Journal of Geriatric Cardiology June 2010 Vol 7, No. 2126

Case Report

Rhabdomyolysis induced by simvastatin-diltiazeminteraction in unrecognized hypothyriodism

Ran Zhang 1, Hai-Hong Ran 2, Cai-Yi Lu 1, Wei Gao 1, Ya Huang 1,Yu-Ling Gao 1, Qiong-Xiang Yang 1

1 Institute of Geriatric Cardiology; 2 Department of Geriatric Hematology, Chinese PLA General Hospital, Beijing 100853, China.

Abstract Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, is widely prescribed to patients withhypercholesteremia and its muscular toxicity has been widely reported. The metabolism of simvastatin depends on the enzymic activityof cytochrome P450 3A4 (CYP3A4) and inhibitors of CYP3A4 can result in clinical events by interacting with simvastatin. Diltiazemis a moderate inhibitor of CYP3A4, which is known to increase the serum concentration of simvastatin. Here we report a patient withunrecognized hypothyroidism who had been stable for more than one year on low-dose simvastatin therapy of hypercholesteremia andrhabdomyolysis occurred with the addition of diltiazem. This is one of scanty reports of rhabdomyolysis induced by simvastatin-diltiazem drug interaction, especially in hypothyroid patient. This case reminds the clinicians that although diltiazem as a moderateCYP3A4 inhibitor can be used cautiously with small doses of CYP3A4-dependent statins (eg, simvastatin), these two commonly useddrugs should be avoided in hypothyroid patient (J Geriatr Cardiol 2010; 7:126-128).

Key Words Simvastatin; diltiazem; drug-interaction; rhabdomyolysis; hypothyriodism

Received 2010-04-24; accepted 2010-05-28.Corresponding author: Dr .Wei Gao, Institute of Geriatric Cardiology, Chinese PLAGeneral Hospital, Beijing 100853, China. Email: cardiomed_zhangran@yahoo.com.cn

Introduction

Statins, the 3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) reductase inhibitors, have significant healthbenefits in patients with high risk for cardiovascular dis-eases and reduce cardiovascular mortality and morbidityby lowering serum cholesterol. Generally, statins are welltolerated and adverse effects include reversible elevation intransaminases, myositis and rhabdomyolysis.1, 2 Rhabdom-yolysis is characterized by myoglobinuria, myalgia and arise in serum level of creatine kinase (CK).3 A case-cross-over study on 93, 831 patients found that an annual inci-dence of statin-induced myopathy or myalgia was around689 per million per year.2 Statins toxicity appears to be drug-dose- and plasma-concentration-related. The metabolism ofsimvastatin is primarily cytochrome P450 3A4 (CYP3A4)-dependent and therefore, when CYP3A4 inhibitors are co-administered, plasma-concentration of simvastatin may in-crease dramatically. Among CYP3A4 inhibitors, diltiazem isa moderate one, which can cause increased plasma-concen-tration of simvastatin and high levels of HMG-CoA reduc-tase inhibitory activity in plasma and is associated with anincreased risk of musculoskeletal toxicity. 4 Hypothyroid-ism as one of the most commonly secondary causes of

hypercholesteremia, accounts for the incidence of 10-15%in hypercholesteremia and it has been reported that about11.7% of patients with undiagnosed hypothyroidism acci-dentally received statins.5 Cholesterol-lowering medicationwi th s ta t i ns has been repor ted t o be l inked torhabdomyolysis in hypothyroid patients. 6 In addition, hy-pothyroidism itself is a common cause of rhabdomyolysis.7

Until now, only several cases have been reported on simva-statin-diltiazem drug interaction related rhabdomyolysis.Herein, we reported a case of hypercholesterolemia sec-ond a r y t o a s ymp t om a t i c hyp ot hyr oi d i s m a n drhabdomyolysis triggered by simvastatin-diltiazem druginteraction. To our knowledge, this is one of few case re-ports that potential simvastatin-diltiazem drug interactionresulted in rhabdomyolysis in unrecognized hypothy-roidism. Meanwhile, we reviewed the literatures publishedin the past years relating to simvastatin-diltiazem drug in-teraction and discussed its clinical significance inhypothyroidism.

