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Statin Use Is Not Associated With Presence of and Severity of Nonalcoholic Fatty Liver Disease
Archives of Medical Research 45 (2014) 52e57
ORIGINAL ARTICLE
Statin Use Is Not Associated With Presence of and Severity of Nonalcoholic Fatty Liver Disease Ebenezer T. Oni,a Pragya Sinha,a Adil Karim,a Seth S. Martin,b Michael J. Blaha,b Arthur S. Agatston,a,c Roger S. Blumenthal,b Romeu S. Meneghelo,d Raquel D. Conceic¸ao,d Raul D. Santos,e and Khurram Nasira,b,c,f a
Center for Prevention and Wellness Research, Baptist Health Medical Group, Miami Beach, Florida b The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, Maryland c Department of Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida d Preventive Medicine Center Hospital Israelita Albert Einstein, Sao Paulo, Brazil e Lipid Clinic-Heart Institute (InCor) University of S~ao Paulo Medical School Hospital, Sao Paulo-S~ao Paulo, Brazil f Department of Epidemiology, Robert Stempel College of Public Health, Florida International University, Miami, Florida Received for publication July 19, 2013; accepted October 11, 2013 (ARCMED-D-13-00391).
Background and Aims. There is concern that statin use may exacerbate nonalcoholic fatty liver disease (NAFLD). We aimed to assess the association of statin use with NALFD and severity of liver fibrosis among NAFLD individuals. Methods. We evaluated 6,385 cross-sectional healthy Brazilian subjects (43 10 years, 79% males) without clinical coronary heart disease between November 2008 and July 2010. NAFLD was diagnosed by ultrasound. Severity of liver fibrosis was predicted by fatty liver index and FIB-4. Results. NAFLD prevalence was 36% (n 5 2310). Overall 552 (9%) individuals were using statins of whom 49% had NAFLD. Statin users were more likely to be men, older age, and have higher burden of risk factors ( p !0.05). In age gender adjusted analysis the odds ratio for NAFLD with statin use was 0.87 (0.61e1.25, p 5 0.46) in the presence of metabolic syndrome and 1.08 (0.88e1.32, p 5 0.56) in its absence. On further adjustment for metabolic risk factors, LDL and smoking the results remained unchanged (OR: 0.89, 95% CI: 0.65e1.32, p 5 0.56 and 0.90 (0.69e1.18, p 5 0.46). There was no significant association between statin use and fatty liver index in a subanalysis of NAFLD individuals (71 18 vs. 69 23, p 5 0.18). Although FIB-4 was mildly elevated with statin use (1.20 0.51 vs. 1.02 0.46, p !0.001), a multivariate analysis adjusted for age, gender and risk factors revealed statin use was not associated with severe fibrosis (FIB O1.45) (OR 0.88, 95% CI: 0.60e1.29, p 5 0.50). Conclusions. The results of this study favor statin use in subjects with NAFLD as its use is not associated with the presence of NAFLD or increased fibrosis Ó 2014 IMSS. Published by Elsevier Inc. Key Words: Statins, NAFLD, Fatty Liver Index, FIB-4 index, Fibrosis.
Introduction 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are central to the management of dyslipidemia (1). They are the most widely prescribed Address reprint requests to: Khurram Nasir, MD, MPH, Center for Prevention and Wellness Research, Baptist Health Medical Group, 1691 Michigan Ave Suite 500; Miami Beach, FL 33139; Phone: þ1-305-5383828; FAX: þ1-305-538-1979; E-mail: [email protected]
medications in the Western world (2), accounting for O10 million prescriptions in the United States in 2003 alone (3). Statins have been shown to have unequivocal benefits in the primary and secondary prevention of cardiovascular disease (CVD) (3,4). The use of statins has also been included as part of the treatment strategy for nonalcoholic fatty liver disease (NAFLD) (4e6). NAFLD is an emerging disease globally and a leading cause of chronic liver disease in the western world. The
0188-4409/$ - see front matter. Copyright Ó 2014 IMSS. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.arcmed.2013.12.003
Statin Use in Nonalcoholic Fatty Liver Disease
prevalence of NAFLD in the general population is |15e30% and 70e90% in persons with obesity or type 2 diabetes (7e10). Several studies have shown that NAFLD is an independent risk factor for increased CVD (11e13). NAFLD shares many common risk factors with vascular disease and the commonest cause of death among NAFLD patients is cardiovascular mortality. This is followed by cancer and then liver-related mortality (12). Although clinically significant liver injury is extremely rare from statins, asymptomatic liver enzyme elevations are common (14). It is the most common cause of incidental abnormal liver tests and elevated serum liver enzymes in the developed world (15,16). Although several studies have examined the safety and efficacy of statins in the prevention of CVD, many physicians are reluctant in prescribing statins in patients with elevated alanine aminotransferase (ALT) levels (17). This is centered on concerns about the risk-to-benefit ratio of statin use in individuals with background NAFLD. These concerns within the medical community range from the notion that statin use may result in the development of NAFLD to the idea that statins could worsen existing disease (15,18). In this study, we aim to assess the association of statin use with the prevalence of NALFD and the severity of liver fibrosis scores in subjects with NAFLD.
