Patients with gout are at a higher risk of cardiovascular disease, which is associated with hyperlipidemia. Management of gout in Taiwan is poor, and the association between urate-lowering therapy (ULT) among gout patients and hyperlipidemia is unclear. We conducted a retrospective cohort study using data from the Longitudinal Health Insurance Database (LHID) of Taiwan on new-onset gout patients and a comparison cohort without gout. A Cox proportional hazards model was used to analyze differences in the risk of hyperlipidemia between patients with and without gout after considering related comorbidities. We also examined the ULT medications on the hepatic expression of lipogenesis-related genes. After adjusting for potential confounders, the case group (44,413 patients) was found to have a higher risk of hyperlipidemia than the control cohort (177,652 patients) [adjusted hazards ratio
Gout is a common form of severe, inflammatory arthritis in adults, especially in males [
Gout-related comorbidities and their treatment may have an effect on the development of gout and on the choice of therapeutic agents for gout. Drugs used to treat acute attacks of gout-related pain and prevent future pain attacks include nonsteroidal anti-inflammatory drugs (NSAIDs), consisting of over-the-counter options for an acute attack; colchicine for an acute attack or prescribed at a low daily dose to prevent future attacks; and corticosteroids to control gout inflammation and pain for patients who cannot take NSAIDs or colchicine [
A meta-analysis revealed that gout was associated with an increased risk of myocardial infarction (MI) [relative risk (RR) 1.45; 95% confidence interval (CI), 1.19–1.75] in both men and women [
Several clinical reports have shown that hypercholesterolemia and hypertriglyceridemia are associated with an increased risk of gout [
A high LDL-C level is a strong risk factor for CVD, and hence, determining its risk factors is clinically relevant as it is an important therapeutic target for preventing CVD [
Liver X receptors (LXRs) are members of a nuclear receptor superfamily that function as ligand-activated transcription factors. There are two isoforms of LXRs, LXR
As the relationship between gout and hyperlipidemia is not fully elucidated in Asian populations and the Nutrition and Health Survey in Taiwan reported prevalence of gout in 8.2% of men and 2.3% of women in Taiwan from 2005 to 2008 [
The NHIRD was established in 1995 by the National Health Insurance Administration, Ministry of Health and Welfare, and consists of comprehensive information covering more than 99% insured persons who reside in Taiwan; it is also known as the Longitudinal Health Insurance Database (LHID). Between March 1995 and the end of 2013, the LHID included registration files and claim data on demographics, dates of clinical visits, and details of disease diagnoses and medical procedures for approximately 28.75 million (living and deceased) beneficiaries registered in the database. Upon request, the National Health Research Institute (the data holder of NHIRD) randomly selected a sample comprising one million individuals with a diagnosis of gout from NHIRD for use in this cohort study. This sample contained all original claim data of outpatient departments, emergency departments, and hospitalization.
Denominator data were based on the Registry of Beneficiaries, a part of NHIRD with records of the demographics, insurance status, residence, and socioeconomic data of all beneficiaries. However, ethnicity data were not available. The data were anonymized and deidentified prior to analysis; therefore, the need for patient consent was waived. Diagnostic codes were defined based on the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes. The Research Ethics Committee of China Medical University Hospital in Taiwan approved the study (CMUH-104-REC2-115-R3).
The date of diagnosis of gout was taken as the index date, and a total of 44,413 patients, who were diagnosed with gout (ICD-9-CM: 274) more than once in outpatient visits or at least once in inpatient visits and who were without hyperlipidemia (ICD-9-CM: 272) before the index date, between January 1, 2000, and December 31, 2013, were identified as the case cohort. Each case was randomly matched with 4 patients without gout during the same study period, and a total of 177,652 patients were recognized as the comparison cohort. Matching variables included sex, age, and index date, and we adopted two study cohorts by frequency matching on age with every 5-year span; hence, the index date of each sample in the comparison cohort was identical to the index date of the corresponding case. The end date of the follow-up period was the date on which hyperlipidemia occurred in patients; patients died or withdrew from NHIRD, or December 31, 2013, whichever was earlier.
The covariates of comorbidity comprised hypertension (ICD-9-CM: 401 to 405), stroke (ICD-9-CM: 430 to 438), diabetes mellitus (ICD-9-CM: 250), chronic obstructive pulmonary disease (COPD) (ICD-9-CM: 491, 492, and 496), coronary artery disease (CAD) (ICD-9-CM: 410 to 414), alcohol-related illness (ICD-9-CM: 291, 303, 305, 571.0, 571.1, 571.2, 571.3, 790.3, and V11.3), and asthma (ICD-9-CM: 493). Patients diagnosed with any of these comorbidities more than once in outpatient visits or at least once in inpatient visits before the index date were included in the study. Antigout treatments were determined by their Anatomical Therapeutic Chemical classification codes. The medications included in the analysis that available in Taiwan were allopurinol, febuxostat, benzbromarone, sulfinpyrazone, probenecid, and colchicine.
