Rosuvastatin-Canagliflozin Combo May Be Toxic, Case Suggests

A 76-year-old Filipina woman who had been taking rosuvastatin 40 mg per day without a problem for more than 5 years started developing pain and weakness in her thighs just days after starting on the diabetes medication canagliflozin (Invokana; Janssen), according to a case report.

The condition worsened to the point that the woman went to the hospital, where lab results showed that the plasma concentration of rosuvastatin was way too high.

“We recognized her presentation as statin toxicity,” senior author David Juurlink, MD, PhD (University of Toronto, Canada), told TCTMD. “We quantified her rosuvastatin level and found it to be 15 times higher than it should be for someone on her dose. She could not have tolerated a rosuvastatin concentration this high for 5 years.”

After exhausting all other possible explanations for the spike, doctors concluded that it must have been related to the initiation of canagliflozin. “This really is the very first case, as far as we can tell, of rosuvastatin toxicity after starting canagliflozin,” Juurlink said.

Juurlink, along with lead author Eugene Brailovski, MD, CM (University of Toronto), and Richard Kim, MD (University of Western Ontario, Toronto), recounted the case in a report published online August 3, 2020, ahead of print in Annals of Internal Medicine.

Hospitalized for 10 Days

The woman described in the case had CAD, stage 3B chronic kidney disease, and type 2 diabetes but was functioning well. In addition to rosuvastatin, she was regularly taking bisoprolol, aspirin, metformin, L-thyroxine, and risedronate. She started taking canagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor thought to carry a low risk for drug interactions, at a dose of 100 mg daily 15 days before landing in the hospital.

Just 3 days after adding canagliflozin to her regimen, the woman developed bilateral thigh pain and weakness. The condition worsened and spread to the upper extremities over the next several days, compelling her to go to the hospital.

Once there, lab studies revealed rhabdomyolysis, hepatocellular injury, elevated levels of thyroid-stimulating hormone and creatinine, and “no C-reactive protein, antinuclear antibodies, or antibodies directed against extractable nuclear antigens.” Plasma rosuvastatin concentration at admission was 176 ng/mL.

Juurlink said they initially suspected that the woman had a complex and previously undescribed drug interaction, as the only recent change in her situation was the addition of canagliflozin.

Doctors stopped both the statin and canagliflozin and administered IV crystalloid. The patient’s muscle pain eased and strength returned over the next few days. When the woman was discharged 10 days after admission, she was ambulating with the assistance of a walker and the lab abnormalities had mostly resolved.

A Potential Explanation

Juurlink said that there are a limited number of ways in which one drug can increase the concentration of another. The main two are by lessening absorption or reducing elimination of the drug.

Research by Janssen, which makes canagliflozin, has shown that the SGLT2 inhibitor has the potential to interfere with drug transporters “that influence the fate of rosuvastatin in the body,” according to Juurlink.

“What we’re suggesting in this case is that those other off-target effects,” specifically on breast cancer resistance protein [BCRP] and organic anion transporting polypeptides, “would be a plausible reason why this patient—and potentially other patients—developed rosuvastatin toxicity,” he said. “In fact, it really is the only potential explanation here. There’s no good alternate hypothesis.”

Patients with type 2 diabetes often require a statin, and many patients are likely taking both rosuvastatin and canagliflozin. So why hasn’t this interaction been seen before?

Juurlink speculated that the patient might have been uniquely susceptible to the toxic interaction because of the presence of a genetic polymorphism that dampened her native BCRP activity. BCRP “reduces intestinal absorption while enhancing biliary and renal elimination” of rosuvastatin, according to the case report. Thus, additional interference of BCRP from canagliflozin in this patient who already had reduced BCRP activity could have increased intestinal absorption and reduced elimination of rosuvastatin, leading to accumulation in the plasma.

Considering the unique genetic makeup of the patient, this interaction might not apply to everyone taking rosuvastatin and canagliflozin together, Juurlink said. Still, the incidence is unknown. “It might be rare, or it might be more common than we realize,” he said. “This is the sort of interaction that could easily fly under the radar for a long period of time and not be appreciated.”

He and his team are planning to look into the issue using larger databases. In the meantime, Juurlink doesn’t recommend any drastic measures, instead calling for physicians to be vigilant.

“We shouldn’t avoid the co-prescription of the drugs, but we should be mindful of the fact that when we drop canagliflozin into the regimen of a patient who’s on rosuvastatin—as our case illustrates—it is conceivable that statin toxicity may result.”