Subjects and Methods We evaluated 6,385 asymptomatic men and women, free of coronary heart disease, who had an obligatory clinical and laboratory health evaluation paid for by their employers from December 2008eDecember 2010 at the Preventive Medicine Center of the Albert Einstein Hospital in S~ao Paulo, Brazil. The examination protocol consisted of a clinical consultation, laboratory evaluation, and abdominal ultrasonography. All individuals provided demographic details, medical history, quantitative alcohol consumption, smoking status, and medication use at the time of their clinical consultation. We included all individuals for whom full information was available for all the covariates of interest. This study excluded individuals with a known history of liver disease from the analysis. Information regarding medical history was obtained via questionnaire. Smoking status was defined as current smoker vs. current nonsmoker. Diabetes mellitus was identified by previous physician diagnosis or by the use of glucose-lowering medication. Hypertension and dyslipidemia were ascertained by a previous history of these conditions or the use of blood pressure-lowering or lipid-lowering medications; those individuals with systolic blood pressure O140 mmHg or diastolic blood pressure O90 mmHg at the clinical evaluation were also labeled as having hypertension. During physical examinations, blood pressure was measured with a mercury sphygmomanometer using the method recommended by the American Heart
53
Association (19). Waist circumference was measured at the smallest diameter between the iliac crest and the costal margin using a plastic anthropometric tape held parallel to the floor. Blood specimens were collected after an overnight fast. Plasma lipid, glucose, and liver transaminase levels (alanine aminotransferase (20) and aspartate aminotransferase [AST]) levels were measured by standardized automated laboratory tests using a Vitros platform (Johnson & Johnson Clinical Diagnostics). High-sensitivity CRP (hsCRP) levels were determined by immunonephelometry (Dade-Behring). All tests were performed at the Central Laboratory of the Albert Einstein Hospital. NAFLD was diagnosed after at least a 6-h fast using an ACUSON XP-10 device (Mountain View, CA) and was identified by the presence of an ultrasonographic pattern of a bright liver with evident contrast between hepatic and renal parenchyma (indicating hepatic steatosis) as previously described (21). All hepatic ultrasounds were read by board-certified radiologists. Obesity was defined as a body mass index (BMI) O30 kg/m2. NAFLD severity was determined by fatty liver index 5 (e 0.953*loge (triglycerides) þ 0.139*BMI þ 0.718*loge (ggt) þ 0.053*waist circumferencee15.745)/(1 þ e 0.953*loge (triglycerides) þ 0.139*BMI þ 0.718*loge (ggt) þ 0.053*waist circumferencee15.745) * 100 and FIB-4 (age (years) x AST [U/l]/(platelets [109/l] x (ALT [U/l])1/2)). An FIB-4 index O1.45 had a negative predictive value of 94.7% to exclude severe fibrosis (22). The use of the FIB-4 index to predict severe liver fibrosis among individuals with NAFLD was validated in a previous study among a Japanese population with NAFLD (22). Metabolic syndrome was defined using criteria from the American Heart Association/National Heart, Lung, and Blood Institute scientific statement on the metabolic syndrome (23). Patients with $3 of the following metabolic risk factors were classified as having the metabolic syndrome: truncal obesity ($102 cm [40 inches] for men and $88 cm [36 inches] for women), high blood pressure (blood pressure $130/ 85 mmHg or the use of antihypertensive medications), hyperglycemia (fasting blood glucose $100 mg/dL), low high-density lipoprotein cholesterol (HDL-C) (#40 mg/ dL for men and #50 mg/dL for women), and hypertriglyceridemia ($150 mg/dL). This study was approved by the local institutional review board, and a waiver for informed consent was obtained (24). Baseline characteristics of individuals in the statin and non-statin groups were compared using the Wilcoxon’s t test for continuous variables and the Pearson’s c2 test for categorical variables. Because of the skewed distribution of ALT, AST, GGT and hs-CRP, median values were used in comparing the two groups using the nonparametric Kruskal-Wallis test. Multivariable logistic regression was used to evaluate associations of statins and NAFLD. For all regression analyses, a hierarchical model
54
Oni et al./ Archives of Medical Research 45 (2014) 52e57
approach was used, adjusting first for age and gender and then simultaneously adjusting for other traditional risk factors (waist circumference, triglycerides, HDL-C, SBP, fasting glucose, LDL-C, triglyceride:HDL-cholesterol ratio and smoking). Subanalysis testing was performed to estimate the odds of FIB-4 O1.45 (severe fibrosis) with statin use among individuals with NAFLD. All statistical analyses were performed using STATA statistical software, release 12 (College Station, TX).
Results The characteristics of the study population stratified by statin use are displayed in Table 1. A total of 6385 subjects were analyzed: 552 were in the statin group and 5833 were in the nonstatin group. There were statistically significant differences in demographic, anthropometric and biochemical profiles between groups. Those on statins were more likely to be men, older age and with a higher burden of risk factors. The statin group was more likely to have the following metabolic risk factors: hyperglycemia, obesity, and hypertension ( p !0.001). The prevalence of NAFLD was 36% among the entire study population. The prevalence was statistically different across the two groups, 48% in the statin group compared to 35% in the nonstatin group ( p !0.001). Individuals in the statin group were more likely to have metabolic syndrome, 34% vs.
