Abstract
Objectives:
Cardiovascular disease is the leading cause of mortality in patients with non-alcoholic fatty liver disease (NAFLD), and statins play a pivotal role in the primary prevention of cardiovascular events. This study investigates statin prescribing in primary care patients with NAFLD to identify opportunities to address cardiovascular disease risk in this cohort.
Study Design:
Retrospective cohort study of primary care electronic health record data from 2012-2018.
Methods:
This cohort included 652 patients with radiographic evidence of hepatic steatosis and no evidence of competing chronic liver disease. A statin prescription identified any time during the study period was the primary outcome. Univariate and multivariable analyses were performed to evaluate the association of clinical signals and comorbidities with statin prescribing.
Results:
Of the 652 patients in the NAFLD cohort, 56% received a statin prescription during the study period. Elevations in aminotransferases were not associated with statin prescribing (aOR 1.17; 95%CI 0.78-1.76), while older patients (aOR 1.06; 95%CI 1.05-1.08) and those with diabetes (aOR 2.61; 95%CI 1.73-3.92), hypertension (aOR 2.76; 95%CI 1.70-4.48), and a BMI ≥ 30 kg/m2 (aOR 1.49; 95%CI 1.01-2.22) had higher odds of having a statin prescribed. Of the 288 patients without a statin prescription, 49% had an indication for statin therapy by atherosclerotic cardiovascular disease risk. In total, 16% of included patients did not have a lipid panel result during the study period.
Conclusions:
This study showed no association between NAFLD and statin prescribing, and highlighted opportunities to improve primary prevention of cardiovascular disease in these at-risk patients.
Keywords: NAFLD, metabolic syndrome, MAFLD, metabolic associated fatty liver disease
Precis:
In this study, authors identified assessed the proportion of patients with NAFLD receiving prescriptions for statins in primary care.
Introduction
Non-alcoholic fatty liver disease (NAFLD) affects more than 30% of the United States population, and its prevalence is anticipated to grow in the coming years.1–3 NAFLD is a major contributor to the growing burden of chronic liver disease (CLD) nationally, and has emerged as a leading cause of cirrhosis, hepatocellular carcinoma, need for liver transplantation, and liver-related mortality.4–7 Despite NAFLD’s immense contribution to severe liver outcomes, the leading cause of death among affected patients is cardiovascular disease (CVD).8,9 NAFLD is associated with other known cardiovascular risk factors including metabolic syndrome, type 2 diabetes (DM), obesity, and hyperlipidemia, which may contribute to the relationship observed with CVD.10–13 However, a recent meta-analysis demonstrated an independent association between NAFLD and CVD risk (HR 1.45; 95% CI 1.31-1.61) when controlling for these aforementioned CVD risk factors.9 It is not well understood how NAFLD may be related to CVD, but it has been suggested that low-grade inflammation and oxidative stress may play a role.14–16
Statin therapy has become standard of care for primary and secondary prevention of cardiovascular events such as stroke and myocardial infarction. Statins are currently indicated in those with elevated CVD risk defined by the presence of diabetes, obesity, hypertension, and hyperlipidemia.17 Despite the link between NAFLD and these drivers of CVD risk, a diagnosis of NAFLD is not yet an indication for statin prescribing. Thus, patients with NAFLD may not receive statin prescriptions despite risk for CVD being heightened.18,19 Additionally, NAFLD is among the leading causes of elevated aminotransferases in primary care. Many patients with aminotransferase abnormalities have not historically received statin prescriptions due to the potential for hepatotoxicity, a safety concern that was allayed with a U.S. Food and Drug Administration safety announcement in 2012.20–22 Multiple studies have continued to verify the safety of statins in patients with aminotransferase abnormalities, and some even demonstrate a decrease in aminotransferases in treated patients.23–25
Our goal was to investigate statin prescribing in primary care patients with NAFLD to determine if and how cardiovascular disease risk is being addressed in this cohort of at-risk patients. We hypothesized that statins would be underutilized in NAFLD patients, especially in those with abnormal aminotransferases.
