- Email: [email protected]
Reply to “statins and non-alcoholic steatohepatitis”
M ET ABOL I SM C L IN I CA L A N D E XP E RI ME N TAL 66 ( 20 1 7 ) e 3 – e 5
Available online at www.sciencedirect.com
Metabolism www.metabolismjournal.com
Reply to “statins and non-alcoholic steatohepatitis”
To the Editor, We thank Athyros et al. for their letter reviewing the use of statins in non-alcoholic steatohepatitis (NASH). We agree with them in that statin therapy in NASH is safe [1] and recommended in this population [2,3]. However, the statement that statins improve steatohepatitis is not supported by current evidence as suggested by Athyros et al. Most studies with statins in this population have been usually relatively small (≤30 patients), uncontrolled, with primary end points based on surrogate markers (not the goldstandard liver biopsy) and/or post-hoc analysis. The clinical trials quoted Athyros et al. [4–6] were all post-hoc analysis from open-label clinical trials that used plasma aminotransferases as the primary end point to establish liver improvement. Plasma ALT is a poor indicator of the severity of NASH and typically decreases in placebo arms of RCTs in NASH, where only a minority of patients have resolution of NASH [2,3]. Our group has also shown that patients with normal compared to elevated ALT often have a similar severity of NASH [7], AST/ALT being a misleading marker of disease severity [8]. Results were also confounded by the lifestyle intervention (i.e., adoption of a low-fat diet, weight loss, and exercise) in at least in 2 of the post-hoc analyses [5,6]. While neither the original nor post-hoc analysis of IDEAL [4] or GREACE [5] reported on post-treatment changes in weight or metabolic parameters, ATTEMPT did show a 9% reduction in body weight with a significant reduction in fasting plasma glucose and an 85% net treatment effect decrease in the number of patients with metabolic syndrome and a 63% reduction in the presence of prediabetes [6]. Weight loss of ~5 to 9% alone can reduce plasma ALT concentration and even improve steatohepatitis [2]. Athyros et al. suggest that statins may have a direct effect in improving liver histology based on 2 other studies [9,10]. The study by Dongiovanni et al. [9], is an observational crosssectional cohort study where statin-treated patients with NASH had less steatosis and necroinflammation compared to patients not exposed to statins (advanced fibrosis was no different). However, because of confounding factors, heterogeneous clinical management among recruiting centers and the inherent limitations of a cross-sectional retrospective design, the authors admitted that one “cannot infer any definite causal relationship between drug exposure and liverrelated outcomes.” Athyros et al. also highlight their study by Kargiotis et al. [10], where 20 male patients with the metabolic http://dx.doi.org/10.1016/j.metabol.2016.10.004 0026-0495/© 2016 Elsevier Inc. All rights reserved.
syndrome and NASH were biopsied before and after treatment with low-dose rosuvastatin (10 mg daily) for 12 months. The results were remarkable in that 19 out of 20 patients had resolution of NASH that the authors attribute to statin therapy. The study is quite unusual in recruiting 20 patients with the worse disease activity (histology grade score of 8 out of 8 in all patients by Brunt criteria, with two pathologists grading them) and 95% achieving a complete resolution with a grade score of 0 out of 8, something never reported in any NASH trial to date, not even after massive weight loss with bariatric surgery [2,3]. However, the authors again fail to take into account the uncontrolled study design and the role of lifestyle intervention they prescribed to participants (i.e, a hypocaloric low-fat diet and at least one hour of walking daily or equivalent physical activity). By the end of the study, none of the patients had the metabolic syndrome and the fasting plasma glucose and A1c were significantly lower. Such beneficial metabolic effects have not been observed during treatment with rosuvastatin (20 mg/day) in a large RCT [11]. Prospective studies with ≥ 10 patients evaluating statin effects on liver histology in NASH are summarized in Table 1 (for an in-depth review by our group see Ref. 12). All studies [13–18] have been relatively small (ranging from 10 to 43 patients) and except one [15], open-label and uncontrolled [13–18]. In the only RCT by Nelson et al. [15], 16 participants with NASH were randomized to simvastatin 40 mg or placebo for 12 months. No histological improvement (or change in aminotransferase levels) was observed compared to placebo [15]. No change in intrahepatic triglycerides (IHTG) was reported with high-dose simvastatin therapy (80 mg daily for 8 weeks) in another study [19]. In a recently published RCT comparing pioglitazone to placebo treatment in patients with prediabetes or T2DM and NASH [21], treatment with mediumto high-dose simvastatin or atorvastatin for 18 months had no effect on liver histology in the placebo arm of the trial (Cusi et al. unpublished). Tziomalos, Athyros et al. even recognize in their own review [22] that while some studies may report an improvement in steatosis or inflammation (Table 1), studies are small and uncontrolled, and that fibrosis was not reduced in any study. Fibrosis is the single most important risk factor for end-stage liver disease and mortality in NASH [2,3].
