A Reappraisal of the Preventive Effect of Statins on the Development of Graves’ Ophthalmopathy: A Hospital-Based Cohort Study

A Reappraisal of the Preventive Effect of Statins on the Development of Graves’ Ophthalmopathy: A Hospital-Based Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article A Reappraisal of the Preventive Effect of Statins on the Development of Graves’ Ophthalmopathy: A Hospital-Based Cohort Study Yi-Hsuan Wei, Grace Chia-Yen Hsu, Shyang-Rong Shih, Shu Lang Liao This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3272425/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background/ Objectives: Recent studies have shown that statins decrease the risk of development of Graves’ ophthalmopathy, although most studies were based on Caucasian cohorts. Our study aims to identify the protective and risk factors for the development of Graves’ ophthalmopathy and the role of statin in newly diagnosed Taiwanese Graves’ disease patients. Subjects/ Methods: This was a tertiary hospital-based retrospective cohort including Graves’ disease patients newly diagnosed between 2010 and 2019 at National Taiwan University Hospital. A total of 3,578 patients with Graves’ disease met the inclusion criteria. Univariate and multivariate logistic regression were used to determine the odds ratio of developing Graves’ ophthalmopathy, with adjustment for sociodemographic factors, management of Graves’ disease and thyroid hormone levels to identify protective and risk factors of Graves’ ophthalmopathy. Results: Usage of statins reduced the risk of Graves’ ophthalmopathy development (odds ratio = 0.2; 95% CI 0.08 ~ 0.50; p < .001) in our multivariate model. Thyroid dysfunction including hyperthyroidism (odds ratio = 4.2; 95% CI 2.97 to 5.88; p < .001) and hypothyroidism (odds ratio = 4.7; 95% CI 3.02 to 7.19; p < .001) both showed an increased risk of developing Graves’ ophthalmopathy. Smoking status and lipid profile did not show as a risk factor. Conclusions: In newly diagnosed Graves’ disease patients, the use of statins decreased the risk of developing Graves’ ophthalmopathy by 80% while serum lipid levels were not found to be risk factors. Further nationwide population-based studies will help clarify the differences in risk factors between ethnic groups. Health sciences/Risk factors Health sciences/Diseases/Endocrine system and metabolic diseases/Thyroid diseases Figures Figure 1 Introduction Graves’ disease (GD) is the most common cause of hyperthyroidism, with an annual incidence of 20 cases per 100,000 persons, and a female to male ratio ranging from 4:1 to 5:1.( 1 , 2 ) GD pathogenesis is by the stimulation of the thyrotropin (thyroid-stimulating hormone, TSH) receptors on thyroid follicular cells by thyrotropin-receptor antibodies.( 3 ) Approximately 25–50% of GD patients develop Graves’ ophthalmopathy (GO),( 4 ) which may be presented as exophthalmos, periorbital edema, lid lag and retraction and exposure keratitis. Visual impairment from optic neuropathy or corneal ulceration is a rare but severe presentation of GO.( 3 , 5 ) The features of GO mainly result from an inflammatory process and increased glycosaminoglycans production causing enlarged extraocular muscles and increased adipose tissue within the orbit.( 6 ) GO is a multifactorial disease with environmental, genetic and immune factors.( 7 ) There is a female to male ratio of 2:1, though men tend to have a more severe form.( 7 ) Studies show that while the prevalence of GO does not differ among ethnic groups, Asian patients develop milder forms of GO than Caucasians do.( 8 ) Other endogenous risk factors include genetics, with immune regulatory and response genes such as the human leukocyte antigen (HLA)-DR3, cytotoxic T lymphocyte antigen (CTLA)-4, and the thyroid-related genes TSHR and thyroglobulin (TG) as candidates. A recent study showed that the allele and genotype frequencies were similar in GO and GD patients.( 9 ) Smoking has been identified as an exogenous risk factor for GO,( 10 ) as have different GD treatments. A recent study revealed that thyroidectomy and statin use reduced GO risk while radioactive iodine (RAI) exposure increased the risk.( 11 ) Thyroid dysfunction, including hyper- and hypothyroidism, has been associated with an increased risk of development or deterioration of GO.( 10 ) Published results investigating the role of TSHR antibodies by measuring thyrotropin binding inhibitory immunoglobulin (TBII) or thyroid-stimulating antibodies (TSI) are inconsistent, while T3 and T4 levels do not predict GO.( 10 , 12 ) GO treatment depends on the severity of the disease. It includes artificial tears and topical glucocorticoids for mild disease,( 2 ) systemic steroids and orbital irradiation for moderate or severe disease, while recent studies show that immunomodulatory drugs are also effective.( 2 , 13 , 14 ) Clinical cohorts and in vitro studies have recently shown that statins may play an active role in GO prevention.( 11 , 15 ) A retrospective study of 34,894 newly diagnosed Swedish GD patients demonstrated that statin users are less likely to develop GO.( 6 ) A phase 2 randomized clinical trial of statins for Graves’ orbitopathy (STAGO) investigating intravenous glucocorticoids with or without atorvastatin for hypercholesterolemic patients with moderate-to-severe GO showed that atorvastatin improved the response to intravenous glucocorticoids. Phase 3 studies are required to confirm this conclusion in patients without hypercholesterolemia.( 16 ) The mechanisms by which statins reduce the risk of GO are not fully understood. Statins may inhibit adipogenesis, tumor necrosis factor alpha (TNF-α) induced inflammation, and transforming growth factor beta (TGF-β)-induced tissue remodeling that underlie GO symptoms.( 15 , 17 , 18 ) Our study recruited a cohort of newly diagnosed GD patients in a tertiary referral hospital. We aimed to identify the risk factors for GO in an Asian population, focusing on the role of statins. Materials/ Subjects and methods This was a single-center, retrospective case-control study approved by the Research Ethics Committee of National Taiwan University Hospital (202202066RINC). We enrolled newly diagnosed GD patients (ICD-9-CM: 242.00, ICD-10-CM/PCS: E05.00) who were 20 years of age or older at diagnosis in National Taiwan University Hospital between 2010 and 2019. Patients diagnosed before 2010 or who presented with GO manifestations during their first consultation were excluded, as were patients with benign or malignant orbital tumors. Individuals without documented GD treatment in our center may have been treated in other faculties and were also excluded. Patients were followed up from their first GD diagnosis until they developed GO or the study ended on December 31, 2019. Those who were followed up for less than 6 months were excluded. After exclusions, 3,578 GD patients were enrolled for further analysis (Fig. 1 ). A GO diagnosis was made if the patient had at least one of the billing codes for eyelid retraction, restrictive strabismus, exophthalmos, exposure keratopathy, or compressive optic neuropathy. Patients who underwent GO-related surgery, such as orbital decompression, mullerectomy, levator muscle recession, lower lid retraction correction, or strabismus surgery were also included as GO patients. A statin user was defined as a patient who received statin prescriptions for over 60 days ( 1 ) within a year before his/ her GO diagnosis, or ( 2 ) any time during follow up for a non-GO patient. The same criteria applied to other cholesterol-lowering agents, hydroxychloroquine, steroids, and COX-2 inhibitors. Patient baseline demographics and clinical characteristics are summarized using means and standard deviations for normally distributed continuous variables while other continuous numerical data are presented as median and interquartile range. Categorical variables are shown as frequencies and percentages. Potential risk factors were identified using the Chi-squared test for nominal factors or the Mann-Whitney U test for ordinal factors. Multivariate logistic regression was used to determine the odds ratio (OR) of developing GO, adjusted for age at GD diagnosis, BMI, thyroid status, TBII levels and statin usage. In the regression model, treatment with antithyroid medication alone was the reference to which other antithyroid treatments (RAI, thyroidectomy) were compared. An exploratory subgroup analysis of patients with dyslipidemia was done. Dyslipidemia was defined according to the 2019 ESC/EAS guidelines,( 19 ) of a low density lipoprotein (LDL) cholesterol > 115 mg/dL, or high density lipoprotein (HDL) cholesterol < 40 mg/dL in men or 190 mg/dL or triglyceride > 150 mg/dL. We also included patients with over 60 days of statin use in our subgroup. Statistical analyses were performed using SAS, 9.4 software (SAS Institute, Cary, NC, USA). For all analyses, two-sided p -values < 0.05 were considered statistically significant and 95% confidence interval (CI) was presented. Results Overall, 372 (10.4%) of the 3,578 GD patients developed GO during follow up. The mean follow up time was 62.6 (SD 37.4) months for the non-GO patients and 9.9 (SD 16.2) months for the GO patients. The mean age at GD diagnosis was significantly higher in GO patients (46.2 years) than in non-GO patients (mean [SD] 46.2 [13.8] vs 43.7 [15.0] years; p < .001), as with other studies.