Statins: safety and pharmacological interactions

Keywords::

• adverse drug reactions
• interactions
• safety
• statins

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are recognized as highly effective in reducing low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (HDL-C) levels. Vast evidence from clinical trials has demonstrated that statins therapy can reduce the risk of myocardial infarction, stroke, death, and the need for coronary revascularization procedures by 20 – 50%. These benefits have been reported in people with and without diabetes or prior diagnosis of cardiovascular disease (CVD), at different ranges of age and in both genders. Lowering LDL-C by around 1 mmol/L (38.6 mg/dL) reduces mortality and morbidity by about 25%. Trials comparing intensive versus standard statin regimens suggest that a further LDL-C reduction of about 0.5 mmol/L (19.3 mg/dL) results in an additional 15% reduction in the risk of a major vascular event [1]. The Cholesterol Treatment Trialists' (CTT) Collaboration has proposed that maximal lowering of LDL-C obtained by pharmacological treatment with statins provides relevant gain in terms of cardiovascular prevention. In a recent CTT publication, reporting treatment of people with a 5-year risk of major vascular events below 10%, each 1 mmol/L (38.6 mg/dL) decrease in LDL-C caused an absolute decrease in major vascular events of about 11 per 1000 over 5 years. This benefit greatly exceeds any known hazards of statins [2].

In spite of some debate about the real effect out of the extremes of statin regimens [3], this position was assumed as a rule by many guidelines across the world. Nevertheless, this ongoing discussion is still relevant to estimate the real risk/benefit ratio of statin therapies when administered at usual doses in practice.

No drug therapy is free of adverse events and statin treatment sometimes induces class-related adverse reactions. Among them, myopathy incidence is difficult to assess from clinical trial data and pharmacoepidemiological research, since the definition of muscle-related events differ among studies, regulatory agencies and scientific institutions across the world [4]. The spectrum of muscle-related toxic effects of statins is broad, ranging from myalgias (with or without creatine kinase increases) to rhabdomyolysis, even including an immune-mediated myositis form. The most generally agreed incidence of myopathy (or muscle-related events) under statin treatment arises from randomized clinical trials and ranges between 1.5 and 5% [4]. Nevertheless, the PRIMO study (an observational research conducted on around 8,000 patients under statin treatment) reported that 10.5% of patients treated with high doses of statins experienced some kind of muscular symptoms [5]. Among 130,000 first-time users of a statin therapy, myopathy incidence (defined as elevations of creatine kinase levels over 10-fold the upper normal limit and muscle symptoms leading to hospitalization) was close to 0.4 per 10,000 patient-years [6]. Rhabdomyolysis seems to be rare, with a rate of 0.7 per 100,000 person-years at the U.S Food and Drug Administration (US FDA) spontaneous reporting system [4]. In clinical trials, the incidence is probably less than 4 per 10,000 patient-years at the highest doses of statins [4]. Several risk factors for muscle toxicity have been identified for a long time: age older than 70 years, high-dose therapy, female gender, impaired hepatic and/or renal function, low body mass index, hypothyroidism, drug and alcohol abuse. Biological plausibility for the non-immune and immune-mediated forms of myopathy is supported by many data from basic science, though the key mechanisms are ill understood. In some cases, pharmacological interactions and specific genotypes of the solute carrier organic anion transporter 1B1 (SLCO1B1) [7] are associated with muscle toxicity.

Hepatotoxicity with statins seems to be a rare event [4]. The most frequent is the increase of hepatic enzymes in plasma without any histological liver abnormality, suggesting an increase of cell permeability with leakage of enzymes. Plasma values of alanine transaminase (AST) or aspartate transaminase (ALT) above threefold the upper normal limit have been reported in 0.5 – 2% of treated patients, being cause of discontinuation for 0.1 – 0.6% of them [8]. Liver failure is very rare, close to 0.5 per 100,000 patient-years [4]. Recent studies suggest that the use of statins in patients with non-alcoholic fatty liver disease, B or C hepatitis or even compensated primary biliary cirrhosis may by safe. Liver function deterioration may result, nevertheless, in an increase of statin concentrations that can be associated with toxicity. Again, drug–drug and/or drug–nutrient interactions account for an increased risk of liver-centered adverse reactions. Despite this, the FDA announced on February 28, 2012 that ALT monitoring was no longer recommended for statins [9].

The association between statin therapy and hematuria remains unclear. Instead, proteinuria seems to be linked to statins treatment that seems to be the result of reduced resorption of albumin at the proximal tubule. At the light of the more recent clinical trials and pharmacoepidemiological research, these effects do not affect renal function and the use of statins does not seem to be a cause for renal disease [4]. Besides, the appropriate use of statins in patients with renal disease appears to be safe.

