Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis

Sanyal, Arun J.; Chalasani, Naga; Kowdley, Kris V.; McCullough, Arthur J.; Diehl, Anna Mae; Bass, Nathan M.; Neuschwander‐Tetri, Brent A.; Lavine, Joel E.; Tonascia, James; Ünalp, Aynur; Natta, Mark Van; Clark, Jeanne M.; Brunt, Elizabeth M.; Kleiner, David E.; Hoofnagle, Jay H.; Robuck, Patricia R.

doi:10.1056/nejmoa0907929

Cited by 2,822 publications

(2,769 citation statements)

References 30 publications

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“…More recently, the dual PPARα/δ agonist elafibranor (GFT505) achieved improvement in steatohepatitis without fibrosis worsening in patients with a NAS score ≥4 and decreased fibrosis in the subgroup of patients with NASH who responded to GFT505 47. PPARγ activation by pioglitazone significantly improves steatosis, ballooning, and inflammation as well as metabolic markers in patients with NASH after 6 or 12 months of treatment 48. A recent 18‐month study in prediabetic and diabetic patients with biopsy‐proven NASH demonstrated that pioglitazone was well tolerated without adverse effect and was associated with long‐term metabolic and histologic improvement 33.…”

Section: Discussionmentioning

confidence: 99%

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

Wettstein

Luccarini

Poekes

et al. 2017

Hepatology Communications

115

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IVA337 is a pan‐peroxisome proliferator‐activated receptor (PPAR) agonist with moderate and well‐balanced activity on the three PPAR isoforms (α, γ, δ). PPARs are regulators of lipid metabolism, inflammation, insulin resistance, and fibrogenesis. Different single or dual PPAR agonists have been investigated for their therapeutic potential in nonalcoholic steatohepatitis (NASH), a chronic liver condition in which steatosis coexists with necroinflammation, potentially leading to liver fibrosis and cirrhosis. Clinical results have demonstrated variable improvements of histologically assessed hepatic lesions depending on the profile of the tested drug, suggesting that concomitant activation of the three PPAR isoforms would translate into a more substantial therapeutic outcome in patients with NASH. We investigated the effects of IVA337 on several preclinical models reproducing the main metabolic and hepatic features associated with NASH. These models comprised a diet‐induced obesity model (high‐fat/high‐sucrose diet); a methionine‐ and choline‐deficient diet; the foz/foz model; the CCl4‐induced liver fibrosis model (prophylactic and therapeutic) and human primary hepatic stellate cells. IVA337 normalized insulin sensitivity while controlling body weight gain, adiposity index, and serum triglyceride increases; it decreased liver steatosis, inflammation, and ballooning. IVA337 demonstrated preventive and curative effects on fibrosis in the CCl4 model and inhibited proliferation and activation of human hepatic stellate cells, the key cells driving liver fibrogenesis in NASH. Moreover, IVA337 inhibited the expression of (pro)fibrotic and inflammasome genes while increasing the expression of β‐oxidation‐related and fatty acid desaturation‐related genes in both the methionine‐ and choline‐deficient diet and the foz/foz model. For all models, IVA337 displayed an antifibrotic efficacy superior to selective PPARα, PPARδ, or PPARγ agonists. Conclusion: The therapeutic potential of IVA337 for the treatment of patients with NASH is supported by our data. (Hepatology Communications 2017;1:524–537)

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Section: Discussionmentioning

confidence: 99%

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

Wettstein

Luccarini

Poekes

et al. 2017

Hepatology Communications

115

View full text Add to dashboard Cite

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“…A large RCT of patients with NASH without diabetes demonstrated that, compared to placebo, pioglitazone 30 mg daily for 96 weeks was associated with improvement in histology and higher rates of NASH resolution 19. More recently, the effects of pioglitazone on NASH in patients with prediabetes and T2D were evaluated 20.…”

Section: Nafld/nash‐specific Therapiesmentioning

confidence: 99%

Management of nonalcoholic fatty liver disease: Lessons learned from type 2 diabetes

Alkhouri

Poordad

Lawitz

2018

Hepatology Communications

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Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of insulin resistance, which is the hallmark of type 2 diabetes (T2D). NAFLD is a known risk factor for developing T2D and has a very high prevalence in those with existing T2D. The diabetes spectrum includes several conditions from prediabetes to T2D to insulin‐dependent diabetes leading to macrovascular and microvascular complications. Similarly, NAFLD has a histologic spectrum that ranges from the relatively benign nonalcoholic fatty liver to the aggressive form of nonalcoholic steatohepatitis with or without liver fibrosis to nonalcoholic steatohepatitis‐cirrhosis leading to end‐stage liver disease. The management of T2D has witnessed significant changes over the past few decades with multiple new drug classes entering the treatment algorithm. Unfortunately, there are no U.S. Food and Drug Administration‐approved medications to treat NAFLD, and guidelines for the management of NAFLD are less established. However, the field of drug development in NAFLD has witnessed a revolution over the past 5 years with the establishment of a regulatory pathway for Food and Drug Administration approval; this has generated substantial interest from pharmaceutical companies. Several diabetes medications have been studied as potential treatments for NAFLD with promising results; moreover, drugs that target specific pathways that play a role in NAFLD development and progression are being developed at a rapid pace. Given the similarities between NAFLD and T2D in terms of pathogenesis, underlying risk factors, and disease spectrum, lessons learned from optimizing treatment for T2D can be extrapolated to the management of NAFLD. The aim of this review is to use the founding principles of the comprehensive type 2 diabetes management algorithm to optimize the management of NAFLD. (Hepatology Communications 2018;2:778‐785)

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“…8 Longer treatment (>1 year) might not result in a more marked reduction of ALT. 25,26 Histological Response (Table 2) Steatosis. All but one 27 trials showed a reduction in steatosis higher than placebo.…”

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%

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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Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis

Abstract: BACKGROUND-Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrhosis. Currently, there is no established treatment for this disease.

Cited by 2,822 publications

References 30 publications

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

Management of nonalcoholic fatty liver disease: Lessons learned from type 2 diabetes

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

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