Can we further optimize statin therapy to increase tolerability?

KEYWORDS:

• Statin
• myalgia
• LILRB5
• immune-mediated necrotizing myopathy
• PCSK9
• bempedoic acid
• nocebo effect
• drucebo effect

1. Introduction

Treatment with statins has become widely used as a result of their proven beneficial preventive effects on cardiovascular (CV) events [1]. According to recent data >25% of US adults >40 years of age take a statin, i.e. more than 25 million [2]. However, while guidelines recommend high intensity statin therapy in very high-risk patients with atherosclerotic cardiovascular disease (ASCVD), too many of these patients are inadequately treated or are not achieving the treatment target values, thus remaining at risk of recurrent CV events. Moreover, many patients to whom statins are prescribed do not adhere to therapy (about 30%) within 1 year of initiation [3], rates being higher for primary vs secondary prevention, as well as for older patients, women, and patients taking concomitant medications. Reasons for discontinuation, aside from the general disaffection by patients for chronic treatments, are many. Furthermore, a large percentage of patients have suboptimal response to statins. This, again in real-world practice, appears to be mainly related to the rapid occurrence of reduced persistence: after 3 years, <40% of patients persist in taking statins for primary and secondary prevention, and only 45% are persistent at 3 years. No exception has been found in high-risk patients, e.g. in diabetics in whose persistence is only 50% at 2 years [4]. In a most recently published multicenter European survey on 8,261 patients with verified CV events or interventions who were interviewed and examined ≥6 months later, 80% were taking statins. Among these very high-risk patients on lipid-lowering drugs only 32% had the target level of LDL-C < 70 mg/dL suggesting either too low doses prescribed or insufficient compliance. Among patients on lipid lowering drugs, 76% reported full prescription compliance [5].

Concerning safety issues, a recently published scientific statement points out that there is, as yet, no convincing evidence for a causal relationship between statins and cancer, cataracts, cognitive dysfunction, peripheral neuropathy, erectile dysfunction, or tendonitis [2]. The risk of statin induced serious muscle injury, including rhabdomyolysis, is <1% and the risk of serious hepatotoxicity ~0.001% [6]. This scientific statement underlines that muscle symptoms, the major complaint associated with statin treatment, are usually not caused by pharmacological effects. Although this conclusion is certainly not shared by all, the lack of placebo-controlled trials specifically addressed to skeletal muscle-associated symptoms is a major weakness. Indeed, re-challenge with statins in these patients is an important approach, especially for patients at high risk of CV events. This procedure is encouraged by a recent meta-analysis [7] as well as by data from the PALM (Patient and Provider Assessment of Lipid Management) study [8], both reporting that a significant proportion of statin users can restart therapy following discontinuation without any serious adverse effects. Re-challenge, however, may not be always satisfactory, although the EAS Consensus Panel pointed out that withdrawal of statin therapy followed by one or more re-challenges (after a washout) can often help in determining causality [9]. On the other hand, re-evaluation of the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-LLA) indicated that a ‘nocebo’ effect is probably more important as assessed in a comparison between blinded and unblinded treatments [10].

2. Statins and myalgia

Asides from randomized controlled studies and expert Consensus statements, in daily clinical practice the predominant side effect of statins is drug-induced myalgia; 7–29% of patients complain of statin-associated muscle symptoms [11]. Interestingly, although reports of severe rhabdomyolysis date back to more than 30 years ago [12], statin myalgia has received an increasing medical attention only in more recent years. The significance of myalgia was, in fact, not brought up by controlled clinical trials where statin intolerance ranges between 3% and 5%, most likely because of careful selection of patients and limitations in the diagnosis of myopathy to patients with certain threshold values of plasma creatine kinase (CK) [13]. Interestingly, the re-analysis of IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) study showed that medication discontinuation was higher in patients given placebo plus simvastatin vs ezetimibe plus simvastatin [14]. Unfortunately, this and similar studies did not lead to effective markers associated with the behavioral response to drug prescription. Re-analysis of the lipid-lowering Arm of the ASCOT-LLA (Anglo-Scandinavian Cardiac Outcomes Trial) clearly indicated that patients’ awareness of statin therapy increased their likelihood of reporting muscle symptoms, i.e. a nocebo effect possibly consequent to negative information on statin adverse-effects in the media [10]. In addition, very recently other Authors described the ‘drucebo’ effect, i.e. that linked to the expectations rather than to real pharmacological action of a drug. The ‘drucebo’ effect was confirmed by a recent study reporting a substantial increase (38–78%) in the incidence of skeletal muscle-associated symptoms with open-label compared to blinded treatment [15]. Some barriers to optimal treatment might further be the physicians’ attitude, including failure to titrate statin dose appropriately, causing the false impression that the lipid-lowering effect of a statin is inadequate [16]. Quantitative data on suboptimal treatment have become widely available. Real-world evidence indicated that among patients with very high CV risk, only 35% received statins with 30% achieving guideline-recommended LDL-C targets [17]. Moreover, among patients with coronary heart disease or acute coronary syndrome only 29.4% and 18.9%, respectively, displayed an LDL-C level below 70 mg/dL [18]; statin choice was mainly restricted to low dosage atorvastatin. Another cause might be a high number of physicians prescribing less potent instead of more potent statins when needed [19], and the apparent inert view by physicians of the importance of LDL-C goal attainment [16]. Although most physicians support the guidelines use, many of them do not use them in everyday practice and on average their knowledge of guidelines and target values is not satisfactory [20]. The final result of these inappropriate medication uses, in particular low adherence to statins, is, as very recently reported, greater risk of dying in ASCVD patients [21].