Methods
This retrospective cohort study of electronic health record (EHR) data from a patient-centered medical home (PCMH) evaluated statin prescribing for primary care patients with presumed NAFLD, identified by radiographic report of hepatic steatosis and the absence of competing liver diseases.26 This primary care, internal medicine PCMH delivers highly coordinated, team-based care to over 12,000 patients and includes physicians, nurses, case managers, and pharmacists in an urban setting.
Study Population
Patients seen in the Internal Medicine PCMH at this institution with at least one abdominal image (ultrasound [US], computed tomography [CT], or magnetic resonance imaging [MRI]) from 2012 through 2018 with evidence of hepatic steatosis were evaluated. Cohort inclusion required aminotransferase and platelet lab results at the time of, or within the 1 year prior to the first abdominal imaging report with steatosis. Patients with a diagnosis, laboratory result, or exposure history (i.e. alcohol use documentation) suggestive of a non-NAFLD chronic liver disease or severe liver disease outcome (e.g. cirrhosis, hepatocellular carcinoma) were excluded (Supplement).26 The Institutional Review Board at this institution approved this study.
Outcome
Statin prescription recorded by the EHR on at least one occasion during the study period was the primary outcome of interest. The PCMH EHR electronic order entry feature was implemented across the institution enterprise in 2012. EHR prescription data included both printed and electronically transmitted scripts and incorporated data from the outpatient, emergency department (ED), and inpatient settings at this institution. Inpatient and ED prescriptions comprised those printed or transmitted to pharmacies, and did not include statins provided during hospital or ED care episodes.
Covariates
Based upon our hypothesis, aminotransferase abnormality served as the primary predictor variable. Aspartate (AST) and alanine (ALT) aminotransferase results occurred within 1 year preceding the image of hepatic steatosis. AST and ALT were categorized as elevated (AST>34 U/L and ALT>45 U/L) using the upper limit of normal thresholds within the institution EHR in an effort to model the aminotransferase signal most likely used by primary care clinicians. AST and ALT were also analyzed as continuous variables.
Age, sex (male/female), body mass index (BMI), and race (Black, non-Black) variables were included. Laboratory variables within the EHR from 2011-2018 (to allow 1 year prior to steatosis for aminotransferases) comprised bilirubin (Bili), alkaline phosphatase (ALP), platelets, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides. All laboratory variables were analyzed as continuous variables, and BMI was categorized as BMI < 30 kg/m2 and BMI ≥ 30 kg/m2. Cholesterol levels came from the first lipid (LDL, HDL, and triglyceride) values identified during the study period and the proportion of patients with lipid results were calculated.
Clinical indications for statin prescribing and other comorbidities were identified using composites of International Classification of Diseases (ICD)-9 and 10 codes from Elixhauser coding algorithms.27,28 Comorbidities included cardiovascular disease (coronary artery disease and cerebrovascular disease), diabetes mellitus, and hypertension. We also included known diagnosis of NAFLD (ICD-9: 571.8; ICD-10: K76.0, K75.8) as a covariate.29 NAFLD severity was estimated using non-invasive advanced fibrosis risk scores. We calculated Fibrosis-4 Index (FIB-4) and NAFLD Fibrosis Scores (NFS) for each patient using the included covariates, and categorized them as high-risk (FIB ≥ 2.67, NFS ≥ 0.676) or not based on each score.30–32 The 2013 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline on Assessment of Cardiovascular Risk was utilized to determine indication for statin use in our cohort patients with no statin prescription.33 This was calculated using the most recent lipid values in the study period. We were unable to calculate atherosclerotic cardiovascular disease (ASCVD) risk for those without lipid panels, and we categorized these patients as without an indication for statin therapy. Patient characteristics were compared by statin indication.
Statistical Analysis
Cohort characteristics were calculated for the overall sample and by aminotransferase elevation. Categorical variables were displayed as proportions and compared by Chi square tests. Continuous variables (except for age) were presented as medians with interquartile ranges (IQR) and compared by Mann Whitney U tests. Age is shown as a mean with standard deviation and compared using a two-sample t-test. The proportion of cohort patients with a prescription for a statin was calculated, and covariates were compared by statin prescription. Logistic regression models for the outcome of a statin prescription were developed. The first model included the primary predictor variable of AST or ALT elevation and comorbidities, many of which play a role in determining an indication for statin therapy: cardiovascular disease, diabetes, and hypertension. A known diagnosis of NAFLD was also included as a categorical covariate. The second model included all covariates from the first model plus age, sex, race, BMI, and FIB-4/NFS risk status. Model covariates were selected a priori. Multicollinearity was assessed. Model 2 initially included bilirubin, alkaline phosphatase and platelets, but these were removed with little change to model fit. Sensitivity analyses were performed using elevated AST and ALT, elevated AST, and elevated ALT as predictor variables. A sensitivity analysis with AST and ALT as continuous predictor variables was also performed. SAS 9.4 (Cary, NC) was used for all analyses.