All chemicals were purchased from Sigma-Aldrich (St. Louis, Missouri, USA) and were of the highest-purity grade available. Chemicals were dissolved in dimethyl sulfoxide (DMSO) at appropriate concentrations before use. Human hepatoma HepaRG™ cells were purchased from Thermo Fisher Scientific (Waltham, Massachusetts, USA). Frozen cells were thawed and maintained in Williams’ E medium (Sigma-Aldrich, St. Louis, Missouri, USA) supplemented with 10% FetalClone™ II serum (Hyclone™, GE Healthcare, Chicago, Illinois, USA),
To evaluate the effects of ULT (allopurinol, febuxostat, benzbromarone, sulfinpyrazone, probenecid, and colchicine) on hepatic lipogenesis-related gene expression, mRNA levels were measured. Total RNA was extracted from differentiated HepaRG under various treatment conditions using a Direct-zol™ RNA MiniPrep kit (ZYMO Research, Irvine, CA, USA) by following the manufacturer’s protocol. The quantity and purity of RNA were confirmed by calculating the ratio of the absorbance at 260 nm to absorbance at 280 nm. Total RNA (1
Sequences of PCR primers.
Gene | Species | Forward primer (5 | Reverse primer (5 |
---|---|---|---|
Human | CGC TCC TCC ATC AAT GAC AA | TGC AGA AAG CGA ATG TAG TCG AT | |
Human | CCG ACG TGG CTT TTT CTT CT | GCG TAC TCC CCT TCT CTT TGA C | |
Human | ACA TCA TCG CTG GTG GTC TG | GGA GCG AGA AGT CAA CAC GA | |
Human | TTC CGA GTC TCC CGG AAG T | ACA GCC CAT CAG CAT CTG AGT | |
Human | GTG TGG ACG TGG GTG ATG TG | TTG ATG TCC TCA GGA TTC AGT TTC | |
Human | CTC TTG ACC CTG GCT GTG TAC TAG | TGA GTG CCG TGC TCT GGA T | |
Human | CGA TC GAG GTG ATG CTT CTG | GGC AAA GTC TTC CCG GTT AT | |
Human | CCT GGC ACC CAG CAC AAT | GCC GAT CCA CAC GGA GTA CT |
For intercohort comparisons, Student’s
Subanalyses stratified by sex, age group, comorbidity, and antigout group were also performed to assess the association of gout with the subsequent risk of hyperlipidemia. Two-sided significance levels of all tests were set at 0.05. All data were analyzed using SAS 9.4 software (SAS Institute Inc., Cary, NC, USA), and cumulative incidence curves were plotted using R software (R version 3.5.3, GNU package).
For
In this study, approximately 22.5% of patients were female, and the remaining were male. Among patients with or without gout, 57.6%, 24.1%, and 18.3% of patients were in the ≤49-, 50–64-, and ≥65-year-old age groups, respectively. The average age in the case cohort was
Demographic characteristics, comorbidities, and medication in patients with and without gout.
Variable | Gout | ||
---|---|---|---|
No | Yes | ||
Sex | 0.99 | ||
Female | 39952 (22.5) | 9988 (22.5) | |
Male | 137700 (77.5) | 34425 (77.5) | |
Age, mean (SD)# | 47.3 (17.1) | 47.9 (16.9) | <0.001 |
Stratified age | 0.99 | ||
≤49 | 102312 (57.6) | 25578 (57.6) | |
50-64 | 42884 (24.1) | 10721 (24.1) | |
65+ | 32456 (18.3) | 8114 (18.3) | |
Comorbidity | |||
Hypertension | 19455 (11.0) | 6396 (14.4) | <0.001 |
Stroke | 6654 (3.75) | 2063 (4.65) | <0.001 |
Diabetes | 4786 (2.69) | 1674 (3.77) | <0.001 |
COPD | 8137 (4.58) | 2507 (5.64) | <0.001 |
CAD | 7870 (4.43) | 2839 (6.39) | <0.001 |
Alcohol-related illness | 7922 (4.46) | 2728 (6.14) | <0.001 |
Asthma | 5049 (2.84) | 1723 (3.88) | <0.001 |
Medication | |||
Allopurinol | 6346 (14.3) | ||
Febuxostat | 93 (0.21) | ||
Benzbromarone | 19286 (43.4) | ||
Sulfinpyrazone | 1275 (2.87) | ||
Probenecid | 226 (0.51) | ||
Colchicine | 22482 (50.6) |
Chi-square test. #Student’s
The Kaplan-Meier curves are shown in Figure
Comparison of cumulative incidence of hyperlipidemia between patients, with and without gout, using the Kaplan-Meier method. Comparison cohort mean follow-up
Table
Comparison of incidence and hazard ratio of hyperlipidemia stratified by sex, age, and comorbidity between patients with and without gout.
