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To identify risk factors for the development of statin-associated diabetes mellitus (DM).The study was conducted in two phases. Phase one involved high-throughput in silico processing of a large amount of biomedical data to identify risk factors for the development of statin-associated DM. In phase two, the most prominent risk factor identified was confirmed in an observational cohort study at Clalit, the largest health care organization in Israel. Time-dependent Poisson regression multivariable models were performed to assess rate ratios (RRs) with 95% CIs for DM occurrence.A total of 39,263 statin nonusers were matched by propensity score to 20,334 highly compliant statin initiators in 2004–2005 and followed until the end of 2010. Within 59,597 statin users and nonusers in a multivariable model, hypothyroidism and subclinical hypothyroidism carried an increased risk for DM (RR 1.53 [95% CI 1.31–1.79] and 1.75 [1.40–2.18], respectively). Hypothyroidism increased DM risk irrespective of statin treatment (RR 2.06 [1.42–2.99] and 1.66 [1.05–2.64] in statin users and nonusers, respectively). Subclinical hypothyroidism risk for DM was prominent only upon statin use (RR 1.94 [1.13–3.34] and 1.20 [0.52–2.75] in statin users and nonusers, respectively). Patients with hypothyroidism treated with thyroid hormone replacement therapy were not at increased risk for DM.Hypothyroidism is a risk factor for DM. Subclinical hypothyroidism-associated risk for DM is prominent only upon statin use. Identifying and treating hypothyroidism and subclinical hypothyroidism might reduce DM risk. Future clinical studies are needed to confirm the findings.