Fatal rhabdomyolysis caused by lipid-lowering therapy.

ABSTRACT: Treatment of hypercholesterolemia has been shown to reduce mortality in patients with coronary artery disease. Patients with severe lipid abnormalities may require high-dose statin therapy, at times used in combination with additional agents. We report a case of fatal rhabdomyolysis caused by the combination of simvastatin and gemfibrozil. Clinicians should be aware of risk factors for rhabdomyolysis, which include underlying renal insufficiency, high-dose statin therapy, and combination therapy with a fibrate.

CARDIOVASCULAR DISEASE is a leading cause of death in the United States. Hypercholesterolemia has been linked conclusively with atherosclerosis, the major cause of cardiovascular disease. (12) The treatment of hypercholesterolemia has proved beneficial in reducing myocardial infarction, coronary bypass procedures, and stroke, as well as mortality in patients with established coronary artery disease. (3-7) The use of 3-hydroxy-3-methylgiutaryl coenzyme A (HMG-CoA) inhibitors (statins) has also been shown to be increasing steadily. (8)

However, the widespread use of these medicines has led to the appreciation of their drug interactions and potential toxicity, including myositis and rhabdomyolysis. We report a case of fatal rhabdomyolysis caused by the concomitant use of the HMG-CoA reductase inhibitor simvastatin and the fibrate, gemfibrozil.

CASE REPORT

A 68-year-old man was admitted to the hospital after complaining of progressive weakness. He had a medical history of type 2 diabetes mellitus with diabetic nephropathy, hypertension, peripheral vascular disease, and dyslipidemia. Four weeks before admission, gemfibrozil was added to his medical regimen after he was found to have a serum triglyceride level of 747 mg/dL. At that time, his serum creatinine value was at his baseline, 3.4 mg/dL. Two weeks after starting gemfibrozil therapy, he noticed progressive weakness of his upper and lower extremities that progressed to the point that he had difficulty getting out of chairs, raising his arms over his head, and walking. He denied myalgias but had dyspnea with exertion over the preceding 3 days.

On presentation to the hospital, his medications included simvastatin (80 mg/day), atenolol (50 mg/day), furosemide (40 mg/day), aspirin (325 mg/day), and gemfibrozil (600 mg twice daily), as well as 70/30 insulin.

On examination, the patient appeared comfortable, but he was lying in bed, unable to stand. He was febrile, with blood pressure of 130/70 mm Hg, pulse rate of 84/min, and oxygen saturation of 91% on room air. He was noted to have markedly diminished strength bilaterally in shoulder abductors, hip flexion, extension and abduction, and finger abduction bilaterally. Findings on cranial nerve and sensory examination were normal. The remainder of the physical examination was unremarkable.

Laboratory values were blood urea nitrogen 80 mg/dL, serum creatinine 3.0 mg/dL, aspartate aminotransferase 576 U/L, alanine aminotransferase 126 U/L, lactate dehydrogenase 883 U/L, and creatine kinase (CK) 22,520 U/L (normal, 0 to 180 U/L). The alkaline phosphatase value was normal. A viral hepatitis screen was negative, and the serum troponin level was normal. Complete blood count showed leukocytosis, with a white blood cell count of 17,000/[mm.sup.3] and a normal differential. Urinalysis revealed 3+ blood and protein. No red blood cells were seen on microscopic examination. Arterial blood gas analysis revealed a pH of 7.30, [Pco.sub.2] of 46 mm Hg, and [Po.sub.2] of 49 mm Hg. A chest roentgenogram showed a retrocardiac opacity thought to be due to either atelectasis, effusion, or infiltrate.

After being admitted, he was initially given intravenous levofloxacin and clindamycin, as well as fluids containing dextrose and sodum bicarbonate. On the third hospital day, hypercapneic and hypoxemic respiratory failure developed due to collapse of the left lung, and mechanical respiration was begun. The left lung re-expanded. Over the next several days, renal function deteriorated, and the GK level rose to [greater than]30,000 U/L. The patient became hypotensive and died on hospital day 7. Autopsy showed significant myositis on microscopic examination. The muscle fibers exhibited evidence of an interstitial inflammatory infiltrate, cellular debris, and phagocytosis. Some fibers were described as atrophic and showing signs of replacement with fibrous tissue. The diaphragm was found to have extensive and severe involvement. Extensive atelectasis of the lung was also found with pulmonary edema and early diffuse alveolar damage.