Results
The primary care NAFLD cohort included 652 patients with a mean age of 55 (SD±14) years, a median BMI of 32.4 kg/m2 (IQR: 27.7, 37.6), median AST of 26 U/L (IQR: 20, 39), and median ALT of 28 (IQR: 19,49) [Table 1]. Of the cohort, 64% were female, 36% were black, and 24%, 46%, and 78% had cardiovascular disease, diabetes, and hypertension, respectively. Serologic advanced fibrosis scores were “high-risk” in 12% (FIB-4) and 18% (NFS) of subjects. One in four patients received a formal diagnosis of NAFLD. 16% of patients did not have lipid results during the study period.
Table 1.
Cohort characteristics overall and by aminotransferase abnormality.
| Elevated AST or ALT | ||||
|---|---|---|---|---|
| Overall | Yes | No | p-value | |
| n=652 | n=245 | n=407 | ||
| Demographics | ||||
| Age, Mean, years (SD) | 54.7 (± 14.1) | 52.5 (± 14.1) | 56.0 (± 13.9) | 0.002a |
| Sex % (n) | 0.004b | |||
| Male | 35.9% (234) | 42.9% (105) | 31.7% (129) | |
| Female | 64.1% (418) | 57.1% (140) | 68.3% (278) | |
| Race % (n) | 0.012b | |||
| Black | 35.9% (234) | 29.8% (73) | 39.6% (161) | |
| Non-Black | 64.1% (418) | 70.2% (172) | 60.4% (246) | |
| Clinical Variables, Median (IQR) | ||||
| BMI, kg/m2 | 32.4 (27.7, 37.6) | 31.6 (27.3, 37.1) | 32.7 (27.8, 38.5) | 0.096c |
| Bili, mg/dL | 0.5 (0.4, 0.8) | 0.6 (0.4, 0.95) | 0.5 (0.4, 0.7) | <0.001c |
| AST, U/L | 26 (20, 39) | 48 (36, 74) | 22 (18, 26) | <0.001c |
| ALT, U/L | 28 (19, 49) | 60 (46, 86) | 22 (17, 28) | <0.001c |
| ALP, U/L | 82 (66, 105) | 89 (68, 122) | 79 (64, 98) | <0.001c |
| Platelets, x109/L | 241 (200, 293) | 233 (185, 290) | 246 (207, 294) | 0.058c |
| Lipid Variables | ||||
| Lipid results % (n) | 86.4% (563) | 85.3% (209) | 87.0% (354) | 0.547b |
| LDL, Median (IQR) | 100 (77, 127) | 102 (78, 132) | 99 (76, 125) | 0.231c |
| HDL, Median (IQR) | 44 (37, 55) | 45 (37, 56) | 44 (37, 54) | 0.599c |
| Triglycerides, Median (IQR) | 135 (92, 203) | 135.5 (90, 213) | 135 (93, 197) | 0.839c |
| Comorbidities % (n) | ||||
| NAFLD (diagnosed) | 25.2% (164) | 33.9% (83) | 19.9% (81) | <0.001b |
| Cardiovascular disease | 23.5% (153) | 22.5% (55) | 24.1% (98) | 0.634b |
| Diabetes | 46.0% (300) | 42.0% (103) | 48.4% (197) | 0.114b |
| Hypertension | 77.8% (507) | 77.1% (189) | 78.1% (318) | 0.769b |
| High-risk Advanced Fibrosis Assessments | ||||
| FIB-4 (≥ 2.67) | 11.5% (75) | 24.1% (59) | 3.9% (16) | <0.001b |
| NFS (≥ 0.676) | 17.9% (117) | 18.8% (46) | 17.4% (71) | 0.668b |
Two sample Student t-test.
