Myopathy and rhabdomyolysis with lipid-lowering drugs

Abstract

Drug-induced myopathy and rhabdomyolysis are rare adverse drug reactions (ADR). They have been seen after the introduction of modern lipid-lowering drugs more regularly. The first description after medication with clofibrate dates back to 1968. Apparently, all fibrates can induce myopathy. It usually starts after a few days of medication, or after prolonged use, showing muscle weakness and/or pain. Concomitantly, the enzyme creatininephosphokinase (CPK) is raised dramatically. Muscular necrosis can follow leading secondarily to kidney failure, and eventually to death. For the class of statins, myopathy was more often seen after their introduction, and it became their most feared adverse effect, especially in combination of statins with other drugs (mibefradil, gemfibrozil, cyclosporin). In animal models the evolution of the disease and the mechanism of action may be elucidated. Though strong epidemiological data are lacking, the incidence of myopathy is probably similar for all lipid-lowering drugs and is in the range of 0.1–0.5% with monotherapy, increasing to 0.5–2.5% with combination therapy. Severe cases of rhabdomyolysis are rarer, but may have a significant mortality. The market success of cerivastatin within a short period has led to 100s of myopathies and some dozens of deaths. Though interactions on metabolism and ensuing high plasma levels can partially explain myopathy as intoxication, there are strong indications that other (endocrine, metabolic, genetic) factors might play a role in the pathophysiology. The patient population at risk should better be defined and withheld from myopathy-inducing drugs.

Introduction

Myopathy, especially when drug-induced, presents itself as muscle weakness and/or pain and might go along with muscle destruction, so-called rhabdomyolysis. Muscle fibre destruction leads to liberation of myoglobins. These large molecules may lead to obstruction of nephrons with ensuing kidney failure.

Rhabdomyolysis has different potential causes and is not a frequently reported adverse reaction of drugs.

Fibrates have been described as myopathy inducing agents, but rhabdomyolysis has been seen only rarely. Rhabdomyolysis, however, is the most feared side effect in the clinical use of lipid lowering medications, particularly of HMG CoA reductase inhibitors known as statins. These, either alone or particularly when associated with fibric acids, may give rise to significant muscle necrosis, as shown by altered biochemical parameters, in particular creatininephosphokinase (CPK) levels, clinical signs of muscle weakness and pain (Pierce et al., 1990). Other interactions have been described, e.g. with cyclosporin or in a case of type I diabetes, where myositis has occurred together with hyperkalemia in a patient concomitantly treated with lisinopril (Edelman and Witztum, 1989).

Recently, hundreds of cases of myopathy were reported after intake of a lipid-lowering drug, cerivastatin, with fatal cases brought into connection with the use of this drug. This increase brought rhabdomyolysis to the media headlines in July/August 2001 and led to the withdrawal of cerivastatin by the manufacturer. Neither the causal connection nor the origin of the drug-induced muscle damage is fully understood, and it seems worthwhile to review this adverse drug reaction (ADR) in connection with lipid-lowering drugs, to discuss the causal connection, and to question if the withdrawal was adequate.

For this purpose, own experience with clofibrate (animal experiments) and ciprofibrate (clinical cases) as well as published literature on fibrates and statins in the last 30 years is reviewed. In comparing the occurrence of myopathy after different drugs differences in frequencies and severities of myopathy are of interest.

Since the muscular lesion could also be induced in animal models, these have also to be reviewed for mechanistic explanation, especially also for rhabdomyolysis which secondarily may lead to severe, sometimes fatal, kidney impairment.