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Management of Statin Intolerance in 2018: Still More Questions Than Answers

Management of Statin Intolerance in 2018: Still More Questions Than Answers Am J Cardiovasc Drugs (2018) 18:157–173 https://doi.org/10.1007/s40256-017-0259-7 REVIEW AR TICLE Management of Statin Intolerance in 2018: Still More Questions Than Answers 1,2 3 3 • • • Peter P. Toth Angelo Maria Patti Rosaria Vincenza Giglio 3 3 3 4,5,6 • • • Dragana Nikolic Giuseppa Castellino Manfredi Rizzo Maciej Banach Published online: 9 January 2018 The Author(s) 2018. This article is an open access publication Abstract Statin therapy is generally well tolerated and very effective in the prevention and treatment of cardio- Key Points vascular disease, regardless of cholesterol levels; however, it can be associated with various adverse events (myalgia, Statins are the gold standard for managing myopathy, rhabdomyolysis, and diabetes mellitus, among dyslipidemia in patients with elevated cardiovascular others). Patients frequently discontinue statin therapy risk. Discontinuation of statin therapy is associated without medical advice because of perceived side effects with an increase in cardiovascular events. and consequently increase their risk for cardiovascular An important issue in the management of patients events. In patients with statin intolerance, it may be with statin intolerance/statin-associated muscle advisable to change the dose, switch to a different statin, or symptoms is the need to avoid statin discontinuation. try an alternate-day regimen. If intolerance is associated Options include step-by-step reduction of the statin with all statins—even at the lowest dose—non-statin drugs dose (dechallenge), switching to a different statin, or and certain nutraceuticals can be considered. This review using intermittent dosages (alternate-day therapy). focuses on the definition of statin intolerance and on the development of clinical and therapeutic strategies for its New non-statin agents, as well as alternative therapy management, including emerging alternative therapies. with nutraceuticals with or without a non-statin drug, may help to improve therapy adherence and reduce the risk for patients with true statin intolerance. Peter P. Toth and Angelo Maria Patti contributed equally to this Further studies in patients intolerant to statins are paper. necessary to confirm the effectiveness and safety of & Maciej Banach nutraceuticals. In addition, these agents will have to maciejbanach77@gmail.com be tested in long-term randomized controlled trials to 1 more definitively assess their efficacy for reducing CGH Medical Center, Sterling, IL, USA cardiovascular risk. Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy Chair of Nephrology and Hypertension, Department of 1 Introduction Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Zeromskiego 113, 90-549 Lodz, Poland Statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG- Polish Mother’s Memorial Hospital Research Institute, Lodz, CoA] reductase inhibitors) effectively reduce the burden of Poland atherogenic lipoprotein in serum [1]. Statins are a mainstay Cardiovascular Research Centre, University of Zielona Gora, globally in cardiovascular (CV) pharmacotherapy [2], not Zielona Gora, Poland 158 P. P. Toth et al. only in patients with dyslipidemia [3] but also in patients \CV risk[. We used the wild-card term ‘‘*’’ to increase with coronary artery disease (CAD), acute coronary syn- the sensitivity of the search strategy. dromes (ACS), diabetes mellitus (DM), stroke, hyperten- The main inclusion criterion was data from studies, sion, and chronic kidney disease (CKD) (with or without trials, and meta-analyses on the association between statin coexistent dyslipidemia) [4]. The decrease in CV mortality intolerance and CVD and on statin intolerance and use of incidence worldwide has been attributed to the lowering of alternative therapies. Two authors (AMP and RVG) cholesterol to prevent CAD and total CV disease (CVD) examined every article separately, also investigating [5]. A 21% decrease in CVD mortality and morbidity reviews, case studies, and experimental studies. Any doubt (stroke and fatal coronary events) can be achieved by or issues were resolved by discussion with a third party lowering low-density lipoprotein cholesterol (LDL-C) by (MB). 1.0 mmol/l (38.7 mg/dl) [6]. The beneficial role of statins in primary and secondary prevention [7–9] is among the 2.2 Epidemiology and Definition of Statin most intensively studied issues in modern medicine. The Intolerance Cholesterol Treatment Trialists (CTT) collaboration demonstrated a 12% reduction in all-cause mortality per Although statins are the mainstay of lipid-lowering treat- mmol/l reduction in LDL-C and corresponding significant ment, as many as 20% of individuals with a clinical indi- reductions in myocardial infarction (MI) or coronary death cation for statin therapy are unable to take a daily statin (23%), the need for coronary revascularization (24%), and because of some degree of intolerance [19], and 40–75% of in fatal or non-fatal stroke (17%) after 5 years of statin patients discontinue their statin therapy within 1–2 years therapy [10]. after initiation [18]. Statins are generally safe and well tolerated, but not all The definition of statin intolerance (Table 1) is a ques- patients are able to use a statin. Statin intolerance is most tion of great interest and debate [20]. Intolerance (partial or frequently attributed to muscle-related adverse events complete) should be defined as an inability to tolerate a [11–14]. Statin discontinuation rates remain high, even suitable dose of a statin required for a given patient’s CV among patients with coronary heart disease (CHD) (over risk (e.g., intolerance of atorvastatin 40–80 mg or rosu- 50% after 1 year) [15, 16]. Unfortunately, statin non-ad- vastatin 20–40 mg by a patient with ACS). Intolerance can herence correlates highly with risk for acute CV events, become clinically apparent with a variety of clinical increasing the risk for recurrent MI and CHD [17, 18]. This adverse effects that significantly impair organ function and/ narrative review discusses the definition, diagnosis, and or quality of life after intake of any statin at any dose management of statin intolerance as well as novel treat- (complete intolerance) with or without associated labora- ment approaches that might be considered. tory abnormality (increase in creatine kinase [CK]), or can manifest with temporal associations between symptoms and the onset of therapy or increased dose (partial intol- 2 Methods erance) (usually within 3–6 months). Discontinuation or dose reduction of the drug (statin dechallenge) or 2.1 Search Strategy replacement with another statin can result in remission of symptoms and confirms a diagnosis of statin intolerance We searched electronic databases (MEDLINE [1990–30 [20]. According to Mancini et al. [21], about 70–80% of April 2017], Embase, and SCOPUS [1993–30 April 2017], statin-treated patients are tolerant to treatment, and DARE [1993–30 April 2017]) and Web of Science Core 20–30% are suspected to be statin intolerant. These authors Collection (up to 30 April 2017), and abstracts from also note that a certain diagnosis of statin intolerance is national and international meetings. Where necessary, the found in about 5–6% of patients [21]. According to an relevant authors were contacted to obtain further data. The evaluation by Banach and colleagues [14, 18], a step-by- main search terms were\statins intolerance[ OR\statin- step approach (very careful physical examination of the associated side effects[ OR \statin-related side effects[ patient, assessing patient history and risk for drug inter- OR \statin-induced