Prevalence and Factors Associated With Statin Use Among Patients With Nonalcoholic Fatty Liver Disease in the TARGET-NASH Study
Authors: Mary J. Thomson, Marina Serper, Vandana Khungar, L. Michael Weiss, Huy Trinh, Roberto Firpi-Morell, Michael Roden, Rohit Loomba, A. Sidney Barritt, Derek Gazis, Andrea R. Mospan, Michael W. Fried, K. Rajender Reddy, Anna S. Lok
Journal: Clinical Gastroenterology and Hepatology (2021)

Patients with nonalcoholic fatty liver disease (NAFLD) are at an increased risk of cardiovascular disease. Hydoxy-3-methyglutaryl-coenzyme reductase inhibitors, statins, reduce the risk of cardiovascular events.1Taylor F. Huffman M.D. Macedo A.F. et al.Statins for the primary prevention of cardiovascular disease.Cochrane Database Syst Rev. 2013; 1: CD004816Crossref PubMed Scopus (604) Google Scholar Studies have shown that statins are safe among patients with liver disease, including those with compensated cirrhosis,2Lewis J.H. Mortensen M.E. Zweig S. et al.Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial.Hepatology. 2007; 46: 1453-1463Crossref PubMed Scopus (233) Google Scholar and their use is associated with lower mortality, hepatic decompensation, and possibly hepatocellular carcinoma.3Kaplan D.E. Serper M.A. Mehta R. et al.Effects of hypercholesterolemia and statin exposure on survival in a large national cohort of patients with cirrhosis.Gastroenterology. 2019; 156: 1693-1706.e12Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar,4Kim R.G. Loomba R. Prokop L.J. et al.Statin use and risk of cirrhosis and related complications in patients with chronic liver diseases: a systematic review and meta-analysis.Clin Gastroenterol Hepatol. 2017; 15: 1521-1530.e8Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar Despite these data, statins are under prescribed among patients with liver disease due to concerns about hepatotoxicity.5Del Ben M. Baratta F. Polimeni L. et al.Under-prescription of statins in patients with non-alcoholic fatty liver disease.Nutr Metab Cardiovasc Dis. 2017; 27: 161-167Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar This study aimed to assess prevalence and patient factors associated with indicated statin use in patients with NAFLD in a real-world cohort. Adults with NAFLD enrolled in the TARGET-NASH study, across 60 sites in the United States, with an indication for statin therapy were included. Statin indication was based on the 2013 American College of Cardiology guidelines for primary and secondary prevention of cardiovascular disease: (1) atherosclerotic cardiovascular disease (ASCVD), (2) low-density lipoprotein cholesterol ≥190 mg/dL, (3) history of diabetes and age 40–75 years, or (4) 10-year ASCVD risk score ≥7.5%.6Stone N.J. Robinson J.G. Lichtenstein A.H. et al.2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.J Am Coll Cardiol. 2014; 63: 2889-2934Crossref PubMed Scopus (3046) Google Scholar Medical records available within 3 years prior to enrollment were reviewed for comorbidities and liver disease severity; statin use within 6 months of enrollment was determined (Supplementary Methods). Patients were classified as having nonalcoholic fatty liver, nonalcoholic steatohepatitis, or compensated or decompensated NAFLD cirrhosis according to clinical assessments previously described.7Barritt A.S. Gitlin N. Klein S. et al.Design and rationale for a real-world observational cohort of patients with nonalcoholic fatty liver disease: The TARGET-NASH study.Contemp Clin Trials. 2017; 61: 33-38Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar Unadjusted and adjusted logistic regression models were fit to assess the association between patient demographic and clinical characteristics with statin use. This analysis included 2214 patients with at least 1 statin indication. Median age was 62 years, 80.2% were White, and 61.1% were female. At enrollment, 26.2% had compensated and 20.1% had decompensated cirrhosis, 73.2% had hypertension, 83.2% had type 2 diabetes, and 62.6% had dyslipidemia. Diabetes plus age 40–75 years was the most common indication for statin use (81.4%) (Supplementary Table 1). Overall, 55.8% of patients