Chi square test.
Mann-Whitney U test.
AST=aspartate aminotransferase. ALT=alanine aminotransferase. SD=standard deviation. IQR=interquartile range. BMI=body mass index. Bili=bilirubin. ALP=alkaline phosphatase. NAFLD=nonalcoholic fatty liver disease. FIB-4=Fibrosis-4 Index. NFS=NAFLD Fibrosis Score.
Elevated AST or ALT values were identified in 38% (245) of the patient sample. Higher proportions of patients with elevated aminotransferases were younger, male, non-Black, and diagnosed with NAFLD compared to those with AST and ALT results in the normal range (Table 1).
Overall, 56% of patients received a prescription for statin therapy. A similar proportion of patients receiving statin prescriptions had AST and ALT abnormalities, and similar AST and ALT values compared to patients not receiving a statin prescription (Table 2). Subjects with a statin ordered were older, had higher BMIs (33.2 vs. 31.5, p=0.025), and had higher proportions of cardiovascular disease (30% vs. 16%, p<0.001), diabetes (59% vs. 30%, p<0.001), and hypertension (90% vs. 62%, p<0.001) than patients without statins prescribed. The proportion of patients with an ICD diagnosis of NAFLD did not differ by statin prescription. The proportion of patients with high-risk FIB-4 scores were similar by statin group, and a higher proportion of patients prescribed a statin had a high-risk NFS compared to those subjects not receiving a statin.
Table 2.
Patient characteristics by statin prescription.
| Statin Rx | |||
|---|---|---|---|
| Yes | No | p-value | |
| n=364 | n=288 | ||
| Aminotransferase Variables | |||
| Elevated AST or ALT | 36.0% (131) | 39.6% (114) | 0.347a |
| Elevated AST | 32.1% (117) | 31.6% (91) | 0.882a |
| Elevated ALT | 26.9% (98) | 30.9% (89) | 0.265a |
| AST, Median (IQR) | 26 (20, 40) | 26.3 (20, 39) | 0.748b |
| ALT, Median (IQR) | 28 (19, 47.5) | 29.8 (20, 49) | 0.498b |
| Demographics | |||
| Age, Mean, years (SD) | 59.5 (± 11.8) | 48.6 (± 14.5) | <0.001c |
| Sex % (n) | 0.575a | ||
| Male | 35.1% (146) | 37.3% (88) | |
| Female | 64.9% (270) | 62.7% (148) | |
| Race % (n) | 0.191a | ||
| Black | 37.7% (157) | 32.6% (77) | |
| Non-Black | 62.3% (259) | 67.4% (159) | |
| Clinical Variables, Median (IQR) | |||
| BMI, kg/m2 | 33.2 (28.6, 37.6) | 31.5 (26.9, 37.6) | 0.025b |
| Bili, mg/dL | 0.5 (0.4, 0.8) | 0.6 (0.4, 0.9) | 0.331b |
| ALP, IU/L | 82 (65.5, 102) | 82.5 (66, 106.5) | 0.688b |
| Platelets, x109/L | 237.5 (200, 289.5) | 245 (203.5, 304) | 0.253b |
| Comorbidities % (n) | |||
| NAFLD, diagnosed | 26.9% (98) | 22.9% (66) | 0.242a |
| Cardiovascular disease (CVD) | 29.7% (108) | 15.6% (45) | <0.001a |
| Diabetes (DM) | 58.8% (214) | 29.9% (86) | <0.001a |
| Hypertension (HTN) | 90.4% (329) | 61.8% (178) | <0.001a |
| Hyperlipidemia (HPL) | 97.0% (353) | 30.9% (89) | <0.001a |
| NAFLD +DM+HTN+HPL | 17.3% (63) | 2.8% (8) | <0.001a |
| 3 of NAFLD /DM/HTN/HPL | 45.9% (167) | 14.6% (42) | <0.001a |
| 2 of NAFLD /DM/HTN/HPL | 70.3% (256) | 71.9% (207) | 0.666 |
| NAFLD only | 0.0% (0) | 5.2% (15) | <0.001a |
| No NAFLD/DM/HTN/HPL | 0.3% (1) | 20.1% (58) | <0.001a |
| High-risk Advanced Fibrosis Assessments | |||
| FIB-4 (≥ 2.67) | 12.4% (45) | 10.4% (30) | 0.439a |
| NFS (≥ 0.676) | 21.4% (78) | 13.5% (39) | 0.009a |
| Lipid Variables | |||
| Lipid results | 97.3% (354) | 72.6% (209) | <0.001a |
| LDL, Median (IQR) | 99 (75, 130) | 102 (79, 125) | 0.998b |
| HDL, Median (IQR) | 43 (37, 54) | 46 (37, 56) | 0.289b |
| Triglycerides, Median (IQR) | 140 (97, 212) | 133 (88, 194) | 0.203b |
Chi square test.