side effects[ OR \statin-associated/ actions, and exclusion of all possible risk factors and related symptoms[ OR \statin associated muscle symp- conditions that might increase the risk of statin intolerance, toms[ OR SAMS OR\statin-associated/related myalgia[ including the so-called ‘‘nocebo effect’’—psychologically OR \statin associated/related myopathy[ AND \new- conditioned symptoms as a result of expectations due to onset diabetes[ OR NOD AND \management[ OR \al- achieved knowledge of drug-related side effects) yields a ternative therapy[ OR \alternate-day therapy[ OR \nu- diagnosis of complete statin intolerance in only 2–3% of traceuticals[ OR \non-statin drugs[ AND patients. \cardiovascular disease[ OR CVD OR \CV event[ OR Management of Statin Intolerance in 2018 159 Table 1 Definitions of statin intolerance Society Definition of statin intolerance Year References National Lipid Association ‘‘Inability to tolerate at least two statins: one statin at the lowest starting daily dose and another 2014 [22] (NLA) statin at any daily dose, due to either objectionable symptoms (real or perceived) or abnormal laboratory determinations, which are temporally related to statin treatment and reversible upon statin discontinuation’’ International Lipid Expert ‘‘Inability to tolerate at least two statins: one statin at the lowest starting daily dose and another 2014 [23] Panel (ILEP) statin at any daily dose, due to either objectionable symptoms (real or perceived) or abnormal laboratory determinations, which are temporally related to statin treatment and reversible upon statin discontinuation. The resolution of symptoms or changes in biomarkers or even significant improvement with dose reduction or withdrawal of treatment; symptoms or changes in biomarkers are not attributable to predispositions (drug–drug interactions and recognized conditions), increasing the risk of statin intolerance’’ European Atherosclerosis ‘‘The assessment of statin-associated muscle symptoms (SAMS) includes the nature of muscle 2015 [24] Society (EAS) symptoms, increased creatine kinase levels and their temporal association with initiation of therapy with statin, and statin therapy suspension and rechallenge’’ Canadian Consensus ‘‘A clinical syndrome, not caused by drug interactions or risk factors for untreated intolerance 2016 [25] Working Group and characterized by significant symptoms and/or biomarker abnormalities that prevent the long-term use and adherence to statins documented by challenge/dechallenge/rechallenge, where appropriate, using at least two statins, including atorvastatin and rosuvastatin, and that leads to failure of maintenance of therapeutic goals, as defined by national guidelines’’ The definition of statin intolerance has evolved over the therapeutic goals, as defined by national guidelines’’ [25]. years. In late 2014, the National Lipid Association (NLA) This is the most complete and a very pragmatic definition defined this syndrome as an inability to tolerate at least two of complete statin intolerance. The explicit inclusion of statins—one statin at the lowest starting daily dose and references to national guidelines and objectives in a defi- another statin at any daily dose—due to either objection- nition of statin intolerance has the intent to ensure that the able symptoms (real or perceived) or abnormal laboratory practical effort is justified for patients, colleagues, regula- determinations that are temporally related to statin treat- tory authorities, and taxpayers [25, 26]. ment and reversible upon statin discontinuation [22]. In addition to this, the International Lipid Expert Panel 2.3 Symptoms and Biomarkers of Statin Intolerance (ILEP) definition included the resolution of symptoms or changes in biomarkers or even significant improvement 2.3.1 Symptoms of Statin Intolerance with dose reduction or withdrawal of treatment; symptoms or changes in biomarkers are not attributable to predispo- The patient’s subjective assessment of the perceived risks sitions (drug–drug interactions and recognized conditions), and disadvantages compared with the benefits of therapy is increasing the risk of statin intolerance [23]. The European important for an effective approach to statin intolerance. Atherosclerosis Society (EAS) consensus paper suggested Most cases of statin intolerance are related to patient a more clinically oriented definition and recommended that complaints; suspension of therapy due to laboratory the assessment of statin-associated muscle symptoms abnormalities is much less common. Statin intolerance is (SAMS) include the nature of muscle symptoms, increased not simply the occurrence of symptoms in general, but CK levels and their temporal association with initiation of rather the symptoms that are perceived as unaccept- statin therapy, and statin therapy suspension and rechal- able [27]. Identifying true cases of statin intolerance is, lenge [24]. In 2016, the Canadian Consensus Working therefore, of great practical importance in order to avoid Group update defined statin intolerance as ‘‘a clinical unnecessary suspension of statin therapy by patients who syndrome, not caused by drug interactions or risk factors would otherwise benefit from them [27]. However, for untreated intolerance and characterized by significant assessing the probability that negative symptoms are cau- symptoms and/or biomarker abnormalities that prevent the sally related to statins is often difficult. Symptoms (more long-term use and adherence to statins documented by than 75%) are more likely to be attributable to statins if challenge/dechallenge/rechallenge, where appropriate, they appear within the first 3 months of statin therapy and using at least two statins, including atorvastatin and rosu- if they improve after suspension and reoccur after rein- vastatin, and that leads to failure of maintenance of troduction [28, 36]. Statins have specific adverse effects 160 P. P. Toth et al. (myalgias 3–5%; myopathy 0.1–0.2%; new-onset diabetes estimation of CV risk and treatment of adverse event risks [NOD] 9–27%, and hepatotoxicity, usually \1%) [27] when nonpharmacological therapy is not effective [35]. demonstrable or not from abnormal blood markers, SAMS, including myalgia—ranging from mild to severe including muscle (e.g., CK) or liver function studies in intensity—muscle stiffness and tenderness, cramps, and (hepatic transaminases—mainly alanine aminotransferase loss of muscle strength [23, 37], are by far the most [ALT]) [27]. For the latter, it is worth emphasizing that in common adverse effects and one of the most important fact there is no confirmed link between statin therapy and reasons for discontinuing statin therapy. The prevalence of liver damage, and most of the current guidelines and SAMS is around 3–5% in randomized controlled trials consensus papers recommend measuring transaminases including patients with dyslipidemia [38] and up to 20% in only before statin therapy initiation and during treatment if observational studies [39, 40], although the EAS consensus symptoms develop [14]. paper reported a SAMS prevalence as high as 29% [24]. The main adverse reactions due to statins include PRIMO (Prediction of Muscular Risk in Observational myalgia, myotoxicity, and NOD [28, 29]. The risk of conditions), a survey conducted in general medicine clinics developing NOD depends on the presence of prediabetes in France, showed that 10.5% of patients receiving statins (insulin resistance, carbohydrate metabolism disorders), the reported muscle symptoms, though the prevalence varied number of metabolic syndrome components (overweight, with individual statins (fluvastatin had the lowest rate of elevated blood pressure, high triglycerides, low high-den- SAMS, whereas simvastatin had the highest) [41]. The