Variable | Gout | Crude HR (95% CI) | Adjusted HR† (95% CI) | |||||
---|---|---|---|---|---|---|---|---|
No | Yes | |||||||
Event | PY | Rate# | Event | PY | Rate# | |||
All | 24485 | 1378799 | 17.8 | 13639 | 293172 | 46.5 | 2.61 (2.55, 2.66) | 2.55 (2.50, 2.61) |
Sex | ||||||||
Female | 7080 | 282065 | 25.1 | 3217 | 59166 | 54.4 | 2.14 (2.06, 2.23) | 2.15 (2.06, 2.24) |
Male | 17405 | 1096734 | 15.9 | 10422 | 234006 | 44.5 | 2.80 (2.73, 2.87) | 2.70 (2.64, 2.77) |
Stratified age | ||||||||
≤49 | 10087 | 850974 | 11.9 | 7382 | 191709 | 40.6 | 3.44 (3.34, 3.55) | 3.08 (2.99, 3.18) |
50-64 | 9290 | 312176 | 29.8 | 4160 | 63233 | 65.8 | 2.19 (2.11, 2.27) | 2.18 (2.10, 2.26) |
65+ | 5108 | 215649 | 23.7 | 2097 | 48229 | 43.5 | 1.82 (1.73, 1.91) | 1.88 (1.79, 1.98) |
Comorbidity‡ | ||||||||
No | 13645 | 1003452 | 13.6 | 10840 | 375347 | 28.9 | 3.40 (3.31, 3.49) | 3.37 (3.28, 3.46) |
Yes | 8639 | 181008 | 47.7 | 5000 | 112164 | 44.6 | 1.57 (1.52, 1.62) | 1.54 (1.49, 1.60) |
PY: person-years; Rate#: incidence rate, per 1,000 person-years; Crude HR: crude hazard ratio; Adjusted HR†: multivariable analysis including age, sex, and comorbidities of hypertension, stroke, diabetes, COPD, CAD, alcohol-related illness, and asthma; Comorbidity‡: patients with any one of the comorbidities of hypertension, stroke, diabetes, COPD, CAD, alcohol-related illness, and asthma were classified as the comorbidity group.
Table
Incidence, crude, and adjusted hazard ratio of hyperlipidemia compared among gout patients with or without antigout treatment and compared between gout patients without antigout treatment and nongout patients.
Variables | Event | PY | Rate# | Crude HR (95% CI) | Adjusted HR† (95% CI) | Adjusted HR† (95% CI) | |
---|---|---|---|---|---|---|---|
Nongout | 177652 | 24485 | 1378799 | 17.8 | 1 | 1 | |
Gout without the selected antigout treatment | 12617 | 4279 | 73332 | 58.4 | 3.26 (3.15, 3.36) | 3.10 (3.00, 3.20) | 1 |
Gout with antigout treatment | |||||||
Febuxostat | 93 | 2 | 860 | 2.33 | 0.13 (0.03, 0.53) | 0.12 (0.03, 0.47) | 0.04 (0.01, 0.17) |
Probenecid | 226 | 77 | 1810 | 42.6 | 2.40 (1.92, 3.00) | 2.42 (1.93, 3.02) | 0.80 (0.64, 1.00) |
Sulfinpyrazone | 1244 | 301 | 9579 | 31.4 | 1.77 (1.58, 1.98) | 1.74 (1.55, 1.95) | 0.57 (0.51, 0.64) |
Allopurinol | 5885 | 1459 | 46659 | 31.3 | 1.76 (1.67, 1.86) | 1.70 (1.62, 1.80) | 0.57 (0.54, 0.61) |
Benzbromarone | 15352 | 5193 | 103671 | 50.1 | 2.81 (2.73, 2.89) | 2.78 (2.69, 2.86) | 0.89 (0.86, 0.93) |
Colchicine | 8996 | 2328 | 57261 | 40.7 | 2.27 (2.18, 2.37) | 2.29 (2.19, 2.39) | 0.72 (0.68, 0.76) |
Number of antigout treatments | |||||||
1 | 17125 | 5314 | 107897 | 49.3 | 2.76 (2.67, 2.84) | 2.67 (2.59, 2.75) | 0.86 (0.82, 0.89) |
2 | 11670 | 3359 | 85575 | 39.3 | 2.21 (2.13, 2.29) | 2.22 (2.14, 2.30) | 0.71 (0.68, 0.75) |
3 | 2764 | 646 | 24083 | 26.8 | 1.52 (1.40, 1.64) | 1.53 (1.41, 1.65) | 0.51 (0.47, 0.55) |
4 | 234 | 41 | 2252 | 18.2 | 1.03 (0.76, 1.40) | 1.02 (0.75, 1.38) | 0.35 (0.25, 0.47) |
5 | 3 | 0 | 34 | 0.00 | — | — | — |
PY: person-years; Rate#: incidence rate, per 1,000 person-years; Crude HR: crude hazard ratio; Adjusted HR†: multivariable analysis including age, sex, and comorbidities of hypertension, stroke, diabetes, COPD, CAD, alcohol-related illness and asthma.
