Background
Statins are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors primarily used for treatment of hyperlipidemia. Recently, they have been shown to inhibit proliferation of uterine fibroid cells and inhibit tumor growth in fibroid animal models.
Objective
We sought to examine the association between statin use and the risk of uterine fibroids and fibroid-related symptoms in a nationally representative sample of commercially insured women diagnosed with hyperlipidemia.
Study Design
We performed a nested case-control study of >190,000 women enrolled in one of the nation’s largest commercial health insurance programs. From a cohort of women aged 18-65 years diagnosed with hyperlipidemia from January 2004 through March 2011, we identified 47,713 cases (women diagnosed with uterine fibroids) and 143,139 controls (women without uterine fibroids) matched at a 1:3 ratio on event/index date (month and year) and age (±1 year). We used conditional and unconditional logistic regression to calculate odds ratios and 95% confidence intervals for the risk of uterine fibroids and fibroid-related symptoms associated with prior use of statins.
Results
Exposure to statins within 2 years before the event/index date was associated with a decreased risk of uterine fibroids (odds ratio, 0.85; 95% confidence interval, 0.83–0.87). In a separate subanalysis restricted to cases, statin users had a lower likelihood of having menorrhagia (odds ratio, 0.88; 95% confidence interval, 0.84–0.91), anemia (odds ratio, 0.84; 95% confidence interval, 0.79–0.88), or pelvic pain (odds ratio, 0.85; 95% confidence interval, 0.81–0.91) and of undergoing myomectomy (odds ratio, 0.76; 95% confidence interval, 0.66–0.87) compared to nonusers.
Conclusion
The use of statins was associated with a lower risk of uterine fibroids and fibroid-related symptoms. Further studies, including randomized controlled trials, may be warranted.
Introduction
Uterine fibroids, also called myomas or leiomyomas, are the most common benign gynecologic tumors, with a lifetime incidence of approximately 70%. They are associated with multiple symptoms, including heavy uterine bleeding and pelvic pain. Currently used treatments include contraceptive steroids, gonadotropin-releasing hormone agonists, progesterone modulators, uterine artery embolization, magnetic resonance imaging–guided focused ultrasound surgery, and radiofrequency ablation. Even though many of these options may improve the symptoms, they possess significant side effects or other limitations. Surgery, whether removing the tumor (myomectomy) or uterus (hysterectomy), is indicated in many cases. In the United States alone, fibroids are associated with >200,000 hysterectomies, with an estimated annual cost of $5.9-34.4 billion. Therefore, there is a need for a successful medical treatment for fibroids.
Statins are a drug family primarily used for hyperlipidemia. In addition to lowering cholesterol, statins have been observed to have antiproliferative effects against certain tumors, including breast, ovarian, leukemia, prostate, lung, and colon cancer. Recently, Liu and colleagues published a meta-analysis of 14 studies, including 12,904 gynecologic cancer patients, and found that statins significantly decreased the incidence of ovarian cancer (relative risk [RR], 0.48; 95% confidence interval [CI], 0.28–0.8). In addition, Graaf and colleagues analyzed records of a Dutch database and reported that statin use was associated with a 20% reduction of cancer incidence in general.
In addition, studies have demonstrated that simvastatin and atorvastatin inhibit progression of certain benign steroid-dependent gynecologic disorders, such as endometriosis. More recent reports demonstrated that simvastatin inhibits proliferation and induces calcium-dependent programmed cell death in fibroid cells. It was also reported to inhibit tumor growth in a patient-derived xenograft mouse model. However, no clinical or population-based studies have examined the association of statin use and the risk of uterine fibroids. The aim of this population-based study was to examine the hypothesis that statin use is associated with a lower risk of uterine fibroids and fibroid-related symptoms.
