Clinical trial: insulin‐sensitizing agents may reduce consequences of insulin resistance in individuals with non‐alcoholic steatohepatitis

İdilman, Ramazan; Mızrak, Dılşa; Çorapçıoğlu, Demet; Bektaş, Mehmet; Doğanay, Birsen; Sayki, Müyesser; Çoban, Şahin; Erden, Esra; Soykan, İrfan; Emral, Rıfat; Uysal, Alper; Ozden, Ali

doi:10.1111/j.1365-2036.2008.03723.x

Cited by 108 publications

(132 citation statements)

References 29 publications

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“…110 Haukeland et al 112 reported a similar lack of efficacy in a larger (n¼48) randomized control trial (RCT) of metformin vs. placebo with a similar dietary and exercise intervention in both groups. Other studies also failed to show major benefit for metformin on hepatic insulin sensitivity, aminotransferases [111][112][113][114][115][116] …”

Section: Metforminmentioning

confidence: 99%

The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association

et al. 2012

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Section: Metforminmentioning

confidence: 99%

The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association

et al. 2012

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“…Human studies have documented a reduction in aminotransferases with metformin. [6][7][8][9][10][11] However, alanine aminotransferase (ALT) breakthrough was reported, 12 suggesting that there is no sustained effect. Other 1-year trials showed no overall significant reduction in ALT values.…”

Section: Efficacy Outcomes In Nashmentioning

confidence: 99%

“…One other trial in which the active arm consisted of either rosiglitazone or metformin and in which end-of-treatment liver biopsy was performed in only a fraction of participants was not included. 11 …”

Section: Study Design and Populationmentioning

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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“…Several studies have tested the effect of metformin on NASH [Loomba et al 2009;de Oliveira et al 2008;Idilman et al 2008;Uygun et al 2004;Marchesini et al 2001] (Table 2). However, only four high-quality RCTs (n ¼ 115) have been conducted.…”

Section: Metforminmentioning

confidence: 99%

The role of insulin-sensitizing agents in the treatment of nonalcoholic steatohepatitis

Wagner

Rinella

2011

Therap Adv Gastroenterol

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Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome, which includes dyslipidemia, central obesity, hypertension, and insulin resistance. These diseases collectively and individually increase the risk of cardiovascular disease. Nonalcoholic steatohepatitis (NASH) is a subset of NAFLD that can progress to cirrhosis in up to 30% of patients and lead to decompensated liver disease requiring liver transplantation in many patients. Insulin resistance is the pathophysiological hallmark of NASH and addressing insulin resistance is an important aspect of NASH management. Lifestyle modifications with diet and exercise improve insulin sensitivity and are the cornerstone of therapy, but are often difficult to maintain long term. Not surprisingly, insulin-sensitizing agents have been a focus of pharmacologic investigation in NASH. Insulin sensitizers such as the thiazolidinediones, biguanides, glucagon-like peptide-1 receptor agonists, and the dipeptidyl peptidase IV inhibitors, also known as incretins, will be discussed with respect to their mechanism of action and how these drugs might target aspects of NASH pathophysiology. Finally, we will summarize the available clinical data and review both the risks and benefits of insulin sensitizers in the treatment of NASH.

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Clinical trial: insulin‐sensitizing agents may reduce consequences of insulin resistance in individuals with non‐alcoholic steatohepatitis

Abstract: SUMMARY BackgroundCurrently, although only a few therapies normalize the liver test abnormalities with ⁄ without improving the liver histology, no pharmacologic therapy has proved to be effective for the treatment of non-alcoholic steatohepatitis.

Cited by 108 publications

References 29 publications

The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association

The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association

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

The role of insulin-sensitizing agents in the treatment of nonalcoholic steatohepatitis

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