Finally, among the heterogeneous group of rare diseases that affect multiple organs and systems, including the muscles, skin, lungs, and joints, the inflammatory myopathies should be acknowledged. Immune-mediated necrotizing myopathy, sometimes referred to as necrotizing autoimmune myopathy, is a relatively newly recognized subgroup of idiopathic inflammatory myopathies in which two thirds of patients present with proximal muscle weaknesses, CK values between 10 and 100 times the upper limit, myopathic electromyography findings, and muscle biopsies showing necrosis or regeneration with minimal lymphocytic infiltrates and no perifascicular atrophy [22]. About two thirds of patients with immune-mediated necrotizing myopathy have autoantibodies recognizing either signal recognition particle or 3-hydroxy 3-methylglutaryl coenzyme-A reductase (HMGCR) [23]. Immune-mediated necrotizing myopathy is in 50% of cases idiopathic and in the rest mainly due to statins [24]. Statin-associated autoimmune myopathy is estimated to occur in approximately 2 or 3 out of every 100,000 patients treated with statins [25], atorvastatin being apparently associated to a higher incidence. The duration of statin exposure required to develop the pathology is 2–3 years on average [26] and the risk is dependent upon statin exposure, male gender, diabetes, and genetic background [9]. This form of statin-associated myopathy persists despite statin withdrawal and thus treatments with immunosuppressive medications, similarly to those for other forms of autoimmune muscle disease, should be initiated early [25].g

3. Mechanism/s of statin intolerance

The mechanism/s of, in particular, muscular side effects have provided a number of reports, both at the clinical and scientific level. Earlier Phillips et al. [27] identified and investigated a group of 30 statin treated patients with normal CK and muscle symptoms. Muscle biopsies showed evidence of mitochondrial dysfunction with increased lipid stores, despite normal blood biochemistry and a characteristic pattern that included breakdown of the T-tubular system and subsarcolemmal rupture. Morphological changes have been well described by the group of Draeger et al. [28] who reported muscle changes occurring in all individuals after exposure to statins. The same authors also provided electron microscopic changes in individuals who had significant muscle pain, in particular persisting for several months after statin withdrawal [29]. Their results suggest that a lack of elevated levels of circulating CK does not rule out structural muscle injury.

Basic studies have mainly explored changes in muscle chloride channels and in the atrogin-1 gene. Cl⁻ channel interference is a typical effect of statins and fibrates in vitro and in vivo [30]. It should be alleviated to allow the muscle to contract normally, without having hypercontractility and the pain as a result of it. Carnitine palmitoyl-2 deficiency and impaired calcium signaling changes have been also reported [31]. Alterations of the gene glycine amidinotransferase (GATM) appear to act as a functional link between lowering of cholesterol by statins and susceptibility to statin induced myopathy [32], although this conclusion has not been shared by other authors [33]. Ballard and Thompson [34] suggested that reduced GATM may be associated with a lower risk of statin myopathy and that creatine production may protect against myopathy but this hypothesis remains to be evaluated. Creatine supplementation to improve muscle function did not reduce the CK response to eccentric exercise (downhill walking at a − 15% grade) in healthy adults on atorvastatin, and severe muscle soreness was not altered [35]. An immunogenic contribution to statin intolerance came from a recently described missense variant (Asp247Gly) in the leukocyte immunoglobulin-like receptor subfamily-B gene (LILRB5), associated with lower CK and lactate dehydrogenase levels. Carriers of at least one copy of this variant showed a more than 30% increased risk of developing statin intolerance and myalgia [36].

