Diabetes Drug Linked to Severe Statin Toxicity Case

A drug interaction between canagliflozin (Invokana) and rosuvastatin (Crestor) was thought to cause liver and muscle toxicity in a woman in Canada, according to a case report.

The 76-year-old woman had been on rosuvastatin 40 mg daily for more than 5 years. Fifteen days after starting treatment with canagliflozin 100 mg daily, she presented to the hospital with new-onset muscle pain and difficulty walking. Her bilateral thigh pain and weakness, first noticed 3 days after starting canagliflozin, had gradually progressed and spread to the upper extremities.

Lab results showed rhabdomyolysis, hepatocellular injury, a thyroid-stimulating hormone concentration of 6.82 mIU/L, a creatinine concentration of 194 μmol/L, and no C-reactive protein, antinuclear antibodies, or antibodies directed against extractable nuclear antigens.

“The plasma rosuvastatin concentration on admission was 176 ng/mL, which is more than 15-fold higher than the mean value expected in patients receiving 40 mg per day,” David Juurlink, MD, PhD, of Sunnybrook Health Sciences Centre in Toronto, and colleagues reported in the Annals of Internal Medicine.

The woman stopped both rosuvastatin and canagliflozin and received IV crystalloid fluids in the hospital. Over the next few days, her muscle pain subsided and her weakness gradually improved. Upon discharge 10 days after admission, she could walk with a walker and had near-complete normalization of all laboratory abnormalities.

“We speculate that, in our patient, the addition of canagliflozin enhanced intestinal rosuvastatin absorption, inhibited its hepatocellular uptake, and impaired its excretion into bile canaliculi and the proximal tubule, resulting in rosuvastatin accumulation and leading to hepatotoxicity and myotoxicity,” the authors said.

Thus, clinicians should watch out for features of such toxicity when canagliflozin and rosuvastatin are co-prescribed, they urged.

“To our knowledge, this is the first published report of a drug interaction between rosuvastatin and canagliflozin. The possibility of such an interaction is important because these drugs are taken by millions of patients worldwide and are increasingly prescribed together,” the authors wrote.

Canagliflozin is approved for glycemic control, cardiovascular prevention, and renal prevention in type 2 diabetes. The SGLT2 inhibitor lowers blood glucose by blocking reabsorption of glucose by the kidney, increasing glucose excretion directly into urine.

FDA reviewers have previously warned of renal and fracture risks associated with the drug. Moreover, an FDA boxed warning has appeared on canagliflozin products since the post-marketing cardiovascular outcomes trial CANVAS showed an uptick in leg and foot amputations among users.

“Additional clinical information would be helpful to understand the relationships between drug initiation and the abnormal liver and renal function,” according to Kenneth Mahaffey, MD, of Stanford University, California, who was not part of Juurlink’s team.

Formal pharmacokinetics studies have been performed with canagliflozin and simvastatin without showing any drug-drug interactions, Mahaffey noted, adding that no statin-canagliflozin interactions were found either in the large CANVAS and CREDENCE programs (for which he was an investigator).

The patient in the case report had a medical history that included coronary artery disease, stage 3B chronic kidney disease, and type 2 diabetes. Besides rosuvastatin and canagliflozin, she had been on bisoprolol, aspirin, metformin, L-thyroxine, and risedronate.

On pharmacogenetic analysis, the patient turned out to be heterozygous for a polymorphism in the ABCG2 gene for breast cancer resistance protein, which reduces intestinal absorption while enhancing biliary and renal elimination.

An in vitro study had previously found canagliflozin to be both a substrate for and competitive inhibitor of breast cancer resistance protein, according to the authors.