Mechanisms of statin-associated skeletal muscle-associated symptoms

Abstract

Statins lower the serum low-density lipoprotein cholesterol and prevent cardiovascular events by inhibiting 3-hydroxy-3-methyl-glutaryl-CoA reductase. Although the safety of statins is documented, many patients ingesting statins may suffer from skeletal muscle-associated symptoms (SAMS). Importantly, SAMS are a common reason for stopping the treatment with statins. Statin-associated muscular symptoms include fatigue, weakness and pain, possibly accompanied by elevated serum creatine kinase activity. The most severe muscular adverse reaction is the potentially fatal rhabdomyolysis. The frequency of SAMS is variable but in up to 30% of the patients ingesting statins, depending on the population treated and the statin used. The mechanisms leading to SAMS are currently not completely clarified. Over the last 15 years, several research articles focused on statin-induced mitochondrial dysfunction as a reason for SAMS. Statins can impair the function of the mitochondrial respiratory chain, thereby reducing ATP and increasing ROS production. This can induce mitochondrial membrane permeability transition, release of cytochrome c into the cytosol and induce apoptosis. In parallel, statins inhibit activation of Akt, mainly due to reduced function of mTORC2, which may be related to mitochondrial dysfunction. Mitochondrial dysfunction by statins is also responsible for activation of AMPK, which is associated with impaired activation of mTORC1. Reduced activation of mTORC1 leads to increased skeletal muscle protein degradation, impaired protein synthesis and stimulation of apoptosis. In this paper, we discuss some of the different hypotheses how statins affect skeletal muscle in more detail, focusing particularly on those related to mitochondrial dysfunction and the impairment of the Akt/mTOR pathway.

Introduction

The first inhibitor of the 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, the rate limiting enzyme of cholesterol synthesis, was discovered by the Japanese Researcher Akiro Endo, who detected that a compound isolated from supernatants of cultures of Penicillium citrinum was able to inhibit cholesterol synthesis in cells [1]. The compound was called compactin and was shown to decrease the serum cholesterol concentration in different animal species and in patients with familial hypercholesterolemia [2]. Shortly later, lovastatin was isolated from cultures of Aspergillus terreus [3]. Lovastatin was successfully developed preclinically and clinically and was approved by the FDA in 1987, whereas compactin did not reach the market. Simvastatin, which is a semisynthetic product obtained by methylation of lovastatin, reached the market already in 1988, an pravastatin, a natural product, followed in 1991. Fluvastatin, atorvastatin, cerivastatin, rosuvastatin and pitavastatin are synthetic compounds and reached the market later. Cerivastatin, a lipophilic statin with a high bioavailability, was frequently associated with severe myopathy (rhabdomyolysis) [4] and had to be withdrawn from the market.

The HMG-CoA reductase inhibitors or statins are the most effective oral drugs for the prevention and treatment of cardiovascular diseases associated with dyslipidemia. Statins inhibit the HMG-CoA reductase competitively, thereby reducing intracellular synthesis of cholesterol. The pharmacological effect of statins is explained by inhibition of the HMG-CoA reductase activity in the liver. This effect lowers the hepatocellular cholesterol content, which is associated with activation of sterol regulatory element binding proteins (SREBP) [5]. Activation of SREBP occurs by proteolytic processing in the Golgi apparatus, yielding active fragments that enter the nucleus and induce the transcription of genes, which favor cholesterol synthesis and LDL-uptake such as the LDL receptor [6]. If this happens in hepatocytes, the final result is lowering of the serum LDL-cholesterol, the desired pharmacological effect of statins. If statins reach the systemic circulation to an extent high enough to inhibit cholesterol synthesis in extrahepatic tissues, this can lead to adverse reactions such as for instance muscle damage. As shown in Fig. 1, inhibition of HMG-CoA reductase not only decreases the synthesis of cholesterol but also of intermediates in cholesterol synthesis such as for instance ubiquinone, geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP) [7]. Since these intermediates are important for normal cell function, inhibition of their synthesis can lead to cell dysfunction or even cell death, which can explain adverse reactions of statins.

Since cardiovascular diseases are very common in most countries, statins belong to most often prescribed drugs worldwide. For instance, in the year 2000, the highest use of statins in Europe was in Norway (59 daily doses per 1000 inhabitants) and the lowest use in Italy (15 doses per 1000 inhabitants) [8]. In Denmark, statin use in patients aged more than 40 years increased from <1% in 1995 to 11% in 2010 [9]. Similar frequencies are reported from the United States of America, where during 2011–2012 26% of the more than 40 years-old persons had a prescription of a cholesterol lowering agent [10]. Accordingly, it is estimated that approximately 25% of the world population older than 65 years is treated with a statin for primary or secondary prevention of cardiovascular diseases [10,11]. Taking into account that the life expectancy is increasing in most countries, this number will most probably continue to increase in the future [12].

Important pharmacological details of the statins are presented in Table 1. Since statins act by decreasing the cholesterol synthesis in the liver, they must be transported efficiently into hepatocytes, resulting in a high hepatic extraction and a low bioavailability. As shown in Table 1, this is the case for most statins. The two exemptions are cerivastatin and pitavastatin, which have bioavailabilities >50%. Cerivastatin was associated with a higher incidence of severe muscle damage compared to other statins [4], whereas muscle damage associated with pitavastatin appears not to be more frequent than for other statins [13]. Regarding pitavastatin, this may be due to a limited transport into skeletal muscle, which is considered to be an active process [14].

As stated above, the pharmacological effect of statins is a consequence of the inhibition of HMG-CoA reductase in hepatocytes. For that, statins have to be transported efficiently across the sinusoidal plasma membrane of hepatocytes. Statins are substrates the organic anion transporting polypeptides (OATP) 1B1, 1B3 and 2B1, of which OATP1B1 and 1B3 have a high expression in hepatocytes and OATB2B1 is also expressed in skeletal muscle [15]. The importance of OATP1B1 has been shown for simvastatin, since patients with polymorphisms in the corresponding gene decreasing the activity of OATP1B1 had a higher incidence of simvastatin-associated myopathy than patients with normal OATP1B1 activity [16]. A reduced activity of OATP1B1, caused by genetic polymorphisms or by drug interactions [15], impairs the hepatic uptake of statins, reducing their pharmacological effect and increasing their potential for toxicity due to increased systemic availability. Compared to the transport of statins into the liver, their transport into skeletal muscle is less well defined, but OATP2B1 may play a role. Different affinity of statins to these (and potentially additional) transporters may explain differences in the myotoxicity of the individual statins [4,15].

As shown in Table 1, lipophilic statins undergo substantial phase 1 metabolism, before they can be conjugated and excreted via the bile or the kidney. Atorvastatin and simvastatin are CYP3A4 substrates, which is a risk factor for interactions with other drugs [17]. It is well established that CYP3A4 inhibitors increase the exposure to simvastatin or atorvastatin and that co-administration of CYP3A4 inhibitors to patients treated with simvastatin or atorvastatin can be associated with rhabdomyolysis [18]. The efficacy of the individual statins depends on the extent of inhibition of the target, HMG-CoA reductase, by the individual statins [19]. Rosuvastatin and atorvastatin are the most efficient statins, with LDL reductions in the range of 60% at the highest dose approved.

Statins are also considered to possess pleiotropic effects on the cardiovascular and other body systems, which are not explained by their pharmacological action [1]. For instance, statins have been found to exhibit antioxidant activity, which may be beneficial in patients with cardiovascular diseases [20,21].