We performed this population-based study to investigate the effects of atorvastatin and rosuvastatin on renal function in patients with type 2 diabetes. From the Taiwan National Health Insurance Pay-for-Performance program for diabetes mellitus database, 2006 to 2009, type 2 diabetic patients aged 40 to 100 years with the first prescription of atorvastatin or rosuvastatin were identified. All the data were linked to the National Health Insurance claims database, 2000 to 2010, to construct longitudinal health care data. The Modification of Diet in Renal Disease equation was used to calculate the estimated glomerular filtration rate (eGFR), and the eGFRs between baseline and the end of follow-up (maximum 2 years) were compared. Totally, 3,601 new users of atorvastatin and 1,968 new users of rosuvastatin were included. The median follow-up was 238 days in atorvastatin users and 210 days in rosuvastatin users. The eGFR at baseline was 72.3 ± 25.9 ml/min/1.73 m 2 in atorvastatin users and 73.7 ± 27.3 ml/min/1.73 m 2 in rosuvastatin users. In both statin groups, we found no significant change in eGFR (+0.1 ml/min/1.73 m 2 , 95% confidence interval −0.4 to 0.7, p = 0.62 in atorvastatin users; −0.1 ml/min/1.73 m 2 , 95% confidence interval −0.8 to 0.6, p = 0.77 in rosuvastatin users). In conclusion, neither treatment with atorvastatin nor rosuvastatin was associated with a significant change of renal function in type 2 diabetic patients.
Several studies have refuted the adverse effect of statin therapy on renal function. However, a few large-scale observational studies reported an association between statins, especially high-potency statins, and acute kidney injury. The aim of this study was to evaluate the effects of 2 high-potency statins, atorvastatin and rosuvastatin, on renal function in adult type 2 diabetic patients in an ethnic Chinese population. A retrospective cohort study using the longitudinal National Health Insurance (NHI) claims data of Taiwan was conducted.
Methods
Taiwan launched a single-payer NHI Program since 1995. As of 2007, >98% of the total Taiwanese population is covered by the program. Patient identification numbers, gender, birthdays, dates of hospital admission and discharge, diagnoses, and drugs dispensed are available in the NHI claims database. The diagnoses are coded according to the International Classification of Diseases, Ninth Revision, Clinical Modification ( ICD-9-CM ) system. Under the NHI system, most health care services are reimbursed on a fee-for-service basis. Since 2001, the NHI program has implemented a Pay-for-Performance (P4P) program for diabetes mellitus. Hospitals and community clinics with qualified physicians can voluntarily apply to participate in the NHI P4P program. The participating physicians then can enroll patients in the NHI P4P program. The NHI P4P program reimburses participating clinicians with additional physician fees and case management fees in addition to regular reimbursement for health care services to increase comprehensive follow-up visits including annual diabetes-specific examinations, such as laboratory tests. Clinical characteristics of the enrolled patients, including habits of smoking and alcohol drinking, body height, body weight, body mass index, and key follow-up laboratory data concerning diabetic care, were reported by the hospitals themselves periodically and were entered into the P4P-specific database automatically.
Our data came from 2 databases. One database contained information collected from the NHI P4P program for the period from January 2006 to December 2010 and was used to obtain major clinical characteristics of patients and physicians. The patients’ NHI P4P records were then linked to the NHI claims database through 2000 to 2010 by patient identification number to identify co-morbidities, drug exposures, and medical utilizations during the baseline period. To comply with privacy regulations, personal identifiers were encrypted, and all data were analyzed anonymously. The study protocol was approved by the Institutional Review Board of the National Taiwan University Hospital.
