of pioglitazone in patients with NASH have shown significant resolution of NASH pathology, including fibrosis 26, 27. On the other hand, rosiglitazone, which is a 5‐fold to 10‐fold more potent PPARγ agonist compared to pioglitazone,22 improved some NASH endpoints but failed to significantly affect fibrosis 27, 28, 29, 30, 31. The dissociation between the affinity for PPARγ and the effectiveness in treating NASH, and particularly hepatic fibrosis, could be explained by the failure of rosiglitazone to achieve adequate effects on the mitochondrial target MPC.…”

mentioning

confidence: 99%

Treating fatty liver disease by modulating mitochondrial pyruvate metabolism

Colca

McDonald

McCommis

et al. 2017

Hepatology Communications

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Modifying the entry of pyruvate into mitochondria may provide a unique approach to treat metabolic disease. The pharmacology of a new class of insulin sensitizers directed against a newly identified mitochondrial target may treat many aspects of nonalcoholic steatohepatitis, including fibrosis. This commentary suggests treating nonalcoholic steatohepatitis through a newly identified mechanism consistent with pathophysiology. (Hepatology Communications 2017;1:193‐197)

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Management of Nonalcoholic Fatty Liver Disease

Afdhal¹

2012

JAMA

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Rosiglitazone for Nonalcoholic Steatohepatitis: One-Year Results of the Randomized Placebo-Controlled Fatty Liver Improvement With Rosiglitazone Therapy (FLIRT) Trial

Cited by 556 publications

References 49 publications

Therapeutic trials in nonalcoholic steatohepatitis: Insulin sensitizers and related methodological issues

Therapeutic trials in nonalcoholic steatohepatitis: Insulin sensitizers and related methodological issues

Treating fatty liver disease by modulating mitochondrial pyruvate metabolism

Management of Nonalcoholic Fatty Liver Disease

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