sity lipoprotein cholesterol [HDL-C], and hyperglycemia), USAGE (Understanding Statin Use in America and Gaps in and the duration and intensity of statin therapy. As the Education) study investigated current and former statin number of metabolic syndrome components increases, so users via an internet-based survey and showed that SAMS does the risk for NOD in statin-treated patients [30]. In occurred in 60% of current and 25% of former users and general, one must treat approximately 1000 patients that SAMS were the primary reason for treatment discon- annually to see one new case of NOD on low-dose statin tinuation [42]. Finally, data from the STOMP (Effect of therapy, or 500 patients per year to see one new case on Statins on Skeletal Muscle Function and Performance) moderate- to high-dose statin therapy [31]. However, tak- study, a randomized, double-blind, placebo-controlled trial, ing into account the available data, it is clear that the indicated that myalgia occurred in 9.4% of patients benefits associated with statin therapy outweigh the risk of receiving atorvastatin but also in 4.6% of subjects receiving NOD (for patients at high and very high CV risk, the placebo, for an overall incidence of statin-at- number needed to treat [NNT] vs. the number needed to tributable SAMS of * 5% [43]. harm [NNH] is [3–5 times higher) [32–35]. The NLA Task Force on Statin Safety (updated in 2014) In the JUPITER primary prevention trial, the CV and [44] classified the clinical presentation of SAMS as four mortality benefits of statin therapy exceeded the diabetes distinct entities: (1) myalgia, (2) myopathy, (3) myositis, hazard, including among those at higher risk for developing and (4) myonecrosis (including rhabdomyolysis). Myalgia diabetes. During a follow-up period of up to 5 years, a total is defined as muscle pain or flu-like symptoms (heaviness, of 86 vascular events or deaths were avoided, with no NOD tenderness, stiffness, aches or cramps) with normal CK diagnosed in patients with no major diabetes risk factors levels [44]. It is very important to know which muscle (CV events - 39%, p = 0.0001; no increase of diabetes, aches are typically associated with SAMS. Based on the p = 0.99), and 93 vascular events or deaths were avoided proposal by the NLA, the SAMS Clinical Index (SAMS- for every 54 NOD cases diagnosed in patients with one or CI) score, recently updated by Rosenson et al. [45], pro- more factors for diabetes development (CV events - 39%, vides the greatest score (3 points) for the typical large p = 0.0001; increase in diabetes 28%, p = 0.01). More- muscle symmetric (e.g., bilateral) aches, 2 points for over, statin therapy was associated with a time to NOD of bilateral aches of the smaller distal or proximal muscula- only 5.4 weeks compared with placebo [36]. To reduce the ture, and 1 point for asymmetric, non-uniform symptoms risk of NOD while receiving statin therapy, patients should [44]. In the STOMP study [43], subjects who reported be advised to exercise, reduce caloric intake, lose weight, myalgia while taking statins reported predominantly leg and stop smoking, all interventions that should be under- symptoms (hip flexor, quadriceps, hamstring, and/or calf taken in any case. aches; quadriceps or calf cramps; and/or quadriceps, Statin therapy should be continued in patients with hamstring, and/or calf fatigue), whereas those receiving NOD. In such cases, patient management includes a placebo reported more diverse symptoms such as whole- hypoglycemic diet, loss of excessive body weight, and body fatigue and groin pain [43, 44]. The SAMS-CI score prescription of antidiabetic drugs, if appropriate [34]. The might be a very useful tool with which to confirm statin- approach to lipid lowering in overweight or obese primary related myalgia and to exclude the nocebo effect. prevention patients is to introduce statins after careful Management of Statin Intolerance in 2018 161 Myopathy with muscle weakness (not attributed to pain) diagnostic yield is low and not cost effective [11]. Statin- can occur with normal or elevated CK [29]. Factors pre- associated liver abnormalities (aminotransferase levels) are disposing to the development of myopathy include age rare, mild, dose-related, and not related to reduction in [75 years, female sex, renal and hepatic dysfunction, LDL-C. Thus, drug- and dose-specific effects are more hypothyroidism, alcohol abuse, excessive physical exer- important determinants of liver and muscle toxicity than tion, genetic susceptibility, perioperative period, and con- magnitude of LDL-C lowering [52, 53]. They are also current use of drugs inhibiting the metabolism of statins, usually temporary, and it is possible to return to baseline such as clarithromycin, erythromycin, azole antifungals, levels after 2–4 weeks [52, 53]. Persistent elevation of diltiazem, verapamil, amiodarone, fibrates (particularly ALT more than three times the upper limit of normal gemfibrozil), cyclosporin, clopidogrel, sulfonamides, and (ULN) were observed in B 1% of patients treated with red yeast rice [23, 34, 37]. It has been also observed that statins. These are dose related, with rates of \0.5% for low levels of vitamin D and coenzyme Q10 (CoQ10) might moderate-dose rosuvastatin and at all doses, and slightly increase the risk of statin intolerance; however, available higher rates (about 1%) with atorvastatin or simvastatin data do not yet enable recommendations on their supple- 80 mg [52]. ALT elevations often improve even when mentation to prevent SAMS [46, 47]. Myopathy is a gen- statin therapy is continued. The incidence of liver failure is eral term encompassing all forms of muscle disease, the same among statin-treated patients as in the general including toxic disorders as well as acquired and herita- population not treated with statins [54]. Finally, it is worth ble metabolic disorders. The term does not necessarily remembering that the use of statins prevents about 33% of connote symptoms or any degree of CK elevation. Muscle major CVD events when compared with placebo, and sta- biopsy also suggests some myopathic statin-induced tins may cause serious liver disease in 1/1,000,000 (NNH is abnormalities that may be present in the context of normal 1 million). Between 10 and 30% of patients do not receive CK levels [43]. statins because of fear of hepatotoxicity [14, 23]. Myositis with muscle inflammation is associated with Other early markers also might predict and diagnose other symptoms (e.g., tenderness to palpation), CK eleva- statin intolerance [11]. One such biomarker being consid- tion, and leukocyte infiltration into muscle tissue. ered, at least in in vitro experiments, is lactate dehydro- Myonecrosis is always associated with muscle injury and genase, but its clinical utility in cases of statin-induced elevation of serum CK [29]. The most serious, and fortu- myopathy has not been validated [56]. A study that treated nately very rare, form of myonecrosis is rhabdomyolysis rats with drugs that are highly toxic to myocytes (carba- (1.6 per 100,000 patient-years), in which muscle break- mate acetylcholinesterase inhibitor; isoproterenol, a syn- down is responsible for a massive release of CK and thetic catecholamine), but not with statins, identified fatty myoglobin, with resulting myoglobinuria and acute renal acid binding protein 3 (FABP3) and myosin light chain 1 failure [29]. However, rhabdomyolysis currently occurs (MLC1) as biomarkers of skeletal muscle toxicity based on principally in cases of genetic predisposition as well as the specific tissue distribution of these proteins [55, 56]. drug–drug interactions [48]. According to the EAS con- Burch et al. [57] evaluated skeletal muscle troponin I sensus paper on SAMS, it is important to remember the (sTnI), myosin