In this study, we also evaluated the effects of allopurinol, febuxostat, benzbromarone, sulfinpyrazone, probenecid, and colchicine on lipogenesis-related gene expression. The concentrations we used were based on the maximum serum drug concentrations [
Viability of HepaRG cells following exposure to antigout drugs. HepaRG cells were exposed to allopurinol (14.7 and 22.1
Expression of hepatic lipogenesis-related genes,
Expression of hepatic lipid metabolism-related genes following treatment with T0901317 and antigout drugs. Differentiated HepaRG cells were treated for 24 h with T0901317 (10
To the best of our knowledge, there are few studies that have investigated the development of hyperlipidemia in gout patients and the medications used for gout therapy in Asian adults. Our study demonstrates the strong association between gout and the risk of hyperlipidemia by comprehensively adjusting for confounders. In this study, examining the correlation between gout and the risk of hyperlipidemia under antigout drug treatment, we observed the following: (1) we used a nationwide, population-based cohort study to comprehensively survey an Asian population and observed a strong association between gout and the incidence of hyperlipidemia; (2) overall incidence risk of hyperlipidemia in gout patients was 2.55-fold compared to that in nongout populations; (3) without ULT, the incidence of hyperlipidemia was higher in patients with gout than in patients without gout (
In a population-based study conducted in USA, researchers estimated that the annual incidence of gout was 0.45 (1977 to 1978), 0.62 (1995 to 1996), and 1.6 and 0.2 (men and women, respectively, 1948 to 1980) per 1000 person-years [
Sustained reduction in serum UA levels is critical for the long-term management of gout. The recommended target serum UA level is <360
Uricosuric agents are more commonly prescribed than XOIs in Taiwan. In Taiwan, 1 in 16 people have gout, but only 1 in 5 affected people are treated with ULT [
Data from previous studies show that allopurinol, benzbromarone, and febuxostat can decrease blood levels of TC and TGs [
A few studies have been conducted to investigate the effects of these antigout drugs on lipid metabolism regulation. New Zealand rabbits fed with a high fat diet showed significantly decreased serum TC and TG levels after administration of febuxostat for 4 weeks through antioxidant and anti-inflammatory mechanisms [
Furthermore, XO-mediated conversion of hypoxanthine/xanthine to UA is associated with the generation of hydrogen peroxide [
The most frequently used urate-lowering drug, allopurinol, is effective, easy to administer (once-daily dosing), inexpensive, and generally well-tolerated. However, it usually causes severe cutaneous adverse reactions, such as hypersensitivity syndrome and Stevens-Johnson syndrome, and is associated with human leukocyte antigen HLA-B
Another XOI, febuxostat, was approved by the European Medicines Agency in 2008 and the United States Food and Drug Administration in 2009 for the treatment of gout [
Benzbromarone, sulfinpyrazone, and probenecid lower serum UA levels by increasing renal urate excretion. Benzbromarone is not available in many countries because of concerns about its hepatotoxicity, and it is not recommended for patients with liver and renal dysfunction [
Colchicine is another commonly used drug for acute gout treatment. In the Acute Gout Flare Receiving Colchicine Evaluation study, although low- (1.8 mg total) and high- (4.8 mg total) dose colchicine regimens were effective in pain reduction, low-dose colchicine had fewer adverse effects [
Hyperuricemia is frequently reported in patients with CVD and is associated with CVD-related mortality, suggesting that it may have a direct vascular effect [
This study has some strengths that are noteworthy. As this study was based on a large and representative population cohort extracted from the Taiwan NHI system, it eliminates bias from selection, nonresponse, or poor recall. The LHID has been shown to have good levels of accuracy and completeness in recording prescriptions and clinical diagnoses. In addition, we adjusted for many potentially confounding factors that are associated with hyperlipidemia and selected 4 times the number of nongout patients to form the control group. Both the case and control groups were studied for a long observation period. This study shows that gout patients had a higher risk of hyperlipidemia with a narrower and statistically significant CI.