DISCUSSION

Lipid-lowering therapy with statins has become the mainstay in the treatment of hyperlipidemia over the past several years. Statins offer the greatest reduction of low-density lipoprotein (LDL) and are often the best tolerated of lipid-lowering therapy options. (9,10) These agents work by inhibiting the enzyme HMG-CoA reductase, which is responsible for production of sterols used to synthesize cholesterol. Blockade of the enzymes with statins results in upregulation of LDL receptors in the liver, leading to enhanced clearance of LDL. (10,11) Currently, six statins are available for clinical use in the United States: simvastatin, lovastatin, pravastatin, fluvastatin, atorvastatin, and cerivastatin (Table). With the exception of pravastatin, these agents are predominantly eliminated by the liver; however, higher plasma levels of some of the agents are observed in patients with severe renal insufficiency. (10,12)

The HMG-CoA reductase inhibitors are generally well tolerated. Mild, transient gastrointestinal disturbances, muscle pain, rash, and headache are the most commonly reported adverse effects. (13) Other rare but serious adverse effects of statin therapy include hepatotoxicity (1% to 2%) and myopathy, which may lead to rhabdomyolysis, either with or without renal failure. (13,14) These side effects are dose-dependent and more likely to occur with escalating doses of statin therapy and/or when used in combination with medications such as fibrates, niacin, or medications that inhibit the cytochrome P-450 system (cyclosporine, erythromycin, clarithromycin, ketoconazole, itraconazole, nefazodone, ritonavir, indinavir, saquinavir, nelfinavir, and amprenavir). (12-16)

Skeletal muscle effects of statins include myalgia, myopathy, and rhabdomyolysis. Myopathy occurs in less than 1% of patients using statins as sole therapy for the treatment of a lipid disorder. (12) However, the incidence approaches 2% when statins are combined with niacin and 5% when combined with fibrates. (12) The incidence is even higher when statins, especially lovastatin and simvastatin, are combined with cyclosporine and other inhibitors of the cytochrome P-450 system. (12,13,17) Risk and severity of myopathy may be increased in patients with hepatic impairment, renal insufficiency, serious infections, hypothyroidism, and advanced age. (13,14,15) Conditions known to predispose patients to rhabdomyolysis include severe infection, hypotension, major trauma, severe metabolic, endocrine or electrolyte disorders, and uncontrolled seizures. (16)

Fibrates or fibric acid derivatives are primarily used to treat hypertriglyceridemia by increasing the rate of triglyceride hydrolysis. Gemfibrozil, fenofibrate, and clofibrate are the currently available products in the United States. These agents are well absorbed from the gastrointestinal tract and are highly protein bound. They are primarily excreted through the kidneys and therefore should be used with caution in patients with severe renal insufficiency. Side effects include gastrointestinal disturbances, gallstone disease, and myopathy.

Treating patients with mixed dyslipidemias sometimes requires combination therapy with statins, fibrates, and/or niacin to achieve goal. The combination of a statin with a fibrate has been shown to be efficacious, with a low risk of toxicity; however, these studies included small numbers of patients treated for relatively short periods. Long-term safety and efficacy of combination therapy have yet to be shown.

Athyros et al (18) conducted a study involving 420 patients, aged 30 to 65, who had familial combined hyperlipidemia refractory to monotherapy. Patients were randomized to receive either a combination of pravastatin and gemfibrozil (20 mg and 1,200 mg per day, respectively), simvastatin and gemfibrozil (20 mg/ 1,200 mg), or simvastatin and ciprofibrate (20 mg/100 mg), with follow-up of 1 to 4 years (average, 29 months). Of the 389 patients who completed the study, none exhibited myopathy or rhabdomyolysis, though 5 patients (1.3%) were withdrawn because of elevated transaminase levels. All 3 regimens more effectively normalized the lipid profile than monotherapy. The authors concluded that the statin-fibrate combinations used in this study are safe and provide favorable results.