( 20 ) No gender difference was noted and female patients were the majority in both groups. Higher BMI levels were associated with an increased risk of GO development (OR = 1.06; 95% CI 1.02 to 1.10; p = 0.003) in the multivariate model. No statistical difference of GO development was noted between non-smokers and smokers. Overall, 3326 (93%) patients received antithyroid medications in the total study cohort. No significant difference was noted regarding medical or other treatments including RAI or surgery between GO and non-GO patients (Tables 1 and 2 ). Table 1 Baseline demographics and clinical characteristics for Graves’ disease patients with Graves’ ophthalmopathy and non-Graves’ ophthalmopathy Mean (SD) Total (n = 3578) Non-GO (n = 3206) GO (n = 372) p-value a Age, year 44.0 (14.9) 43.7 (15.0) 46.2 (13.8) .001 Gender, No. (%) .149 Male 771 (21.6) 680 (21.2) 91 (24.5) Female 2807 (78.5) 2526 (78.8) 281 (75.5) BMI 22.8 (3.7) 22.7 (3.7) 23.24 (3.6) .008 Smoking status, No. (%) .339 Non-smoker 2106 (84.8) 1836 (85.2) 270 (82.3) Ever smoker 122 (4.9) 105 (4.9) 17 (5.2) Smoker 255 (10.3) 214 (9.9) 41 (12.5) Follow up time, month 57.2 (39.2) 62.6 (37.4) 9.9 (16.2) < .001 Treatment for GD, No. (%) .797 Anti-thyroid medication 3326 (92.96) 2979 (92.9) 347 (93.3) Others b 252 (7.0) 227 (7.1) 25 (6.7) Statin, No. (%) 340 (9.5) 332 (10.4) 8 (2.2) .99 COX-2 inhibitors, No. (%) 20 (0.6) 17 (0.5) 3 (0.8) .456 Thyroid status, No. (%) < .001 Hyperthyroidism 1154 (33.6) 960 (31.3) 194 (53.0) Euthyroid 1907 (55.5) 1808 (58.9) 99 (27.1) Hypothyroidism 374 (10.9) 301 (9.8) 73 (20.0) TBII, Median, IQR 49.3 (49.2) 47.8 (48.9) 59.7 (46) < .001 Anti-TPO antibody, Median, IQR 155 (678.8) 185 (47) 38.4 (332) < .001 Serum cholesterol, Median, IQR HDL-cholesterol 53 (18) 53 (19) 46 (18) .013 LDL-cholesterol 104 (41) 105 (41) 99 (40) .109 Total cholesterol 180 (54) 180 (47) 183 (83) .639 a. comparison between GO and non-GO patients; statistically significant values with a p < 0.05 were highlighted in bold b. radioactive iodine or surgery c. including fenofibrate, ezetimibe, gemfibrozil and cholestyramine resin Continuous variables with normal distribution were presented as means and standard deviations (SD) otherwise as median and interquartile range (IQR); Categorical variables were showed as frequencies and percentages. Anti-TPO, antithyroid peroxidase; BMI, body mass index; COX-2, cyclooxygenase-2; GD, Graves’ disease; GO, Graves’ ophthalmopathy; HDL, high density lipoprotein; LDL, low density lipoprotein; TBII, thyrotropin binding inhibitory immunoglobulins. Table 2 Univariate and multivariate logistic regression models for GO risk factor. Univariate model Multivariate model OR (95% CI) p-value OR (95% CI) p-value a Age 1.01 (1.0–1.02) .002 1.02 (1.02–1.03) < .001 Female 1.2 (0.94–1.55) .149 BMI 1.04 (1.01–1.07) .008 1.06 (1.02–1.10) .003 Smoking status Non-smoker reference NA NA NA Ever smoker 1.1 (0.65–1.87) .721 NA NA Smoker 1.3 (0.91–1.86) .147 NA NA Treatment Anti-thyroid medication 1.06 (0.69–1.62) .797 NA NA Others b reference NA NA NA Other medications c Statin 0.19 (0.10–0.39) < .001 0.2 (0.08–0.50) < .001 Hydroxychloroquine 1.04 (0.51–2.09) .922 NA NA Other cholesterol lowering agents 0.86 (0.11–6.75) .887 NA NA COX-2 inhibitors 1.53 (0.45–5.23) .499 NA NA Thyroid status Hyperthyroidism 3.69 (2.86–4.76) < .001 4.18 (2.97–5.88) < .001 Euthyroid reference NA ref NA Hypothyroidism 4.43 (3.20–6.14) < .001 4.66 (3.02–7.19) < .001 TBII 1.01 (1.01–1.02) < .001 1.02 (1.01–1.02) < .001 HDL-cholesterol 0.97 (0.94–0.99) .007 NA NA LDL-cholesterol 0.99 (0.98–1.0) .101 NA NA Total cholesterol 0.99 (0.94–1.04) .639 NA NA Dyslipidemia 1.06 (0.74–1.51) .753 NA NA a. comparison between GO and non-GO patients; statistically significant values with a p < 0.05 were highlighted in bold b. radioactive iodine or surgery c. including fenofibrate, ezetimibe, gemfibrozil and cholestyramine resin Anti-TPO, antithyroid peroxidase; BMI, body mass index; CI, confidence interval; COX-2, cyclooxygenase-2; GD, Graves’ disease; GO, Graves’ ophthalmopathy; HDL, high density lipoprotein; LDL, low density lipoprotein; NA, not applicable; OR, odds ratio; TBII, thyrotropin binding inhibitory immunoglobulins. Statins significantly decreased the risk of developing GO in the univariate model (OR = 0.19; 95% CI 0.10 to 0.39; p < .001). After adjusting for age, BMI, thyroid status, and TBII, statins significantly decreased GO by 80% in the multivariate model (OR = 0.2; 95% CI 0.08 to 0.50; p < .001). No significant difference was noted between groups regarding use of hydroxychloroquine, COX-2 inhibitors or other cholesterol-lowering treatments including fenofibrate, ezetimibe, gemfibrozil and cholestyramine resin. Compared to euthyroid status, hyperthyroidism (OR = 4.2; 95% CI 2.97 to 5.88; p < .001) and hypothyroidism (OR = 4.7; 95% CI 3.02 to 7.19; p < .001) both increased the risk of developing GO in the multivariate model, as did an elevated TSH receptor antibody level (OR = 1.02; 95% CI 1.01 to 1.02; p < .001). HDL-cholesterol showed a protective effect against GO development in the univariate model, though with an OR of 0.97 (95% CI 0.94 to 0.99; p = 0.007). LDL-cholesterol, total cholesterol (T-CHO), triglyceride (TG) levels or dyslipidemia status showed no significant correlations and were not included in our multivariate model. We conducted a subgroup analysis of patients with dyslipidemia to clarify whether statin’s lipid-lowering effect or other pleiotropic mechanisms decreased GO development (Table 3 ). Statin use decreased 86% of the risk of GO (OR = 0.14; 95% CI 0.05 to 0.35; p < .001) in the multivariate model. HDL- and LDL-cholesterol did not affect GO development (OR = 0.97; 95% CI 0.93 to 1.00; p = 0.06 and OR = 0.99; 95% CI 0.98 to 1.00; p = 0.12 respectively), suggesting that statins may exert their influence via a pleiotropic effect. Table 3 Univariate and multivariate logistic regression models for GD patients with dyslipidemia. (Total n = 763; Non-GO n = 680; GO n = 83) Univariate model Multivariate model OR (95% CI) p-value OR (95% CI) p-value a Statin 0.11 (0.05–0.25) < .001 0.14 (0.05–0.35) < .001 Thyroid status Hyperthyroidism 4.50 (2.69–7.54) < .001 3.23 (1.84–5.68) < .001 Euthyroid reference reference NA Hypothyroidism 2.99 (1.51–6.0) .002 2.55 (1.22–5.36) .013 TBII 1.01 (1.00–1.02) .032 1.003 (0.99–1.01) .472 Anti TPO antibody 0.99 (0.99–1.00) .089 NA NA HDL-cholesterol 0.97 (0.93–1.00) .063 NA NA LDL-cholesterol 0.99 (0.98–1.00) .122 NA NA a. comparison between GO and non-GO patients; statistically significant values with a p < 0.05 were highlighted in bold. Anti-TPO, antithyroid peroxidase; CI, confidence interval; GD, Graves’ disease; GO, Graves’ ophthalmopathy; HDL, high density lipoprotein; LDL, low density lipoprotein; NA, not applicable; OR, odds ratio; TBII, thyrotropin binding inhibitory immunoglobulins. Discussion Our study demonstrated that statins play a significant role in decreasing the development of GO by 80% (OR = 0.2; 95% CI 0.08 to 0.50; p < .001). The results are independent of the patient’s lipid profile or dyslipidemia status, suggesting mechanisms other than its lipid-lowering effects. There is increasing evidence that statin use by GD patients may reduce GO risk. Stein et. al. demonstrated that statins were associated with decreased GO development by 40% in a nationwide cohort in the United States in 2015.( 11 ) Nilsson et. al. also found that statin users were less likely to develop GO (HR = 0.87, p = 0.04).( 6 ) A recent Korean study compared statin effects according to sex, showing that higher doses of statins were associated with a higher risk of GO in men (HR = 1.27, p = 0.05) and lower risk in women (HR = 0.37, p < .001).( 21 ) The STAGO phase II randomized clinical trial demonstrated that oral atorvastatin improved the treatment response of GO patients to intravenous glucocorticoids.( 16 ) However, the mechanism by which statins or cholesterol levels influence the development of GO is not fully understood. A previous longitudinal study showed no protective effect against GO, of non-statin cholesterol-lowering drugs or other anti-inflammatory drugs.( 11 ) Besides its hypolipidemic role, statins also have pleiotropic anti-inflammatory, immunomodulatory, and antifibrotic effects.( 22 ) Simvastatin has been demonstrated to inhibit the expression of TNF-α-induced proinflammatory factor cysteine-rich protein 61 (CYR61), which is noted in many inflammatory diseases, including GO development.