Open Access Research BMJ Open: first published as 10.1136/bmjopen-2017-015935 on 30 June 2017. Downloaded from Lipid-lowering drugs and risk of new- onset diabetes: a cohort study using Japanese healthcare data linked to clinical data for health screening Nobuhiro Ooba,1 Soko Setoguchi,2 Tsugumichi Sato,3 Kiyoshi Kubota4 To cite: Ooba N, Setoguchi S, ABSTRACT Strengths and limitations of this study Sato T, et al. Lipid-lowering Objective To investigate whether lipid-lowering drugs drugs and risk of new-onset are associated with new-onset diabetes after adjusting for diabetes: a cohort study ► This was not a randomised controlled trial but a baseline clinical risk factors for diabetes. using Japanese healthcare retrospective cohort study using health insurance data linked to clinical data for Design A retrospective cohort study. claims data linked to clinical and laboratory data health screening. BMJ Open Setting Japanese employees of large corporations and for annual health screenings and subject to the 2017;7:e015935. doi:10.1136/ their dependents using health insurance claims data confounding bias even if the bias was adjusted as bmjopen-2017-015935 linked to clinical and laboratory data for annual health much as possible. screenings. Prepublication history for ► Our study population included those who worked in ► Participants All persons aged 20 to 74 years with this paper is available online. relatively large corporations and their relatives, aged To view these files please visit dyslipidaemia between 1 January 2005 and 31 March between 20 and 74 years, which means our findings the journal online (http:// dx. doi. 2011. We defined the index date as the first date when might not be readily generalised to those working in org/ 10. 1136/ bmjopen- 2017- the person met the criteria for dyslipidaemia. Persons small corporations or self-employed individuals and 015935). were excluded if they had lipid-lowering drugs, or had old people aged ≥75 years. a diagnosis, a treatment or a laboratory test result The diagnosis code for diabetes was not validated Received 11 January 2017 ► (haemoglobin A1c ≥6.5% or fasting blood glucose in our database, and therefore the outcome Revised 13 May 2017 ≥126 mg/dL) indicating diabetes during the 6-month Accepted 24 May 2017 in sensitivity analyses was defined using an period before the index date. antidiabetic drug with or without the diagnosis code Main outcome measures New-onset diabetes. for diabetes. http://bmjopen.bmj.com/ Results We identified 68 620 persons with dyslipidaemia. ► Although the information on some of potential During the mean follow-up period of 1.96 years, 3674 confounders such as smoking, alcohol consumption persons started treatment with a lipid-lowering drug: and physical exercise was not available, we could 979 with a low potency statin, 2208 with a high potency adjust for several important risk factors of diabetes statin and 487 with a fibrate. Of 3674 new users of a such as HbA1c and fasting blood glucose essential lipid-lowering drug, 3621 had a period of non-use of any in diagnosis of diabetes, as well as body mass index, lipid-lowering drugs before starting a lipid-lowering drug. blood pressure, uric acid, low-density lipoprotein Among statin users, the incidence rate of new-onset cholesterol cholesterol, high-density lipoprotein diabetes was 124.6 per 1000 person-years compared with cholesterol cholesterol, triglyceride and urinary on September 25, 2021 by guest. Protected copyright. 22.6 per 1000 person-years in non-users. After adjusting glucose. for confounding factors including clinical data in health ► Our study suggested that the use of statins was 1Department of Clinical screening using Cox proportional hazards models, the HR associated with an increased risk of new-onset Pharmacy, Nihon University was 1.91 (95% CI 1.38 to 2.64) for low potency statins and diabetes, compared with the period of non-use, School of Pharmacy, Funabashi, 2.61 (2.11 to 3.23) for high potency statins. despite adjusting for risk factors for diabetes (eg, Chiba, Japan Conclusion The use of statins was associated with a 1.9- HbA1c and body mass index) obtained in the annual 2Institute for Health, Health Care fold to 2.6-fold increase in the risk of new-onset diabetes health screening. Policy and Aging Research, in a Japanese population of working age, despite adjusting ► We also found that the risk of new-onset diabetes Rutgers University and Rutgers for clinical risk factors for diabetes. Robert Wood Johnson Medical using high potency statins (atorvastatin, rosuvastatin School, New Brunswick, New and pitavastatin) was higher than that of low potency statins (fluvastatin, pravastatin and simvastatin). Jersey, USA INTRODUCTION 3Department of Pharmacy, Tokyo University of Science, Yamazaki, Hyperlipidaemia is an established risk factor Noda, Chiba, Japan for cardiovascular diseases. In Japan, the 4NPO Drug Safety Research Unit estimated number of patients with hyper- general, although