Case report

A 59-year-old man (weight, 74 kg; height, 172 cm; bodymass index, 25.01 kg/m2) sought medical help at the Insti-tute of Geriatric Cardiology of Chinese PLA General Hospi-tal with complaint of myalgia for 25 days in September 2008.He denied vigorous physical exercise and alcohol use be-fore the suffering. His medical history included hyperc-

Journal of Geriatric Cardiology June 2010 Vol 7, No. 2 127

holesteremia, bronchial asthma, allergic rhinitis, esophagealulcer, fatty liver and coronary heart disease (CHD). Prior tothe admission, the patient has been taking simvastatin (20mg p.o.,q.n.) for more than one year when diagnosed ashypercholesteremia and CHD. One month before admission,he developed angina pectoris and daily dose of diltiazem(30 mg p.o.,b.i.d.) was started.

On physical examination, the patient's vital signs were:temperature, 36.5℃; pulse, 80 beats per minute; bloodpressure, 110/60; and respirations, 18 breaths per minute.Physical examination also showed palpebral edema, but wasotherwise largely unremarkable. Laboratory evaluation atadmission revealed serum creatine kinase (CK) of 5,885.4 U/L(normal up to 200); serum creatinine of 140.5μmol/L (normalup to 110); cholesterol of 6.29 mmol/L (normal up to 5.70);aspartate aminotransferase (ALT) of 45.9 U/L (normal up to40); aspartate amino transferase (AST) of 141.1 U/L; MMisoenzymes of CK (CK-MM) of 99.5 U/L (normal up to 16);lactic acid dehydrogenase (LDH) of 316.3 U/L (normal up to 250).

The pat ient was diagnosed as rhabdomyolys is .Simvastatin and diltiazem were discontinued immediatelyafter the admission. Intravenous fluids were immediatelystarted. He was given forced alkaline diuresis (intravenousnormal saline with bicarbonate). The level of CK peaked at6,884.0 U/L on the 3rd day. Although there were no remark-able related symptoms in this patient, it was highly suspect-able that he might have asymptomatic hypothyroidism.Thyroid function tests confirmed the diagnosis of severehypothyroidism: TT3, 0.84 nmol/L; TT4, 16.92 nmol/L; FT3,2.57 pmol/L; FT4, 6.48 pmol/L; and TSH, >150mU/L. Thediagnosis was further supported by ultrasonograpy, whichrevealed diffuse atrophy of thyroid gland. Levothyroxine(50μg p.o.,q.d. Merck KGaA, Germany), as replace therapy,was prescribed to the patient at once. Two weeks later, an-other 25μg was added. The levels of serum cholesterol,ALT, AST, CK, and CK-MM were monitored regularly dur-ing the hospitalization. At discharge, laboratory test resultswere a CK level of 159.3 U/L and a cholesterol level of 5.59mmol/L. Diltiazem (30 mg p.o.,b.i.d.) was restarted. The pa-tient complained some mild residual weakness until 1 monthafter hospitalization, but has otherwise made a full recovery.Palpebral edema disappeared and levels of creatinine andtransaminase were also normalized.

The latest follow-up was carried out on September 2009.Thyroid function was completely rectified. The biochemicaltest values were as follows: TC 5.46 mmol/L, LDL-C 2.64mmol/L, HDL-C 1.54 mmol/L, ALT 18.5 U/L, AST 16.5 U/L,CK 188.9U/L and CK-MM 7.2 U/L. The patient continued tobe on levothyroxine (100μg p.o.,q.d.), diltiazem (60 mg p.o.,b.i.d) and aspirin 100 mg p.o.q.d.