All type 2 diabetic patients aged between 40 and 100 years with the first prescription of atorvastatin or rosuvastatin were identified from the NHI P4P database through 2006 to 2009, and their longitudinal claims data were extracted from the NHI claims database. The date on which the first statin was prescribed was operationally set as the index date. Background characteristics and co-morbidities of the enrolled subjects were assessed within the baseline 6-month period before the index date. Patients who had received any type of statin or any type of renal replacement therapy during the baseline 6-month period were excluded. Besides, we also excluded subjects receiving >1 statin at the index date, subjects without baseline serum creatinine level, and subjects with abnormally high baseline serum alanine aminotransferase levels (>1,000 IU/L). Only subjects with at least 1 report of serum creatinine level during the follow-up period were retained in the study cohort.
All subjects were followed from their index dates until they had a prescription of another type of statin, no refill for statins after 1.5 times the duration of their last prescription of statins, died, withdrawal from health insurance coverage, initiation of any renal replacement therapy, maximum 2 years of follow-up, or reached the end of the study at December 31, 2010, whichever came first.
The abbreviated Modification of Diet in Renal Disease equation was used to calculate the estimated glomerular filtration rate (eGFR). The baseline eGFR was calculated based on the last record of serum creatinine level before the index date, and the follow-up eGFR was calculated based on the last record of serum creatinine level before the end of follow-up (last observation carried forward approach). The change of eGFR between end of follow-up and baseline was calculated for each subject accordingly.
In addition to baseline age at prescription of specific study drugs and gender, we assessed the potential confounders such as smoking, alcohol drinking, body mass index, key laboratory data at baseline, co-morbidities, history of exposure to nephrotoxic drugs, specialty of prescribing physicians, and medical utilizations within the baseline 6-month period. The laboratory data (also using last observation carried forward approach) included fasting blood glucose, glycated hemoglobin (HbA1c), alanine aminotransferase, uric acid, low-density lipoprotein cholesterol, and baseline eGFR. The stage of chronic kidney disease (CKD) was defined according to baseline eGFR. Most of the co-morbidities were extracted based on the revised ICD-9-CM coding algorithms for Elixhauser Index except for myocardial infarction (410.x and 412.x) and cerebrovascular disease (362.34 and 430.x to 438.x). Only those co-morbidities with a prevalence of >1% were retained in the analysis ( Table 1 ). The list of potential nephrotoxic drugs were acetaminophen, aspirin, nonsteroidal anti-inflammatory drugs, allopurinol, penicillins, cephalosporins, sulfonamides, aminoglycosides, quinolones, thiazide diuretics, loop diuretics, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), H 2 -receptor antagonists, and proton pump inhibitors. The specialty of prescribing physicians included family medicine, internal medicine, cardiology, nephrology, and endocrinology. Medical utilizations were defined as number of outpatient visits and number of hospitalizations during baseline 6-month period.
