Rosuvastatin Myotoxicity After Starting Canagliflozin Treatment.

Abstract

TO THE EDITOR: Brailovski and colleagues (1) attributed their patient's rosuvastatin-induced myotoxicity to a possible rosuvastatin–canagliflozin interaction. The assumed interaction was based on known and speculated factors. The known factors include the roles of organic anion-transporting polypeptides (OATPs) 1B1 and 1B3 in facilitating rosuvastatin uptake into hepatocytes and breast cancer resistance protein (BCRP) in facilitating its intestinal absorption and biliary/renal elimination. Subsequent speculation was that rosuvastatin accumulation resulted from inhibition of the OATPs and BCRP by canagliflozin. However, this speculation is not supported by the cited study. Canagliflozin had less than 50% in vitro inhibition of OATP1B1 and OATP1B3, and canagliflozin in vivo inhibition of the uptake transporters was determined not to be expected according to basic models. Moreover, canagliflozin was not found to be an inhibitor of BCRP at the highest feasible concentration in the used assay (2). We believe that the development of rhabdomyolysis in this case was multifactorial and involved patient and drug characteristics. Patients of Asian descent have been shown to have an approximately 2-fold increase in rosuvastatin exposure compared with White patients at similar doses. Hence, a rosuvastatin dosage of 40 mg/d is contraindicated in Asian patients in Canadian prescribing information (3). Furthermore, this patient's pharmacogenetic testing showed a c421 C>A polymorphism in the ABCG2 gene encoding for BCRP; this could have played a role in this patient's rosuvastatin-altered pharmacokinetics. The baseline plasma rosuvastatin level at which patients can tolerate this medication varies widely on the basis of clinical and pharmacogenetic predictors (4). Change in renal function after canagliflozin initiation also should be considered. In the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial, canagliflozin initiation was associated with an initial short-term reduction in estimated glomerular filtration rate (5). This patient's chronic kidney disease (stage 3B) at baseline predisposed her to a decrease in estimated creatinine clearance to less than 30 mL/min/1.73 m2 after canagliflozin initiation and a potential 3-fold increase in rosuvastatin exposure. The rosuvastatin dosage should not have exceeded 10 mg/d per dosing recommendations (3). In summary, a more plausible explanation for this patient's development of rhabdomyolysis is short-term worsening of renal function secondary to canagliflozin initiation in addition to her predisposing factors (that is, Asian descent, receipt of a rosuvastatin dosage of 40 mg/d, advanced age [76 years], and stage 3B chronic kidney disease) that resulted in rosuvastatin accumulation, subsequent rhabdomyolysis, and associated hepatic injury. Nevertheless, this case remains valuable because it highlights the importance of considering an initial decrease in renal function with canagliflozin, especially in patients with chronic kidney disease. Close monitoring and appropriate dose adjustments are warranted in such patients.