Rhabdomyolysis With Concurrent Atrovastatin and Sitagliptin in the Setting of Vitamin D Deficiency

Abstract

The role of statin metabolism and Vitamin D have been established and even associated with statin induced myopathy. This case suggests a plausible link between myopathy and the use of sitagliptin concurrently with atorvastatin, in a patient with low vitamin D. We highlight the crucial interaction of cytochrome P450 metabolism that may contribute to statin toxicity. CASE PRESENTATION:A 69-year-old man with past medical history of CAD status post PCI (1 year ago), diabetes mellites type 2, hypertension, and dyslipidemia presented with a 2-month history of progressive fatigue, dyspnea on exertion, muscle weakness of upper and lower extremities. He was started on sitagliptin 25 mg Qday 8 months ago and had been on atorvastatin 80mg Qday. ECG and echocardiogram were without acute changes. Pertinent labs were AST/ALT 210/254, moderate blood on UA without RBCs, CPK 9923, TSH 2.31, ESR 20, CRP 14.9, Vitamin D level 12, B12 level 127. He was started on IV fluids, atorvastatin and sitagliptin were held, and vitamin D supplementation was started. Methylprednisolone was later added to the regimen after the biopsy. Muscle biopsy showed scattered basophilic regenerating muscle fibers and a very few necrotic muscle fibers consistent with toxic myopathy related to statin and immune-mediated necrotizing myopathy. HMG Coenzyme A reductase antibody test resulted positive, which can be associated with necrotizing autoimmune myopathy.DISCUSSION: Vitamin D is responsible for upregulating the transcription of a cytochrome P450 enzyme called CYP3A4 in the gastrointestinal mucosa and the liver. Atorvastatin, which is metabolized by the liver, is a substrate for CYP3A4. Interaction/ inhibition of CYP3A4 is known to cause increase level of atorvastatin, seen in patient with low Vitamin D. Sitagliptin is in part metabolized by CYP3A4. In vivo, sitagliptin alone showed no inhibitory effect on the enzyme CYP3A4. However, several case reports highlight statin induced rhabdomyolysis in patients using sitagliptin. This link is based on a possible competitive substrate interaction with CYP3A4 which in turn decreases statin metabolism.CONCLUSIONS: Our patient's vitamin D deficiency with sitagliptin and statin use could have a collaborative effect leading to myopathy. Vitamin D deficiency leading to low levels of available CYP3A4 enzyme and sitagliptin as a competitive inhibitor can all together limit the number of active sites. This can lead to increased statin levels and thus higher chance of myopathy. As DPP4 inhibitors grow in popularity given the positive cardiac profile, it would be crucial to monitor the drug interactions between statins that use the same metabolic enzymes and choose agents appropriately. It would also be worthwhile to be more vigilant to screen for low Vitamin D levels.