This is the first study to examine an Asian population by using a population-based, nationwide cohort study to evaluate the effects of antigout therapy on hyperlipidemia in gout patients. However, our study has several limitations. First, patients’ information concerning lifestyle, smoking status, alcohol consumption, environmental exposure, body mass index, and family history of hyperlipidemia was unavailable in the LHIRD. The aforementioned factors may contribute as confounding factors to the development of hyperlipidemia. LHIRD claims data are used mainly for administrative billing purposes. Therefore, the additional information was anonymous, and it was not possible to directly contact the patients for additional information. Second, no data on diets were available in this study, and dietary intake may contribute to the patients’ lipid profiles. Third, exact laboratory data in the LHIRD were limited; therefore, we did not know the serum UA status in gout patients after ULT treatment. Fourth, the LHIRD lacks complete information regarding patients’ liver disease by Child-Pugh classification, which might highly correlate with the development of hyperlipidemia. Therefore, our study reduced the confounding effects of the medications by adjusting for comorbidities. In addition, the severity of gout and disease duration may also affect blood lipid levels. This is an epidemiological study that can only provide evidence to show the association between gout and hyperlipidemia and cannot show a causal relationship. It is necessary to obtain more information from other databases or questionnaires to conduct a prospective study or randomized controlled trial to investigate such a relationship between gout, ULT, and hyperlipidemia. Therefore, the essential part of the optimization of care of patients with gout is likely to be physician education to improve knowledge and promote interest in gout. However, our results provide evidence that recommendations and guidelines for clinical management of gout patients can effectively mitigate long-term consequences of hyperlipidemia such as the possibility of developing CVD. Although we cannot identify the levels of each type of lipid or the levels of serum UA, we identified gout patients without ULT who may have had high levels of UA, which could be correlated with high serum LDL-C, TG, and TC levels and with low levels of HDL-C. Peng et al. identified HDL-C as a protective factor for CVD risk, which is inversely correlated to serum UA levels, but positively correlated with levels of LDL-C and TGs [
This population-based cohort study demonstrates a substantial association between gout, ULT, and the risk of hyperlipidemia. We confirm that management of gout in Taiwan remains poor, with 28.4% of gout patients not being prescribed ULT, which could contribute to elevated serum UA levels and increased gout flares with major adverse consequences such as hyperlipidemia. Due to the strong association between gout and hyperlipidemia, appropriate treatment guidelines such as changes in lifestyle, diet, and measurement of serum parameters should be developed to improve serum UA levels and understand the therapeutic mechanism of action of these drugs. We provide evidence of the benefits of these common antigout drugs for hyperlipidemia in gout patients through the reduction in the expression of lipogenesis-related genes.
The data used to support the findings of this study are included within the article.
The authors declare no conflict of interest.
Y.J.F., T.Y.W., and Y.P.L. are responsible for the conceptualization. T.Y.W., C.L.L., C.Y.S., J.R.L., and Y.P.L. are assigned to the methodology. C.L.L. and Y.P.L. acquired the software. Y.J.F. and T.Y.W. performed the validation. C.L.L., C.Y.S., and J.R.L. performed the formal analysis. T.Y.W. and Y.P.L. performed the investigation. C.L.L. and Y.P.L. acquired the resources. C.L.L. and Y.P.L. performed the data curation. All authors did the writing—original draft preparation, review and editing, and visualization. Y.J.F., T.Y.W., and Y.P.L. are responsible for the supervision. Y.P.L. is assigned to the project administration. Y.J.F., T.Y.W., and Y.P.L. are responsible for the funding acquisition. Yi-Jen Fang and Tien-Yuan Wu contributed equally to this work.
This study was supported by the Ministry of Science and Technology, Taiwan, R.O.C. (MOST107-2320-B-039-042-MY3); China Medical University Hospital, Taichung, Taiwan (DMR-107-109); China Medical University, Taichung, Taiwan (CMU109-MF-92); Show Chwan Memorial Hospital, Changhua, Taiwan (SRD-109026); and Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation (TTCRD109-25) and partially supported by Taiwan Ministry of Health and Welfare Clinical Trial Center (MOHW109-TDU-B-212-114004), MOST Clinical Trial Consortium for Stroke (MOST108-2321-B-039-003), and Tseng-Lien Lin Foundation, Taichung, Taiwan.