19%, p !0.001. Individuals on statin therapy were also more likely to have a higher systolic blood pressure compared to the non-statin group, 123 mmHg vs. 118 mmHg, p !0.001. There was a similar association with diastolic blood pressure. The statin group was significantly more likely to have higher liver enzymes compared to the non-statin group. The use of statins was significantly associated with the level of all cholesterols. Individuals on statins were more likely to have a higher triglyceride level and lower HDL and LDL cholesterol levels compared to the nonstatin group. Although the mean uric acid level among the statin group was higher compared to the nonstatin group, 6.0 vs. 5.8, p 5 0.002; there was however no significant difference in the level of the hs-C-reactive protein. The median triglyceride-HDL cholesterol ratio (TG:HDL), a marker for insulin resistance, was higher in the statin group compared to the non-statin group, 2.85 vs. 2.43, p !0.001. In subanalyses of individuals with NAFLD, fatty liver index was not different between the statin and nonstatin groups (Figure 1). The statin group, however, was more likely to have a higher FIB-4 index compared to the nonstatin group (1.20 vs. 1.02, p !0.001, Figure 2). Table 2 presents multivariable regression analyses of different models adjusting for confounding variables in the association between use of statins and prevalence of NAFLD. The analysis was stratified by the presence of metabolic syndrome. There was no independent association between statins and NAFLD prevalence in those with or
Table 1. Baseline characteristics of study population
Clinical, anthropometric, and biochemical characteristics Male (%) Mean age, years (SD) NAFLD present (%) Mean BMI, kg/m2 (SD) Mean WC, cm (SD) Obesity, BMI $30 kg/m2 (%) Mean SBP, mmHg (SD) Mean DBP, mmHg (SD) Hypertension present (%) Median AST, U/L (interquartile range) Median ALT, U/L (interquartile range) Median GGT, mg/dL (interquartile range) Median triglycerides, mg/dL (interquartile range) Mean HDL, mg/dL (SD) Mean LDL, mg/dL (SD) Mean FBG, mg/dL (SD) Median hs-CRP, mg/dL (interquartile range) High hs-CRP ($3 mg/dL) (%) Mean uric acid, mg/dL (SD) Antihypertensive (%) Current smoker (%) Platelet, 109/L (SD) Subjects with MetS (%) Median TG:HDL-C (interquartile range) MetS, metabolic syndrome.
Combined n 5 6385
Statin (þ) n 5 552
Statin (e) n 5 5833
p
79 43 (10) 36 25 (4) 92 (12) 23 119 (13) 76 (8) 13 29 (25e34) 33 (25e44) 31 (22e45) 116 (83e165) 48 (13) 131 (33) 89 (10) 1.2 (0.6e2.4) 31 5.8 (1.4) 12 9 241 (56) 20 2.5 (1.6e4.0)
90 51 (9) 49 28 (3) 97 (10) 33 123 (13) 79 (8) 38 31 (27e36) 38 (30e48) 38 (27e52) 128 (98e176) 46 (11) 113 (33) 93 (10) 1.2 (0.7e2.1) 34 6.0 (1.3) 39 10 235 (54) 34 2.9 (2.0e4.0)
78 43 (9) 35 26 (4) 91 (12) 22 118 (12) 77 (8) 10 29 (25e34) 32 (25e44) 30 (22e44) 114 (82e164) 48 (13) 132 (33) 89 (10) 1.2 (0.6e2.4) 31 5.8 (1.4) 10 9 242 (56) 19 2.4 (1.6e3.9)
!0.001 !0.001 !0.001 !0.001 !0.001 !0.001 !0.001 !0.001 !0.001 !0.001 !0.001 !0.001 0.009 0.004 !0.001 !0.001 0.3138 0.111 0.002 !0.001 0.256 0.010 !0.001 !0.001
Statin Use in Nonalcoholic Fatty Liver Disease
55
Table 2. Multivariate analysis of the association of hepatic steatosis with statin use
MetS (þ) Model 1a Model 2b MetS (e) Model 1a Model 2b
Odds ratio
95% CI
p
0.87 0.89
0.61e1.25 0.60e1.32
0.46 0.56
1.08 0.90
0.85e1.36 0.69e1.18
0.54 0.46
MetS, metabolic syndrome. a Adjusted for age and gender. b Adjusted for age gender, metabolic risk factors (waist circumference, triglyceride, HDL, SBP, fasting glucose) LDL, TG:HDL ratio and smoking.
Figure 1. Comparison of fatty liver with statin use.
without metabolic syndrome. Table 3 presents a multivariate regression analysis results for liver fibrosis, a subanalysis of individuals with NAFLD. The analysis shows a lack of independent association of statin use with the possibility of a severity of liver fibrosis (FIB-4 index O1.45). Discussion This study of 6385 asymptomatic men and women without coronary heart disease assessed the association of statin use with the prevalence or severity of NAFLD. About 9% of the population was on statins. Whereas the prevalence of NAFLD was higher in the statin group, after adjustments, there was no independent association. Our analysis of the fatty liver index among subjects with NAFLD showed no difference between the statin and nonstatin groups. There was a difference based on the FIB-4 index; however, this was abrogated by adjustment for confounders.
Our cross-sectional findings are compatible with the existing literature supporting the safety of statin therapy with regards to NAFLD (4). Although there is a higher prevalence of NAFLD among subjects taking statins, this was explained by age and gender in our study. Moreover, NAFLD has been identified as the hepatic manifestation of the metabolic syndrome (25) and from this study the statin group had a higher burden of risk factors. There are arguments for the role of statins on hepatic insulin resistance and its effect on glucose metabolism (26,27). In this study, the statin group had a higher mean blood glucose level and a higher TG:HDL-C ratio, a surrogate for insulin resistance; this may however be explained by the higher prevalence of metabolic risk factors in the population. Although there are concerns among physicians about the use of statins because of the increase in alanine aminotransferase (ALT), these concerns seem discordant with existing science on statin safety (17). A recent liver expert panel stated that patients with NAFLD are not at increased risk of statin hepatotoxicity and routine transaminase monitoring is not warranted in these patients (28). Several studies have shown the safety of statins in individuals with NAFLD. In a pilot study, atorvastatin treatment reduced serum aminotransferase and lipid levels in NAFLD patients (29). In another small randomized controlled trial, 1 year of simvastatin did not change liver histology in 16 patients with NASH (28,30). The post-hoc analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study, which evaluated the safety and efficacy of statins in 437 patients (80% men, Table 3. Multivariate analysis of the risk of severe fibrosis (FIB4O1.45) with statin use among hepatic steatosis patients
Model 1a Model 2b a
Figure 2. Comparison of FIB-4 index with statin use. (A color figure can be found in the online version of this article.)
