Statins are generally well tolerated, with a low frequency of adverse events, but since statins are prescribed on a long-term basis, many patients will typically receive pharmacological therapy for concomitant conditions during the course of statin treatment and potentially interacting combinations are still frequently prescribed and deserve particular attention.
Statins are a well-established class of drugs for the treatment of hypercholesterolemia with a proven long-term safety profile. Statins have been shown to reduce the risk of cardiovascular morbidity and mortality in patients with or at risk for coronary heart disease (Catapano et al., 2016). Statin use is expanding and approximately 25 per cent of the world population older than 65 years takes a statin on a long-term basis both for primary or secondary prevention of Cardiovascular Disease (CVD) (Gu et al., 2014). The recent recommendations by ATPIV (Stone et al., 2014) and ESC/EAS 2016 (Catapano et al., 2016) have further supported statin therapy for primary and secondary prevention of atherosclerotic CVDs. Thus, the safety and adverse effects of statins, especially in patients receiving multiple medications at risk of drug-drug interactions (DDIs), are a matter of special concern. Statin monotherapy is generally well tolerated but patients concomitantly receiving multiple medications are at an increased risk of adverse events including statin-associated muscle symptoms.
A DDI generally occurs when either the Pharmacokinetics (PK) or Pharmacodynamics (PD) of one drug is altered by prior or concomitant administration of another drug resulting in an effect different from the expected effects of each drug given alone (Wiggins et al., 2016). This may result in a change in either drug efficacy or toxicity for one or both of the interacting drugs (Corsini et al., 1999). Many clinically significant DDIs have a PK origin, and are often due to induction or inhibition of drug metabolising enzymes and/or transporter involved in drug disposition (Bellosta and Corsini, 2012). Drugs that induce the Cytochrome P450 (CYP) enzymes may reduce the plasma concentration of a drug metabolised via this pathway, whereas inhibitors of CYP enzymes, particularly CYP3A4, confer a risk for DDIs when co-prescribed with statins metabolised via this route. Statins are very selective inhibitors of HMG-CoA reductase and usually do not show any relevant affinity towards other enzymes or receptor systems (Corsini et al., 1999). This implies that, at the PD level (i.e., at their site of action), statins do not interfere with other drugs. However, the available statins have important PK differences, including half-life, systemic exposure, peak of maximum serum concentration (Cmax), bioavailability, protein binding, lipophilicity, metabolism, presence of active metabolites, and excretion routes.
Statins are subjected to an important hepatic first-pass effect thus explaining their low systemic bioavailability. Most of the statins undergo extensive microsomal metabolism by the CYP isoenzymes system, while pravastatin is transformed enzymatically in the liver cytosol. The CYP3A4 isoenzyme metabolises lovastatin, simvastatin, and atorvastatin, while fluvastatin is metabolised primarily by the CYP2C9 enzyme, with CYP3A4 and CYP2C8 contributing to a lesser extent (Corsini et al., 1999). Lovastatin and simvastatin are more sensitive substrates of CYP3A4 than atorvastatin, thus they are more sensitive to CYP3A4 inhibition. Pravastatin and rosuvastatin do not undergo substantial metabolism via CYP pathways, although rosuvastatin interacts with CYP2C9 (Corsini et al., 1999). Pitavastatin is protected from CYP3A4-mediated metabolism by its cyclopropyl moiety on its base structure and is marginally metabolised by CYP2C9 and CYP2C8 (Corsini and Ceska, 2011).
Statins are also recognised by drug transporters in the liver, gut and kidney that modulate statin disposition and represent potential mechanisms for statin DDIs. Organic anion-transporting polypeptide 1B1 (OATP1B1, gene name SLCO1B1) mediates the hepatic uptake of all the statins (Ieiri et al., 2009). Other transporter systems involved in the uptake and efflux of statins include OATP1B3 (SLCO1B3), OATP2B1 (SLCO2B1), multi-drug resistance associated proteins such as P-glycoprotein (ABCB1), MRP2 (ABCC2), breast cancer resistance protein (BCRP, ABCG2) and sodium-dependent taurocholate co-transporting polypeptide (NTCP, SLC10A1).