with at least 1 indication used a statin, with the highest use among patients with clinical ASCVD (63.0%) (Figure 1A). Patients on an indicated statin were older (63 years of age vs 61 years of age; P < .0001), with more cardiovascular comorbidities, and were less often female (58.9% vs 63.8%; P < .019) (Supplementary Table 1). The proportions of patients who received an indicated statin were lower in patients with more advanced liver disease (60.8%, 61.6%, 55.1%, and 42.2%, in patients with nonalcoholic fatty liver, nonalcoholic steatohepatitis, compensated cirrhosis, and decompensated cirrhosis, respectively) (Supplementary Figure 1). In a multivariable analysis adjusting for demographics, liver disease severity, and other clinical characteristics, ≥65 years of age (odds ratio [OR], 1.44; 95% confidence interval [CI], 1.11–1.88), no cirrhosis vs decompensated cirrhosis (OR, 1.88; 95% CI 1.34–2.65), compensated vs decompensated cirrhosis (OR, 1.44; 95% CI, 1.04–1.99), history of hypertension (OR, 1.32; 95% CI, 1.03–1.69), type 2 diabetes (OR, 1.96; 95% CI, 1.44–2.67), dyslipidemia (OR, 5.42; 95% CI, 4.34–6.77), and clinical ASCVD (OR, 1.49; 95% CI, 1.16–1.92) were independently associated with higher odds of statin use (Figure 1B). There was a nonsignificant trend toward higher statin use in patients without cirrhosis compared with those with compensated cirrhosis (OR, 1.31; 95% CI, 1.00–1.72). Female sex (OR, 0.70; 95% CI, 0.56–0.88) and platelet count <100,000/μL (OR, 0.7; 95% CI, 0.50–0.97) were associated with lower odds of statin use. In this study, only 56% of patients with NAFLD were taking guideline-recommended statin therapy. Older patients as well as those with dyslipidemia or hypertension were more likely to be on a statin. Statin use decreased as NAFLD became more advanced, likely reflecting safety concerns in patients with decompensated cirrhosis.8Kaplan D.E. The use of statins in patients with cirrhosis.Gastroenterol Hepatol (N Y). 2018; 14: 485-487PubMed Google Scholar Women were less likely to be on an indicated statin compared with men, even after adjusting for cardiovascular risk factors and liver disease severity. There were several limitations to this study. The majority of patients were seen in academic gastroenterology or hepatology practices, and statin use may be lower in other settings. Clinical information was extracted from clinic notes, which depends on accurate and complete documentation. The pragmatic NAFLD diagnoses utilized may be inaccurate in classifying disease severity; however, this reflects real-world practice in which biopsies are uncommonly done. Finally, follow-up was not long enough to determine the effect on cardiovascular or hepatic outcomes. Similar to other studies of statin use in the general population and in NAFLD patients, this analysis of a large national real-world sample showed that guideline-recommended statins continue to be underutilized and were not prescribed in 40% of NAFLD patients with clear indications. Ongoing studies on the potential benefit of statins in preventing cirrhosis complications may broaden statin indications beyond cardiovascular disease in the future. Further steps are needed to educate providers and patients on statin safety and its benefits in preventing cardiovascular disease in at-risk NAFLD patients. The TARGET-NASH study is a longitudinal observational cohort of patients with nonalcoholic fatty liver (NAFL) disease managed at 60 sites, 47 academic and 13 community based, in the United States, representing hepatology, gastroenterology, and endocrinology practices. This analysis included patients ≥18 years of age enrolled between August 1, 2016, and April 20, 2020. Clinical information from the electronic medical records is extracted and uploaded into a secured database. The study was approved by central or local institutional review boards and consent was obtained from all patients. Details of the study methodology have been previously described.1Barritt AS. Gitlin N. Klein S. et al.Design and rationale for a real-world observational cohort of patients with nonalcoholic fatty liver disease: The TARGET-NASH study.Contemp Clin Trials. 