e4
M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 6 6 ( 2 01 7 ) e 3 – e5
Table 1 – Prospective studies evaluating the effects of statins on liver histology in patients with NAFLD. Study
Ref. # n having a Design biospy/total
Control Duration group
Statin
Steatosis Necroinflammation Fibrosis
Georgescu et al. (2007) Hyogo et al. (2008) Nelson et al. (2009) Kimura et al. (2010) Hyogo et al. (2011) Nakahara et al. (2012) Kargiotis et al. (2015)
13 14 15 16 17 18 10
No No Yes No No No No
Atorvastatin Atorvastatin Simvastatin Atorvastatin Pitavastatin Rosuvastatin Rosuvastatin
↓ ↓ ↔ ↓ ↔ ↔ ↓
10 of 10 17 of 31 10 of 16 22 of 43 13 of 20 9 of 19 20 of 20
Open label Open label RCT Open label Open label Open label Open label
9.5 months 24 months 12 months 12 months 12 months 24 months 12 months
In conclusion, we stand by our previous statement that “most studies with statins have been of poor quality and were not conducted specifically in patients with biopsy-proven NASH” and that “there is consensus that statins do not improve histology in NASH but can be safely prescribed to ameliorate their increased cardiovascular risk.” The effects on histology, if any, have not been evident in most studies. Larger, controlled studies are needed. We do share the view by Athyros et al. that statins should be prescribed to patients with NAFLD/NASH to reduce their increased cardiovascular risk, in agreement with current clinical practice recommendations [2,3].
Authors' Contributions
[2]
[3]
[4]
[5]
DB and KC have participated in the writing and editing of this manuscript. All authors read and approved the final manuscript.
Competing Interests Kenneth Cusi (KC) has received research grant support from Janssen Pharmaceutical of Johnson & Johnson and Novartis Pharmaceuticals. He is a consultant for Janssen Pharmaceutical of Johnson & Johnson, Eli Lilly and Company, Pfizer and Tobira Therapeutics. Diana Barb (DB) has no competing interests.
Diana Barb Kenneth Cusi* Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Florida College of Medicine, Gainesville, FL Division of Endocrinology, Diabetes, and Metabolism at Malcom Randall Veterans Affairs Medical Center, Gainesville, FL *Corresponding author at: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Florida College of Medicine, 1600 SW Archer Rd, Room H-2 Gainesville, FL 32610. Tel.: +1 352 273 8662 E-mail addresses: [email protected] [email protected]
[6]
[7]
[8]
[9]
[10]
[11] REFERENCES [12] [1] Cohen DE, Anania FA, Chalasani N, National Lipid Association Statin Safety Task Force Liver Expert P. An
↔ ↔ ↔ ↓ ↔ ↔ ↓
↔ ↔ ↔ ↔ ↔ ↔ not reported
assessment of statin safety by hepatologists. Am J Cardiol 2006;97:77C–81C. EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver diseaseDiabetologia 2016;59:1121–40. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. 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. Hepatology 2012;55:2005–23. Tikkanen MJ, Fayyad R, Faergeman O, Olsson AG, Wun CC, Laskey R, et al. Effect of intensive lipid lowering with atorvastatin on cardiovascular outcomes in coronary heart disease patients with mild-to-moderate baseline elevations in alanine aminotransferase levels. Int J Cardiol 2013;168:3846–52. Athyros VG, Giouleme O, Ganotakis ES, Elisaf M, Tziomalos K, Vassiliadis T, et al. Safety and impact on cardiovascular events of long-term multifactorial treatment in patients with metabolic syndrome and abnormal liver function