Many DDIs have been demonstrated in clinical experience with statins. The risk of DDIs varies among different statins thus affecting differently statin safety and tolerability (Bellosta and Corsini, 2012). The adverse effects that occur when statins are co-administered with other drugs usually correlate with increased systemic concentrations of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor which has been regarded as an index of potential untoward effects in peripheral tissues (Corsini et al., 1999). In particular, DDIs with a drug that increase statin exposure may lead to an increased risk of muscle-related adverse events such as myalgia, myopathy and (more rarely and more seriously) rhabdomyolysis (Bottorff, 2006).
Drugs that reduce statin metabolism by inhibiting CYP enzymes (mainly CYP3A4) or interfering with drug transporters (Bellosta and Corsini, 2012; Corsini and Bellosta, 2008; FDA, 2012), such as OATP1B1 and P-gp, (Table 1) can lead to increased systemic exposure of the statin and increase the risk of myopathy. The different physicochemical and PK properties of statins may explain the significant differences in their interaction potential that are evident at the PK level affecting drug absorption, distribution, metabolism and excretion.
Many drugs have the potential to cause PK interactions with statins increasing the risk for myopathy and rhabdomyolysis (Table 2), highlighting the importance of considering their DDI profile when selecting a statin for an individual patient. Another potential risk of DDIs is represented by nutraceutical preparations containing red yeast rice, a popular nonprescription treatment for hyperlipidemia. Rice fermented with red yeast contains varying amounts of monacolin K (chemically similar to lovastatin) and side effects similar to those observed with statins have been reported in some people using this nutraceutical. Combination of red yeast with statins is not recommended due to the increased risk of DDIs and myopathy (Catapano et al., 2016).
A comprehensive and updated review on statins drug-drug interactions has been recently published (Bellosta and Corsini, 2018).
As many patients receiving statin treatment are elderly and/or have comorbid cardio-metabolic conditions, they will generally be prescribed multiple medications that may increase the risk of DDIs. About 3 per cent of general hospital admissions occur as a direct result of DDIs (Shapiro and Shear, 1999), and the prevalence of DDIs in the elderly population is approximately 50 per cent (Venturini et al., 2011). DDIs represent approximately 15 per cent of avoidable prescription errors, and their consequences constitute a serious health problem in the elderly population (Santos et al., 2017). Furthermore, the effects of those consequences can be confounded by the worsening of pre-existing diseases or treatment inefficacy (Hines and Murphy, 2011). In fact, DDIs are common among community-dwelling older adults and are associated with the number of medications and hospitalisation in the previous year (Hanlon et al., 2017).
As age increases, the majority of physiological processes decrease gradually, including renal and liver function (Kinirons and Crome, 1997). Indeed, all the PK phases, from absorption to excretion, are affected by ageing thus increasing the risk of DDIs. Elderly patients on multiple drugs should be regularly reevaluated for the risk of DDIs (Corsini and Ceska, 2011). Under-treatment is also frequently present in the elderly and a clear relationship between polypharmacy and under-prescribing has been established.
Elderly patients at elevated risk of CV disease almost inevitably are treated with statins and are likely receiving concomitant therapies that may increase their risk of DDIs (Corsini and Ceska, 2011). Moreover, aging patients are more prone to statin-induced muscle problems since muscle mass and the activity of enzymes involved in drug metabolism and disposition are reduced by age (Kellick et al., 2014). Altogether, in elderly patients receiving multiple therapies, especially for those receiving agents with a narrow therapeutic window, is important to implement a systematic approach to drug monitoring for achieving a more appropriate prescribing model. Attention in the prescription of medications, a consistent review of medication lists, and a re-evaluation of the indications and outcomes of the prescriptions are essential to ensure that polypharmacy is minimised and safety for patients is maximised.