rare adverse reactions Japan, Tokyo, Japan lipidaemia was approximately 1.9 million at such as liver dysfunction and rhabdomyolysis 1 3 Correspondence to 2011. Statins are widely used for primary can occur. According to recent studies, the Dr Kiyoshi Kubota; kubotape- and secondary prevention of cardiovascular use of statins is associated with an increased tky@ umin. net diseases2 and have a good safety profile in risk of new-onset diabetes.4–6 As with Ooba N, et al. BMJ Open 2017;7:e015935. doi:10.1136/bmjopen-2017-015935 1 Open Access BMJ Open: first published as 10.1136/bmjopen-2017-015935 on 30 June 2017. Downloaded from hyperlipidaemia, diabetes is an established risk factor the heath guidance outcome. The data for 215 307 bene- for cardiovascular diseases,7 and therefore the possible ficiaries aged between 20 and 74 years in the study period increased risk of new-onset diabetes by the drugs used (1 January 2005 to 31 March 2011) were collected and to treat hyperlipidaemia may attenuate the effect of maintained by Japan Medical Data Centre Co.13 Infor- reducing the risk of cardiovascular diseases. mation on healthcare utilisation, such as outpatient visits Meta-analyses of randomised trials report that the use and hospitalisation, drugs, medical procedures and diag- of statins was associated with a modestly increased risk noses, was available from the claims data. With respect to of diabetes (overall OR=1.09, 95% CI: 1.02 to 1.17) and drug information14 within the claims, more than 20 000 the OR for individual statins ranged from 0.98 to 1.18.4 local codes are used to specify the trade name and dosage However, randomised trials may not accurately represent form for all approved drugs. Codes for medical proce- actual practice or patients. The results from observa- dures include order of laboratory tests such as HbA1c, tional studies are not consistent. A study using data from triglyceride (TG), total cholesterol, low-density lipopro- the women’s health initiative found that high potency tein (LDL) cholesterol and high-density lipoprotein statins (HR 1.45) and low potency statins (HR 1.48) were (HDL) cholesterol. The 10th revision of the International similarly associated with the increased risk of diabetes.5 Classification of Diseases was used for diagnoses. The On the other hand, in a study using the administrative enrolment data contained the dates of enrolment and healthcare database of Ontario,6 high potency statins had disenrollment. Annual health screening is mandatory for a slightly higher risk than that of low/moderate potency employees irrespective of whether they have already had statins (HR 1.22 vs 0.97/1.11). The association between cardiovascular and other diseases under the Industrial fibrates and new-onset diabetes indicated inconsistent Safety and Health Act, and optional for their depen- results in a small number of previous studies.8 9 dents.15 The health screening data contained values of One potential reason for the inconsistency in assessing BMI, systolic and diastolic blood pressure, total choles- the magnitude of diabetes risk, arising from previous terol, LDL cholesterol, HDL cholesterol, TG, HbA1c, observational studies, may be due to the unavailability FBG, serum creatinine (SCre), uric acid (UA), urinary of information on the important confounders, such as glucose and urinary protein. cholesterol level, blood pressure, body mass index (BMI), haemoglobin A1c (HbA1c) and fasting blood glucose Study cohort (FBG). The inability to control for these factors that poten- We identified 94 630 subjects with or without prior tially introduce confounding by indication or severity cardiovascular diseases who had either total cholesterol may have created an association between the use of a ≥220 mg/dL, LDL cholesterol ≥140 mg/dL, HDL choles- statin with new-onset diabetes variably targeting different terol <40 mg/dL or TG ≥150 mg/dL measured at the study populations in previous studies. It is also unclear annual health screening period between 1 January 2005 http://bmjopen.bmj.com/ whether the risk of new-onset diabetes is specific to statins and 31 March 2011 (figure 1).16 17 We defined the index or common to lipid-lowering drugs (LLDs) including date as the first date when one of these criteria was met fibrates. In addition, there have been few reports on the and the baseline period as the period when the data on association between statins and the incidence of diabetes claims and health screening were available, after the date in the Asian population.10 11 We conducted a cohort study of enrolment but before the index date. Subjects were using claims data linked to the health screening data excluded if they had a baseline period of <6 months, had including blood pressure, BMI, HbA1c, FBG and other a diagnosis of diabetes, had used an antidiabetic drug laboratory test results to assess the association between or had a test result indicating diabetes (HbA1c≥6.5% or on September 25, 2021 by guest.