Atrogin-1 induction by statins leads to muscle damage by a mechanism demonstrated in cultured mouse myotubes as well as in zebrafish embryos [37]. Apparently, this toxic mechanism may be antagonized by over-expression of PPAR-γ coactivator-1alpha (PGC-1 α), a transcriptional coactivator that induces mitochondrial biogenesis and protects against development of muscle atrophy. Atrogin-1 is a muscle-specific E3 ubiquitin ligase [37] and activation may be improved by metformin, an antidiabetic drug increasing the PGC 1-αα thus acting as a stimulator of mitochondrial production [38]. As statins also alter the effect of Fork Head Box proteins (FOXO1 and FOXO3A) thus possibly increasing the risk for diabetes mellitus [39], the role of metformin as a drug preventing adverse effects of statins may be worthy of investigation [40].

4. Expert opinion

Statin induced myalgia may be beneficially affected by aerobic exercise [41], as possibly exemplified by apoE KO hypercholesterolemic mice, reporting improved muscle function, without apparent soreness. However, although some practitioners advise suspension of a statin a day or two before a marathon or other strenuous exercise, RCTs investigating muscle performance did not highlight differences between statin- and placebo-treated participants [2]. Conversely, most professional athletes with severe FH do not tolerate any of the statins available [42].

Gene expression profiling in statin treated patients pointed out, instead, alterations in pathways including cellular stress, apoptosis, cell senescence, and DNA repair associated with activation of pro-inflammatory responses [43]. This type of potential clinical approach involving, among others, the activity of statins in reducing protein prenylation and altered ubiquitination leading to enhanced catabolism, has not been evaluated so far by pharmacological tools.

Increased incidence of muscle pain in subjects with genetic alterations of the solute carrier protein B1 (SLCO1B1), responsible for the liver uptake of statins, indicates that when statins are taken up at a reduced extent by the liver, the consequent increased delivery to muscle will lead to an increased muscle risk [44]. Knowledge of the genetics may possibly improve statin adherence due to reduced toxicity. However, a targeted study providing information on the SLCO1B1 genetic status provided evidence that this knowledge may improve statin re-initiation and LDL-C reduction but did not improve self-reported statin adherence [45]. These findings, on the other hand, as also suggested by Marz et al., should be probably best incorporated into a prediction algorithm, comprehensive of both genetic and non-genetic conditions including age, co-morbidities, and concomitant drug treatments [46].

The use of alternate-day versus daily treatment with statins to reduce side effects has been attempted by numerous investigators [47]. This may be applicable only for statins with long half lives, i.e. rosuvastatin or atorvastatin. Different studies have shown that rosuvastatin once or twice weekly in patients who previously have experienced adverse effects may lead to a modest reduction of LDL-C (−23%) but higher tolerability (more than 70% of patients) [48]. This approach, although attractive and possibly acceptable from the subjective point of view has, however, never been tested in terms of CV events prevention. As the pleiotropic effects of statins occur at well-known blood levels of these drugs, it is not unlikely that these effects may be lost at spaced administrations.

Finally, to achieve LDL-C target levels in patients who are statin intolerant, the alternative can be treatment with PCSK9 inhibitors [49]. Despite their relatively high cost and parenteral administration, the use of these drugs is today accepted in most countries. However, the occurrence of muscle symptoms in patients treated with PCSK9 inhibitors in a real-world experience was similar in familial hypercholesterolemic patients with and without statin intolerance [50], as clearly reported in the Lareb database indicating an incidence of 12.8% of treated patients [51]. Inclisiran, found to lower efficiently LDL-C levels in patients at high CV risk, might be another solution for statin intolerant patients. It inhibits translation of PCSK9 mRNA and thus switches off PCSK9 production providing advantages over PCSK9 monoclonal antibodies with an infrequent parenteral dosing interval of only twice a year [52].

Bempedoic acid, a drug whose NDA is currently being evaluated by the FDA, can add an LDL-C reduction of 28.5% to background treatment with ezetimibe. This looks promising for patients with statin intolerance needing to achieve target LDL-C levels. The lowering effect is larger in patients who are not on statin background therapy when compared with patients on low statin doses: −34.7 vs −20.5%, respectively [53]. However, neither for bempedoic acid nor for inclisiran, there are presently data on decreased CV events and mortality.

The problem of statin intolerance is unlikely to be solved within a reasonable time. Careful selection and motivation of patients, without justification to treat extremely old patients (aged > 85 years) [54] or patients on complex therapies for other diseases will allow clinicians to better handle this frequent clinical problem.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

One referee declares having received royalties from Inova Diagnostics related to the intellectual property of anti-HMGCR autoantibody testing. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

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Funding

This manuscript has not been funded.