As stated above, the clinical benefits of statins have expanded their use in clinical practice in patients with CVD risk, especially in elderly populations who are often receiving multiple medications for comorbidities thus increasing the risk of drug-drug interactions with statins. Furthermore, the effect can be increased by the worsening of pre-existing diseases or treatment inefficacy. In addition, elderly patients consume the largest number of self-medications or over-the-counter medications, including vitamins, minerals, nutraceuticals and foodstuffs (e.g. grapefruit) that contribute to the complexity of the therapy but also increase adverse drug reactions due to DDIs, including statin-associated muscle symptoms (SAMS) (du Souich et al., 2017; Mancini et al., 2016; Stroes et al., 2015), and statin-induced hepatotoxicity (Benes et al., 2016). The SAMS, that occur after a pharmacokinetic interaction, increase the systemic exposure to statins and are also responsible for nonadherence to and/or discontinuation of treatment (du Souich et al., 2017; Mancini et al., 2016; Stroes et al., 2015), As a consequence the exposure of patients to CVD risk remains high. In perspective, to improve this clinical scenario, it will be important to define more appropriate interventions, for example, by providing physicians and clinicians with prescribing guidance and tools to support the delivery of effective medication protocols, with a rationalisation of prescribing needs and an effective communication of outcomes to patients and to all prescribers involved in providing health care.
A question, that still remains to be properly addressed, is which type of adverse drug reaction is related to DDIs with statins. Myopathy, due to an increased circulating plasma levels of statins following the co-administration with a CYP enzyme inhibitor, is a well established phenomenon, which has been characterised either from a pharmacological point of view (Bellosta and Corsini, 2012; Catapano et al., 2016; Kellick et al., 2014) or from the evaluation of the pathophysiology of SAMS (Apostolopoulou et al., 2015; du Souich et al., 2017; Mancini et al., 2016; Stroes et al., 2015). On the contrary, much less is known about the relationship between DDIs and other statin-induced side effects, including the alteration of blood glucose levels and the incidence of new onset of diabetes, cognitive adverse effects, proteinuria and liver toxicity (Catapano et al., 2016). Although FDA has determined that serious liver injury with statins is a rare adverse event and that periodic monitoring of liver enzymes is not useful (FDA, 2015), potential DDIs, particularly in older patients who may have multiple chronic conditions requiring concomitant therapies, can alter a drug toxicity profile and therefore potentially result in hepatotoxicity (Corsini and Bortolini, 2013). However, causality assessment in drug-induced liver injury (DILI) cases can be challenging and the last prescribed drug cannot be always assumed to be the culprit or the only responsible agent (Shapiro and Lewis, 2007).
The inhibition and induction of drug metabolising enzymes are important causes of DDIs leading to DILI. A build-up of drugs or their metabolites can be potentially toxic through competitive inhibition and lead to a greater risk of adverse events. Numerous drugs have been identified as CYP3A4 inhibitors, including antibiotics, anti-fungals, antidepressants, calcium channel blockers, steroids, and antiretrovirals (Table 1). However, few evidence on statin-induced liver injury after DDIs have been reported so far, and additional investigations are required to better define this important aspect.
Another interesting question that will have to be fully explored in the future is the potential interaction between statins and therapeutic proteins such as monoclonal antibodies. The different pharmacological behaviours between these two classes of drugs is suggestive of a low risk of DDIs and of a safe profile. However, long term clinical data are still required before reaching a definitive conclusion on the log-term safety of this therapeutical combination. Finally, only few clinical data is available on statin DDIs in special populations, such as patients with familial hypercholesterolemia, paediatric patients and different ethnic populations that require chronic therapy with statins (Kellick et al., 2014) and more information is needed to better define statin safety issues.
Altogether, although statins are a class of drugs which has been available in clinical practice for more than 25 years, their expanded use among patients leaves open several important questions that are still waiting to receive a definite answer. Only a better and more profound knowledge of the potential DDIs among statins and other therapeutic options will help physicians in selecting the more effective and less harmful treatment for their patients.
Statin clinical use is expanding particularly in elderly patients who are often receiving multiple medications for comorbid conditions, thus exposing them to an increased risk of ADR due to DDIs, including statin-associated muscle symptoms (du Souich et al., 2017; Mancini et al., 2016; Stroes et al., 2015), and statin-induced hepatotoxicity (Benes et al., 2016). Differences in pharmacokinetic profiles of the different statins may influence their adverse effect profile (Bellosta and Corsini, 2012; Corsini et al., 1999). This could be crucial when considering DDI risks when co-administering drugs in patients receiving a statin therapy. Caution should be taken to balance the potential clinical benefits versus the risks of statin treatment to improve overall outcomes and provide patients with an evidence-based, safe and cost-effective clinical support.