Odds ratio
95% CI
p
1.0 0.88
0.70e1.42 0.60e1.29
0.98 0.50
Adjusted for age and gender. Adjusted for age gender, metabolic risk factors (waist circumference, triglyceride, HDL, SBP, fasting glucose) LDL, TG:HDL ratio and smoking. b
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Oni et al./ Archives of Medical Research 45 (2014) 52e57
51% diabetic and 91% with metabolic syndrome), reported that statins generally improved liver function, reduced LDL-cholesterol and significantly reduced CVD events in NAFLD subjects (31). From the St. Francis Heart study RCT, atorvastatin combined with antioxidants was effective in reducing the odds of having hepatic steatosis by 71% in healthy individuals with NAFLD at baseline after 4 years of active therapy (32). Although our study did not specify the type and dosage of the statin used by the subjects, the benefit and safety of statin use in individuals with cardiovascular risk and background NAFLD is not limited to a particular type of drug in the statin family. The safety and efficacy of simvastatin in NAFLD or NASH has been reported in several shortduration studies (15,30,33). Lovastatin has also been reported to lower serum liver transaminase activities and the aspartate aminotransferase (AST) to platelet ratio index (APRI) in patients with NASH (34). Although information on the efficacy and safety of pravastatin in NAFLD is lacking, it was reported to improve histological findings in biopsy-proven steatohepatitis (35). In an open-label pilot of the efficacy of pitavastatin in biopsy-proven NASH, there was improvement in metabolic parameters and the severity of hepatic steatosis (36). The post-hoc analysis of the GREACE study demonstrated the efficacy and safety of atorvastatin. The efficacy and safety of rosuvastatin in ultrasound-diagnosed NAFLD was evaluated in a prospective study. A normalization of serum transaminase, total cholesterol, triglyceride and LDL-cholesterol levels were reported (37). Study Limitations This study does have some limitations. First, the design of the study is cross-sectional and, as such, temporality of associations cannot be ascertained. Second, the diagnosis of NAFLD was ultrasound based. Although ultrasound is a useful non-invasive tool for identifying NAFLD, its sensitivity for detecting fatty changes within the liver is reduced when the NAFLD is less than moderate in severity (24,38). Ultrasound imaging can only detect NAFLD when greater that a third of the liver is affected. Third, as mentioned above, we did not have information on the type of statins taken, as well as the dosage used or duration of treatment. Fourth, there may be some residual bias on the reasons for statin use. Strength This study also has its strengths. The large number of participants of both genders, each of whom had undergone extensive cardiovascular risk factor assessment, is a unique strength. This allowed for adjustment for potentially confounding risk factors. The broadly representative cohort also allowed for evaluation of the relationship within demographic and clinical subgroups. The use of individuals
without known CVD may help make this data and its findings most relevant. Implications Our study provides additional reassurance for the use of statin therapy in patients who need them regardless of an underlying hepatic steatosis or minimally impaired liver enzymes. Patients with higher metabolic risk factors and NAFLD are at risk of CVD morbidity and mortality. The use of statins in this group will allow them to benefit from the primary prevention benefit of the statins. Moreover, it is estimated that $10 billion per year is spent in the United States for the monitoring of statin patients with liver function tests (17,39). Synthesizing our findings with other studies, and recent expert recommendations, reducing this spending should be a future goal. There are also implications for future studies. There is need for future studies using the different statins among a diverse ethnic population to add to what is already known about statins and NAFLD. Follow-up studies on the long-term hepatic effect of statins are also very essential. In conclusion, the benefits of statins in the primary and secondary prevention of CVD events may outweigh concerns about their effect on the liver. From this study, statin use was not associated with the presence or severity of NAFLD. There is a place for the use of statins to improve CVD morbidity and mortality and also improve liver function in individuals with NAFLD. Whereas we still seek a better understanding of the impact of this lipid lowering medication on the liver, current evidence is convincing that statins are safe in NAFLD. Physicians should therefore not be too cautious in the use of statins in patients with NAFLD.