| Variable | Atorvastatin | Rosuvastatin | P value |
|---|---|---|---|
| (n=3601) | (n=1968) | ||
| Age (years) | 62.8 ± 10.5 | 61.7 ± 10.2 | <0.0001 |
| Men | 1683 (47%) | 980 (50%) | 0.029 |
| Smoker | 1672 (46%) | 835 (42%) | 0.004 |
| Alcohol use | 1679 (47%) | 813 (41%) | <0.001 |
| Body mass index (kg/m 2 ) | 26.4 ± 3.7 | 26.5 ± 3.9 | 0.27 |
| Baseline | |||
| Fasting glucose (mg/dL) | 151.8 ± 50.0 | 155.1 ± 57.4 | 0.037 |
| Glycated hemoglobin (%) | 7.9 ± 1.6 | 8.0 ± 1.7 | 0.019 |
| Alanine aminotransferase (IU/L) | 29.1 ± 22.5 | 28.2 ± 19.6 | 0.25 |
| Uric acid (md/dL) | 6.3 ± 1.8 | 6.2 ± 1.6 | 0.36 |
| LDL-C (mg/dL) | 136.4 ± 32.2 | 139.7 ± 34.5 | <0.001 |
| Creatinine (mg/dL) | 1.1 ± 0.5 | 1.1 ± 1.1 | 0.31 |
| eGFR (mL/min/1.73m 2 ) | 72.3 ± 25.9 | 73.7 ± 27.3 | 0.06 |
| Chronic kidney disease stage | 0.37 | ||
| 1 | 856 (24%) | 476 (24%) | |
| 2 | 1608 (45%) | 876 (45%) | |
| 3 | 964 (27%) | 541 (27%) | |
| 4 | 152 (4%) | 62 (3%) | |
| 5 | 21 (1%) | 13 (1%) | |
| Comorbidities | |||
| Myocardial infarction | 22 (1%) | 14 (1%) | 0.65 |
| Cerebrovascular disease | 236 (7%) | 128 (7%) | 0.94 |
| Congestive heart failure | 145 (4%) | 40 (2%) | <0.0001 |
| Cardiac arrhythmia | 117 (3%) | 74 (4%) | 0.32 |
| Valvular heart disease | 51 (1%) | 23 (1%) | 0.44 |
| Peripheral vascular disorder | 83 (2%) | 41 (2%) | 0.59 |
| Hypertension | 1981 (55%) | 1046 (53%) | 0.18 |
| Paralysis | 25 (1%) | 5 (0%) | 0.035 |
| Other neurological disorder | 42 (1%) | 18 (1%) | 0.38 |
| Chronic pulmonary disease | 277 (8%) | 111 (6%) | 0.004 |
| Hypothyroidism | 38 (1%) | 31 (2%) | 0.09 |
| Liver disease | 296 (8%) | 173 (9%) | 0.46 |
| Peptic ulcer disease, excluding bleeding | 265 (7%) | 125 (6%) | 0.16 |
| Cancer | 131 (4%) | 60 (3%) | 0.25 |
| Collagen vascular disease | 109 (3%) | 38 (2%) | 0.015 |
| Psychosis | 26 (1%) | 21 (1%) | 0.18 |
| Depression | 116 (3%) | 44 (2%) | 0.035 |
| Exposure to nephrotoxic drugs | |||
| Acetaminophen | 1559 (43%) | 804 (41%) | 0.08 |
| Aspirin | 131 (4%) | 44 (2%) | 0.004 |
| NSAIDs | 1693 (47%) | 936 (48%) | 0.70 |
| Allopurinol | 104 (3%) | 48 (2%) | 0.33 |
| Penicillins | 561 (16%) | 294 (15%) | 0.53 |
| Cephalosporins | 648 (18%) | 355 (18%) | 0.97 |
| Sulfonamides | 281 (8%) | 159 (8%) | 0.72 |
| Aminoglycosides | 121 (3%) | 65 (3%) | 0.91 |
| Quinolones | 117 (3%) | 67 (3%) | 0.76 |
| Thiazide diuretics | 206 (6%) | 107 (5%) | 0.66 |
| Loop diuretics | 281 (8%) | 159 (8%) | 0.72 |
| ACEIs | 666 (18%) | 316 (16%) | 0.023 |
| Angiotensin receptor blockers | 1207 (34%) | 639 (32%) | 0.43 |
| H 2 -receptor antagonists | 501 (14%) | 253 (13%) | 0.27 |
| Proton pump inhibitors | 136 (4%) | 87 (4%) | 0.24 |
| Specialty of prescribing physicians | <0.0001 | ||
| Family medicine | 456 (13%) | 71 (4%) | |
| Internal medicine | 580 (16%) | 290 (15%) | |
| Cardiology | 223 (6%) | 124 (6%) | |
| Nephrology | 79 (2%) | 52 (3%) | |
| Endocrinology | 1930 (54%) | 1391 (71%) | |
| Medical utilizations | |||
| Outpatient visits | 14.9 ± 11.9 | 14.4 ± 11.5 | 0.16 |
| Hospitalizations | 0.1 ± 0.4 | 0.1 ± 0.4 | 0.55 |
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