( 18 , 23 ) In addition, simvastatin reportedly downregulated adipogenesis and inhibited TGF-β-induced myofibroblast differentiation in cultured orbital fibroblasts from GO patients.( 15 , 24 ) Recent studies suggest that increased cholesterol levels may be a risk factor, or even a predictor of higher clinical activity scores (CAS) in GO.( 20 , 25 )A retrospective study of 86 GD patients showed higher LDL-cholesterol (135 mg/dL versus 107 mg/dL) and total cholesterol (212 mg/dL versus 176 mg/dL) levels in GO patients than in their non-GO counterparts. HDL-cholesterol and TG levels did not show any differences.( 25 ) A cross-sectional study of 250 GD patients showed that a total cholesterol level higher than 191 mg/dL or LDL-cholesterol level higher than 118 mg/dL was associated with an increased risk of GO. Further, higher total cholesterol levels were indicative of higher CAS.( 20 ) Baseline LDL-cholesterol levels higher than 190 mg/dL reportedly predict a poorer response to parenteral corticosteroids.( 26 ) In the Korean study, higher total cholesterol levels increased GO development in women (HR = 1.04, p = 0.003) though not in men (HR = 1.04, p = 0.117).( 21 ) In our study, although serum lipid profiles showed no significant influence on GO development, some points are still noteworthy. The overall average LDL-cholesterol level was 105.2 mg/dL while the average levels in GO and non-GO patients were 98.1 mg/dL and 105.5 mg/dL respectively. These LDL-cholesterol levels in our cohort are much lower than in several previous cohorts. Similarly, both GO and non-GO patients have lower total cholesterol levels (183 mg/dL and 180 mg/dL respectively) than the Caucasian cohorts mentioned above. In the Korean study, the median total cholesterol levels were 173.5 mg/dL in men and 179 mg/dL in women. Only the latter showed a significant association with GO development. It is possible that our cohort did not demonstrate significant lipid level effects due to the overall lower cholesterol levels in our ethnicity. This should be considered when identifying risk factors in different populations. Further studies will be needed to clarify the role of serum lipid profiles in GO development in the Asian population. Studies have shown that thyroid dysfunction is associated with an increased risk of developing GO and more severe disease, which our results support.( 27 ) TSH receptor antibody levels also positively correlate with the activity and severity of GO.( 28 ) A recent systematic review showed that antithyroid peroxidase (anti-TPO) antibody’s role in GO remains unclear while our study revealed no statistical significance.( 29 ) Although smoking has been widely recognized as a risk factor for developing GO, our study did not find a significant association. Our results were comparable to those of the Korean study.( 21 ) In both cohorts, approximately 6% of women were smokers or ex-smokers. As the cohort consisted mostly of women, the number of smokers may have been too low to show the impact of smoking on GO development. Further, the lack of documentation regarding the intensity and duration of smoking, and secondhand smoke exposure (a recognized risk) may have been important factors.( 27 ) Among females, secondhand smoke exposure may be more prevalent than active smoking. This study had some limitations. Firstly, patients in a tertiary center were likely to have a more severe form of GO that required surgical intervention. Patients who had received prior treatment elsewhere were excluded, which lowered the rate of GO in the cohort. Secondly, patients with GO were identified according to billing codes such as eyelid retraction, strabismus, exophthalmos, or those who received thyroid eye surgery. However, in clinical practice, patients with mild GO may not have such billing codes assigned to them, particularly if they have not visited an ophthalmologist. Therefore, the GO patients we identified would have more severe presentations. Thirdly, our study did not differentiate between statins or consider the dosages used. Studies have shown different results for atorvastatin and simvastatin before dosage adjustment.( 6 ) Additionally, the patients prescribed other cholesterol-lowering agents were too few to include in the multivariate analysis. These limitations should be considered when interpreting our study findings. Future research should aim to address these limitations to improve the understanding of the relationship between statin use and GO development. Conclusion This hospital-based cohort study demonstrated a significant reduction in the development of GO associated with statin use, with an OR of 0.2 (95% CI 0.08 to 0.50; p < .001). Thyroid dysfunction was also associated with an increased risk of developing GO. It is important to consider population differences, including variations in smoking prevalence or average serum lipid levels, when identifying GO risk factors in different ethnicities. Declarations Acknowledgment The authors would like to express their thanks to the staff of Department of Medical Research for providing clinical data from National Taiwan University Hospital-integrative Medical Database (NTUH-iMD) and to the staff of National Taiwan University Hospital-Statistical Consulting Unit (NTUH-SCU) for statistical consultation and analyses. Conflict of Interest The authors have no financial or proprietary interest in any materials or methods mentioned in this article. Funding None. References Hussain YS, Hookham JC, Allahabadia A, Balasubramanian SP. Epidemiology, management and outcomes of Graves' disease-real life data. Endocrine. 2017;56(3):568–78. Smith TJ, Hegedus L. Graves' Disease. N Engl J Med. 2016;375(16):1552–65. Bahn RS, Heufelder AE. Pathogenesis of Graves' ophthalmopathy. N Engl J Med. 1993;329(20):1468–75. San Miguel I, Arenas M, Carmona R, Rutllan J, Medina-Rivero F, Lara P. 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Lanzolla G, Sabini E, Profilo MA, Mazzi B, Sframeli A, Rocchi R, et al. Relationship between serum cholesterol and Graves' orbitopathy (GO): a confirmatory study. J Endocrinol Invest. 2018;41(12):1417–23. Naselli A, Moretti D, Regalbuto C, Arpi ML, Lo Giudice F, Frasca F, et al. Evidence That Baseline Levels of Low-Density Lipoproteins Cholesterol Affect the Clinical Response of Graves' Ophthalmopathy to Parenteral Corticosteroids. Front Endocrinol (Lausanne). 2020;11:609895. Gontarz-Nowak K, Szychlinska M, Matuszewski W, Stefanowicz-Rutkowska M, Bandurska-Stankiewicz E. Current Knowledge on Graves' Orbitopathy. J Clin Med. 2020;10(1). Roos JCP, Paulpandian V, Murthy R. Serial TSH-receptor antibody levels to guide the management of thyroid eye disease: the impact of smoking, immunosuppression, radio-iodine, and thyroidectomy. Eye (Lond). 2019;33(2):212–7. Kyriakos G, Patsouras A, Voutyritsa E, Gravvanis C, Papadimitriou E, Farmaki P, et al. The Role of TPOAb in Thyroid-Associated Orbitopathy: A Systematic Review. Ocul Immunol Inflamm. 2022;30(7–8):1740–6. Additional Declarations There is no conflict of interest Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3272425","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":235132395,"identity":"dc28059c-377e-4282-a8cd-65f2bc670615","order_by":0,"name":"Yi-Hsuan Wei","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAy0lEQVRIiWNgGAWjYFACxoYDHypsGBgkiNfCfPDhjDNpSFrYCGphSzbmbDtMghaD2z1m0oxt5xP7ZzcffMBQYxPNIN9jgF/LnTNm0gXnbifOuHMs2YDhWFpuAxsPfi1mN3LMpGeU3U5sADIkGBsOA7XwbiCshYftXOJ8ErSkJRvztB1I3EC0FvsbyaBATjbeCNRrkAD0Sxtb/ge8WiRnJIKi0k52HlDvgw81Nrn9zMcS8GqBAccGEAlSSzgmYQ4kVuEoGAWjYBSMQAAAHBJNuk4DqhgAAAAASUVORK5CYII=","orcid":"","institution":"National Taiwan University Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yi-Hsuan","middleName":"","lastName":"Wei","suffix":""},{"id":235132396,"identity":"e752fd1c-ff69-4b79-a709-37f81a4ec23c","order_by":1,"name":"Grace Chia-Yen Hsu","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Grace","middleName":"Chia-Yen","lastName":"Hsu","suffix":""},{"id":235132397,"identity":"552ce364-3986-4aee-b726-26279e87443d","order_by":2,"name":"Shyang-Rong Shih","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Shyang-Rong","middleName":"","lastName":"Shih","suffix":""},{"id":235132398,"identity":"90357c4c-3cda-473a-90e8-c1f63c450d01","order_by":3,"name":"Shu Lang Liao","email":"","orcid":"https://orcid.org/0000-0002-4312-5351","institution":"National Taiwan University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shu","middleName":"Lang","lastName":"Liao","suffix":""}],"badges":[],"createdAt":"2023-08-17 13:46:52","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3272425/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3272425/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":43793654,"identity":"b271c750-f30a-4399-b2ce-4dd143dde18c","added_by":"auto","created_at":"2023-09-27 21:56:59","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":79390,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of patient enrollment and subgroup analysis. GD, Graves’ disease; NTUH, National Taiwan University Hospital; HDL, high density lipoprotein; LDL, low density lipoprotein.