Similarly, Murdock et al (17) performed a prospective study evaluating the safety and efficacy of the combination of gemfibrozil (600 mg bid) and either pravastatin, simvastatin, fluvastatin, lovastatin, or atorvastatin at various dosages in patients with established vascular disease (titrated to reduce LDL to lower than 100 mg/dL). Patients were between 33 and 86 years of age and had follow-up for a mean of 2.4 years. Myalgias without CK elevations occurred in 6 patients (2%), while 1 patient (0.4%) had myositis, with CK elevation 12 times the upper limit of normal, after 1 year of treatment with the combination of simvastatin and gemfibrozil. The authors concluded that risk of toxicity is low enough to consider combination therapy for patients at high risk of future atherosclerotic complications. However, patients taking immunosuppressants or with serum creatinine levels [greater than]2.4 mg/dL were excluded.

The exact mechanism by which statins and fibric acid induce muscle damage is not clearly known, but many different theories have been postulated. Statins may decrease serum levels of coenzyme Q10, which is a necessary cofactor in the electron-transfer system, in addition to possessing antioxidant properties that help maintain cell integrity. (19,20)

Furthermore, statins inhibit the conversion of HMG-CoA to mevalonic acid. (21) Some of the metabolic products of mevalonic acid play a role in the formation of the cellular membrane. It is possible that decrease in the concentration of these products may destroy muscle fibers. However, it is not clear why the skeletal muscles should be the target tissue. It is possible that muscle tissue, if dependent primarily on endogenous synthesis of cholesterol rather than cellular uptake of preformed cholesterol, might be more sensitive to toxic effects of these medications. (16) Lipophilic statins, such as lovastatin and simvastatin, are more readily able to enter skeletal muscle and accumulate than the nonlipophilic or hydrophilic statins, such as pravastatin. (12,30)

One theory postulated to account for fibrate-induced myopathy suggests that drug-induced membrane destabilizing effects lead to myofibrillar degeneration. (16) The mechanism that causes the destruction of muscle fibers during statin or fibrate therapy is unknown. Additionally, fibrates may alter hepatic function and decrease the elimination of the statins and their metabolities. (16)

CONCLUSION

Although it has been recognized that the combination of a statin and a fibrate can cause rhabdomyolysis, this is the first reported case of fatal rhabdomyolysis caused by the combination of simvastatin and gemfibrozil. Muscle toxicity led to rhabdomyolysis and diaphragmatic weakness, causing atelectasis and intermittent pulmonary collapse. It is possible that our patient might have been at increased risk for rhabdomylosis because of his underlying renal insufficiency, the high dose of simvastatin, the concomitant use of a statin and fibrate, and perhaps a superimposed infection. We recommend avoiding high doses of statins in combination with fibrates in patients whose renal function is compromised. Clinicians should be aware of the potentially serious consequences of this combination and be vigilant in the early detection of toxicity should it arise.

References

(1.) Kannel WB, Castelli WP, Gordon T, et al: Serum cholesterol, lipoproteins, and the risk of coronary heart disease. Ann Intern Med 1971; 74:1-12

(2.) Levine GN, Keaney JF Jr, Vita JA: Cholesterol reduction in cardiovascular disease: clinical benefits and possible mechanisms. N Engl J Med 1995; 332:512-521

(3.) Sheperd J, Cobbe SM, Ford I, et al: Prevention of coronary heart disease with pravastatin. men with hypercholeserolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995; 333:1301-1307

(4.) Sacks FM, Pfeffer MA, Moye LA, et al: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial Investigators. N Engl J Med 1996; 335:1001-1009

(5.) Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998; 339:1349-1357

(6.) Downs JR, Clearfield M, Weis S, et al: Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998; 279:1615-1622

(7.) Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344:1383-1389

(8.) Siegel D, Lopez J, Meier J: Use of cholesterol-lowering medications in the United States from 1991 to 1997. Am J Med 2000; 108:496-499