light chain 3 (MYL3 [S3]), CK isoform M cut-off point value of 4, above which muscle symptoms (CKM), and FABP3 compared with CK in the monitoring seem to be more attributable to statin therapy [24]. of drug-induced skeletal muscle injury. sTnI, MYL3, CKM, and FABP3 all outperformed CK and/or added value 2.3.2 Biomarkers of Statin Intolerance for the diagnosis of drug-induced novel skeletal muscle injury (i.e., myocyte degeneration/necrosis) [57]. In addi- New biomarkers for statin-induced myopathy are emerg- tion, when used in conjunction with CK, sTnI, MYL3, ing. Unfortunately, most cannot be commonly used CKM, and FABP3 individually and collectively improved because of complexities in methodology and costs, and diagnostic sensitivity and specificity, as well as diagnostic their sensitivity and specificity still need to be defined [11]. certainty, for novel skeletal muscle injury and responded in The most widely used serum marker is the serum CK level a sensitive manner to low levels of novel skeletal muscle [49], but its exclusive use as a diagnostic marker is inad- injury degeneration/necrosis in rats. CKM showed the equate and non-specific because high serum levels are not strongest correlation (r = 0.47, p\0.0001), followed by always associated with myopathy [50]. CK levels can be FABP3 (r = 0.52, p\0.0001), MYL3 (r = 0.48, elevated by exercise in a dose-independent manner [29] p\0.0001), sTnI (r = 0.47, p\0.0001), aspartate and by drug interactions, genetic variants, CoQ10 defi- transaminase (AST; r = 0.46, p\0.0001), and CK ciency, and vitamin D deficiency [51]. (r = 0.32, p\0.0001) [57]. These findings support the Routine liver function analyses are no longer recom- suggestion that sTnI, MYL3, CKM, and FABP3 are suit- mended in the management of statin therapy because the able for voluntary use, in conjunction with CK, in 162 P. P. Toth et al. regulatory safety studies in rats to monitor drug-induced day post-MI, median CRP was significantly higher in the skeletal muscle injury and for the potential translational use group from whom statins had been withdrawn. of these exploratory biomarkers in early clinical trials to Complete statin intolerance, which requires statin dis- ensure patient safety [57]. Dobkin [58] suggested the continuation, affects \5% of patients with statin intoler- functional evaluation of hip-flexor and abductor perfor- ance symptoms [23, 25]. Numerous approaches to mance (because it occurred independently of CK levels). maintaining statin persistence have been published Wu et al. [59] proposed the evaluation of the kinetics of [24, 25, 29, 34]. Therefore, we would especially like to recovery exercise phosphocreatine by means of phosphorus focus on combination therapy for patients not able to tol- magnetic resonance spectroscopy ( P-MRS). In this study, erate suitable statin doses. Briefly, we can always consider patients were treated for 4 weeks with statin therapy and step-by-step reduction of the dose (dechallenge) and were shown to have a prolonged metabolic recovery time intermittent dosages (alternate-day therapy). We know this in the calf despite no change in serum CK levels [59]. does not significantly influence the magnitude of LDL-C Unfortunately, several drawbacks are associated with these reduction for rosuvastatin and atorvastatin [66]. The muscle-specific markers: rapid clearance, dependence of lipophilicity and hydrophilicity of statins seems to be renal dysfunction, heterogeneous response depending on important, and changing from a hydrophilic to a lipophilic the type of myotoxicants in general, and the difficulty and statin may be of some benefit in the SAMS setting [23, 24]. high costs of measurements [11, 60]. We have also observed that both statin groups had the same Laaksonen et al. [61] proposed lipidomic evaluation of effects concerning efficacy and safety in patients with ACS plasma muscle gene profiles, which helped to identify [67]. Hydrophilic statins (rosuvastatin and pravastatin) several sensitive biomarkers of metabolic alterations seem to cause fewer statin intolerance symptoms, and this induced in skeletal muscle by high-dose statin regimens is especially important for elderly patients [23] (Table 2). (increased expression of arachidonic acid 5-lipoxygenase activating protein, phospholipase C, numerous species of 2.4 Alternative Drug Treatment phosphatidylethanolamine, selective pools of long-chain triglycerides, and phosphocholine ether). However, such The use of lipid-lowering therapy in clinical practice has complex genomic and combined lipidomic analyses are become progressively more challenging because exagger- very difficult to perform and, above all, to interpret rou- ated patient concerns over side effects and potential toxi- tinely in clinical practice. Two microRNAs (miRNAs; city can lead to poor adherence to statin therapy or 133a/b and 499-5p) were evaluated as potential biomarkers discontinuation [15, 22] despite the highly established of tissue damage because of their long half-lives in serum. benefits of LDL-C reduction [68, 69]. The use of ezetimibe The serum levels of miR-133a/b were reported as sensitive monotherapy is still limited (due to US FDA recommen- and specific markers of cardiac and skeletal muscle toxicity dations in the USA as well as restricted reimbursement in [62]; miR-499-5p might serve as a biomarker for statin- Europe, leading to use in \5–10% of the patients who enhanced muscle injury during exercise because it was require it according to guideline recommendations) [13], increased in the plasma of runners after a marathon and and use of the monoclonal antibodies directed against increased when muscle contraction was combined with proprotein convertase subtilisin kexin type 9 (PCSK9) exposure to statins [63]. Further studies are still necessary tends to be severely restricted by managed care formula- to confirm the specificity and sensitivity of innovative ries. Statin monotherapy or statin combination therapy with biomarkers in statin-treated patients. other currently available drugs do not all have the same capacity to induce appropriate reductions in LDL-C in 2.3.3 Statin Intolerance Management patients at high CV risk [70]. Therefore, there is a clinical need for new therapies, alone or in combination with cur- Probably the most important issue in the management of rent drugs (Table 2), to lower LDL-C. patients with statin intolerance/SAMS is the need to con- Bempedoic acid (ETC-1002) has a unique mechanism of tinue statin therapy. It is especially critical for patients with action (adenosine triphosphate-citrate lyase inhibition) high and very high CV risk, as therapy discontinuation for [71, 72]. The efficacy of combination therapy with statins 4–6 weeks might cause atheroma plaque instability [64] and bempedoic acid has been evaluated in a randomized and increases the risk of CV events [17]. A further aspect to controlled trial (NCT02072161) [73]. A total of 134 consider is inflammation. Sposito et al. [65] assessed the patients who had been treated with one of a series of statin existence of a rebound inflammatory effect after statin regimens (atorvastatin 10 or 20 mg; simvastatin 5, 10, or withdrawal in the acute phase of MI. At baseline, statin 20 mg; rosuvastatin 5 or 10 mg; or pravastatin 10, 20, or users presented with a lower C-reactive protein (CRP) than 40 mg) for at least 3 months before the trial began were patients not receiving a statin before the MI. By the fifth randomized to bempedoic acid 120 or 180 mg or placebo Management of Statin Intolerance in 2018 163 Table 2 Therapeutic possibilities for the treatment of statin-intolerant patients and their influence on low-density lipoprotein cholesterol levels Agent Subjects Dose Duration LDL-C levels References BA with low-dose