Acute renal failure with the combined use of rosuvastatin and fenofibrate

Abstract

Among the lipid-lowering drugs, the statins and fibrates are the most commonly used agents. Either class of drug is considered relatively safe. Though a variety of albeit uncommon adverse side effects have been observed with both classes, most of these therapeutic complications can be managed without discontinuation of the offending drug. Sometimes, especially in patients with extremely high cholesterol and/or triglyceride levels, a combination regimen is deemed necessary. However, the combined use of lipid-lowering drugs increases the incidence and severity of adverse events. In this article, we report an unusual case of acute renal failure (ARF) in a patient who had been prescribed both a statin (rosuvastatin) and a fibrate (fenofibrate).

Keywords:

• acute renal failure
• rhabdomyolysis
• rosuvastatin
• fenofibrate

INTRODUCTION

Lipid-lowering drugs are widely used worldwide. Among the several classes of lipid-lowering drugs, statins and fibrate derivates are the most commonly used ones. They are beneficial in patients with dyslipidemia for both primary and secondary prevention of coronary artery disease.¹ Several adverse effects have been reported with statins and fenofibrate, though these adverse effects are relatively uncommon. Among these, hepatic dysfunction and muscle injury are the most frequent.^2,3 In this article, we report on a patient with acute renal failure (ARF) that was deemed secondary to the combined use of a statin (rosuvastatin) and a fibrate (fenofibrate) drug.

CASE REPORT

A 37-year-old woman was referred to our emergency department with complaints of generalized muscle weakness, nausea, vomiting, and increasing fatigue. Ten days earlier, she had been referred to another hospital for atypical chest pain. At the time, she was found to have a normal electrocardiogram (ECG). A stress ECG was attempted, but not deemed adequate because of poor patient compliance. Consequently, angiography was undertaken, which revealed 40 and 30% stenosis in the right coronary artery (RCA) and left anterior descending artery (LAD), respectively. Her fasting laboratory profile during the initial hospitalization included AST, 32 IU/L (0–40); ALT, 39 IU/L (0–41); ALP, 85 IU/L (30–120); GGT, 28 IU/L (5–40); urea, 38 mg/dL; creatinine, 1.02 mg/dL (0.5–1.2); triglycerides, 888 mg/dL (<200); total cholesterol, 412 mg/dL (<200); LDL cholesterol, 238 mg/dL (<130); HDL cholesterol, 59 mg/dL (lipid profile confirmed). HBsAg and anti-HCV were negative. All remaining routine laboratories and a TSH level were normal.

In addition to 25 mg metoprolol and 2.5 mg ramipril, the patient was started on 10 mg rosuvastatin and 250 mg fenofibrate. Several days later, she began to experience gradually increasing complaints, so she was referred to our hospital. On admission, her physical examination was unremarkable, except for generalized muscle weakness. Her past medical history was unremarkable for any disease or regular drug use. Prominent laboratory profiles are shown in Table 1. The patient's serum electrolytes, calcium, and phosphorous were normal, except a mild elevation in K⁺ and uric acid levels [K⁺ 5.5 mmol/L (3.5–5.0), uric acid 8.5 mg/dL (2.8–7.3)]. She had red to brown urine, and urinalysis revealed 3+ hematuria and +1 proteinuria; however, on microscopic analysis no erythrocytes or erythrocyte casts were detected. On the basis of her history, examination, and laboratory results, the patient was diagnosed with renal failure due to rhabdomyolysis. She was treated supportively and discharged on the seventh day post-admission. By the time of her 30-day follow-up visit, she had recovered completely. Once the patient had completely recovered, we gave her 10 mg pravastatin daily under close monitoring, and we observed no further adverse reactions.

TABLE 1.  Main laboratory profiles of the patient

	AST (IU/L)	ALT (IU/L)	CK (IU/L)	Urea (mg/dL)	Creatinine (mg/dL)	LDH (IU/L)
1st day^a	32	39		38	1.02
10th day^b	1760	443	>21,000	58	2.36	6088
15th day	1296	401	5310	102	3.19	3348
22nd day	244	171	3133	52	1.45	1521
30th day	35	38		35	1.19	224

Notes: Normal values: AST (5–40); ALT (10–40); CK (30–235); Urea (10–50); Creatinine (0.5–1.2); LDH (100–250).

^aOn admission to previous center.

^bOn admission to our center.

DISCUSSION

Myopathic syndromes that have been associated with statin therapy range from myalgias to myositis to overt rhabdomyolysis.⁴ Having said this, these complications are rather rare. Rhabdomyolysis so severe as to cause renal failure has not been reported when a statin drug has been used alone, except when predisposing factors have been present, such as hypothyroidism, an underlying inflammatory myopathy (like polymyositis or dermatomyositis), or concomitant drug use.⁵ Susceptibility to myopathy is substantially increased in statin-using patients receiving concurrent therapy with a number of drugs, particularly those that inhibit CYP3A4, like cyclosporine, gemfibrozil, macrolide antibiotics, and azole antifungal agents.^5–8 However, rhabdomyolysis so severe as to cause acute renal dysfunction has been reported in a few isolated instances. Oldmeyer et al. reported ARF in a patient in whom pravastatin and fenofibrate were switched to simvastatin and gemfibrozil.⁹ More recently in this journal, Unal et al. reported two cases of ARF with the combined use of lipid-lowering drugs: one in association with the concomitant use of atorvastatin and fenofibrate and the other with combined pravastatin and fenofibrate.¹⁰ In both instances, rhabdomyolysis occurred when fenofibrate was added to statin monotherapy. As mentioned above, the combined use of a statin agent with some other lipid-lowering drug increases the risk of myopathy. In one large study, relative to statin monotherapy, the rate of hospitalization was approximately 10-fold higher when fibrates and statins were combined.¹¹

Of the statin drugs, pravastatin, fluvastatin, and to a lesser extent rosuvastatin appear to be associated with the lowest myopathy risk, since they are not extensively metabolized by CYP3A.^4,11–13 Fibrate derivates are the most commonly used non-statin lipid-lowering drugs. Among these, gemfibrozil has the highest myopathy potential.^3,7 Fenofibrate has been considered to have a very low potential for myopathy, and thus, is the preferred drug when some combination with a statin is required.^3,7 Therefore, as in our case, the combination of rosuvastatin and fenofibrate should be relatively safe. Reviewing the literature, we identified only one instance in which ARF occurred in a patient taking this same combination.¹⁴ In the reported patient, ARF occurred when fenofibrate was added to rosuvastatin,¹⁴ demonstrating that even seemingly-safe combinations can produce unexpected adverse reactions.

In summary, we want to emphasize several points. First, our patient had been taking low-dose rosuvastatin (10 mg) and a fenofibrate. Even with this low dose of a statin drug, severe rhabdomyolysis occurred. This also is one of the very few reports of ARF occurring together with this drug combination, suggesting a severe synergistic adverse interaction. Moreover, even reviewing the literature for relatively safe combinations (e.g., pravastatin and fenofibrate, fluvastatin and fenofibrate, and rosuvastatin and fenofibrate), this sort of reactions can be observed. Consequently, in any patient with extremely high cholesterol and triglyceride levels in whom a combination regimen is deemed necessary, the prescribing physician should monitor closely for adverse events.