Discussion

Rhabdomyolysis has been recognized as a potentially

life-threatening clinical syndrome derived from striatedmuscle dissolution or disintegration, with the clinical symp-toms of myalgia, weakness and muscle cramps, and mainlaboratory finding of increase in serum CK greater than 10times the upper limits of normal. The most common predis-posing factors accounting for rhabdomyolysis are crushinjury, muscle overexertion, alcohol abuse and certain medi-cines and toxic substances.8 Statins use and hypothyroid-ism are both underlying causes of rhabdomyolysis.7-9 In thepresent case, rhabdomyolysis happened following the co-administration of simvastatin and diltiazem in the setting ofundiagnosed hypothyroidism.

Statins, such as simvastatin, lovastatin, and atorvastatin,are the substrates of CYP3A4 and their metabolism dependson the enzymic activity of CYP 3A4; therefore, drug toxicityis common when potent CYP3A4 inhibitors such as mac-rolide antibiotics, azole antifungals, protease inhibitors andnefazodone, or moderate CYP3A4 inhibitors such asamiodarone, ciclosporineA, danazol, diltiazem and verapamilare co-administrated with such statins. In clinical practice, itis common that patients who take statins to prevent or treatCHD concurrently take some other drugs for cardiovascu-lar disorders, in particular, calcium channel blockers suchas verapamil and diltiazem that can inhibit the activity ofCYP3A4. A naturalistic study by Molden et al 10 showedthat in 245 co-prescriptions of CYP3A4 inhibitors withsimvastatin, diltiazem (35.10 %), verapamil (29.39 %), eryth-romycin (19.59 %) and clarithromycin (11.84 %) were themost commonly co-prescribed CYP3A4 inhibitors. Co-ad-ministration with inhibitors of CYP3A4 may increase theplasma concentrations of statins that are metabolized bythe isoenzyme. The effects of diltiazem on the pharmacoki-netics of simvastatin have been investigated in severalstudies. 11 Diltiazem significantly increased the mean peakserum concentration of simvastatin by 3.6-fold, simvastatinacid by 3.7, the area under the serum concentration-timecurve (AUC) of simvastatin by 5 and the elimination half-life by 2.3-fold.4 Simvastatin-diltiazem drug interaction re-sulting in rhabdomyolysis has been sporadically reportedin cardiac transplant recipient,12 renal transplant patient,13 ,14

liver transplant patients 15 and other patients. 16, 17 The un-derlying cause of the seemingly higher incidence ofsimvastatin-diltiazem drug interaction in transplant patientsmay be that transplant patients are at higher risk of devel-oping hyperlipidemia, which contributes to CHD and car-diovascular events. The occurrence of statin-relatedrhabdomyolysis is usually associated with increased plasmaconcentration of statins.18 Furthermore, Masica and coau-thors' work 19 suggested that the interaction of lovastatinwith diltiazem do not occur systemically and be primarily afirst-pass effect, because such kind of drug interaction usu-ally happens in oral dosing but not in intravenous dosing.Diltiazem as a weak or moderate CYP3A4 inhibitor can beused cautiously with small doses of CYP3A4-dependent

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statins,20 but patients who take both simvastatin anddiltiazem may need lower doses of simvastatin to achievethe recommended reduction in cholesterol.21

In the present case, the patient had suffered unrecog-nized hypothyroidism for an uncertain but probably a longtime and simvastatin was prescribed for hypercholesteremiaand CHD. Rhabdomyolysis did not occur until the additionof diltiazem. Knowledge of the pharmacokinetic and phar-macodynamic properties of statins and the mechanisms ofdrug interaction with other drugs may help to avoid theseadverse effects. Patients taking atorvastatin, lovastatin, andsimvastatin, the substrates of CYP3A4, should avoid con-current use of CYP3A4 inhibitors, especially when predis-posing factors of rhabdomyolysis (eg, hypothyroidism) co-exist. If the use of CYP3A4 inhibitors is necessary,fluvastatin, pravastatin and rosuvastatin that do not inter-act with inhibitors of CYP3A4 should be considered. Allpatients taking statins should be educated to be alert toelevated hepatic transaminases, any unexplained myalgiaor weakness.

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