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25. Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003;37:917e923. 26. Shah RV, Goldfine AB. Statins and risk of new-onset diabetes mellitus. Circulation 2012;126:e282ee284. 27. Minder CM, Blumenthal RS, Blaha MJ. Statins for primary prevention of cardiovascular disease: the benefits outweigh the risks. Curr Opin Cardiol 2013;28:554e560. 28. Musso G, Cassader M, Gambino R. Cholesterol-lowering therapy for the treatment of nonalcoholic fatty liver disease: an update. Curr Opin Lipidol 2011;22:489e496. 29. Gomez-Dominguez E, Gisbert JP, Moreno-Monteagudo JA, et al. A pilot study of atorvastatin treatment in dyslipemid, non-alcoholic fatty liver patients. Aliment Pharmacol Ther 2006;23:1643e1647. 30. Nelson A, Torres DM, Morgan AE, et al. A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: a randomized placebo-controlled trial. J Clin Gastroenterol 2009;43:990e994. 31. Athyros VG, Tziomalos K, Gossios TD, 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;376:1916e1922. 32. Foster T, Budoff MJ, Saab S, et al. Atorvastatin and antioxidants for the treatment of nonalcoholic fatty liver disease: the St Francis Heart Study randomized clinical trial. Am J Gastroenterol 2011;106:71e77. 33. Abel T, Feher J, Dinya E, et al. Safety and efficacy of combined ezetimibe/simvastatin treatment and simvastatin monotherapy in patients with non-alcoholic fatty liver disease. Med Sci Monit 2009;15:MS6e11. 34. Mihaila RG, Nedelcu L, Fratila O, et al. Effects of lovastatin and pentoxyphyllin in nonalcoholic steatohepatitis. Hepatogastroenterology 2009;56:1117e1121. 35. Rallidis LS, Drakoulis CK, Parasi AS. Pravastatin in patients with nonalcoholic steatohepatitis: results of a pilot study. Atherosclerosis 2004;174:193e196. 36. Hyogo H, Ikegami T, Tokushige K, et al. Efficacy of pitavastatin for the treatment of non-alcoholic steatohepatitis with dyslipidemia: an open-label, pilot study. Hepatol Res 2011;41:1057e1065. 37. Antonopoulos S, Mikros S, Mylonopoulou M, et al. Rosuvastatin as a novel treatment of non-alcoholic fatty liver disease in hyperlipidemic patients. Atherosclerosis 2006;184:233e234. 38. Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002; 123:745e750. 39. Bader T. The myth of statin-induced hepatotoxicity. Am J Gastroenterol 2010;105:978e980.
ORIGINAL ARTICLE
Statin Use Is Not Associated With Presence of and Severity of Nonalcoholic Fatty Liver Disease Ebenezer T. Oni,a Pragya Sinha,a Adil Karim,a Seth S. Martin,b Michael J. Blaha,b Arthur S. Agatston,a,c Roger S. Blumenthal,b Romeu S. Meneghelo,d Raquel D. Conceic¸ao,d Raul D. Santos,e and Khurram Nasira,b,c,f a
Center for Prevention and Wellness Research, Baptist Health Medical Group, Miami Beach, Florida b The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, Maryland c Department of Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida d Preventive Medicine Center Hospital Israelita Albert Einstein, Sao Paulo, Brazil e Lipid Clinic-Heart Institute (InCor) University of S~ao Paulo Medical School Hospital, Sao Paulo-S~ao Paulo, Brazil f Department of Epidemiology, Robert Stempel College of Public Health, Florida International University, Miami, Florida Received for publication July 19, 2013; accepted October 11, 2013 (ARCMED-D-13-00391).
Background and Aims. There is concern that statin use may exacerbate nonalcoholic fatty liver disease (NAFLD). We aimed to assess the association of statin use with NALFD and severity of liver fibrosis among NAFLD individuals. Methods. We evaluated 6,385 cross-sectional healthy Brazilian subjects (43 10 years, 79% males) without clinical coronary heart disease between November 2008 and July 2010. NAFLD was diagnosed by ultrasound. Severity of liver fibrosis was predicted by fatty liver index and FIB-4. Results. NAFLD prevalence was 36% (n 5 2310). Overall 552 (9%) individuals were using statins of whom 49% had NAFLD. Statin users were more likely to be men, older age, and have higher burden of risk factors ( p !0.05). In age gender adjusted analysis the odds ratio for NAFLD with statin use was 0.87 (0.61e1.25, p 5 0.46) in the presence of metabolic syndrome and 1.08 (0.88e1.32, p 5 0.56) in its absence. On further adjustment for metabolic risk factors, LDL and smoking the results remained unchanged (OR: 0.89, 95% CI: 0.65e1.32, p 5 0.56 and 0.90 (0.69e1.18, p 5 0.46). There was no significant association between statin use and fatty liver index in a subanalysis of NAFLD individuals (71 18 vs. 69 23, p 5 0.18). Although FIB-4 was mildly elevated with statin use (1.20 0.51 vs. 1.02 0.46, p !0.001), a multivariate analysis adjusted for age, gender and risk factors revealed statin use was not associated with severe fibrosis (FIB O1.45) (OR 0.88, 95% CI: 0.60e1.29, p 5 0.50). Conclusions. The results of this study favor statin use in subjects with NAFLD as its use is not associated with the presence of NAFLD or increased fibrosis Ó 2014 IMSS. Published by Elsevier Inc. Key Words: Statins, NAFLD, Fatty Liver Index, FIB-4 index, Fibrosis.
Introduction 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are central to the management of dyslipidemia (1). They are the most widely prescribed Address reprint requests to: Khurram Nasir, MD, MPH, Center for Prevention and Wellness Research, Baptist Health Medical Group, 1691 Michigan Ave Suite 500; Miami Beach, FL 33139; Phone: þ1-305-5383828; FAX: þ1-305-538-1979; E-mail: [email protected]
medications in the Western world (2), accounting for O10 million prescriptions in the United States in 2003 alone (3). Statins have been shown to have unequivocal benefits in the primary and secondary prevention of cardiovascular disease (CVD) (3,4). The use of statins has also been included as part of the treatment strategy for nonalcoholic fatty liver disease (NAFLD) (4e6). NAFLD is an emerging disease globally and a leading cause of chronic liver disease in the western world. The
0188-4409/$ - see front matter. Copyright Ó 2014 IMSS. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.arcmed.2013.12.003
Statin Use in Nonalcoholic Fatty Liver Disease
prevalence of NAFLD in the general population is |15e30% and 70e90% in persons with obesity or type 2 diabetes (7e10). Several studies have shown that NAFLD is an independent risk factor for increased CVD (11e13). NAFLD shares many common risk factors with vascular disease and the commonest cause of death among NAFLD patients is cardiovascular mortality. This is followed by cancer and then liver-related mortality (12). Although clinically significant liver injury is extremely rare from statins, asymptomatic liver enzyme elevations are common (14). It is the most common cause of incidental abnormal liver tests and elevated serum liver enzymes in the developed world (15,16). Although several studies have examined the safety and efficacy of statins in the prevention of CVD, many physicians are reluctant in prescribing statins in patients with elevated alanine aminotransferase (ALT) levels (17). This is centered on concerns about the risk-to-benefit ratio of statin use in individuals with background NAFLD. These concerns within the medical community range from the notion that statin use may result in the development of NAFLD to the idea that statins could worsen existing disease (15,18). In this study, we aim to assess the association of statin use with the prevalence of NALFD and the severity of liver fibrosis scores in subjects with NAFLD.