Materials and Methods
Data source
This population-based study used administrative health data from Clinformatics DataMart (CDM) Database (OptumInsight, Eden Prairie, MN), a database of one of the nation’s largest commercial health insurance programs. CDM data have been used to examine health services and drug utilization in numerous studies. Persons enrolled in this insurance program may be included in either a fee-for-service plan or a managed care plan, which includes health maintenance organizations, preferred provider organizations, and exclusive provider organizations. For each of these plans, providers are required to submit complete claims to receive reimbursement.
We used a combination of outpatient, inpatient, and pharmacy claims data. The pharmacy database contains eligibility and claims information for medications from retail pharmacies through a member’s pharmacy benefit. This study was approved by the institutional review board of the University of Texas Medical Branch at Galveston.
Overall study cohort
The overall study cohort included women aged 18-65 years who had continuous enrollment in CDM for at least 3 years and diagnoses of hyperlipidemia during the study period (January 1, 2004, through March 31, 2011). Hyperlipidemia was diagnosed using the International Classification of Diseases, Ninth Revision, Clinical Modification ( ICD-9-CM ) diagnosis code (272.X). The Appendix includes a list of ICD-9-CM codes used in this study.
Because statins are commonly prescribed for hyperlipidemia, we restricted the overall study cohort to women with hyperlipidemia so that all cases and controls had a diagnosis of the potentially confounding condition, hyperlipidemia.
Cases
Within the overall study cohort, we identified cases who received first-time diagnoses of uterine fibroids, identified by ICD-9-CM code 218.X. We defined a first-time diagnosis as a patient with no uterine fibroid diagnosis in the previous 2 years (look-back period). The date of uterine fibroid diagnosis served as the event date for all subsequent analyses.
Controls
From the overall study cohort, controls (women without diagnoses of uterine fibroids) were selected to match cases on event/index month and age (±1 year) at a 3:1 ratio. The initial starting dates for controls were assigned to match the month and year of diagnosis of the cases (index date). We performed matching using a conventional methodology as previously described.
Sociodemographic characteristics of the study population included age and region (Midwest, Northeast, South, and West). Elixhauser comorbidity index was generated based on claims within the year prior to the diagnosis/index date. This database did not include race/ethnicity data; therefore, we were unable to analyze these variables.
Statin use
Information on statin use was collected from the prescription data files of CDM. Patients were considered exposed to statins if they filled statin prescriptions within the 2 years before the event/index date. A statin prescription fill was assessed using the generic name (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin).
Statistical analysis
Descriptive statistics were used to assess the demographic and clinical variables in cases and controls. Conditional logistic regression was used to examine the risk of uterine fibroids in association with statin use, calculated as odds ratios (ORs) with 95% CIs.
To adjust for geographic regions and unbalanced comorbidities, we added these variables in the conditional logistic regression to calculate adjusted ORs (aORs). To examine the robustness of results, we performed sensitivity analyses with statin prescriptions within the 90- and 30-day periods before the diagnosis/index date, based on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement. To examine the association among different age groups and different statins, we performed stratified analyses.
To examine the association of statin use and fibroid-related symptoms among the fibroid case group, we performed a separate exploratory subanalysis where we used unconditional logistic regression to further analyze the risk for menorrhagia, anemia, pelvic pain, myomectomies, and hysterectomies that occurred within 1 year following the diagnosis of uterine fibroids.
In this study, we used ICD-9-CM and Current Procedural Terminology codes ( Appendix ). All analyses were performed using software (SAS, Version 9.3; SAS Institute Inc, Cary, NC). All statistical tests were 2-sided with P < .05 considered to be statistically significant.
Materials and Methods
Data source
This population-based study used administrative health data from Clinformatics DataMart (CDM) Database (OptumInsight, Eden Prairie, MN), a database of one of the nation’s largest commercial health insurance programs. CDM data have been used to examine health services and drug utilization in numerous studies. Persons enrolled in this insurance program may be included in either a fee-for-service plan or a managed care plan, which includes health maintenance organizations, preferred provider organizations, and exclusive provider organizations. For each of these plans, providers are required to submit complete claims to receive reimbursement.