tests: a post hoc analysis of the randomised ATTEMPT study. Arch Med Sci 2011;7:796–805. Athyros VG, Tziomalos K, Gossios TD, Griva T, Anagnostis P, Kargiotis K, et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study: a post-hoc analysis. Lancet 2010;376(9756): 1916–22. Maximos M, Bril F, Portillo Sanchez P, Lomonaco R, Orsak B, Biernacki D, et al. The role of liver fat and insulin resistance as determinants of plasma aminotransferase elevation in nonalcoholic fatty liver disease. Hepatology 2015;61: 153–60. Portillo-Sanchez P, Bril F, Maximos M, Lomonaco R, Biernacki D, Orsak B, et al. High prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and normal plasma aminotransferase levels. J Clin Endocrinol Metab 2015;100:2231–8. Dongiovanni P, Petta S, Mannisto V, Mancina RM, Pipitone R, Karja V, et al. Statin use and non-alcoholic steatohepatitis in at risk individuals. J Hepatol 2015;63:705–12. Kargiotis K, Athyros VG, Giouleme O, Katsiki N, Katsiki E, Anagnostis P, et al. Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome. World J Gastroenterol 2015;21: 7860–8. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto Jr AM, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195–207. Lomonaco R, Sunny N, Bril F, Cusi K. Nonalcoholic fatty liver disease: current issues and novel treatment approaches. Drugs 2013;73:1–14.
M ET ABOL I SM C L IN I CA L A N D E XP E RI ME N TAL 66 ( 20 1 7 ) e 3 – e 5
[13] Georgescu EF, Georgescu M. Therapeutic options in nonalcoholic steatohepatitis (NASH). Are all agents alike? Results of a preliminary study. J Gastrointestin Liver Dis 2007;16:39–46. [14] Hyogo H, Tazuma S, Arihiro K, Iwamoto K, Nabeshima Y, Inoue M, et al. Efficacy of atorvastatin for the treatment of nonalcoholic steatohepatitis with dyslipidemia. Metabolism 2008;57:1711–8. [15] Nelson A, Torres DM, Morgan AE, Fincke C, Harrison SA. A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: a randomized placebo-controlled trial. J Clin Gastroenterol 2009;43:990–4. [16] Kimura Y, Hyogo H, Yamagishi S, Takeuchi M, Ishitobi T, Nabeshima Y, et al. Atorvastatin decreases serum levels of advanced glycation endproducts (AGEs) in nonalcoholic steatohepatitis (NASH) patients with dyslipidemia: clinical usefulness of AGEs as a biomarker for the attenuation of NASH. J Gastroenterol 2010;45:750–7. [17] Hyogo H, Ikegami T, Tokushige K, Hashimoto E, Inui K, Matsuzaki Y, et al. Efficacy of pitavastatin for the treatment
[18]
[19]
[21]
[22]
e5
of non-alcoholic steatohepatitis with dyslipidemia: an openlabel, pilot study. Hepatol Res 2011;41:1057–65. Nakahara T, Hyogo H, Kimura Y, Ishitobi T, Arihiro K, Aikata H, et al. Efficacy of rosuvastatin for the treatment of nonalcoholic steatohepatitis with dyslipidemia: an open-label, pilot study. Hepatol Res 2012;42:1065–72. Szendroedi J, Anderwald C, Krssak M, Bayerle-Eder M, Esterbauer H, Pfeiler G, et al. Effects of high-dose simvastatin therapy on glucose metabolism and ectopic lipid deposition in nonobese type 2 diabetic patients. Diabetes Care 2009;32: 209–14. Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, et al. Long-term pioglitazone treatment for patients with NASH and prediabetes or type 2 diabetes mellitus: a randomized controlled trial. Ann Intern Med 2016. http://dx. doi.org/10.7326/M15-1774 [Epub ahead of print]. Tziomalos K, Athyros VG, Paschos P, Karagiannis A. Nonalcoholic fatty liver disease and statins. Metabolism 2015;64: 1215–23.