Mann-Whitney U test.
Two sample Student t test.
Rx=prescription. AST=aspartate aminotransferase. ALT=alanine aminotransferase. SD=standard deviation. IQR=interquartile range. BMI=body mass index. Bili=bilirubin. ALP=alkaline phosphatase. NAFLD=nonalcoholic fatty liver disease. FIB-4=Fibrosis-4 Index. NFS=NAFLD Fibrosis Score.
Subjects with multiple components of metabolic syndrome, including hypertension, diabetes, hyperlipidemia, and NAFLD had higher proportions of patients receiving statin therapies compared to those with only a single component (Table 2). Of the 15 patients with NAFLD and no diagnosis of hypertension, diabetes or hyperlipidemia, zero had a statin prescribed (p<0.001, Table 2).
The first logistic regression model (Model 1) demonstrated no significant association between elevated AST or ALT values with a statin prescription outcome (aOR 0.88; 95% CI 0.62 - 1.25 [Table 3]) when adjusting for medical comorbidities. Cardiovascular disease (aOR 1.52; 95% CI 1.00 - 2.32), diabetes (aOR 2.29; 95% CI 1.61 - 3.26), and hypertension (aOR 4.20; 95% CI 2.71 - 6.53) were associated with higher odds of receiving a statin prescription. No significant association was observed between diagnosed NAFLD (aOR 1.18; 95% CI 0.79 - 1.75) and the statin outcome.
Table 3.
Estimated odds ratios for multivariable logistic regression models for the outcome of receiving a statin prescription.
| Model 1 | Model 2a | |||
|---|---|---|---|---|
| OR | 95% CI | OR | 95% CI | |
| Aminotransferase Variable | ||||
| Elevated AST or ALT | 0.88 | 0.62 - 1.25 | 1.17 | 0.78 - 1.76 |
| Comorbidities | ||||
| NAFLD, diagnosed | 1.18 | 0.79 - 1.75 | 1.29 | 0.84 - 1.98 |
| Cardiovascular disease | 1.52 | 1.00 - 2.32 | 1.72 | 1.09 - 2.71 |
| Diabetes | 2.29 | 1.61 - 3.26 | 2.61 | 1.73 - 3.92 |
| Hypertension | 4.20 | 2.71 - 6.53 | 2.76 | 1.70 - 4.48 |
| Demographics | ||||
| Age, years | 1.06 | 1.05 - 1.08 | ||
| Male (Female ref.) | 0.77 | 0.52 - 1.13 | ||
| Black (non-Black ref.) | 1.04 | 0.68 - 1.58 | ||
| Clinical Variables | ||||
| BMI ≥ 30 kg/m2 | 1.49 | 1.01 - 2.22 | ||
| High-risk Advanced Fibrosis Assessments | ||||
| FIB-4 (≥ 2.67) | 0.87 | 0.45 - 1.68 | ||
| NFS (≥ 0.676) | 0.59 | 0.34 - 1.04 | ||
Bilirubin, alkaline phosphatase, and plaletet count were originally included in the model, but were not significant and removal did not impact overall model fit (c=0.794). Sensitivity analyses with: elevated AST and ALT, elevated AST, elevated ALT, AST (continuous), and ALT (continuous) were performed with no significant change in results.
OR=odds ratio. CI=confidence interval. AST=aspartate aminotransferase. ALT=alanine aminotransferase. FIB-4=Fibrosis-4 Index. NFS=NAFLD Fibrosis Score.