statins 134 120 mg/day 12 weeks - 17.3 ± 4.0% [73] hypercholesterolemic (p\0.01) pts 180 mg/day - 24.3 ± 4.2% (p\0.001) PL - 4.2 ± 4.2% BA 56 240 mg/day vs. PL 8 weeks - 28.7% (p\0.001) [74] hypercholesterolemic (increase pts by 60 mg q2w) BA with or without EZE 177 120 mg/day 12 weeks -27.5 ± 1.3 mg/dl [75] hypercholesterolemic (p = 0.0008) pts 180 mg/day - 30.1 ± 1.3 mg/dl (p\0.0001) EZE 10 mg/day - 21.2 ± 1.3 mg/dl (p\0.0001) 120 mg ? EZE 10 mg/day - 43.1 ± 2.6 mg/dl (p\0.0001) 180 mg ? EZE 10 mg/day - 47.7 ± 2.8 mg/dl (p\0.0001) BA 12,600 statin-intolerant 180 mg/day 6 years Ongoing [76] pts expected ATO 60 10 mg/day 6 weeks 100 ± 25 mg/dl [129] hypercholesterolemic (p = 0.3) pts 20 mg/alternate day 68 ± 28 mg/dl (p\1.0) 20 mg/day 96 ± 41 mg/dl (p\1.0) ROS 45 20 mg/alternate day 6 weeks - 40.9% (p\0.0001) [130] hypercholesterolemic 10 mg/day - 78.5% (p\0.0001) pts ATO 61 20 mg/alternate day 3 months - 95 ± 31 mg/dl [131] hypercholesterolemic (p\0.05) pts 20 mg/day - 94 ± 28 mg/dl (p\0.05) ROS 37 dyslipidemic pts 10 mg/alternate day 6 weeks -57 ± 1.2 mg/dl [132] (p\0.01) 10 mg/day - 60 ± 1.0 mg/dl (p\0.01) PRA 104 dyslipidemic pts Half-dose alternate days vs. daily 4 months 113 ± 21 mg/dl [133] (p\0.04) 104 ± 24 mg/dl (p\0.04) ATO 54 10 mg/day 6 weeks No statistically [134] hypercholesterolemic significant differences 10 mg/alternate day pts between the three 20 mg/alternate day groups regarding total or a percentage ATO 40 20 mg/alternate day 12 weeks No statistically [135] hypercholesterolemic significant differences 20 mg/day pts between the two groups ATO 60 pts with CAD 10 mg/alternate day 6 weeks 105 ± 26 mg/dl [136] (p\0.008) 10 mg/day 88 ± 21 mg/dl (p\0.008) 164 P. P. Toth et al. Table 2 continued Agent Subjects Dose Duration LDL-C levels References FLU 23 40 mg/alternate day 6 weeks 144 ± 21 mg/dl [137] hypercholesterolemic (p\0.05) pts 20 mg/day 138 ± 19 mg/dl (p\0.05) ROS 80 pts with primary 10 mg/alternate day 8 weeks 105.07 ± 26.30 mg/dl [138] hypercholesterolemia (p\0.001) 10 mg/day 94.10 ± 40.16 mg/dl (p\0.001) ATO 100 dyslipidemic pts 10 mg/alternate day 3 months 73.6 ± 14.71 mg/dl [139] (p\0.0001) 10 mg/day 93.79 ± 17.48 mg/dl (p\0.0001) ATO 141 pts with Alternate day vs. daily 12 weeks Alternate-day dosing of [140] dyslipidemia or CAD ATO was inferior to daily dosing in maintaining the NCEP-ATP III goal EZE 432 pts with primary 5 mg/day 12 weeks - 15.7% (p\0.01) [141] hypercholesterolemia 10 mg/day - 18.5% (p\0.01) EZE ? statins 769 pts with primary Statin ? EZE 10 mg/day 8 weeks - 25.1% (p\0.001) [142] hypercholesterolemia Statin ? PL - 3.7% (p\0.001) EZE ? SIM 720 pts with FH SIM ? EZE 10 mg/day 24 months 141.3 ± 52.6 mg/dl [143] (p\0.01) EZE ? SIM 1128 pts with EZE/SIM 10/20 mg/day 6 weeks - 49.6% (p\0.001) [144] hypercholesterolemia EZE/SIM 10/40 mg/day - 53.9% (p\0.001) and metabolic syndrome EZE ? ROS 239 pts with high risk EZE/ROS 10/40 mg/day 6 weeks - 70% (p\0.001) [145] of CHD ROS 40 mg - 56% (p\0.001) PCSK9 inhibitor EVO 1117 primary 140 mg vs. PL 10 weeks 66–75% (p\0.001) [83] with moderate- and hypercholesterolemia 420 mg vs. PL 12 weeks 63–65% (p\0.001) high- intensity statins and mixed dyslipidemia pts PCSK9 inhibitor EVO 1359 dyslipidemic pts 70 mg q2w ? statin or EZE 12 weeks - 40.20% (p\0.001) [86] with statin or EZE 105 mg q2w ? statin or EZE - 52.86% (p\0.001) 140 mg q2w ? statin or EZE - 59.26% (p\0.001) 280 mg q4w ? statin or EZE - 42.55% (p\0.001) 350 mg q4w ? statin or EZE - 47.00% (p\0.001) 420 mg q4w or EZE - 52.66% (p\0.001) PCSK9 inhibitor EVO 511 pts with 420 mg/month 24 weeks - 102.9 mg/dl [88] with statin uncontrolled LDL-C (p\0.001) and history of intolerance to two or more statins PCSK9 inhibitor ALI 361 pts at moderate to ALI 75 mg q2w 24 weeks -102.9 mg/dl [96] with EZE high CV risk with (p\0.001) statin intolerance EZE 10 mg - 31.2 mg/dl (p\0.001) Inclisiran with statin 501 pts at high CVD Single dose of 200–500 mg/day 180 days 27.9–41.9% after a [98] risk with elevated or double dose of single dose LDL-C 100–300 mg/day 35.5–52.6% after two doses (for both p\0.001) Management of Statin Intolerance in 2018 165 Table 2 continued Agent Subjects Dose Duration LDL-C levels References Red yeast rice DS 83 pts in dietary 2.4 g/day red yeast rice 12 weeks From 4.47 ± 0.70 to [99] treatment 3.49 ± 0.70 (p\0.05) Plant extracts (red yeast 39 pts with moderate Red yeast rice 166.67 mg (0.4% 16 weeks - 14.1% (p\0.001) [102] rice, sugar cane-derived hypercholesterolemia monacolin K), sugar cane policosanols, and extract 3.70 mg (90% artichoke leaf extracts) policosanols–octacosanol 60%), artichoke leaf dry extract 200 mg (5–6% chlorogenic acid) daily Natural nutraceuticals 933 dyslipidemic pts 1 tablet/day associated with diet 16 weeks - 23.5% (p\0.001) [103] (red yeast, policosanol, and berberine) Nutraceutical 30 pts with moderate Berberine 500 mg, policosanols 8 weeks - 21.1% (p\0.001) [104] combination (red yeast CV risk 10 mg, folic acid 0.2 mg, rice extract, berberine, CoQ10 2.0 mg, astaxanthin policosanol, 0.5 mg daily astaxanthin, CoQ10, folic acid) Acid ethyl ester 702 statin-treated pts 4 or 2 g/day 12 weeks - 6.2% (p = 0.0067) [112] (AMR101) Chokeberry flavonoid 44 pts after MI 85 mg tid of chokeberry flavonoid 6 weeks Ox-LDL levels - 29% [114] extract extract (Aronia melanocarpa E.) (p\0.000) Spirulina 312 pts 1–10 g/day 2–12 months - 41.32 mg/dl [116] (p\0.001) BER vs. EZE 228 pts with primary Berberine 500 mg, policosanol 6 months - 31.7% (p\0.001) [146] hypercholesterolemia 10 mg, red yeast rice 200 mg EZE 10 mg/day - 25.4% (p\0.001) AEs adverse events, ALI alirocumab, ATO atorvastatin,BA bempedoic acid, BER berberine, CAD coronary artery disease, CHD coronary heart disease, CoQ10 coenzyme Q10, CV cardiovascular, CVD cardiovascular disease, DS dietary supplement, EVO evolocumab, EZE ezetimibe, FH familial hypercholesterolemia, FLU fluvastatin, LDL-C low-density lipoprotein cholesterol, MI myocardial infarction, NCEP-ATP III National Cholesterol Education Program Adult Treatment Panel III, ND not defined, Ox-LDL oxidized low-density lipoprotein, PCSK9 proprotein convertase subtilisin/kexin type 9, PL placebo, PRA pravastatin, pts patients, qxw every x weeks, ROS rosuvastatin, SIM simvastatin, tid three times daily [73]. LDL-C was reduced significantly with bempedoic not adequately managed with statins [77–79]. Evolocumab acid 120 or 180 mg daily, respectively, compared with and alirocumab have recently received marketing autho- placebo: - 17.3 ± 4.0% (p\0.01) and - 24.3 ± 4.2% rization in the EU and the USA [79]. The approved indi- (p\0.001) [73]. Thompson et al. [74] conducted a multi- cations for evolocumab are (1) adults with primary center, double-blind, 8-week trial in a group of patients hypercholesterolemia (heterozygous familial hypercholes- intolerant to at least one statin and reported that ETC-1002 terolemia [HeFH] and non-familial), unable to achieve was effective at reducing LDL-C (by almost 29%) and was LDL-C goals with the maximum tolerated dose of a statin well tolerated in patients with SAMS. A recent phase IIb or alone or in combination with other lipid-lowering ther- trial in which patients with and without statin intolerance apies in patients who are intolerant to statins, or for whom received daily treatment with ETC-1002 120 or 180 mg a statin is contraindicated; (2) adults and adolescents aged alone or with ezetimibe confirmed these results. These C 12 years with homozygous familial hypercholestero- treatments reduced LDL-C more than did ezetimibe alone laemia (HoFH) in combination with other lipid-lowering and had a similar tolerability profile [75]. It is worth therapies [80]. Alirocumab is approved for adults with mentioning that a new phase III trial (NCT02993406) primary hypercholesterolemia (HeFH and non-familial) or investigating whether treatment with bempedoic acid ver- mixed dyslipidemia, in patients unable to achieve their sus placebo decreases the risk of CV events in 12,600 LDL-C goals with maximum tolerated dose of a statin or, statin-intolerant patients has commenced [76] (Table 2). alone or in combination with other lipid-lowering thera- PCSK9 monoclonal antibodies constitute a breakthrough pies, in patients who are intolerant to statins or for whom a for statin-intolerant patients or those in whom LDL-C is statin is contraindicated [81]. 