\u003c/p\u003e","description":"","filename":"GOflowchart20230711.png","url":"https://assets-eu.researchsquare.com/files/rs-3272425/v1/6f0d66aa0242cd7d9d174244.png"},{"id":44794200,"identity":"948e7747-1267-4910-bc4b-bf971de2c4c9","added_by":"auto","created_at":"2023-10-17 15:11:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":297161,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3272425/v1/c027b253-8b37-4264-ac49-a7fbae1568a8.pdf"}],"financialInterests":"There is no conflict of interest","formattedTitle":"A Reappraisal of the Preventive Effect of Statins on the Development of Graves’ Ophthalmopathy: A Hospital-Based Cohort Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGraves\u0026rsquo; disease (GD) is the most common cause of hyperthyroidism, with an annual incidence of 20 cases per 100,000 persons, and a female to male ratio ranging from 4:1 to 5:1.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) GD pathogenesis is by the stimulation of the thyrotropin (thyroid-stimulating hormone, TSH) receptors on thyroid follicular cells by thyrotropin-receptor antibodies.(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) Approximately 25\u0026ndash;50% of GD patients develop Graves\u0026rsquo; ophthalmopathy (GO),(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) which may be presented as exophthalmos, periorbital edema, lid lag and retraction and exposure keratitis. Visual impairment from optic neuropathy or corneal ulceration is a rare but severe presentation of GO.(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) The features of GO mainly result from an inflammatory process and increased glycosaminoglycans production causing enlarged extraocular muscles and increased adipose tissue within the orbit.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eGO is a multifactorial disease with environmental, genetic and immune factors.(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) There is a female to male ratio of 2:1, though men tend to have a more severe form.(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) Studies show that while the prevalence of GO does not differ among ethnic groups, Asian patients develop milder forms of GO than Caucasians do.(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) Other endogenous risk factors include genetics, with immune regulatory and response genes such as the human leukocyte antigen (HLA)-DR3, cytotoxic T lymphocyte antigen (CTLA)-4, and the thyroid-related genes TSHR and thyroglobulin (TG) as candidates. A recent study showed that the allele and genotype frequencies were similar in GO and GD patients.(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eSmoking has been identified as an exogenous risk factor for GO,(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) as have different GD treatments. A recent study revealed that thyroidectomy and statin use reduced GO risk while radioactive iodine (RAI) exposure increased the risk.(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) Thyroid dysfunction, including hyper- and hypothyroidism, has been associated with an increased risk of development or deterioration of GO.(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) Published results investigating the role of TSHR antibodies by measuring thyrotropin binding inhibitory immunoglobulin (TBII) or thyroid-stimulating antibodies (TSI) are inconsistent, while T3 and T4 levels do not predict GO.(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eGO treatment depends on the severity of the disease. It includes artificial tears and topical glucocorticoids for mild disease,(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) systemic steroids and orbital irradiation for moderate or severe disease, while recent studies show that immunomodulatory drugs are also effective.(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) Clinical cohorts and in vitro studies have recently shown that statins may play an active role in GO prevention.(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eA retrospective study of 34,894 newly diagnosed Swedish GD patients demonstrated that statin users are less likely to develop GO.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) A phase 2 randomized clinical trial of statins for Graves\u0026rsquo; orbitopathy (STAGO) investigating intravenous glucocorticoids with or without atorvastatin for hypercholesterolemic patients with moderate-to-severe GO showed that atorvastatin improved the response to intravenous glucocorticoids. Phase 3 studies are required to confirm this conclusion in patients without hypercholesterolemia.(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) The mechanisms by which statins reduce the risk of GO are not fully understood. Statins may inhibit adipogenesis, tumor necrosis factor alpha (TNF-α) induced inflammation, and transforming growth factor beta (TGF-β)-induced tissue remodeling that underlie GO symptoms.(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) Our study recruited a cohort of newly diagnosed GD patients in a tertiary referral hospital. We aimed to identify the risk factors for GO in an Asian population, focusing on the role of statins.\u003c/p\u003e"},{"header":"Materials/ Subjects and methods","content":"\u003cp\u003e This was a single-center, retrospective case-control study approved by the Research Ethics Committee of National Taiwan University Hospital (202202066RINC). We enrolled newly diagnosed GD patients (ICD-9-CM: 242.00, ICD-10-CM/PCS: E05.00) who were 20 years of age or older at diagnosis in National Taiwan University Hospital between 2010 and 2019. Patients diagnosed before 2010 or who presented with GO manifestations during their first consultation were excluded, as were patients with benign or malignant orbital tumors. Individuals without documented GD treatment in our center may have been treated in other faculties and were also excluded. Patients were followed up from their first GD diagnosis until they developed GO or the study ended on December 31, 2019. Those who were followed up for less than 6 months were excluded. After exclusions, 3,578 GD patients were enrolled for further analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eA GO diagnosis was made if the patient had at least one of the billing codes for eyelid retraction, restrictive strabismus, exophthalmos, exposure keratopathy, or compressive optic neuropathy. Patients who underwent GO-related surgery, such as orbital decompression, mullerectomy, levator muscle recession, lower lid retraction correction, or strabismus surgery were also included as GO patients.\u003c/p\u003e \u003cp\u003eA statin user was defined as a patient who received statin prescriptions for over 60 days (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) within a year before his/ her GO diagnosis, or (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) any time during follow up for a non-GO patient. The same criteria applied to other cholesterol-lowering agents, hydroxychloroquine, steroids, and COX-2 inhibitors.\u003c/p\u003e \u003cp\u003ePatient baseline demographics and clinical characteristics are summarized using means and standard deviations for normally distributed continuous variables while other continuous numerical data are presented as median and interquartile range. Categorical variables are shown as frequencies and percentages. Potential risk factors were identified using the Chi-squared test for nominal factors or the Mann-Whitney U test for ordinal factors. Multivariate logistic regression was used to determine the odds ratio (OR) of developing GO, adjusted for age at GD diagnosis, BMI, thyroid status, TBII levels and statin usage. In the regression model, treatment with antithyroid medication alone was the reference to which other antithyroid treatments (RAI, thyroidectomy) were compared.\u003c/p\u003e \u003cp\u003eAn exploratory subgroup analysis of patients with dyslipidemia was done. Dyslipidemia was defined according to the 2019 ESC/EAS guidelines,(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) of a low density lipoprotein (LDL) cholesterol\u0026thinsp;\u0026gt;\u0026thinsp;115 mg/dL, or high density lipoprotein (HDL) cholesterol\u0026thinsp;\u0026lt;\u0026thinsp;40 mg/dL in men or \u0026lt;\u0026thinsp;45 mg/dL in women, or total cholesterol\u0026thinsp;\u0026gt;\u0026thinsp;190 mg/dL or triglyceride\u0026thinsp;\u0026gt;\u0026thinsp;150 mg/dL. We also included patients with over 60 days of statin use in our subgroup. Statistical analyses were performed using SAS, 9.4 software (SAS Institute, Cary, NC, USA). For all analyses, two-sided \u003cem\u003ep\u003c/em\u003e-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant and 95% confidence interval (CI) was presented.