Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus

Cusi, Kenneth; Orsak, Beverly; Bril, Fernando; Lomonaco, Romina; Hecht, Joan; Ortiz-López, Carolina; Tio, Fermin O.; Hardies, Jean; Darland, Celia; Musi, Nicolas; Webb, Amy; Portillo-Sánchez, Paola

doi:10.7326/m15-1774

Cited by 793 publications

(740 citation statements)

References 59 publications

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“…The efficacy of the molecule reaches 100% for hPPARα and hPPARβ/δ and 80% for hPPARγ. The potency of IVA337 for PPARα and PPARγ is in the same range as that of fenofibrate (EC 50 , 2 µM; PPARα) and pioglitazone (EC 50 , 0.3 µM; PPARγ), two clinically used and well‐tolerated PPAR agonists with a good efficacy/safety ratio 33. The balanced activity of IVA337 is further supported by preclinical and clinical results that show target engagement for the different PPARs, and pharmacological active doses are all in a similar dose range.…”

Section: Discussionmentioning

confidence: 95%

“…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. As selective targeting of each PPAR isoform confers some therapeutic benefit for patients with NASH, it is therefore expected that combined activation of the three PPAR isoforms might bring substantial advantage over specific and dual agents by interacting on different pathways in the NASH to fibrosis sequence.…”

Section: Discussionmentioning

confidence: 99%

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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

111

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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: 95%

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

111

View full text Add to dashboard Cite

show abstract

“…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. Fifty‐one percent of patients that received pioglitazone 45 mg daily for 72 weeks had resolution of NASH and improvement in several histologic features, including liver fibrosis.…”

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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“…Randomized clinical trials have documented that pioglitazone treatment improves hepatic steatosis and necroinflammation, but not hepatic fibrosis, in patients with NASH and that its interruption may frequently determine the re-appearance of the liver damage 1,3,118,119 . Recently, a randomized, double-blind, placebo-controlled trial (including 101 patients with T2DM or pre-diabetes and biopsy-proven NASH randomly treated with pioglitazone, 45 mg/day, or placebo for 18 months, followed by an 18-month open-label phase with pioglitazone treatment) reported that 51% of patients treated with pioglitazone had resolution of NASH 122 . Pioglitazone treatment was also associated with reduced intra-hepatic triglyceride content and improved systemic and hepatic insulin sensitivity.…”

Section: Management and Treatment Options For Nafldmentioning

confidence: 99%

Non-alcoholic fatty liver disease: an emerging driving force in chronic kidney disease

2017

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Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus

Abstract: Burroughs Wellcome Fund and American Diabetes Association.

Cited by 793 publications

References 59 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

Non-alcoholic fatty liver disease: an emerging driving force in chronic kidney disease

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