166 P. P. Toth et al. Evolocumab and alirocumab have been studied in therapy). The addition of evolocumab to statin therapy numerous phase II and phase III clinical trials involving (with or without ezetimibe) significantly reduced the pri- high-risk patients, including those with statin intolerance mary endpoint (composite of CV death, MI, stroke, hos- and those with familial hypercholesterolemia (FH) pitalization for unstable angina, or coronary [82–88]. Evolocumab reduces LDL-C by approximately revascularization) and key secondary endpoints (composite 60–65%, influences all other lipid profile parameters, and of CV death, MI, or stroke) of the trial by 15% (hazard has favorable effects on lipoprotein(a) [89–92]. Evolocu- ratio [HR] 0.85; 95% confidence interval [CI] 0.79–0.92; mab is also very well tolerated as monotherapy, added to p\0.001) and 20% (HR 0.80; 95% CI 0.73–0.88; statins, or added to statins plus ezetimibe [82], without p\0.001), respectively [95]. major adverse effects such as myalgia, CK elevations, The available evidence for alirocumab suggests that this NOD [93], or neurocognitive disorders [94]. In a pooled treatment is also (similarly) effective in reducing LDL-C analysis of four phase III studies, the effectiveness and and is well tolerated. The results of the ODYSSEY safety of evolocumab was comparable in patients with or ALTERNATIVE trial in patients with statin intolerance without type 2 DM (T2DM) and did not differ between demonstrated good tolerability and efficacy [96]. The T2DM subgroups [82]. Toth et al. [87] reported a com- ODYSSEY phase III program includes more than 23,000 prehensive safety assessment of evolocumab in 6026 patients and 14 studies with alirocumab alone or in com- patients in 12 phase II and III parent trials with a median bination with other lipid-lowering agents, and as exposure of 2.8 months, and in 4465 of those patients who monotherapy in patients with primary HeFH, non-FH, or continued with a median follow-up of 11.1 months in two statin intolerance [97]. The ODYSSEY OUTCOMES study open-label extension (OLE) trials, demonstrating a favor- is not yet completed (it will likely be presented at the able benefit–risk profile for evolocumab. Overall adverse American College of Cardiology meeting in March 2018) event (AE) rates were similar between evolocumab and and is assessing the CV benefit of alirocumab in 18,600 control groups in the parent trials (51.1 vs. 49.6%) and in patients (at higher risk than in the FOURIER trial), over year 1 of the OLE trials (70.0 vs. 66.0%), as were those for approximately 5 years of follow-up (the mean follow-up serious AEs (SAEs). Elevations of serum transaminases, will be at least 3 years). A subgroup analysis of 2341 bilirubin, and CK were infrequent and similar between patients with and without T2DM in ODYSSEY LONG- groups [87]. Muscle-related AEs were similar between TERM showed that alirocumab effects were also consis- evolocumab and control groups. Neurocognitive AEs were tent, regardless of the clinical history of patients with infrequent and balanced during the double-blind parent T2DM at baseline [97] (Table 2). studies (five events [0.1%] in the evolocumab groups vs. Another approach to PCSK9 inhibition is in develop- six events [0.3%] in the control groups). No neutralizing ment. The ORION-1 (Trial to Evaluate the Effect of ALN- anti-evolocumab antibodies were detected [87]. The PCSSC Treatment on LDL-C) trial found that inclisiran, a GAUSS-3 (Goal Achievement after using an anti-PCSK9 chemically synthesized small interfering RNA designed to antibody Intolerant statins subject-3) trial was a statin target PCSK9 messenger RNA, lowered PCSK9 and LDL- intolerance study that included 511 adult patients with a C levels among patients at high CV risk who had elevated history of intolerance to two or more statins [88]. Patients LDL-C levels [98]. In this trial, over the course of were treated with non-statin therapies (evolocumab vs. 180 days, 501 patients received a single dose of inclisiran ezetimibe). After 2 years, LDL-C levels were significantly 200, 300, or 500 mg or two doses (at days 1 and 90) of more reduced (by 36.1%) in the evolocumab group than in inclisiran 100, 200, or 300 mg [98]. At day 180, inclisiran the ezetimibe group (p\0.001). Muscle symptoms were significantly reduced (p\0.001 vs. placebo) LDL-C levels reported in 28.8% of ezetimibe-treated patients and 20.7% from 27.9 to 41.9% after a single dose and 35.5 to 52.6% of evolocumab-treated patients (p = 0.17) [88]. The after two doses. Two doses of inclisiran 300 mg produced recently published FOURIER (Further Cardiovascular the greatest reduction in LDL cholesterol levels at day 180 Outcomes Research with PCSK9 Inhibition in Subjects (48% of patients had LDL-C \50 mg/dl [\1.3 mmol/l]) with Elevated Risk) trial provided strong evidence on CV [98]. At day 240, PCSK9 and LDL-C levels remained endpoints and additional long-term safety (mean significantly lower than at baseline with all inclisiran reg- 26 months) in 27,564 patients with established CVD (MI, imens. Inclisiran may emerge as an important therapeutic ischemic stroke, or symptomatic peripheral artery disease). option for statin-intolerant patients, as lipid-lowering Patients were randomized to receive either subcutaneous occurs with few serious AEs or symptoms of immune evolocumab 140 mg every 2 weeks, subcutaneous evolo- system activation [98] (Table 2). An advantage of this drug cumab 420 mg every month, or matching placebo injec- is that it can be can be administered every 6 months. tions [95]. All patients were receiving background statin This class of new drugs will be used in the long term, therapy (almost 70% receiving high-intensity statin generally for the rest of the treated patients’ lives. Despite Management of Statin Intolerance in 2018 167 claims that millions of patients with dyslipidemia could devoid of the safety risks associated with synthetic phar- benefit from these PCSK9 inhibitors, these treatments will macological therapy because it has a combination of low actually meet the health needs of a small population of doses of its active ingredients—low enough not to be patients (at very high CV risk who benefit the most) associated with untoward effects but high enough to exert because of the high costs in all countries in which they are therapeutic effects in combination with other complemen- marketed. tary substances [105]. Armolipid Plus can reduce total cholesterol (11–21%) and LDL-C (15–31%) levels, which 2.5 Alternative Nutraceutical Therapy is equivalent to changes associated with low-dose statins. In patients with mild to moderate hyperlipidemia intolerant It is known that lipid-lowering therapy might not be to statins who do not achieve LDL-C targets with ezetim- enough to completely attenuate the risk of CVD, residual ibe, Armolipid Plus can promote a further 10% reduction risk still exists, and that alternative therapy with in total cholesterol and LDL-C. Moreover, Armolipid nutraceuticals may help improve therapy adherence and Plus offers additional benefits in terms of improvements reduce the risk of patients with statin intolerance [37]. in vascular stiffness, which is an independent predictor