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eOverall, 372 (10.4%) of the 3,578 GD patients developed GO during follow up. The mean follow up time was 62.6 (SD 37.4) months for the non-GO patients and 9.9 (SD 16.2) months for the GO patients. The mean age at GD diagnosis was significantly higher in GO patients (46.2 years) than in non-GO patients (mean [SD] 46.2 [13.8] vs 43.7 [15.0] years; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001), as with other studies.(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) No gender difference was noted and female patients were the majority in both groups. Higher BMI levels were associated with an increased risk of GO development (OR\u0026thinsp;=\u0026thinsp;1.06; 95% CI 1.02 to 1.10; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003) in the multivariate model. No statistical difference of GO development was noted between non-smokers and smokers. Overall, 3326 (93%) patients received antithyroid medications in the total study cohort. No significant difference was noted regarding medical or other treatments including RAI or surgery between GO and non-GO patients (Tables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline demographics and clinical characteristics for Graves\u0026rsquo; disease patients with Graves\u0026rsquo; ophthalmopathy and non-Graves\u0026rsquo; ophthalmopathy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean (SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;3578)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon-GO\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;3206)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGO\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;372)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44.0 (14.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43.7 (15.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e46.2 (13.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender, No. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.149\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e771 (21.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e680 (21.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e91 (24.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2807 (78.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2526 (78.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e281 (75.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22.8 (3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.7 (3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23.24 (3.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e.008\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking status, No. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.339\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-smoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2106 (84.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1836 (85.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e270 (82.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEver smoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e122 (4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e105 (4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (5.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e255 (10.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e214 (9.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e41 (12.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFollow up time, month\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57.2 (39.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62.6 (37.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.9 (16.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment for GD, No. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.797\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-thyroid medication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3326 (92.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2979 (92.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e347 (93.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e252 (7.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e227 (7.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25 (6.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStatin, No. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e340 (9.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e332 (10.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (2.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHydroxychloroquine, No. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e84 (2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75 (2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.923\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther cholesterol lowering agents, No. (%)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCOX-2 inhibitors, No. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (0.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (0.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.456\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThyroid status, No. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyperthyroidism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1154 (33.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e960 (31.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e194 (53.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEuthyroid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1907 (55.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1808 (58.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e99 (27.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypothyroidism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e374 (10.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e301 (9.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e73 (20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTBII, Median, IQR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49.3 (49.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47.8 (48.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e59.7 (46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-TPO antibody, Median, IQR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e155 (678.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e185 (47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38.4 (332)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum cholesterol, Median, IQR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHDL-cholesterol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53 (18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53 (19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e46 (18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e.013\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDL-cholesterol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e104 (41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e105 (41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e99 (40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.109\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal cholesterol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e180 (54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e180 (47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e183 (83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.639\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003ea. comparison between GO and non-GO patients; statistically significant values with a p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were highlighted in bold\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eb. radioactive iodine or surgery\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003ec. including fenofibrate, ezetimibe, gemfibrozil and cholestyramine resin\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eContinuous variables with normal distribution were presented as means and standard deviations (SD) otherwise as median and interquartile range (IQR); Categorical variables were showed as frequencies and percentages.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAnti-TPO, antithyroid peroxidase; BMI, body mass index; COX-2, cyclooxygenase-2; GD, Graves\u0026rsquo; disease; GO, Graves\u0026rsquo; ophthalmopathy; HDL, high density lipoprotein; LDL, low density lipoprotein; TBII, thyrotropin binding inhibitory immunoglobulins.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eUnivariate and multivariate logistic regression models for GO risk factor.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eUnivariate model\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eMultivariate model\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep-value\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.01 (1.0\u0026ndash;1.