We used a combination of outpatient, inpatient, and pharmacy claims data. The pharmacy database contains eligibility and claims information for medications from retail pharmacies through a member’s pharmacy benefit. This study was approved by the institutional review board of the University of Texas Medical Branch at Galveston.
Overall study cohort
The overall study cohort included women aged 18-65 years who had continuous enrollment in CDM for at least 3 years and diagnoses of hyperlipidemia during the study period (January 1, 2004, through March 31, 2011). Hyperlipidemia was diagnosed using the International Classification of Diseases, Ninth Revision, Clinical Modification ( ICD-9-CM ) diagnosis code (272.X). The Appendix includes a list of ICD-9-CM codes used in this study.
Because statins are commonly prescribed for hyperlipidemia, we restricted the overall study cohort to women with hyperlipidemia so that all cases and controls had a diagnosis of the potentially confounding condition, hyperlipidemia.
Cases
Within the overall study cohort, we identified cases who received first-time diagnoses of uterine fibroids, identified by ICD-9-CM code 218.X. We defined a first-time diagnosis as a patient with no uterine fibroid diagnosis in the previous 2 years (look-back period). The date of uterine fibroid diagnosis served as the event date for all subsequent analyses.
Controls
From the overall study cohort, controls (women without diagnoses of uterine fibroids) were selected to match cases on event/index month and age (±1 year) at a 3:1 ratio. The initial starting dates for controls were assigned to match the month and year of diagnosis of the cases (index date). We performed matching using a conventional methodology as previously described.
Sociodemographic characteristics of the study population included age and region (Midwest, Northeast, South, and West). Elixhauser comorbidity index was generated based on claims within the year prior to the diagnosis/index date. This database did not include race/ethnicity data; therefore, we were unable to analyze these variables.
Statin use
Information on statin use was collected from the prescription data files of CDM. Patients were considered exposed to statins if they filled statin prescriptions within the 2 years before the event/index date. A statin prescription fill was assessed using the generic name (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin).
Statistical analysis
Descriptive statistics were used to assess the demographic and clinical variables in cases and controls. Conditional logistic regression was used to examine the risk of uterine fibroids in association with statin use, calculated as odds ratios (ORs) with 95% CIs.
To adjust for geographic regions and unbalanced comorbidities, we added these variables in the conditional logistic regression to calculate adjusted ORs (aORs). To examine the robustness of results, we performed sensitivity analyses with statin prescriptions within the 90- and 30-day periods before the diagnosis/index date, based on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement. To examine the association among different age groups and different statins, we performed stratified analyses.
To examine the association of statin use and fibroid-related symptoms among the fibroid case group, we performed a separate exploratory subanalysis where we used unconditional logistic regression to further analyze the risk for menorrhagia, anemia, pelvic pain, myomectomies, and hysterectomies that occurred within 1 year following the diagnosis of uterine fibroids.
In this study, we used ICD-9-CM and Current Procedural Terminology codes ( Appendix ). All analyses were performed using software (SAS, Version 9.3; SAS Institute Inc, Cary, NC). All statistical tests were 2-sided with P < .05 considered to be statistically significant.
Results
We identified 47,713 cases with uterine fibroids and 143,139 age-matched controls, nested within a cohort of women who were diagnosed with hyperlipidemia from January 2006 through March 2011. First, we looked at the demographic and clinical characteristics of the study population ( Table 1 ). As expected, most of the cases were in the age groups of 40-48 years (41.79%) and 50-59 years (36.29%). In addition, most cases came from the southern geographic region (51.91%). We also assessed 31 comorbidities in both cases and controls using Elixhauser comorbidity index. Except for congestive heart failure, uncomplicated diabetes, paralysis, and pulmonary circulation disorders, comorbidities were not balanced between case and control groups. Therefore, we adjusted for these unbalanced comorbidities in subsequent analyses.