Model 2 incorporated demographic, clinical, and high-risk fibrosis assessment variables (Table 3). Again, AST or ALT elevations were not significantly associated with statin prescribing (aOR 1.17; 95% CI 0.78 - 1.76). Cardiovascular disease (aOR 1.72; 95% CI 1.09 - 2.71), diabetes (aOR 2.61; 95% CI 1.73 - 3.92), hypertension (aOR 2.76; 95% CI 1.70 - 4.48), advancing age (aOR 1.06; 95% CI 1.05 - 1.08), and BMI ≥ 30 kg/m2 (aOR 1.49; 95% CI 1.02 - 2.22) were associated with higher odds of receiving a statin. Diagnoses of NAFLD (aOR 1.29; 95% CI 0.84 - 1.98) and high-risk fibrosis assessments (FIB-4 aOR 0.87; 95% CI 0.45 - 1.68; NFS aOR 0.59; 95% CI 0.34 - 1.04) were not significantly associated with statin prescription outcomes.
Of the 288 patients with no statin prescription, 49% (141) had an indication for a statin using the ASCVD risk calculator and patients’ most recent lipid inputs (Table 4). There was no difference in the proportion of patients with a NAFLD diagnosis by statin indication (24.1% vs 21.8%, p=0.636). Higher proportions of patients with an indication for statin therapy had diabetes (50.4% vs 10.2%, p<0.001), hypertension (77.3% vs 46.9%, p<0.001), and hyperlipidemia (41.8% vs 20.4%, p<0.001) compared to subjects without an ASCVD risk indication.
Table 4.
Cohort patients without a statin prescription by atherosclerotic cardiovascular disease (ASCVD) risk indication for statin therapy.
| ASCVD risk indication | ||||
|---|---|---|---|---|
| Overall | Yes | No | p-value | |
| n=288 | n=141 | n=147 | ||
| Demographics | ||||
| Age, Mean, years (SD) | 48.6 (± 14.5) | 53.6 (± 14.2) | 43.9 (± 13.0) | <0.001a |
| Sex % (n) | 0.048b | |||
| Male | 39.6% (114) | 45.4% (64) | 34.0% (50) | |
| Female | 60.4% (174) | 54.6% (77) | 66.0% (97) | |
| Race % (n) | 0.260b | |||
| Black | 32.3% (93) | 35.5% (50) | 29.3% (43) | |
| Non-Black | 67.7% (195) | 64.5% (91) | 70.8% (104) | |
| Clinical Variables | ||||
| BMI ≥ 30 kg/m2 | 56.3% (162) | 53.9% (76) | 58.5% (86) | 0.431b |
| Comorbidities % (n) | ||||
| NAFLD (diagnosed) | 22.9% (66) | 24.1% (34) | 21.8% (32) | 0.636b |
| Diabetes | 29.9% (86) | 50.4% (71) | 10.2% (15) | <0.001b |
| Hypertension | 61.8% (178) | 77.3% (109) | 46.9% (69) | <0.001b |
| Hyperlipidemia | 30.9% (89) | 41.8% (59) | 20.4% (30) | <0.001b |
Two sample Student t test.
Chi square test. ASCVD=atherosclerotic cardiovascular disease, as calculated by 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk.
SD=standard deviation. =body mass index. NAFLD=nonalcoholic fatty liver disease.
Discussion:
Overall, 56% of this primary care NAFLD cohort received a prescription for a statin during the study period, but statin prescribing did not differ by aminotransferase abnormalities or NAFLD diagnosis. Contrarily, statin prescribing was more prevalent in patients with diabetes and hypertension. While we do not fully understand NAFLD’s association with cardiovascular disease, numerous studies have demonstrated an association between the two and therefore many patients with NAFLD would surely benefit from statin therapy, if not based on a diagnosis of NAFLD alone then perhaps due to their other comorbidities.14,23,34
Our data also shows that 16% of patients included in this study had no lipid panel completed throughout the study period (2012-2018). The association between NAFLD and metabolic syndrome has now been shown in numerous studies, and therefore investigating lipids in patients with NAFLD is warranted. No national guideline or recommendation to treat isolated NAFLD with statin therapy for primary or secondary prevention existed during the study period, nor does one currently exist. The results of this study demonstrate an opportunity for providers to address cardiovascular disease risk by acquiring lipid panels and calculating ASCVD risk scores in patients with NAFLD.