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e.002\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1.02 (1.02\u0026ndash;1.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.2 (0.94\u0026ndash;1.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.149\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.04 (1.01\u0026ndash;1.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e.008\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1.06 (1.02\u0026ndash;1.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e.003\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSmoking status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNon-smoker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ereference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEver smoker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.1 (0.65\u0026ndash;1.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.721\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSmoker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.3 (0.91\u0026ndash;1.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.147\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTreatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnti-thyroid medication\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.06 (0.69\u0026ndash;1.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.797\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOthers\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ereference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOther medications\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.19 (0.10\u0026ndash;0.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.2 (0.08\u0026ndash;0.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydroxychloroquine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.04 (0.51\u0026ndash;2.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.922\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOther cholesterol lowering agents\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.86 (0.11\u0026ndash;6.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.887\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCOX-2 inhibitors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.53 (0.45\u0026ndash;5.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.499\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eThyroid status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHyperthyroidism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.69 (2.86\u0026ndash;4.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e4.18 (2.97\u0026ndash;5.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEuthyroid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ereference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eref\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHypothyroidism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.43 (3.20\u0026ndash;6.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e4.66 (3.02\u0026ndash;7.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTBII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.01 (1.01\u0026ndash;1.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1.02 (1.01\u0026ndash;1.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHDL-cholesterol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.97 (0.94\u0026ndash;0.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e.007\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLDL-cholesterol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.99 (0.98\u0026ndash;1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.101\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal cholesterol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.99 (0.94\u0026ndash;1.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.639\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDyslipidemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.06 (0.74\u0026ndash;1.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.753\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003ea. comparison between GO and non-GO patients; statistically significant values with a p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were highlighted in bold\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003eb. radioactive iodine or surgery\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003ec. including fenofibrate, ezetimibe, gemfibrozil and cholestyramine resin\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003eAnti-TPO, antithyroid peroxidase; BMI, body mass index; CI, confidence interval; COX-2, cyclooxygenase-2; GD, Graves\u0026rsquo; disease; GO, Graves\u0026rsquo; ophthalmopathy; HDL, high density lipoprotein; LDL, low density lipoprotein; NA, not applicable; OR, odds ratio; TBII, thyrotropin binding inhibitory immunoglobulins.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eStatins significantly decreased the risk of developing GO in the univariate model (OR\u0026thinsp;=\u0026thinsp;0.19; 95% CI 0.10 to 0.39; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001). After adjusting for age, BMI, thyroid status, and TBII, statins significantly decreased GO by 80% in the multivariate model (OR\u0026thinsp;=\u0026thinsp;0.2; 95% CI 0.08 to 0.50; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001). No significant difference was noted between groups regarding use of hydroxychloroquine, COX-2 inhibitors or other cholesterol-lowering treatments including fenofibrate, ezetimibe, gemfibrozil and cholestyramine resin.\u003c/p\u003e\n\u003cp\u003eCompared to euthyroid status, hyperthyroidism (OR\u0026thinsp;=\u0026thinsp;4.2; 95% CI 2.97 to 5.88; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001) and hypothyroidism (OR\u0026thinsp;=\u0026thinsp;4.7; 95% CI 3.02 to 7.19; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001) both increased the risk of developing GO in the multivariate model, as did an elevated TSH receptor antibody level (OR\u0026thinsp;=\u0026thinsp;1.02; 95% CI 1.01 to 1.02; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001). HDL-cholesterol showed a protective effect against GO development in the univariate model, though with an OR of 0.97 (95% CI 0.94 to 0.99; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007). LDL-cholesterol, total cholesterol (T-CHO), triglyceride (TG) levels or dyslipidemia status showed no significant correlations and were not included in our multivariate model.\u003c/p\u003e\n\u003cp\u003eWe conducted a subgroup analysis of patients with dyslipidemia to clarify whether statin\u0026rsquo;s lipid-lowering effect or other pleiotropic mechanisms decreased GO development (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Statin use decreased 86% of the risk of GO (OR\u0026thinsp;=\u0026thinsp;0.14; 95% CI 0.05 to 0.35; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001) in the multivariate model. HDL- and LDL-cholesterol did not affect GO development (OR\u0026thinsp;=\u0026thinsp;0.97; 95% CI 0.93 to 1.00; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.06 and OR\u0026thinsp;=\u0026thinsp;0.99; 95% CI 0.98 to 1.00; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.12 respectively), suggesting that statins may exert their influence via a pleiotropic effect.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eUnivariate and multivariate logistic regression models for GD patients with dyslipidemia. (Total n\u0026thinsp;=\u0026thinsp;763; Non-GO n\u0026thinsp;=\u0026thinsp;680; GO n\u0026thinsp;=\u0026thinsp;83)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eUnivariate model\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eMultivariate model\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep-value\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.11 (0.05\u0026ndash;0.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.14 (0.05\u0026ndash;0.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eThyroid status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHyperthyroidism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.50 (2.69\u0026ndash;7.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.23 (1.84\u0026ndash;5.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEuthyroid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ereference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ereference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHypothyroidism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.99 (1.51\u0026ndash;6.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e.002\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.55 (1.22\u0026ndash;5.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e.013\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTBII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.01 (1.00\u0026ndash;1.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e.032\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.003 (0.99\u0026ndash;1.