2017; 61: 33-38Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar,2Barritt A.S. Watkins S. Gitlin N. et al.Patient determinants for histologic diagnosis of NAFLD in the real world: a TARGET-NASH study.Hepatol Commun. 2021 Feb 21; ([E-pub ahead of print])Crossref Scopus (7) Google Scholar Patients were classified, at the time of enrollment, as having a clinical indication for statin therapy based on the 2013 American College of Cardiology guidelines for primary and secondary prevention of cardiovascular disease.3Stone N.J. Robinson J.G. Lichtenstein A.H. et al.2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.J Am Coll Cardiol. 2014; 63: 2889-2934Crossref PubMed Scopus (3176) Google Scholar Patients who met 1 of the following 4 criteria were included as having a statin indication: (1) clinical atherosclerotic cardiovascular disease (ASCVD), (2) low-density lipoprotein cholesterol ≥190 mg/dL, (3) diabetes and age 40–75 years, and 4) 10-year ASCVD risk score ≥7.5%.3Stone N.J. Robinson J.G. Lichtenstein A.H. et al.2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.J Am Coll Cardiol. 2014; 63: 2889-2934Crossref PubMed Scopus (3176) Google Scholar Patients with a history of any use of the following medications: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin within 6 months before or after the index date were considered to have ever used a statin. The following clinical characteristics were ascertained: age, sex, race, severity of liver disease, laboratory values, systolic blood pressure, practice location, physician specialty, body mass index, history of comorbid disease, and ASCVD. Comorbidities and liver disease staging were assessed based on data from the 3-year retrospective period prior to enrollment; statin use, laboratory values, and blood pressure measurements were ascertained within a 6-month window prior to or after the date of enrollment. Patients were classified post enrollment as having NAFL, nonalcoholic steatohepatitis, or compensated or decompensated NAFL disease cirrhosis.2Barritt A.S. Watkins S. Gitlin N. et al.Patient determinants for histologic diagnosis of NAFLD in the real world: a TARGET-NASH study.Hepatol Commun. 2021 Feb 21; ([E-pub ahead of print])Crossref Scopus (7) Google Scholar,4Moon A.M. Watkins S.E. Lok A.S. et al.Opioid use is more common in non-alcoholic fatty liver disease patients with cirrhosis, higher body mass index and psychiatric disease.Dig Dis. 2020 Aug 24; ([E-pub ahead of print])Crossref Scopus (6) Google Scholar,5Weinberg E.M. Trinh H.N. Firpi R.J. et al.Lean Americans with nonalcoholic fatty liver disease have lower rates of cirrhosis and co-morbid diseases.Clin Gastroenterol Hepatol. 2020 Jul 3; ([E-pub ahead of print])Google Scholar NAFL was defined as the presence of hepatic steatosis not attributable to other causes (eg, heavy alcohol consumption) and without evidence of biochemical or histological inflammation. Nonalcoholic steatohepatitis was defined as the presence of steatohepatitis on biopsy or steatosis on biopsy or imaging and elevated alanine aminotransferase (>19 U/L for women, >30 U/L for men) with an additional metabolic risk factor (body mass index ≥30 kg/m2, type 2 diabetes, dyslipidemia). Cirrhosis was based on clinical determination (eg, imaging findings, platelet count <140,000/μL) or liver biopsy. Decompensation was defined as history of ascites, variceal bleeding, or encephalopathy. Descriptive statistics were reported as medians with interquartile ranges for continuous variables and counts and percentages for categorical variables. Demographic and patient characteristics were compared using the Cochran-Mantel-Haenszel general association test for categorical variables and the Kruskal-Wallis test for continuous variables. Unadjusted and adjusted logistic regression models were fit to assess the association between patient demographic and clinical characteristics with statin use. A P value <.05 was considered statistically significant. All analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC). Results were reported as odds ratios with 95% confidence intervals for statin use.Supplemental