Can ezetimibe increase the risk of rhabdomyolysis?/nThe question concerns a 44-year-old man with di

Fråga: Can ezetimibe increase the risk of rhabdomyolysis? The question concerns a 44-year-old man with diabetes mellitus type I and renal insufficiency. After having taken ezetimibe (Ezetrol) for two days he was affected by muscular stiffness in his thighs and hips. He was admitted to hospital four days later. In this connection substantially elevated muscle enzyme values were assessed: Myoglobin 9287 ug/L, CKMB 176 ug/mL, CK 90 ukat/L and Troponin I 15.2 ug/L (maximum values). The patient´s other medication included atorvastatin (Lipitor) 20mgx1 (since more than one year), metoprolol (Seloken ZOC) 100 mgx1, losartan (Cozaar) 12.5 mgx2, lisinopril (Zestril) 10 mgx1, insulin lispro (Humalog) and insulinglargin (Lantus).

Sammanfattning: There are a few case reports, but still no certain evidence that addition of ezetimibe to a statin increases the risk of myopathy.

Svar: Ezetimibe is an inhibitor of cholesterol uptake in the small intestine (1). Thus, its mechanism of action is different from other antihyperlipidemic agents.

Whereas statins carry a myotoxic potential (reported incidence 1-7 %) ranging from myalgia to rhabdomyolysis, ezetimibe in monotherapy has not been associated with such adverse effects (2). Pooled data from the manufacturer shows that combinations of ezetimibe and statins increase the risk of myalgia from 2.4 % to 3.2 % (1). Yet, the significance of this data is unclear.

In the Swedish adverse drug reaction register there is one report of myalgia for ezetimibe (out of totally nine reports on this substance) (3). In the WHO database there are nineteen reports of myalgia, two of myopathy, four of increased creatine phosphokinase and one report of rhabdomyolysis (4). However, in this database not all reports are evaluated with reference to the cause relationship.

There are at least two published case reports of myopathy in patients treated with combinations of ezetimibe and statins where importance of the ezetimibe component can be suspected.

One case concerns a 43-year-old man who was affected by severe pain in both thighs and Achilles tendons and increased CK activity (3.72 ukat/L, ref <1.34 ukat/L) three weeks after starting treatment with ezetimibe. Eighteen months before presentation the patient had had an acute myocardial infarction. Atorvastatin 80 mg/d was started on account of familial hypercholesterolemia. At a regular check-up 7 weeks before presentation creatinine kinase activity had been normal (0.47 ukat/L). Ezetimibe was added since the serum cholesterol level was still unsatisfactory (6.22 mmol/L). The patient´s symptoms diminished after withdrawal of both atorvastatin and ezetimibe, and CK activity returned to normal within five days. Atorvastatin 80 mg/d was reintroduced three weeks later. No increase in CK activity or other adverse effects occurred (2).

The second case, reported by the same authors, concerns a 52-year-old man who was found to have elevated CK activity (2.56 ukat/L) at a regular check-up. CK activity had not been measured before and he had no symptoms of myopathy. The patient had been treated with fluvastatin 80 mg/d for eight months on account of hypercholesterolemia. Ezetimibe 10 mg/d was added eight weeks before presentation since cholesterol levels had remained high. Within two weeks after withdrawal of ezetimibe CK activity decreased to 1.52 ukat/L. Within another two weeks it had returned to normal (1.09 ukat/L). Fluvastatin was not discontinued, and, as in the previous case, no increase in CK occurred, nor other adverse effects (2).

Regarding pharmacokinetics, ezetimibe is conjugated in the liver and small intestine into the pharmacologically active glucuronide. The parent compound as well as the glucuronide is highly bound to plasma proteins (> 90 %), and both are excreted in urine (15 %) and bile (85 %) (1). Atorvastatin is metabolised by CYP3A4. It is also a subject of cellular membrane transport by organic anion-transporting polypeptide (OATP) C and P-glycoprotein (Pgp)(5).

There is no known mechanism of a possible pharmacokinetic interaction between ezetimibe and atorvastatin. Both ezetimibe and atorvastatin (but not fluvastatin) undergo glucuronidation, which might be a candidate site. Another possibility is an influence on OATP2 (2) or Pgp. Still, these proposals are speculative and require more studies or investigation.