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.472\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnti TPO antibody\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.99 (0.99\u0026ndash;1.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e.089\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHDL-cholesterol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.97 (0.93\u0026ndash;1.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e.063\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLDL-cholesterol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.99 (0.98\u0026ndash;1.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e.122\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003ea. comparison between GO and non-GO patients; statistically significant values with a p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were highlighted in bold.\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003eAnti-TPO, antithyroid peroxidase; CI, confidence interval; GD, Graves\u0026rsquo; disease; GO, Graves\u0026rsquo; ophthalmopathy; HDL, high density lipoprotein; LDL, low density lipoprotein; NA, not applicable; OR, odds ratio; TBII, thyrotropin binding inhibitory immunoglobulins.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study demonstrated that statins play a significant role in decreasing the development of GO by 80% (OR\u0026thinsp;=\u0026thinsp;0.2; 95% CI 0.08 to 0.50; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001). The results are independent of the patient\u0026rsquo;s lipid profile or dyslipidemia status, suggesting mechanisms other than its lipid-lowering effects. There is increasing evidence that statin use by GD patients may reduce GO risk. Stein et. al. demonstrated that statins were associated with decreased GO development by 40% in a nationwide cohort in the United States in 2015.(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) Nilsson et. al. also found that statin users were less likely to develop GO (HR\u0026thinsp;=\u0026thinsp;0.87, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04).(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) A recent Korean study compared statin effects according to sex, showing that higher doses of statins were associated with a higher risk of GO in men (HR\u0026thinsp;=\u0026thinsp;1.27, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.05) and lower risk in women (HR\u0026thinsp;=\u0026thinsp;0.37, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001).(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) The STAGO phase II randomized clinical trial demonstrated that oral atorvastatin improved the treatment response of GO patients to intravenous glucocorticoids.(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) However, the mechanism by which statins or cholesterol levels influence the development of GO is not fully understood. A previous longitudinal study showed no protective effect against GO, of non-statin cholesterol-lowering drugs or other anti-inflammatory drugs.(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) Besides its hypolipidemic role, statins also have pleiotropic anti-inflammatory, immunomodulatory, and antifibrotic effects.(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) Simvastatin has been demonstrated to inhibit the expression of TNF-α-induced proinflammatory factor cysteine-rich protein 61 (CYR61), which is noted in many inflammatory diseases, including GO development.(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) In addition, simvastatin reportedly downregulated adipogenesis and inhibited TGF-β-induced myofibroblast differentiation in cultured orbital fibroblasts from GO patients.(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eRecent studies suggest that increased cholesterol levels may be a risk factor, or even a predictor of higher clinical activity scores (CAS) in GO.(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e)A retrospective study of 86 GD patients showed higher LDL-cholesterol (135 mg/dL versus 107 mg/dL) and total cholesterol (212 mg/dL versus 176 mg/dL) levels in GO patients than in their non-GO counterparts. HDL-cholesterol and TG levels did not show any differences.(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) A cross-sectional study of 250 GD patients showed that a total cholesterol level higher than 191 mg/dL or LDL-cholesterol level higher than 118 mg/dL was associated with an increased risk of GO. Further, higher total cholesterol levels were indicative of higher CAS.(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) Baseline LDL-cholesterol levels higher than 190 mg/dL reportedly predict a poorer response to parenteral corticosteroids.(\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) In the Korean study, higher total cholesterol levels increased GO development in women (HR\u0026thinsp;=\u0026thinsp;1.04, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003) though not in men (HR\u0026thinsp;=\u0026thinsp;1.04, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.117).(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) In our study, although serum lipid profiles showed no significant influence on GO development, some points are still noteworthy. The overall average LDL-cholesterol level was 105.2 mg/dL while the average levels in GO and non-GO patients were 98.1 mg/dL and 105.5 mg/dL respectively. These LDL-cholesterol levels in our cohort are much lower than in several previous cohorts. Similarly, both GO and non-GO patients have lower total cholesterol levels (183 mg/dL and 180 mg/dL respectively) than the Caucasian cohorts mentioned above. In the Korean study, the median total cholesterol levels were 173.5 mg/dL in men and 179 mg/dL in women. Only the latter showed a significant association with GO development. It is possible that our cohort did not demonstrate significant lipid level effects due to the overall lower cholesterol levels in our ethnicity. This should be considered when identifying risk factors in different populations. Further studies will be needed to clarify the role of serum lipid profiles in GO development in the Asian population.\u003c/p\u003e \u003cp\u003eStudies have shown that thyroid dysfunction is associated with an increased risk of developing GO and more severe disease, which our results support.(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e) TSH receptor antibody levels also positively correlate with the activity and severity of GO.(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e) A recent systematic review showed that antithyroid peroxidase (anti-TPO) antibody\u0026rsquo;s role in GO remains unclear while our study revealed no statistical significance.(\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eAlthough smoking has been widely recognized as a risk factor for developing GO, our study did not find a significant association. Our results were comparable to those of the Korean study.(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) In both cohorts, approximately 6% of women were smokers or ex-smokers. As the cohort consisted mostly of women, the number of smokers may have been too low to show the impact of smoking on GO development. Further, the lack of documentation regarding the intensity and duration of smoking, and secondhand smoke exposure (a recognized risk) may have been important factors.(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e) Among females, secondhand smoke exposure may be more prevalent than active smoking.\u003c/p\u003e \u003cp\u003eThis study had some limitations. Firstly, patients in a tertiary center were likely to have a more severe form of GO that required surgical intervention. Patients who had received prior treatment elsewhere were excluded, which lowered the rate of GO in the cohort. Secondly, patients with GO were identified according to billing codes such as eyelid retraction, strabismus, exophthalmos, or those who received thyroid eye surgery. However, in clinical practice, patients with mild GO may not have such billing codes assigned to them, particularly if they have not visited an ophthalmologist. Therefore, the GO patients we identified would have more severe presentations. Thirdly, our study did not differentiate between statins or consider the dosages used. Studies have shown different results for atorvastatin and simvastatin before dosage adjustment.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) Additionally, the patients prescribed other cholesterol-lowering agents were too few to include in the multivariate analysis. These limitations should be considered when interpreting our study findings. Future research should aim to address these limitations to improve the understanding of the relationship between statin use and GO development.