Risk of New-Onset Diabetes Mellitus Versus Reduction in Cardiovascular Events With Statin Therapy Kang-Ling Wang, MDa,b,c,e, Chia-Jen Liu, MDc,e,f, Tze-Fan Chao, MDc,e, Su-Jung Chen, MDc,e,f, Cheng-Hsueh Wu, MDc,e, Chi-Ming Huang, MDe, Chun-Chin Chang, MDc, Ko-Fan Wang, MDc, Tzeng-Ji Chen, MD, PhDd, Shing-Jong Lin, MD, PhDb,c,e, and Chern-En Chiang, MD, PhDa,b,c,e,* The Food and Drug Administration recently updated the safety warning concerning the association between statin therapy and new-onset diabetes mellitus (NODM). For prediabetes, little information is available for statins on cardiovascular outcome reduction and diabetogenic consequences. This study aimed to examine the risk of NODM and the reduction of cardiovascular events and death (MACE) after statin therapy in the prediabetic subjects. The medical and pharmacy claims of the prediabetic beneficiaries were retrieved from Taiwan National Health Insurance research database. The occurrence of NODM, MACE, and morbidity indexed by hospitalizations and emergency visits was ascertained by ambulatory and inpatient database. A propensity scoreematched model was constructed for statin users and nonusers. During follow-up (4.1 – 2.5 years), NODM and MACE occurred in 23.5% and 16.7%, respectively, of nonusers and 28.5% and 12.0%, respectively, of users. Statin therapy was associated with a greater risk of NODM (hazard ratio 1.20, 95% confidence interval 1.08 to 1.32) and less risk of MACE (hazard ratio 0.70, 95% confidence interval 0.61 to 0.80), both in dose-dependent fashions. The earlier and more persistent use correlated with the greater increase in risk of NODM offset by the proportionally larger reduction in MACE. Furthermore, the early persistent users had the lowest rate of hospitalizations and emergency visits. In conclusion, our findings suggested that the relation between NODM and therapeutic advantages of statins was parallel in the prediabetic population. Treatment benefits outweighed diabetic consequences in subjects receiving the earlier and more persistent treatment. Ó 2013 Elsevier Inc. All rights reserved. (Am J Cardiol 2013;-:-e-) Statins effectively reduce atherosclerotic complications, irrespective of the level of glucose metabolism disturbance.1,2 However, statin therapy is associated with an increased risk of new-onset diabetes mellitus (NODM).3 Previous analyses indicated that the risk of NODM was significantly outweighed by the reduction in vascular events or deaths among subjects with cardiovascular disease (CVD).4,5 Post hoc analyses of clinical trials identified that subjects with diabetes mellitus (DM) risk factors were at greater risk of NODM after statin therapy,6,7 particularly those who had impaired fasting glucose.8 Because clinical trials enrolled subjects who can be randomized into therapeutic allocations among prespecified

a

General Clinical Research Center, bDepartment of Medical Research and Education, cDepartment of Medicine, and dDepartment of Family Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; and eSchool of Medicine and fInstitute of Public Health, National Yang-Ming University, Taipei, Taiwan. Manuscript received August 7, 2013; revised manuscript received and accepted October 29, 2013. Drs. Kang-Ling Wang and Chia-Jen Liu contributed equally to this study. This work was supported in part by grant DOH99-TD-B-111-008 from the Department of Health (Taipei, Taiwan), NSC99-2314-B-075-038-MY3 from the National Science Council (Taipei, Taiwan), and grants V102B028, V102C-002, and V100D-002-3 from Taipei Veterans General Hospital (Taipei, Taiwan). See page 6 for disclosure information. *Corresponding author: Tel: (þ886) 2-28757602; fax: (þ886) 2-28745422. E-mail address: [email protected] (C.-E. Chiang). 0002-9149/13/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.10.043

populations, the conducts in trials do not always reflect usual clinical practice. Meanwhile, the population studies demonstrated the ethnic differences in the risk of NODM and in the distributions of metabolic risk factors attributed to CVD.9,10 The purpose of this study was to evaluate the disadvantages and advantages of statin therapy with regards to NODM and the reduction of major adverse cardiovascular events (MACEs) in the prediabetic population and to explore whether the earlier and more persistent statin therapy attenuates subsequent adverse outcomes in prediabetic subjects. Methods The Taiwan National Health Insurance research database (NHIRD) is the representative healthcare database of the Taiwan population. The longitudinal data from 2001 to 2010 were obtained for this retrospective analysis. Prediabetic subjects as the presence of International Classification of Diseases, Ninth Revision codes for abnormal glucose in the medical claims, who had not been prescribed antidiabetic medications at the consecutive visits (
30 days apart), were identified. Among them, subjects aged
45 years, who continuously received statins
7 days before having a DM diagnosis, or those naive to statins before a DM diagnosis were enrolled. Those who had endocrine disorders, who ever received systemic steroid or hypolipidemic agents other than statins, or who had followup