Available online at www.sciencedirect.com
Metabolism www.metabolismjournal.com
Reply to “statins and non-alcoholic steatohepatitis”
To the Editor, We thank Athyros et al. for their letter reviewing the use of statins in non-alcoholic steatohepatitis (NASH). We agree with them in that statin therapy in NASH is safe [1] and recommended in this population [2,3]. However, the statement that statins improve steatohepatitis is not supported by current evidence as suggested by Athyros et al. Most studies with statins in this population have been usually relatively small (≤30 patients), uncontrolled, with primary end points based on surrogate markers (not the goldstandard liver biopsy) and/or post-hoc analysis. The clinical trials quoted Athyros et al. [4–6] were all post-hoc analysis from open-label clinical trials that used plasma aminotransferases as the primary end point to establish liver improvement. Plasma ALT is a poor indicator of the severity of NASH and typically decreases in placebo arms of RCTs in NASH, where only a minority of patients have resolution of NASH [2,3]. Our group has also shown that patients with normal compared to elevated ALT often have a similar severity of NASH [7], AST/ALT being a misleading marker of disease severity [8]. Results were also confounded by the lifestyle intervention (i.e., adoption of a low-fat diet, weight loss, and exercise) in at least in 2 of the post-hoc analyses [5,6]. While neither the original nor post-hoc analysis of IDEAL [4] or GREACE [5] reported on post-treatment changes in weight or metabolic parameters, ATTEMPT did show a 9% reduction in body weight with a significant reduction in fasting plasma glucose and an 85% net treatment effect decrease in the number of patients with metabolic syndrome and a 63% reduction in the presence of prediabetes [6]. Weight loss of ~5 to 9% alone can reduce plasma ALT concentration and even improve steatohepatitis [2]. Athyros et al. suggest that statins may have a direct effect in improving liver histology based on 2 other studies [9,10]. The study by Dongiovanni et al. [9], is an observational crosssectional cohort study where statin-treated patients with NASH had less steatosis and necroinflammation compared to patients not exposed to statins (advanced fibrosis was no different). However, because of confounding factors, heterogeneous clinical management among recruiting centers and the inherent limitations of a cross-sectional retrospective design, the authors admitted that one “cannot infer any definite causal relationship between drug exposure and liverrelated outcomes.” Athyros et al. also highlight their study by Kargiotis et al. [10], where 20 male patients with the metabolic http://dx.doi.org/10.1016/j.metabol.2016.10.004 0026-0495/© 2016 Elsevier Inc. All rights reserved.
syndrome and NASH were biopsied before and after treatment with low-dose rosuvastatin (10 mg daily) for 12 months. The results were remarkable in that 19 out of 20 patients had resolution of NASH that the authors attribute to statin therapy. The study is quite unusual in recruiting 20 patients with the worse disease activity (histology grade score of 8 out of 8 in all patients by Brunt criteria, with two pathologists grading them) and 95% achieving a complete resolution with a grade score of 0 out of 8, something never reported in any NASH trial to date, not even after massive weight loss with bariatric surgery [2,3]. However, the authors again fail to take into account the uncontrolled study design and the role of lifestyle intervention they prescribed to participants (i.e, a hypocaloric low-fat diet and at least one hour of walking daily or equivalent physical activity). By the end of the study, none of the patients had the metabolic syndrome and the fasting plasma glucose and A1c were significantly lower. Such beneficial metabolic effects have not been observed during treatment with rosuvastatin (20 mg/day) in a large RCT [11]. Prospective studies with ≥ 10 patients evaluating statin effects on liver histology in NASH are summarized in Table 1 (for an in-depth review by our group see Ref. 12). All studies [13–18] have been relatively small (ranging from 10 to 43 patients) and except one [15], open-label and uncontrolled [13–18]. In the only RCT by Nelson et al. [15], 16 participants with NASH were randomized to simvastatin 40 mg or placebo for 12 months. No histological improvement (or change in aminotransferase levels) was observed compared to placebo [15]. No change in intrahepatic triglycerides (IHTG) was reported with high-dose simvastatin therapy (80 mg daily for 8 weeks) in another study [19]. In a recently published RCT comparing pioglitazone to placebo treatment in patients with prediabetes or T2DM and NASH [21], treatment with mediumto high-dose simvastatin or atorvastatin for 18 months had no effect on liver histology in the placebo arm of the trial (Cusi et al. unpublished). Tziomalos, Athyros et al. even recognize in their own review [22] that while some studies may report an improvement in steatosis or inflammation (Table 1), studies are small and uncontrolled, and that fibrosis was not reduced in any study. Fibrosis is the single most important risk factor for end-stage liver disease and mortality in NASH [2,3].