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis hospital-based cohort study demonstrated a significant reduction in the development of GO associated with statin use, with an OR of 0.2 (95% CI 0.08 to 0.50; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001). Thyroid dysfunction was also associated with an increased risk of developing GO. It is important to consider population differences, including variations in smoking prevalence or average serum lipid levels, when identifying GO risk factors in different ethnicities.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to express their thanks to the staff of Department of Medical Research for providing clinical data from National Taiwan University Hospital-integrative Medical Database (NTUH-iMD) and to the staff of National Taiwan University Hospital-Statistical Consulting Unit (NTUH-SCU) for statistical consultation and analyses.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no financial or proprietary interest in any materials or methods mentioned in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHussain YS, Hookham JC, Allahabadia A, Balasubramanian SP. Epidemiology, management and outcomes of Graves' disease-real life data. Endocrine. 2017;56(3):568\u0026ndash;78.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSmith TJ, Hegedus L. Graves' Disease. N Engl J Med. 2016;375(16):1552\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBahn RS, Heufelder AE. Pathogenesis of Graves' ophthalmopathy. N Engl J Med. 1993;329(20):1468\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSan Miguel I, Arenas M, Carmona R, Rutllan J, Medina-Rivero F, Lara P. Review of the treatment of Graves' ophthalmopathy: The role of the new radiation techniques. Saudi J Ophthalmol. 2018;32(2):139\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBartalena L, Tanda ML. Clinical practice. Graves' ophthalmopathy. N Engl J Med. 2009;360(10):994\u0026ndash;1001.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNilsson A, Tsoumani K, Planck T. 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Thyroid. 2010;20(7):777\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStein JD, Childers D, Gupta S, Talwar N, Nan B, Lee BJ, et al. Risk factors for developing thyroid-associated ophthalmopathy among individuals with Graves disease. JAMA Ophthalmol. 2015;133(3):290\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNoh JY, Hamada N, Inoue Y, Abe Y, Ito K, Ito K. Thyroid-stimulating antibody is related to Graves' ophthalmopathy, but thyrotropin-binding inhibitor immunoglobulin is related to hyperthyroidism in patients with Graves' disease. Thyroid. 2000;10(9):809\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePerez-Moreiras JV, Gomez-Reino JJ, Maneiro JR, Perez-Pampin E, Romo Lopez A, Rodriguez Alvarez FM, et al. Efficacy of Tocilizumab in Patients With Moderate-to-Severe Corticosteroid-Resistant Graves Orbitopathy: A Randomized Clinical Trial. Am J Ophthalmol. 2018;195:181\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eParidaens D, van den Bosch WA, van der Loos TL, Krenning EP, van Hagen PM. The effect of etanercept on Graves' ophthalmopathy: a pilot study. Eye (Lond). 2005;19(12):1286\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShahida B, Johnson PS, Jain R, Brorson H, Asman P, Lantz M, et al. Simvastatin downregulates adipogenesis in 3T3-L1 preadipocytes and orbital fibroblasts from Graves' ophthalmopathy patients. Endocr Connect. 2019;8(9):1230\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLanzolla G, Sabini E, Leo M, Menconi F, Rocchi R, Sframeli A, et al. Statins for Graves' orbitopathy (STAGO): a phase 2, open-label, adaptive, single centre, randomised clinical trial. Lancet Diabetes Endocrinol. 2021;9(11):733\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBifulco M, Ciaglia E. 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Thyroid. 2018;28(3):386\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee J, Kang J, Ahn HY, Lee JK. Sex-specific risk factors associated with graves' orbitopathy in Korean patients with newly diagnosed graves' disease. Eye (Lond). 2023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGreenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol. 2006;6(5):358\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLantz M, Vondrichova T, Parikh H, Frenander C, Ridderstrale M, Asman P, et al. Overexpression of immediate early genes in active Graves' ophthalmopathy. J Clin Endocrinol Metab. 2005;90(8):4784\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWei YH, Liao SL, Wang SH, Wang CC, Yang CH. Simvastatin and ROCK Inhibitor Y-27632 Inhibit Myofibroblast Differentiation of Graves' Ophthalmopathy-Derived Orbital Fibroblasts via RhoA-Mediated ERK and p38 Signaling Pathways. Front Endocrinol (Lausanne). 2020;11:607968.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLanzolla G, Sabini E, Profilo MA, Mazzi B, Sframeli A, Rocchi R, et al. Relationship between serum cholesterol and Graves' orbitopathy (GO): a confirmatory study. J Endocrinol Invest. 2018;41(12):1417\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNaselli A, Moretti D, Regalbuto C, Arpi ML, Lo Giudice F, Frasca F, et al. Evidence That Baseline Levels of Low-Density Lipoproteins Cholesterol Affect the Clinical Response of Graves' Ophthalmopathy to Parenteral Corticosteroids. Front Endocrinol (Lausanne). 2020;11:609895.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGontarz-Nowak K, Szychlinska M, Matuszewski W, Stefanowicz-Rutkowska M, Bandurska-Stankiewicz E. Current Knowledge on Graves' Orbitopathy. J Clin Med. 2020;10(1).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoos JCP, Paulpandian V, Murthy R. Serial TSH-receptor antibody levels to guide the management of thyroid eye disease: the impact of smoking, immunosuppression, radio-iodine, and thyroidectomy. Eye (Lond). 2019;33(2):212\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKyriakos G, Patsouras A, Voutyritsa E, Gravvanis C, Papadimitriou E, Farmaki P, et al. The Role of TPOAb in Thyroid-Associated Orbitopathy: A Systematic Review. Ocul Immunol Inflamm. 2022;30(7\u0026ndash;8):1740\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3272425/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3272425/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground/ Objectives: Recent studies have shown that statins decrease the risk of development of Graves’ ophthalmopathy, although most studies were based on Caucasian cohorts. Our study aims to identify the protective and risk factors for the development of Graves’ ophthalmopathy and the role of statin in newly diagnosed Taiwanese Graves’ disease patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSubjects/ Methods: This was a tertiary hospital-based retrospective cohort including Graves’ disease patients newly diagnosed between 2010 and 2019 at National Taiwan University Hospital. A total of 3,578 patients with Graves’ disease met the inclusion criteria. Univariate and multivariate logistic regression were used to determine the odds ratio of developing Graves’ ophthalmopathy, with adjustment for sociodemographic factors, management of Graves’ disease and thyroid hormone levels to identify protective and risk factors of Graves’ ophthalmopathy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eResults: Usage of statins reduced the risk of Graves’ ophthalmopathy development (odds ratio = 0.2; 95% CI 0.08 ~ 0.50; p \u0026lt; .001) in our multivariate model. Thyroid dysfunction including hyperthyroidism (odds ratio = 4.2; 95% CI 2.97 to 5.88; p \u0026lt; .001) and hypothyroidism (odds ratio = 4.7; 95% CI 3.02 to 7.19; p \u0026lt; .001) both showed an increased risk of developing Graves’ ophthalmopathy. Smoking status and lipid profile did not show as a risk factor.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConclusions: In newly diagnosed Graves’ disease patients, the use of statins decreased the risk of developing Graves’ ophthalmopathy by 80% while serum lipid levels were not found to be risk factors. Further nationwide population-based studies will help clarify the differences in risk factors between ethnic groups.\u003c/p\u003e","manuscriptTitle":"A Reappraisal of the Preventive Effect of Statins on the Development of Graves’ Ophthalmopathy: A Hospital-Based Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-09-27 21:56:55","doi":"10.21203/rs.3.rs-3272425/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1e754337-0f89-4e96-901e-4d0acd159b0b","owner":[],"postedDate":"September 27th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":24901168,"name":"Health sciences/Risk factors"},{"id":24901169,"name":"Health sciences/Diseases/Endocrine system and metabolic diseases/Thyroid diseases"}],"tags":[],"updatedAt":"2023-10-17T15:03:13+00:00","versionOfRecord":[],"versionCreatedAt":"2023-09-27 21:56:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3272425","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3272425","identity":"rs-3272425","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}