of Natural products can be used in combination with a non- CV events [105]. statin (as well as with small doses of synthetic or natural The mechanism of action of policosanol, a mix of eight statins) in subjects with statin intolerance. long-chain aliphatic alcohols derived from the fermentation Monacolins such as policosanols and bergamot inhibit of sugar cane, rice, wheatgerm, or sunflower seeds is not HMG-CoA reductase, and red yeast rice extract (Monascus yet clear [106]. Data on the lipid-lowering effects of purpureus) contains a variety of monacolins [99]. A 2005 policosanols are contradictory. The down-regulation of cell study in 111 Caucasian individuals demonstrated that a HMG-CoA reductase by this formulation has been pro- brand dietary supplement comprising M. purpureus titrated posed [107]. Its lipid-lowering activity might be compa- extract and octacosanols, which contain a low dose of rable to that of statins, and it may be even more effective at niacin, resulted in LDL-C lowering by 20% (p\0.001) and increasing HDL-C and lowering side effects [108]; how- a reduction of triglyceride plasma level by 16% (p\0.01) ever, the data on their actual effectiveness are still con- in patients with moderate hypercholesterolemia with no tradictory [106, 109–111]. Further research is needed to clinically relevant changes in muscle and liver toxicity determine with certainty whether policosanols have bene- markers [100]. LDL-C lowering was similar to that ficial lipid-lowering effects and whether they might have obtained with pravastatin [100]. Red yeast rice used in beneficial effects for patients who are intolerant to statins. combination with plant sterols mimicked the effect of The efficacy of icosapent ethyl (IPE; Vascepa [for- statins and ezetimibe by significantly lowering LDL-C by merly AMR101]; Amarin Pharma Inc., Bedminster, NJ, 33% and total cholesterol by 19% in only 6 weeks of USA) in improving lipid parameters was demonstrated in a nutraceutical therapy [101]. Red yeast rice extract contains 12-week randomized, placebo-controlled trial (ANCHOR) nine varieties of bioactive constituents (monacolins) with that enrolled statin-treated patients at high CV risk with the same formulation as lovastatin. Furthermore, co-ad- well-controlled LDL-C levels and persistently high ministration of leaf extracts and red yeast rice significantly triglyceride levels (C 200 and \500 mg/dl) [112]. Com- reduced LDL-C (21.4%; p\0.001) and total cholesterol pared with placebo, IPE 4 and 2 g daily reduced median (14.1%; p\0.001) after 16 weeks [102]. The combination triglyceride levels from baseline by 21.5% (p\0.0001) and of berberine with red yeast rice significantly improved 10.1% (p = 0.0005), respectively, without increasing different lipid parameters (i.e., lowered total cholesterol, LDL-C levels. The 4-g daily dose decreased LDL-C levels LDL-C, and triglyceride levels [p\0.001 for all] and by 6.2% (p = 0.007) and significantly reduced other lipid increased HDL-C concentration [p\0.001]) after parameters compared with a light liquid paraffin placebo, 16 weeks of treatment [103]. Comparable results were including apolipoprotein B (9.3%; p\0.0001), very low- observed in another clinical trial [104]. This study showed density lipoprotein cholesterol (VLDL-C) (24.4%; results similar to those with pravastatin in subjects with p\0.0001), lipoprotein-associated phospholipase A2 moderate dyslipidemia and metabolic syndrome: the same (19.0%; p\0.0001), and high-sensitivity CRP (hsCRP) combination induced an increase of 4.8% in HDL-C and a (22.0%; p = 0.0005) [112]. One study of IPE in statin- lowering of 21.1% in total cholesterol and 21.1% in LDL-C intolerant patients suggested it might be potentially effec- [104]. In the setting of statin intolerance, Armolipid Plus , tive in this group of patients [113]. a formulation that contains natural substances (red yeast In a double-blind study, Naruszewicz et al. [114] used rice, policosanol, and berberine combined with folic acid, chokeberry extract in 44 patients (11 women and 33 men, astaxanthin, and coQ10) with putative complementary mean age 66 years) who survived an MI and received statin lipid-lowering properties, offers an effective alternative therapy for at least 6 months (80% dose of simvastatin 168 P. P. Toth et al. 40 mg daily) [114]. Subjects were randomized to receive in patients with SAMS, enabling effective reduction of either chokeberry flavonoid extract (Aronia melanocarpa LDL-C and possibly a lower statin dose [120]. Curcumin E.) 85 mg three times daily or placebo for 6 weeks. The may modulate the production of HDL and biomarkers of study extract comprised the following constituents: antho- HDL functionality by increasing apolipoprotein AI (apo- cyanins (about 25%), polymeric procyanidins (about 50%), AI) and lecithin cholesterol acyl transferase (LCAT) and and phenolic acids (about 9%) [114]. Compared with pla- decreasing cholesteryl ester transfer protein (CETP), cebo, flavonoids significantly reduced serum 8-isoprostans paraoxonase-1 (PON1), myeloperoxidase (MPO), and (p\0.000) and oxidized LDL levels (p\0.000) (by 38 and lipoprotein-associated phospholipase A2 (Lp-PLA2) [121]. 29%, respectively), as well as hsCRP (p\0.007) and Curcumin is safe to consume, even at dosages of up to monocyte chemoattractant protein-1 (MCP-1) (p\0.001) 8–12 g daily [122]; however, so far, its low bioavailability levels (by 23 and 29%, respectively). In addition, signifi- and efficacy profile in vivo has limited its clinical appli- cant increases in adiponectin (p\0.03) levels and reduc- cation [123]. Further clinical trials with curcumin formu- tions in systolic and diastolic blood pressure, by a mean lations with improved bioavailability are necessary to average of 11 and 7.2 mmHg, respectively, were found examine its effects on lipid metabolism and SAMS [114]. The abovementioned results mean this extract is treatment. potentially beneficial for statin-intolerant patients, but Several nutraceuticals exert lipid-lowering and athero- further studies in these subjects are necessary to defini- protective properties [124–126]. Berberine, curcumin, tively confirm its effectiveness and safety profile. polydatin, n-3 PUFA-enriched fish oil, docosahexaenoic Spirulina is a filamentous, water blue-green microalga acid (DHA)-enriched canola oil, marine n-3 PUFAs, and (Cyanobacterium) [115]. The hypolipemic properties of quercetin-3-O-b-D-glucoside have been identified as able to spirulina have not been conclusively studied. One meta- lower PCSK9 levels, an important regulator of lipid analysis [116] of seven randomized controlled trials metabolism and an efficient target for plasma LDL-C showed a significant effect from supplementation with reduction [127]. In particular, the use of some of these spirulina, with reduced plasma concentrations of total agents is supported by data from human trials in patients cholesterol (- 46.76 mg/dl; p\0.001), LDL-C (- with at least one condition related to the metabolic syn- 41.32 mg/dl; p\0.001), triglycerides (- 44.23 mg/dl; drome, HeFH, or dyslipidemia. Administration of a pill p\0.001), and elevated levels of HDL-C (6.06 mg/dl; containing berberine 500 mg for 6 months reduced LDL-C p = 0.001). The impact of spirulina on plasma concentra- by 10.5% (p\0.0001) in patients with HeFH, an effect the tions of total cholesterol and triglycerides was independent authors suggested was associated with an indirect berber- of administered dose (dose range: 1–10 g/day). Spirulina ine-mediated inhibitory effect on PCSK9 [127]. Xuezhi- contains high levels of antioxidants (e.g., beta-carotene), kang is a cholestin extract that contains a mixture of phycocyanin, microelements (K, Na, Ca, Mg, Fe, Zn), lovastatin (dominant compound), plant sterols, and