e4
M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 6 6 ( 2 01 7 ) e 3 – e5
Table 1 – Prospective studies evaluating the effects of statins on liver histology in patients with NAFLD. Study
Ref. # n having a Design biospy/total
Control Duration group
Statin
Steatosis Necroinflammation Fibrosis
Georgescu et al. (2007) Hyogo et al. (2008) Nelson et al. (2009) Kimura et al. (2010) Hyogo et al. (2011) Nakahara et al. (2012) Kargiotis et al. (2015)
13 14 15 16 17 18 10
No No Yes No No No No
Atorvastatin Atorvastatin Simvastatin Atorvastatin Pitavastatin Rosuvastatin Rosuvastatin
↓ ↓ ↔ ↓ ↔ ↔ ↓
10 of 10 17 of 31 10 of 16 22 of 43 13 of 20 9 of 19 20 of 20
Open label Open label RCT Open label Open label Open label Open label
9.5 months 24 months 12 months 12 months 12 months 24 months 12 months
In conclusion, we stand by our previous statement that “most studies with statins have been of poor quality and were not conducted specifically in patients with biopsy-proven NASH” and that “there is consensus that statins do not improve histology in NASH but can be safely prescribed to ameliorate their increased cardiovascular risk.” The effects on histology, if any, have not been evident in most studies. Larger, controlled studies are needed. We do share the view by Athyros et al. that statins should be prescribed to patients with NAFLD/NASH to reduce their increased cardiovascular risk, in agreement with current clinical practice recommendations [2,3].
Authors' Contributions
[2]
[3]
[4]
[5]
DB and KC have participated in the writing and editing of this manuscript. All authors read and approved the final manuscript.
Competing Interests Kenneth Cusi (KC) has received research grant support from Janssen Pharmaceutical of Johnson & Johnson and Novartis Pharmaceuticals. He is a consultant for Janssen Pharmaceutical of Johnson & Johnson, Eli Lilly and Company, Pfizer and Tobira Therapeutics. Diana Barb (DB) has no competing interests.
Diana Barb Kenneth Cusi* Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Florida College of Medicine, Gainesville, FL Division of Endocrinology, Diabetes, and Metabolism at Malcom Randall Veterans Affairs Medical Center, Gainesville, FL *Corresponding author at: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Florida College of Medicine, 1600 SW Archer Rd, Room H-2 Gainesville, FL 32610. Tel.: +1 352 273 8662 E-mail addresses: [email protected] [email protected]
[6]
[7]
[8]
[9]
[10]
[11] REFERENCES [12] [1] Cohen DE, Anania FA, Chalasani N, National Lipid Association Statin Safety Task Force Liver Expert P. An
↔ ↔ ↔ ↓ ↔ ↔ ↓
↔ ↔ ↔ ↔ ↔ ↔ not reported
assessment of statin safety by hepatologists. Am J Cardiol 2006;97:77C–81C. EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver diseaseDiabetologia 2016;59:1121–40. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. 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. Hepatology 2012;55:2005–23. Tikkanen MJ, Fayyad R, Faergeman O, Olsson AG, Wun CC, Laskey R, et al. Effect of intensive lipid lowering with atorvastatin on cardiovascular outcomes in coronary heart disease patients with mild-to-moderate baseline elevations in alanine aminotransferase levels. Int J Cardiol 2013;168:3846–52. Athyros VG, Giouleme O, Ganotakis ES, Elisaf M, Tziomalos K, Vassiliadis T, et al. Safety and impact on cardiovascular events of long-term multifactorial treatment in patients with metabolic syndrome and abnormal liver function