| Characteristics | Fibroid cases | Controls a | P value |
|---|---|---|---|
| All subjects, no. | 47,713 | 143,139 | |
| Age, no. (%) | .9999 | ||
| 18–29 y | 414 (0.87) | 1242 (0.87) | |
| 30–39 y | 5355 (11.24) | 16,065 (11.22) | |
| 40–49 y | 19,940 (41.79) | 59,820 (41.79) | |
| 50–59 y | 17,315 (36.29) | 51,945 (36.29) | |
| 60–65 y | 4689 (9.83) | 14,067 (9.83) | |
| Mean ± SD | 48.74 ± 7.82 | 48.74 ± 7.82 | |
| Geographic region, no. (%) | <.001 | ||
| Northeast | 8197 (17.18) | 16,173 (11.30) | |
| Midwest | 8590 (18.00) | 34,470 (24.08) | |
| South | 24,768 (51.91) | 72,834 (50.88) | |
| West | 6135 (12.86) | 19,627 (13.71) | |
| Unknown | 23 (0.05) | 35 (0.02) | |
| Comorbidities, no. (%) | |||
| AIDS/HIV | 112 (0.23) | 177 (0.12) | <.001 |
| Alcohol abuse | 229 (0.48) | 833 (0.58) | .010 |
| Blood loss anemia | 1095 (2.29) | 878 (0.61) | <.001 |
| Cardiac arrhythmia | 2890 (6.06) | 7067 (4.94) | <.001 |
| Chronic pulmonary disease | 5757 (12.07) | 16,734 (11.69) | .028 |
| Coagulopathy | 604 (1.27) | 1356 (0.95) | <.001 |
| Congestive heart failure | 701 (1.47) | 1980 (1.38) | .167 |
| Deficiency anemia | 4314 (9.04) | 6060 (4.23) | <.001 |
| Depression | 6623 (13.88) | 22,033 (15.39) | <.001 |
| Diabetes complicated | 1309 (2.74) | 4435 (3.10) | <.001 |
| Diabetes uncomplicated | 7672 (16.08) | 23,356 (16.32) | .223 |
| Drug abuse | 153 (0.32) | 649 (0.45) | .001 |
| Fluid and electrolyte disorders | 2051 (4.30) | 5466 (3.82) | <.001 |
| Hypertension complicated | 1580 (3.31) | 3822 (2.67) | <.001 |
| Hypertension uncomplicated | 19,888 (41.68) | 55,788 (38.97) | <.001 |
| Hypothyroidism | 10,782 (22.60) | 30,367 (21.22) | <.001 |
| Liver disease | 2650 (5.55) | 4893 (3.42) | <.001 |
| Lymphoma | 179 (0.38) | 434 (0.30) | .016 |
| Metastatic cancer | 341 (0.71) | 534 (0.37) | <.001 |
| Obesity | 5011 (10.50) | 12,582 (8.79) | <.001 |
| Other neurological disorders | 772 (1.62) | 2664 (1.86) | <.001 |
| Paralysis | 106 (0.22) | 345 (0.24) | .462 |
| Peptic disease excluding bleeding | 351 (0.74) | 752 (0.53) | <.001 |
| Peripheral vascular disorders | 1164 (2.44) | 2876 (2.01) | <.001 |
| Psychoses | 220 (0.46) | 829 (0.58) | .003 |
| Pulmonary circulation disorders | 306 (0.64) | 833 (0.58) | .145 |
| Renal failure | 536 (1.12) | 1789 (1.25) | .029 |
| Rheumatoid arthritis/collagen | 2093 (4.39) | 5550 (3.88) | <.001 |
| Solid tumor without metastasis | 2630 (5.51) | 5078 (3.55) | <.001 |
| Valvular disease | 3051 (6.39) | 6986 (4.88) | <.001 |
| Weight loss | 803 (1.68) | 1934 (1.35) | <.001 |
| Statin use, no. (%) | <.001 | ||
| Yes | 13,498 (28.29) | 45,155 (31.55) | |
| No | 34,215 (71.71) | 97,984 (68.45) |
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