Subjects and Methods We evaluated 6,385 asymptomatic men and women, free of coronary heart disease, who had an obligatory clinical and laboratory health evaluation paid for by their employers from December 2008eDecember 2010 at the Preventive Medicine Center of the Albert Einstein Hospital in S~ao Paulo, Brazil. The examination protocol consisted of a clinical consultation, laboratory evaluation, and abdominal ultrasonography. All individuals provided demographic details, medical history, quantitative alcohol consumption, smoking status, and medication use at the time of their clinical consultation. We included all individuals for whom full information was available for all the covariates of interest. This study excluded individuals with a known history of liver disease from the analysis. Information regarding medical history was obtained via questionnaire. Smoking status was defined as current smoker vs. current nonsmoker. Diabetes mellitus was identified by previous physician diagnosis or by the use of glucose-lowering medication. Hypertension and dyslipidemia were ascertained by a previous history of these conditions or the use of blood pressure-lowering or lipid-lowering medications; those individuals with systolic blood pressure O140 mmHg or diastolic blood pressure O90 mmHg at the clinical evaluation were also labeled as having hypertension. During physical examinations, blood pressure was measured with a mercury sphygmomanometer using the method recommended by the American Heart
53
Association (19). Waist circumference was measured at the smallest diameter between the iliac crest and the costal margin using a plastic anthropometric tape held parallel to the floor. Blood specimens were collected after an overnight fast. Plasma lipid, glucose, and liver transaminase levels (alanine aminotransferase (20) and aspartate aminotransferase [AST]) levels were measured by standardized automated laboratory tests using a Vitros platform (Johnson & Johnson Clinical Diagnostics). High-sensitivity CRP (hsCRP) levels were determined by immunonephelometry (Dade-Behring). All tests were performed at the Central Laboratory of the Albert Einstein Hospital. NAFLD was diagnosed after at least a 6-h fast using an ACUSON XP-10 device (Mountain View, CA) and was identified by the presence of an ultrasonographic pattern of a bright liver with evident contrast between hepatic and renal parenchyma (indicating hepatic steatosis) as previously described (21). All hepatic ultrasounds were read by board-certified radiologists. Obesity was defined as a body mass index (BMI) O30 kg/m2. NAFLD severity was determined by fatty liver index 5 (e 0.953*loge (triglycerides) þ 0.139*BMI þ 0.718*loge (ggt) þ 0.053*waist circumferencee15.745)/(1 þ e 0.953*loge (triglycerides) þ 0.139*BMI þ 0.718*loge (ggt) þ 0.053*waist circumferencee15.745) * 100 and FIB-4 (age (years) x AST [U/l]/(platelets [109/l] x (ALT [U/l])1/2)). An FIB-4 index O1.45 had a negative predictive value of 94.7% to exclude severe fibrosis (22). The use of the FIB-4 index to predict severe liver fibrosis among individuals with NAFLD was validated in a previous study among a Japanese population with NAFLD (22). Metabolic syndrome was defined using criteria from the American Heart Association/National Heart, Lung, and Blood Institute scientific statement on the metabolic syndrome (23). Patients with $3 of the following metabolic risk factors were classified as having the metabolic syndrome: truncal obesity ($102 cm [40 inches] for men and $88 cm [36 inches] for women), high blood pressure (blood pressure $130/ 85 mmHg or the use of antihypertensive medications), hyperglycemia (fasting blood glucose $100 mg/dL), low high-density lipoprotein cholesterol (HDL-C) (#40 mg/ dL for men and #50 mg/dL for women), and hypertriglyceridemia ($150 mg/dL). This study was approved by the local institutional review board, and a waiver for informed consent was obtained (24). Baseline characteristics of individuals in the statin and non-statin groups were compared using the Wilcoxon’s t test for continuous variables and the Pearson’s c2 test for categorical variables. Because of the skewed distribution of ALT, AST, GGT and hs-CRP, median values were used in comparing the two groups using the nonparametric Kruskal-Wallis test. Multivariable logistic regression was used to evaluate associations of statins and NAFLD. For all regression analyses, a hierarchical model
54
Oni et al./ Archives of Medical Research 45 (2014) 52e57
approach was used, adjusting first for age and gender and then simultaneously adjusting for other traditional risk factors (waist circumference, triglycerides, HDL-C, SBP, fasting glucose, LDL-C, triglyceride:HDL-cholesterol ratio and smoking). Subanalysis testing was performed to estimate the odds of FIB-4 O1.45 (severe fibrosis) with statin use among individuals with NAFLD. All statistical analyses were performed using STATA statistical software, release 12 (College Station, TX).