Table 1Characteristics of Adult TARGET-NASH Study Participants With Statin Indication by Statin UseCharacteristicsParticipants with an indication (n = 2214)Statin use (n = 1236)No statin use (n = 978)P value (yes vs no statin use)aP values for categorical variables are from the Cochran-Mantel-Haenszel general association test and P values for continuous variables are from the Kruskal-Wallis test.DemographicsAge at study entry, y Median (n)62 (2214)63 (1236)61 (978) IQR (distance between quartiles 1 and 3)55–68 (13)56–69 (13)53–67 (14)<.0001Sex n22141236978 Female1352 (61.07)728 (58.90)624 (63.80) Male862 (38.93)508 (41.10)354 (36.20).019Race n22141236978.50 White1776 (80.22)990 (80.10)786 (80.37) Black or African American152 (6.87)82 (6.63)70 (7.16) American Indian or Alaska Native10 (0.45)6 (0.49)4 (0.41) Asian152 (6.87)84 (6.80)68 (6.95) Other57 (2.57)29 (2.35)28 (2.86) Not reported67 (3.03)45 (3.64)22 (2.25)Ethnicity n22141236978.48 Hispanic or Latino249 (11.25)129 (10.44)120 (12.27) Not Hispanic or Latino1896 (85.64)1065 (86.17)831 (84.97) Not reported52 (2.35)32 (2.59)20 (2.04) Other17 (0.77)10 (0.81)7 (0.72)BMI category n21991231968.18 ≤25 kg/m2 (healthy weight)197 (8.96)102 (8.29)95 (9.81) >25–30 kg/m2 (overweight)558 (25.38)321 (26.08)237 (24.48) >30–35 kg/m2 (obese class I)584 (26.56)345 (28.03)239 (24.69) >35–40 kg/m2 (obese class II)465 (21.15)255 (20.71)210 (21.69) >40 kg/m2 (obese class III)395 (17.96)208 (16.90)187 (19.32) Not available15510Insurance type2214 (100.00)1236 (100.00)978 (100.00)— Private1192 (53.84)666 (53.88)526 (53.78) Medicare914 (41.28)534 (43.20)380 (38.85) Medicaid260 (11.74)139 (11.25)121 (12.37) Other215 (9.71)118 (9.55)97 (9.92)Site type n22141236978.46 Academic1510 (68.20)835 (67.56)675 (69.02) Community704 (31.80)401 (32.44)303 (30.98)Site specialty n22141236978.0001 Endocrinology93 (4.20)70 (5.66)23 (2.35) Gastroenterology/hepatology2121 (95.80)1166 (94.34)955 (97.65)Liver disease stageDisease stage n22141236978<.0001 NAFL357 (16.12)217 (17.56)140 (14.31) NASH830 (37.49)511 (41.34)319 (32.62) Compensated cirrhosis581 (26.24)320 (25.89)261 (26.69) Decompensated cirrhosis446 (20.14)188 (15.21)258 (26.38)Lab values (closest to enrollment, within ±6 mo)Platelets n18661026840<.0001 ≥100,0001490 (79.85)879 (85.67)611 (72.74) <100,000376 (20.15)147 (14.33)229 (27.26) Not available348210138Albumin, g/dL Median (n)4.20 (1974)4.20 (1111)4.10 (863)<.0001 Minimum–maximum1.4–6.81.4–5.31.6–6.8AST, IU/L Median (n)32.0 (2023)31.0 (1129)34.0 (894).0027 Minimum–maximum2–2394–2392–231ALT, IU/L Median (n)33.0 (2029)34.0 (1131)32.0 (898).31 Minimum–maximum3–3865–2743–386Total bilirubin, mg/dL Median (n)0.60 (2003)0.60 (1117)0.70 (886)<.0001 Minimum–maximum0.1–25.00.1–25.00.1–10.4Comorbidities at enrollmentHypertension (from medical history)1620 (73.17)968 (78.32)652 (66.67)<.0001Type 2 diabetes mellitus1843 (83.24)1054 (85.28)789 (80.67).004Dyslipidemia (from medical history)1385 (62.56)986 (79.77)399 (40.80)<.0001Indications for statin useClinical ASCVDbClinical events classified as ASCVD included acute coronary syndrome, coronary angioplasty, acute myocardial infarction, coronary arterial stent insertion, angina pectoris, coronary artery bypass, angina unstable, coronary artery disease, aortic aneurysm, coronary artery stenosis, aortic aneurysm repair, ischemic cardiomyopathy, aortic arteriosclerosis, ischemic stroke, aortic bypass, lacunar infarction, arterial bypass operation, lacunar stroke, arterial stenosis, myocardial infarction, arterial stent insertion, myocardial ischemia, arteriosclerosis, percutaneous coronary intervention, arteriosclerosis coronary artery, peripheral arterial occlusive disease, basal ganglia infarction, peripheral artery occlusion, carotid arteriosclerosis, peripheral vascular disorder, carotid artery disease, peripheral venous disease, carotid artery occlusion, renal artery arteriosclerosis, carotid artery stenosis, renal artery stenosis, carotid artery stent insertion, subclavian artery stenosis, carotid endarterectomy, thrombotic cerebral infarction, cerebral arteriosclerosis, transient ischemic attack, cerebral artery occlusion, vascular