tests: a post hoc analysis of the randomised ATTEMPT study. Arch Med Sci 2011;7:796–805. Athyros VG, Tziomalos K, Gossios TD, Griva T, Anagnostis P, Kargiotis K, et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study: a post-hoc analysis. Lancet 2010;376(9756): 1916–22. Maximos M, Bril F, Portillo Sanchez P, Lomonaco R, Orsak B, Biernacki D, et al. The role of liver fat and insulin resistance as determinants of plasma aminotransferase elevation in nonalcoholic fatty liver disease. Hepatology 2015;61: 153–60. Portillo-Sanchez P, Bril F, Maximos M, Lomonaco R, Biernacki D, Orsak B, et al. High prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and normal plasma aminotransferase levels. J Clin Endocrinol Metab 2015;100:2231–8. Dongiovanni P, Petta S, Mannisto V, Mancina RM, Pipitone R, Karja V, et al. Statin use and non-alcoholic steatohepatitis in at risk individuals. J Hepatol 2015;63:705–12. Kargiotis K, Athyros VG, Giouleme O, Katsiki N, Katsiki E, Anagnostis P, et al. Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome. World J Gastroenterol 2015;21: 7860–8. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto Jr AM, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195–207. Lomonaco R, Sunny N, Bril F, Cusi K. Nonalcoholic fatty liver disease: current issues and novel treatment approaches. Drugs 2013;73:1–14.
M ET ABOL I SM C L IN I CA L A N D E XP E RI ME N TAL 66 ( 20 1 7 ) e 3 – e 5
[13] Georgescu EF, Georgescu M. Therapeutic options in nonalcoholic steatohepatitis (NASH). Are all agents alike? Results of a preliminary study. J Gastrointestin Liver Dis 2007;16:39–46. [14] Hyogo H, Tazuma S, Arihiro K, Iwamoto K, Nabeshima Y, Inoue M, et al. Efficacy of atorvastatin for the treatment of nonalcoholic steatohepatitis with dyslipidemia. Metabolism 2008;57:1711–8. [15] Nelson A, Torres DM, Morgan AE, Fincke C, Harrison SA. A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: a randomized placebo-controlled trial. J Clin Gastroenterol 2009;43:990–4. [16] Kimura Y, Hyogo H, Yamagishi S, Takeuchi M, Ishitobi T, Nabeshima Y, et al. Atorvastatin decreases serum levels of advanced glycation endproducts (AGEs) in nonalcoholic steatohepatitis (NASH) patients with dyslipidemia: clinical usefulness of AGEs as a biomarker for the attenuation of NASH. J Gastroenterol 2010;45:750–7. [17] Hyogo H, Ikegami T, Tokushige K, Hashimoto E, Inui K, Matsuzaki Y, et al. Efficacy of pitavastatin for the treatment
[18]
[19]
[21]
[22]
e5
of non-alcoholic steatohepatitis with dyslipidemia: an openlabel, pilot study. Hepatol Res 2011;41:1057–65. Nakahara T, Hyogo H, Kimura Y, Ishitobi T, Arihiro K, Aikata H, et al. Efficacy of rosuvastatin for the treatment of nonalcoholic steatohepatitis with dyslipidemia: an open-label, pilot study. Hepatol Res 2012;42:1065–72. Szendroedi J, Anderwald C, Krssak M, Bayerle-Eder M, Esterbauer H, Pfeiler G, et al. Effects of high-dose simvastatin therapy on glucose metabolism and ectopic lipid deposition in nonobese type 2 diabetic patients. Diabetes Care 2009;32: 209–14. Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, et al. Long-term pioglitazone treatment for patients with NASH and prediabetes or type 2 diabetes mellitus: a randomized controlled trial. Ann Intern Med 2016. http://dx. doi.org/10.7326/M15-1774 [Epub ahead of print]. Tziomalos K, Athyros VG, Paschos P, Karagiannis A. Nonalcoholic fatty liver disease and statins. Metabolism 2015;64: 1215–23.