Results The characteristics of the study population stratified by statin use are displayed in Table 1. A total of 6385 subjects were analyzed: 552 were in the statin group and 5833 were in the nonstatin group. There were statistically significant differences in demographic, anthropometric and biochemical profiles between groups. Those on statins were more likely to be men, older age and with a higher burden of risk factors. The statin group was more likely to have the following metabolic risk factors: hyperglycemia, obesity, and hypertension ( p !0.001). The prevalence of NAFLD was 36% among the entire study population. The prevalence was statistically different across the two groups, 48% in the statin group compared to 35% in the nonstatin group ( p !0.001). Individuals in the statin group were more likely to have metabolic syndrome, 34% vs.
19%, p !0.001. Individuals on statin therapy were also more likely to have a higher systolic blood pressure compared to the non-statin group, 123 mmHg vs. 118 mmHg, p !0.001. There was a similar association with diastolic blood pressure. The statin group was significantly more likely to have higher liver enzymes compared to the non-statin group. The use of statins was significantly associated with the level of all cholesterols. Individuals on statins were more likely to have a higher triglyceride level and lower HDL and LDL cholesterol levels compared to the nonstatin group. Although the mean uric acid level among the statin group was higher compared to the nonstatin group, 6.0 vs. 5.8, p 5 0.002; there was however no significant difference in the level of the hs-C-reactive protein. The median triglyceride-HDL cholesterol ratio (TG:HDL), a marker for insulin resistance, was higher in the statin group compared to the non-statin group, 2.85 vs. 2.43, p !0.001. In subanalyses of individuals with NAFLD, fatty liver index was not different between the statin and nonstatin groups (Figure 1). The statin group, however, was more likely to have a higher FIB-4 index compared to the nonstatin group (1.20 vs. 1.02, p !0.001, Figure 2). Table 2 presents multivariable regression analyses of different models adjusting for confounding variables in the association between use of statins and prevalence of NAFLD. The analysis was stratified by the presence of metabolic syndrome. There was no independent association between statins and NAFLD prevalence in those with or
Table 1. Baseline characteristics of study population
Clinical, anthropometric, and biochemical characteristics Male (%) Mean age, years (SD) NAFLD present (%) Mean BMI, kg/m2 (SD) Mean WC, cm (SD) Obesity, BMI $30 kg/m2 (%) Mean SBP, mmHg (SD) Mean DBP, mmHg (SD) Hypertension present (%) Median AST, U/L (interquartile range) Median ALT, U/L (interquartile range) Median GGT, mg/dL (interquartile range) Median triglycerides, mg/dL (interquartile range) Mean HDL, mg/dL (SD) Mean LDL, mg/dL (SD) Mean FBG, mg/dL (SD) Median hs-CRP, mg/dL (interquartile range) High hs-CRP ($3 mg/dL) (%) Mean uric acid, mg/dL (SD) Antihypertensive (%) Current smoker (%) Platelet, 109/L (SD) Subjects with MetS (%) Median TG:HDL-C (interquartile range) MetS, metabolic syndrome.
Combined n 5 6385
Statin (þ) n 5 552
Statin (e) n 5 5833
p
79 43 (10) 36 25 (4) 92 (12) 23 119 (13) 76 (8) 13 29 (25e34) 33 (25e44) 31 (22e45) 116 (83e165) 48 (13) 131 (33) 89 (10) 1.2 (0.6e2.4) 31 5.8 (1.4) 12 9 241 (56) 20 2.5 (1.6e4.0)
90 51 (9) 49 28 (3) 97 (10) 33 123 (13) 79 (8) 38 31 (27e36) 38 (30e48) 38 (27e52) 128 (98e176) 46 (11) 113 (33) 93 (10) 1.2 (0.7e2.1) 34 6.0 (1.3) 39 10 235 (54) 34 2.9 (2.0e4.0)
78 43 (9) 35 26 (4) 91 (12) 22 118 (12) 77 (8) 10 29 (25e34) 32 (25e44) 30 (22e44) 114 (82e164) 48 (13) 132 (33) 89 (10) 1.2 (0.6e2.4) 31 5.8 (1.4) 10 9 242 (56) 19 2.4 (1.6e3.9)
!0.001 !0.001 !0.001 !0.001 !0.001 !0.001 !0.001 !0.001 !0.001 !0.001 !0.001 !0.001 0.009 0.004 !0.001 !0.001 0.3138 0.111 0.002 !0.001 0.256 0.010 !0.001 !0.001
Statin Use in Nonalcoholic Fatty Liver Disease
55
Table 2. Multivariate analysis of the association of hepatic steatosis with statin use
MetS (þ) Model 1a Model 2b MetS (e) Model 1a Model 2b
Odds ratio
95% CI
p
0.87 0.89
0.61e1.25 0.60e1.32
0.46 0.56
1.08 0.90
0.85e1.36 0.69e1.18
0.54 0.46
MetS, metabolic syndrome. a Adjusted for age and gender. b Adjusted for age gender, metabolic risk factors (waist circumference, triglyceride, HDL, SBP, fasting glucose) LDL, TG:HDL ratio and smoking.
Figure 1. Comparison of fatty liver with statin use.
without metabolic syndrome. Table 3 presents a multivariate regression analysis results for liver fibrosis, a subanalysis of individuals with NAFLD. The analysis shows a lack of independent association of statin use with the possibility of a severity of liver fibrosis (FIB-4 index O1.45). Discussion This study of 6385 asymptomatic men and women without coronary heart disease assessed the association of statin use with the prevalence or severity of NAFLD. About 9% of the population was on statins. Whereas the prevalence of NAFLD was higher in the statin group, after adjustments, there was no independent association. Our analysis of the fatty liver index among subjects with NAFLD showed no difference between the statin and nonstatin groups. There was a difference based on the FIB-4 index; however, this was abrogated by adjustment for confounders.