stent insertion, cerebral infarction, vascular stent stenosis, cerebrovascular accident, venous stent insertion, and computerized tomogram coronary artery abnormal. Yes641 (28.95)404 (32.69)237 (24.23)<.0001 No1573 (71.05)832 (67.31)741 (75.77)LDL-C ≥190 mg/dLcThe LDL value used is the measurement closest to enrollment, within 6 months on either side. Use of lipid-lowering medications includes any use within 6 months on either side of enrollment. Yes23 (1.04)10 (0.81)13 (1.33).0004 No1047 (47.29)630 (50.97)417 (42.64) Unknown1144 (51.67)596 (48.22)548 (56.03)Diabetes + age 40–75 y Yes1803 (81.44)1024 (82.85)779 (79.65).055 No411 (18.56)212 (17.15)199 (20.35)10-y ASCVD risk ≥7.5dASCVD risk is based on measurements closest to enrollment, within 6 months on either side. Risk score is N/A for patients who are not 40–79 years of age or have total cholesterol outside the range of 130–320 mg/dL, high-density lipoprotein outside the range of 20–100 mg/dL, or systolic blood pressure outside the range of 90–200 mm Hg. Risk score is unknown for patients with insufficient data for calculation of 10-year ASCVD risk. For patients with an out-of-range value and insufficient data, risk score is N/A. Yes536 (24.21)302 (24.43)234 (23.93)<.0001 No159 (7.18)86 (6.96)73 (7.46) N/A234 (10.57)168 (13.59)66 (6.75) Unknown1285 (58.04)680 (55.02)605 (61.86)NOTE. Values are n (%), unless otherwise indicated.ALT, alanine aminotransferase; AST, aspartate aminotransferase ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; LDL-C, low-density lipoprotein cholesterol; N/A, not available; NAFL, nonalcoholic fatty liver; NASH, nonalcoholic steatohepatitis.a P values for categorical variables are from the Cochran-Mantel-Haenszel general association test and P values for continuous variables are from the Kruskal-Wallis test.b Clinical events classified as ASCVD included acute coronary syndrome, coronary angioplasty, acute myocardial infarction, coronary arterial stent insertion, angina pectoris, coronary artery bypass, angina unstable, coronary artery disease, aortic aneurysm, coronary artery stenosis, aortic aneurysm repair, ischemic cardiomyopathy, aortic arteriosclerosis, ischemic stroke, aortic bypass, lacunar infarction, arterial bypass operation, lacunar stroke, arterial stenosis, myocardial infarction, arterial stent insertion, myocardial ischemia, arteriosclerosis, percutaneous coronary intervention, arteriosclerosis coronary artery, peripheral arterial occlusive disease, basal ganglia infarction, peripheral artery occlusion, carotid arteriosclerosis, peripheral vascular disorder, carotid artery disease, peripheral venous disease, carotid artery occlusion, renal artery arteriosclerosis, carotid artery stenosis, renal artery stenosis, carotid artery stent insertion, subclavian artery stenosis, carotid endarterectomy, thrombotic cerebral infarction, cerebral arteriosclerosis, transient ischemic attack, cerebral artery occlusion, vascular stent insertion, cerebral infarction, vascular stent stenosis, cerebrovascular accident, venous stent insertion, and computerized tomogram coronary artery abnormal.c The LDL value used is the measurement closest to enrollment, within 6 months on either side. Use of lipid-lowering medications includes any use within 6 months on either side of enrollment.d ASCVD risk is based on measurements closest to enrollment, within 6 months on either side. Risk score is N/A for patients who are not 40–79 years of age or have total cholesterol outside the range of 130–320 mg/dL, high-density lipoprotein outside the range of 20–100 mg/dL, or systolic blood pressure outside the range of 90–200 mm Hg. Risk score is unknown for patients with insufficient data for calculation of 10-year ASCVD risk. For patients with an out-of-range value and insufficient data, risk score is N/A. Open table in a new tab NOTE. Values are n (%), unless otherwise indicated. ALT, alanine aminotransferase; AST, aspartate aminotransferase ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; LDL-C, low-density lipoprotein cholesterol; N/A, not available; NAFL, nonalcoholic fatty liver; NASH, nonalcoholic steatohepatitis.