(9.) Farnier M, Davignon J: Current and future treatment of hyperlipidemia: the role of statins. Am J Cardiol 1998; 82:3J-10J

(10.) Grundy SM: HMG-CoA reductase inhibitors for treatment of hypercholesterolemia. N Engl J Med 1988; 319:24-33

(11.) Kwiterovich PO: State-of-the-art update and review: clinical trials of lipid-lowering agents. Am J Camdiol 1998; 82:3U-17U

(12.) Garnett WR: Interactions with hydroxymethylglutaryl-coenzyme A reductase inhibitors. Am J Health Syst Pharm 1995; 52:1639-1644

(13.) Abramowicz M (ed): Choice of lipid lowering drugs. Med Lett 1998; 40:117-122

(14.) Kastrup EK (ed): Drug Facts and Comparisons. St. Louis, Facts and Comparisons, 2000, pp 536-542

(15.) Zocor. Drug Product Information. Whitehouse Station, NJ, Merck & Co Inc, 1996

(16.) Pierce RL, Wysowki DK, Gross TP: Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA 1990; 264:71-75

(17.) Murdock DK, Murdock AK, Murdock RW, et al: Long-term safety and efficacy of combination gemfibrozil and HMG-CoA reductase inhibitor for the treatment of mixed lipid disorders. Am Heart J 1999; 138:151-155

(18.) Athyros VG, Papageorgiou AA, Hatzikonstandinou HA, et al: Safety and efficacy of long-term statin-fibrate combinations in patients with refractory familial combined hyperlipidemia. Am J Cardiol 1997; 80:608-613

(19.) Ghirlanda G, Oradei A, Manto A, et al: Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study. J Clin Pharmacol 1993; 33:226-229

(20.) Maltz HC, Baolog DL, Cheigh JS: Rhabdomyolysis associated with concomitant use of atorvastatin and cyclosporine. Ann Pharmacother 1999; 33:1176-1179

(21.) Van Puijenbroek EP, Du Buf-Vereijken PW, Spooren PF, et al: Possible increased risk of rhabdomyolysis during concomitant use of simvastatin and gemfibrozil. J Intern Med 1996; 120:403-404

TABLE.

Pharmacokinetics of HMG-CoA Reductase Inhibitors (*)


Drug            Bioavailability     Half-life        Excretion

Atorvastatin  14%; first pass          14      [less than]2% (urine)
              metabolism
              CYP3A4)
Gerivastatin  60%; first pass          2-3          24% (urine)
              metabolism                            70% (feces)
              (CYP3A4)
Fluvastatin   24%; extensive first     1       [less than]6% (urine)
              pass metabolism                       90% (feces)
              (CYP3A4)
Lovastatin    5%; extensive first      3-4          10% (urine)
              pass metabolism                       83% (feces)
              (GYP3A4)
Pravastatin   17%; extensive first     2            20% (urine)
              pass metabolism                       70% (feces)
Simvastatin   5%; extensive first      3            13% (urine)
              pass metabolism                       60% (feces)
              (CYP3A4)

              Protein       Effects of Renal/Hepatic
Drug          Binding              Impairment

Atorvastatin    98%    Plasma levels not affected by renal
                       disease; increased with chronic
                       alcohlic liver disease
Gerivastatin    99%    Increased plasma levels with
                       moderate to severe renal impairment

Fluvastatin     98%    Potential drug accunsulation with
                       hepatic insufficiency

Lovastatin      95%    Increased plasma levels with
                       severe renal disease

Pravastatin     50%    Increased plasma levels in
                       cirrhotic patients
Simvastatin     95%    Increased plasma levels may occur
                       in severe renal insufficiency


(*)From Drug Facts and Comparisons. (14)

KEY POINTS

* The risk of myopathy is increased with escalating doses of statins.

* Myopathy is more likely to occur when a statin is used in combination with fibrates, niacin, or inhibitors of the cytochrome p-450 system.

* Patients with underlying renal dysfunction or infection are at increased risk of myopathy.