Does Reduced Creatine Synthesis Protect Against Statin Myopathy?

Abstract

Statins, widely used to lower cholesterol levels, cause myopathy in some patients. Mangravite et al. (2013) show that a single nucleotide polymorphism decreasing expression of glycine amidinotransferase (GATM), the enzyme regulating creatine biosynthesis, is associated with reduced statin myopathy. Whether reduced creatine production protects against statin myopathy remains to be determined.

Hydroxy-methyl-glutaryl Co-A (HMG CoA) reductase inhibitors or “statins” inhibit mevalonate production, ultimately reducing low-density lipoprotein (LDL) cholesterol concentrations and cardiovascular morbidity and mortality. Statins are extremely well-tolerated, but can produce skeletal muscle adverse effects in some patients, ranging from myalgia (muscle pain), cramps, weakness, and stiffness to markedly elevated creatine kinase (CK) levels, indicating skeletal muscle damage, and rhabdomyolysis (muscle breakdown). It is assumed that all of these muscle complaints are produced by the same mechanism, but this is not certain and at least one muscle side-effect, an autoimmune myositis (muscle inflammation), is associated with antibodies against HMG CoA reductase (Mohassel and Mammen, 2013). Statin-induced rhabdomyolysis and autoimmune myositis are extremely rare, but the STOMP (Effect of Statins on Muscle Performance) study (Parker et al., 2013) reported that treatment with high dose atorvastatin, one of the most commonly prescribed statins, doubled the incidence of myalgia compared with placebo from 4.6% to 9.4%, suggesting that the overall incidence of statin myalgia is approximately 5%. Statins are among the most widely prescribed medicines world-wide, making prediction of who can and cannot tolerate these drugs an important issue. Numerous possible genetic variants affecting statin myopathy have been identified (Ghatak et al., 2010). Mangravite and colleagues (Mangravite et al., 2013) now identify a variant in the gene for glycine amidinotransferase (GATM), the rate-limiting enzyme required for creatine biosynthesis, as a possible genetic contributor to statin myopathy.

The findings of Mangravite et al. add to the growing list of genetic variants associated with increased muscle complaints. These include the gene for the organic anion transporter, SLCO1B1. The SLCO1B1 *5 variant (rs4149056) is associated with reduced hepatic statin uptake and increased myalgia (Voora et al., 2009) and rhabdomyolysis (Link et al., 2008), suggesting that reduced hepatic uptake increases the amount of statin that survives hepatic passage and can enter skeletal muscle. Variants in genes in the cytochrome P enzyme system (CYP), which catabolize statins, may also affect the frequency of statin myopathy, although these variants, in CYP3A4/5, CYP2D6, and CYP2C9, appear most important when statins are combined with other drugs metabolized by the same CYP enzyme (Ghatak et al., 2010). Variants in the COQ2 gene, a component of the coenzyme Q10 (CoQ10) production pathway, have also been proposed to affect statin myalgia. CoQ10 is a mitochondrial electron transport protein that is also produced by the mevalonate pathway. Reductions in CoQ10 production could adversely affect cellular energy production. These are only three of multiple possible genetic variants affecting statin myopathy (Ghatak et al., 2010).

Mangravite and colleagues (Mangravite et al., 2013) are the first to identify creatine biosynthesis as another possible contributor to statin myopathy. Creatine, or methylguanidine acetic acid, is synthesized predominantly in the liver and kidneys by a two reaction pathway utilizing glycine, arginine, and methionine. Creatine is then transported to skeletal muscle where it combines with inorganic phosphate to form creatine phosphate (CP). CP is rapidly split by CK to produce creatine and inorganic phosphate. The latter combines with ADP to form ATP. CP thus serves as an important cellular energy source for rapid re-synthesis of ATP to meet the energy demands of intense activities.

Mangravite et al. (2013) used a genome-wide expression quantitative trait loci (eQTL) analysis in lymphoblastoid cell lines (LCLs) from 480 middle-aged healthy volunteers from a simvastatin treatment trial. LCLs, which are a common model system to screen for genetic variants, were exposed to simvastatin or control buffer for 24 hours. Six eQTL were identified that interact with simvastatin exposure. These included a single nucleotide polymorphism rs9806699 in GATM. Simvastatin exposure produced a 2-fold greater reduction in GATM expression in cells from rs9806699 carriers than in cells from non-carriers. Reduced GATM expression should reduce creatine synthesis. Furthermore, the relationship between the GATM differential eQTL locus expression with simvastatin exposure and statin-induced myopathy was examined in two separate population-based cohorts comprising 172 cases of myopathy (Link et al., 2008; Mareedu et al., 2009). Calculation of an odds ratio to quantify the association between presence of the rs9806699 variant and statin myopathy resulted in an overall odds ratio of 0.60 (95% confidence interval = 0.45–0.81) with meta-analysis of these two cohorts, suggesting that reduced GATM expression, and probable reduced creatine synthesis, is associated with a reduced incidence of statin-induced myopathy. Collectively, these novel data are the first to identify a genetic variant regulating creatine synthesis and highlight reduced intramuscular creatine as a potential protector against statin-induced muscle problems. The authors propose that simvastatin reduced GATM expression in rs9806699 carriers, reducing creatine availability and CP storage. They speculate that reduced CP storage modifies skeletal muscle cellular energy pathways leading to reduced susceptibility to statin myopathy (Figure 1).

Figure 1. Proposed Mechanism by Which Reduced GATM Activity Reduces Statin Myopathy Risk.

Simvastatin reduced GATM transcriptional expression and this effect was associated with a reduced incidence of statin myopathy (Mangravite et al., 2013). Reduced intramuscular Cr may protect against statin-induced myopathy. GATM = glycine amidinotransferase; CP = creatine phosphate; Cr = creatine.

This is a novel hypothesis, but questions remain. No prior studies, including several genome-wide association studies (GWAS) (Link et al., 2008; Ruano et al., 2011), have identified the GATM gene as a contributor to statin myopathy. In the study by Mangravite et al. (Mangravite et al., 2013), statin myopathy in their cohorts was defined by CK elevations 3–10 times the upper normal limits (Link et al., 2008; Mareedu et al., 2009). But perhaps the rs9806699 variant has indirect effects on CK levels that are independent of myopathy. Arguing against this possibility is the observation that plasma CK levels measured before and after statin treatment were not associated with the GATM variant in subjects without myopathy (Mangravite et al., 2013), but this does not address the possibility that intramuscular CK levels are related to the GATM genotype. Also, in contrast to the authors’ hypothesis (Mangravite et al., 2013), GATM deficiency was associated with a myopathy in two siblings that improved with oral creatine treatment (Edvardson et al., 2010), suggesting that depleting intramuscular creatine does not protect against, but causes, myopathy. Over-the-counter creatine supplementation actually appeared to reduce statin-associated muscle complaints in 10 patients with statin myalgia, but these data (Shewmon and Craig, 2010) warrant investigation in a much larger cohort.

In summary, these novel data (Mangravite et al., 2013) identifying a statin-responsive genetic variant in GATM expression associated with reduced susceptibility to statin-induced myopathy are intriguing, but require additional study to determine their significance.