Diabetes incidence is increased under statin therapy. A relative risk excess ranking between 10 and 40% was reported at several studies, being slightly higher with highest doses [10]. Biological plausibility of this association remains to be clarified. The effects on insulin resistance are inconsistent, and it is unclear whether insulin secretion is affected under statin therapy. It has been proposed that this effect on diabetes incidence may differ among the diverse statins. While simvastatin and atorvastatin have been shown to interfere with insulin secretion and reduce insulin sensitivity at different experimental models, pravastatin has demonstrated some positive effects on insulin sensitivity [10]. There is also significant evidence that pravastatin may reduce insulin resistance and increase insulin sensitivity in experimental models [11], via increased adiponectin messenger RNA expression and subsequent secretion [12]. Besides, a neutral effect on the risk of incident diabetes was noticed in the Lipid Study [13] and a slight decrease on this risk was observed at the WOSCOP trial [14] both including pravastatin, though the dose of pravastatin used may be considered low, and thus, not enough to disturb the glucose metabolism [10]. In general, clinical trials support the option for the hydrophilic statins pravastatin, rosuvastatin and pitavastatin as compared to more lipophilic agents [15]. In a recent study comparing the effect of simvastatin (40 mg) versus rosuvastatin (10 mg) versus simvastatin plus ezetimibe (10 mg/10 mg) after 12 weeks of treatment, all three regimens were associated with significant increases in HOMA-IR (a surrogate of insulin resistance) and fasting insulin levels when compared with baseline values. No significant difference was observed between groups [16]. Evidence of drug–drug or drug–nutrient interactions increasing the risk for incident diabetes is lacking: even when plausible, a profound analysis of a concomitant effect of beta-blockers, diuretics, etc., is still pending. Deeper efforts in this area are highly advisable.

Other adverse effects have been linked to statin treatment. Sleep disturbances and some psychiatric disorders, including cognitive impairment, seem to be more frequently reported among patients receiving statins (in special, the more lipophilic ones). Nevertheless, this association remains still controversial [17]. Alopecia under statins is rare, and the association between erectile dysfunction and statins use is unclear [4]. Extremely rare cases of interstitial lung disease have been reported, but both the strength and impact of this association as well as its biological plausibility remain uncertain [18].

A recent article by Corsini et al. [19] addressed on the statin interactions and their potential impact on clinically relevant statin-associated adverse events. As mentioned before, pharmacological interactions play a relevant role in the incidence of at least some of the statin-induced drug reactions. Besides, patients at high cardiovascular risk usually receive treatment involving multiple pharmacological agents, which increases the risk for drug–drug interaction [20]. As described in the above-mentioned paper, more than 50% of patients experiencing statin-associated rhabdomyolysis are concomitantly treated with cytochrome P450 3A4 (CYP3A4) inhibitors, and 20% are co-treated with fibrates. The cytochrome-P450 sub-families are not the only target for pharmacological interaction with statin: some transmembrane transport-associated proteins (several organic anion transport polypeptides subfamilies [OATP], the breast cancer resistance protein [BCRP], P-glycoprotein, etc.) may participate in drug–drug or drug–nutrient interactions that lead to a clinically relevant increase in the statin concentration. Many of the interactions at statin metabolism and/or transport and elimination are associated with some specific single nucleotide polymorphisms related to the above-mentioned target mechanisms. Epigenetic factors may not be excluded, but the real meaning of these factors in practice remains to be elucidated. Concomitantly, pharmacokinetic changes induced by other drugs, different than those registered on metabolism and transmembrane transport, may modify statin concentrations and drive to adverse events. Drugs modifying distribution volume, clearance, intestinal or hepatic blood flow, intestinal bile salt concentrations, etc., may affect statin plasma exposure leading to myopathy, hepatotoxicity, and other events.

As mentioned in the beginning, statins are highly effective in reducing the likelihood of myocardial infarction, stroke, death, and the need for coronary revascularization in a wide spectrum of individuals at risk. Taking all the safety issues into consideration above, it is our belief that the net cardiovascular benefit in high-risk subjects is still strongly in favor of statin therapy. Treatment of low-risk patients is still a matter of debate. For all the cases, a better knowledge about the potential drug–drug and drug–nutrient pharmacodynamic and pharmacokinetic interactions with statins will be of great help in preventing adverse reactions, facilitating treatment and therapy intensification at a lower risk of undesirable effects.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.