Many barriers exist to increasing statin prescriptions in those with NAFLD. One of the most significant barriers is that many patients in the early stages of NAFLD are asymptomatic, resulting in significant underdiagnosis.35 It is also possible that many providers are unaware that CVD is the leading cause of mortality in NAFLD patients, and thus we do not always make the association between NAFLD and risk of CVD events. Statins are regularly used in primary and secondary prevention of cardiovascular disease, and are routinely initiated based on 10-year atherosclerotic cardiovascular disease (ASCVD) risk scoring over a certain threshold. Our data demonstrated that 49% of subjects without statin prescriptions had an indication for statin therapy based on the 2013 ASCVD risk ACC/AHA Guidelines, identifying a significant gap in cardiovascular risk reduction in NAFLD cohort patients. Additionally, a portion of those classified as “No ASCVD risk indication” for statin therapy were categorized this way due to an absence of lipid panel results, which likely results in a conservative underestimation of the scale of unmet care need in this patient sample. The ASCVD scoring system currently accounts for diabetes, sex, smoking history, hyperlipidemia and hypertension diagnoses. The U.S. Preventive Services Task Force recommends statins for primary prevention in those aged 40-75 years with one or more CVD risk factors, and a calculated 10-year risk of cardiovascular events 10% or higher. The CVD risk factors listed in the USPSTF recommendation include dyslipidemia, diabetes, hypertension or smoking.11,36 In this study, NAFLD was not associated with ASCVD risk indication. Neither the USPSTF nor ASCVD risk scoring directly account for a NAFLD diagnosis as a CVD risk factor, though other diagnoses such as dyslipidemia, hypertension and diabetes are included. This could certainly explain why diabetes and hypertension had statistically significant associations with statin prescribing throughout our study whereas NAFLD did not have any association at all. As providers, we do not typically consider risk factors outside of what is recommended in the current guidelines, and thus NAFLD is not routinely accounted for in these situations.
We had also hypothesized that abnormal LFTs may play a role in preventing statin prescribing in those with NAFLD given the historically well-known hepatotoxicity of statins, as many NAFLD patients present with abnormal aminotransferases. Contrarily, our data showed that proportions of patients with abnormal aminotransferases (36% vs. 40%, p=0.35) were similar in patients with and without statin prescriptions, suggesting LFT abnormalities did not heavily influence prescription practices. Other studies have shown that in recent years, statin use has increased among those with liver disease (NAFLD included) and abnormal aminotransferases. Unfortunately, statins are still heavily underutilized overall, especially in primary prevention.19
Limitations
We recognize limitations in this study. Data was extracted from a single center which may threaten the generalizability of the findings. However, the primary care focus and the characteristics of the cohort are representative of many primary care practices in the U.S. Additionally, no causation can be elicited from this retrospective cohort study. Our study could only include those patients with abdominal imaging results, which likely excluded many other NAFLD patients in this primary care setting. We were unable to see when the statin prescriptions were started, and the cohort did not include those with multiple liver disease etiologies.
Conclusions:
Our study demonstrates that NAFLD does not have a statistically significant association with statin prescriptions in this patient-centered medical home. Alternatively, other diagnoses such as hypertension and diabetes are associated with higher proportions of statin prescribing. Cardiovascular events are the leading cause of death in those with NAFLD, and the beneficial effects of statins in cardiovascular disease are well-established. Evidence points towards the opinion that the majority of patients with NAFLD would also benefit from statin therapy as primary prevention of CVD. This study presents an opportunity to improve primary prevention in this population at risk for CVD, though further studies are indicated to determine the best way of doing so. It is imperative to shift our practices toward focusing on reducing cardiovascular risk in these patients, including increasing statin utilization in this growing population.
Supplementary Material
Grant Support:
National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK K23DK118200 PI: Schreiner). This project is also supported in part by the SSCI Research Scholar Award (PI: Schreiner). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Southern Society for Clinical Investigation (SSCI). This project was also supported by the South Carolina Clinical & Translational Research Institute with an academic home at the Medical University of South Carolina CTSA National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) under UL1 TR001450.
Footnotes
Conflicts of Interest: All authors report no conflicts of interest with this work.
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