Risk of Myopathy Associated With DPP-4 Inhibitors in Combination With Statins: A Disproportionality Analysis Using Data From the WHO and French Spontaneous Reporting Databases.

Recently, a pharmacovigilance safety warning was released by the European Medicines Agency concerning the risk of myopathy and rhabdomyolysis associated with the use of dipeptidyl peptidase 4 (DPP-4) inhibitors (1,2). The warning was based on several cases in which DPP-4 inhibitors were used in association with statins; a drug-drug interaction was suggested (3). As statin use is likely to be common in patients with diabetes, it is important to investigate this potential serious risk and the underlying drug-drug interaction hypothesis. This need is enforced by the recentmarketing in several countries of fixed combinations containing both statins and DPP-4 inhibitors (4). The aim of the study, therefore, was to assess the association betweenmyopathy and the use of DPP-4 inhibitors, alone and in combination with statins, by analyzing data from two pharmacovigilance spontaneous reporting databases. Data from the French Base Nationale de Pharmacovigilance (BNPV) and the World Health Organization (WHO) global individual case safety reports database, VigiBase, were analyzed for the 2009– 2015 time period. Cases consisted of all reported adverse drug reactions (ADRs) of muscular injury, which were identified in both databases by using the dedicated Standardized MedDRA Queries (“myopathy/rhabdomyolysis”). All reports of other ADRs were considered noncases. The exposures of interest were the use of DPP-4 inhibitors along with statins at the time the ADR occurred, as we were investigating a potential drug-drug interaction between DPP-4 inhibitors and statins. We conducted complementary analyses considering exposures to all noninsulin antidiabetes agents other than DPP-4 inhibitors and to fibrates. As other noninsulin antidiabetes agents share indications with DPP-4 inhibitors, the absence of an association between those drugs and myopathy would argue against a potential indication bias in which DPP-4 inhibitors might seem to be associated with myopathy owing to specific susceptibility among patients with type 2 diabetes; the same would hold true for fibrates, statins, and patients with dyslipidemia as a background influence. In the BNPV, disproportionality analyses based upon the case/noncase approach were performed (5). Unconditional logistic regression was used to derive reporting odds ratios (RORs) adjusted for age, sex, use of glucose-lowering drugs (DPP-4 inhibitors or other noninsulin antidiabetes agents), and use of lipid-lowering drugs (fibrates or statins) for each drug combination being evaluated. The likelihood that a given ADR resulted froma suspected drugdrug interactionwas estimatedby theROR value for the drug combination being evaluated. According to the interaction additivemodel (6), a ROR value for coexposure that exceeds the sum of the RORs estimated for each individual class of drug supports a potential drug-drug interaction. In VigiBase, analyses used the Bayesian estimators specifically developed by theWHOUppsalaMonitoring Centre for this database: the information component for evaluating the association between a given ADR and an individual drug and the omega value for estimating the relationship between a given ADR and a drug combination. In BNPV, the use of DPP-4 inhibitors without statins and without fibrates was significantly associated with reports of myopathy. Conversely, no increase in reports of myopathy was found for other noninsulin antidiabetes agents in the same conditions. Assessment of drug-drug interaction showed an increase in reports of myopathy for the concomitant use of DPP-4 inhibitors and statins, but it was lower than that found for statins alone and thus did not support a potential drug-drug interaction according to the additive model (Table 1). In this database, concomitant use of DPP-4 inhibitors and statins had been reported in 19 ADR cases (12 were serious, 4 of them associated with renal