Our cross-sectional findings are compatible with the existing literature supporting the safety of statin therapy with regards to NAFLD (4). Although there is a higher prevalence of NAFLD among subjects taking statins, this was explained by age and gender in our study. Moreover, NAFLD has been identified as the hepatic manifestation of the metabolic syndrome (25) and from this study the statin group had a higher burden of risk factors. There are arguments for the role of statins on hepatic insulin resistance and its effect on glucose metabolism (26,27). In this study, the statin group had a higher mean blood glucose level and a higher TG:HDL-C ratio, a surrogate for insulin resistance; this may however be explained by the higher prevalence of metabolic risk factors in the population. Although there are concerns among physicians about the use of statins because of the increase in alanine aminotransferase (ALT), these concerns seem discordant with existing science on statin safety (17). A recent liver expert panel stated that patients with NAFLD are not at increased risk of statin hepatotoxicity and routine transaminase monitoring is not warranted in these patients (28). Several studies have shown the safety of statins in individuals with NAFLD. In a pilot study, atorvastatin treatment reduced serum aminotransferase and lipid levels in NAFLD patients (29). In another small randomized controlled trial, 1 year of simvastatin did not change liver histology in 16 patients with NASH (28,30). The post-hoc analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study, which evaluated the safety and efficacy of statins in 437 patients (80% men, Table 3. Multivariate analysis of the risk of severe fibrosis (FIB4O1.45) with statin use among hepatic steatosis patients
Model 1a Model 2b a
Figure 2. Comparison of FIB-4 index with statin use. (A color figure can be found in the online version of this article.)
Odds ratio
95% CI
p
1.0 0.88
0.70e1.42 0.60e1.29
0.98 0.50
Adjusted for age and gender. Adjusted for age gender, metabolic risk factors (waist circumference, triglyceride, HDL, SBP, fasting glucose) LDL, TG:HDL ratio and smoking. b
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Oni et al./ Archives of Medical Research 45 (2014) 52e57
51% diabetic and 91% with metabolic syndrome), reported that statins generally improved liver function, reduced LDL-cholesterol and significantly reduced CVD events in NAFLD subjects (31). From the St. Francis Heart study RCT, atorvastatin combined with antioxidants was effective in reducing the odds of having hepatic steatosis by 71% in healthy individuals with NAFLD at baseline after 4 years of active therapy (32). Although our study did not specify the type and dosage of the statin used by the subjects, the benefit and safety of statin use in individuals with cardiovascular risk and background NAFLD is not limited to a particular type of drug in the statin family. The safety and efficacy of simvastatin in NAFLD or NASH has been reported in several shortduration studies (15,30,33). Lovastatin has also been reported to lower serum liver transaminase activities and the aspartate aminotransferase (AST) to platelet ratio index (APRI) in patients with NASH (34). Although information on the efficacy and safety of pravastatin in NAFLD is lacking, it was reported to improve histological findings in biopsy-proven steatohepatitis (35). In an open-label pilot of the efficacy of pitavastatin in biopsy-proven NASH, there was improvement in metabolic parameters and the severity of hepatic steatosis (36). The post-hoc analysis of the GREACE study demonstrated the efficacy and safety of atorvastatin. The efficacy and safety of rosuvastatin in ultrasound-diagnosed NAFLD was evaluated in a prospective study. A normalization of serum transaminase, total cholesterol, triglyceride and LDL-cholesterol levels were reported (37). Study Limitations This study does have some limitations. First, the design of the study is cross-sectional and, as such, temporality of associations cannot be ascertained. Second, the diagnosis of NAFLD was ultrasound based. Although ultrasound is a useful non-invasive tool for identifying NAFLD, its sensitivity for detecting fatty changes within the liver is reduced when the NAFLD is less than moderate in severity (24,38). Ultrasound imaging can only detect NAFLD when greater that a third of the liver is affected. Third, as mentioned above, we did not have information on the type of statins taken, as well as the dosage used or duration of treatment. Fourth, there may be some residual bias on the reasons for statin use. Strength This study also has its strengths. The large number of participants of both genders, each of whom had undergone extensive cardiovascular risk factor assessment, is a unique strength. This allowed for adjustment for potentially confounding risk factors. The broadly representative cohort also allowed for evaluation of the relationship within demographic and clinical subgroups. The use of individuals
without known CVD may help make this data and its findings most relevant. Implications Our study provides additional reassurance for the use of statin therapy in patients who need them regardless of an underlying hepatic steatosis or minimally impaired liver enzymes. Patients with higher metabolic risk factors and NAFLD are at risk of CVD morbidity and mortality. The use of statins in this group will allow them to benefit from the primary prevention benefit of the statins. Moreover, it is estimated that $10 billion per year is spent in the United States for the monitoring of statin patients with liver function tests (17,39). Synthesizing our findings with other studies, and recent expert recommendations, reducing this spending should be a future goal. There are also implications for future studies. There is need for future studies using the different statins among a diverse ethnic population to add to what is already known about statins and NAFLD. Follow-up studies on the long-term hepatic effect of statins are also very essential. In conclusion, the benefits of statins in the primary and secondary prevention of CVD events may outweigh concerns about their effect on the liver. From this study, statin use was not associated with the presence or severity of NAFLD. There is a place for the use of statins to improve CVD morbidity and mortality and also improve liver function in individuals with NAFLD. Whereas we still seek a better understanding of the impact of this lipid lowering medication on the liver, current evidence is convincing that statins are safe in NAFLD. Physicians should therefore not be too cautious in the use of statins in patients with NAFLD.
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