iso- vitamins (tocopherols), eight necessary amino acids, flavones. Administration of xuezhikang 1200 mg daily for polyunsaturated fatty acids (PUFAs)—especially c-li- 8 weeks increased plasma PCSK9 levels by 34% nolenic acid—and phenolic compounds [117]; however, (p = 0.006) and decreased LDL-C and total cholesterol by the active components responsible for the hypolipidemic 28 and 22% (p = 0.001, p = 0.002), respectively [127]. effects of spirulina are not fully understood. This meta- Enrichment of canola oil with DHA was shown to lower analysis was the first to evaluate the effects of spirulina circulating PCSK9 and triacylglycerol levels by 6%. Fur- supplementation on serum lipid parameters based on the thermore, circulating PCSK9 levels were found to be sig- results from randomized controlled trials, but further well- nificantly and positively associated with LDL-C, designed trials are required to clarify the clinical value of triacylglycerol, and apolipoprotein B (apoB) levels, spirulina supplementation as an add-on to conventional and whereas no association was found between PCSK9 and novel lipid-lowering therapies in patients with HDL-C levels [127]. Consumption of marine n-3 PUFAs dyslipidemia. 2200 mg daily for 12 weeks decreased circulating PCSK9 Curcumin, a natural dietary polyphenol responsible for levels by 11.4 and 9.8% in premenopausal and post- the yellow color of the Indian spice turmeric (Curcuma menopausal women, respectively. In contrast, plasma longa L.), has analgesic, antioxidant [118], and anti-in- LDL-C levels showed no significant changes [127]. flammatory properties relevant to the treatment of SAMS Therefore, some nutraceuticals such as berberine and as it prevents and reduces muscular fatigue, blocks the curcumin are suggested as useful adjuncts to statin therapy inflammatory pathway of the nuclear factor, attenuates because of their inhibition of PCSK9 independent of sterol- muscular atrophy, and improves regeneration of muscle responsive element-binding protein. Nevertheless, evi- fibers after injuries [119]. Since curcumin also has lipid- dence from well-designed randomized controlled trials is modifying properties, it may serve as an additive to therapy required to support the added value of such a combination Management of Statin Intolerance in 2018 169 Open Access This article is distributed under the terms of the in reducing CV events compared with statin monotherapy Creative Commons Attribution-NonCommercial 4.0 International [127] (Table 2). License (http://creativecommons.org/licenses/by-nc/4.0/), which per- mits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons 3 Conclusions license, and indicate if changes were made. Statins are generally safe and very efficacious agents for reducing the burden of atherogenic lipoproteins in serum References and the risk for acute CV events, including MI, stroke, death, and need for revascularization. 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Drug Discov receive financial or professional help with the preparation of the Today. 2017;22:85–96. manuscript. 12. Gluba-Brzozka A, Franczyk B, Toth PP, et al. Molecular mechanisms of statin intolerance. Arch Med Sci. Conflict of interest Maciej Banach has no conflicts of interest that 2016;12:645–58. might be relevant to the contents of this manuscript. Peter P. Toth has 13. Patel J, Martin SS, Banach M. Expert opinion: the therapeutic previously received consulting fees and/or honoraria from AbbVie, challenges faced by statin intolerance. Expert Opin Pharma- Amarin, Amgen, Gemphire, Kowa, Merck, Regeneron, and Sanofi cother. 2016;17:1497–507. and payment for lectures from Amarin, Amgen, Kowa, Merck, 14. Banach M, Rizzo M, Toth PP, et al. Statin intolerance—an Regeneron, and Sanofi. Rosaria Vincenza Giglio, Giuseppa Cas- attempt at a unified definition. Position paper from an Interna- tellino, Angelo Maria Patti, and Dragana Nikolic have participated in tional Lipid Expert Panel. 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Management of Statin Intolerance in 2018: Still More Questions Than Answers

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Springer Journals
Copyright
Copyright © 2018 by The Author(s)
Subject
Medicine & Public Health; Cardiology; Pharmacotherapy; Pharmacology/Toxicology
ISSN
1175-3277
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1179-187X
DOI
10.1007/s40256-017-0259-7
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29318532
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Abstract

Am J Cardiovasc Drugs (2018) 18:157–173 https://doi.org/10.1007/s40256-017-0259-7 REVIEW AR TICLE Management of Statin Intolerance in 2018: Still More Questions Than Answers 1,2 3 3 • • • Peter P. Toth Angelo Maria Patti Rosaria Vincenza Giglio 3 3 3 4,5,6 • • • Dragana Nikolic Giuseppa Castellino Manfredi Rizzo Maciej Banach Published online: 9 January 2018 The Author(s) 2018. This article is an open access publication Abstract Statin therapy is generally well tolerated and very effective in the prevention and treatment of cardio- Key Points vascular disease, regardless of cholesterol levels; however, it can be associated with various adverse events (myalgia, Statins are the gold standard for managing myopathy, rhabdomyolysis, and diabetes mellitus, among dyslipidemia in patients with elevated cardiovascular others). Patients frequently discontinue statin therapy risk. Discontinuation of statin therapy is associated without medical advice because of perceived side effects with an increase in cardiovascular events. and consequently increase their risk for cardiovascular An important issue in the management of patients events. In patients with statin intolerance, it may be with statin intolerance/statin-associated muscle advisable to change the dose, switch to a different statin, or symptoms is the need to avoid statin discontinuation. try an alternate-day regimen. If intolerance is associated Options include step-by-step reduction of the statin with all statins—even at the lowest dose—non-statin drugs dose (dechallenge), switching to a different statin, or and certain nutraceuticals can be considered. This review using intermittent dosages (alternate-day therapy). focuses on the definition of statin intolerance and on the development of clinical and therapeutic strategies for its New non-statin agents, as well as alternative therapy management, including emerging alternative therapies. with nutraceuticals with or without a non-statin drug, may help to improve therapy adherence and reduce the risk for patients with true statin intolerance. Peter P. Toth and Angelo Maria Patti contributed equally to this Further studies in patients intolerant to statins are paper. necessary to confirm the effectiveness and safety of & Maciej Banach nutraceuticals. In addition, these agents will have to maciejbanach77@gmail.com be tested in long-term randomized controlled trials to 1 more definitively assess their efficacy for reducing CGH Medical Center, Sterling, IL, USA cardiovascular risk. Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy Chair of Nephrology and Hypertension, Department of 1 Introduction Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Zeromskiego 113, 90-549 Lodz, Poland Statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG- Polish Mother’s Memorial Hospital Research Institute, Lodz, CoA] reductase inhibitors) effectively reduce the burden of Poland atherogenic lipoprotein in serum [1]. Statins are a mainstay Cardiovascular Research Centre, University of Zielona Gora, globally in cardiovascular (CV) pharmacotherapy [2], not Zielona Gora, Poland 158 P. P. Toth et al. only in patients with dyslipidemia [3] but also in patients \CV risk[. We used the wild-card term ‘‘*’’ to increase with coronary artery disease (CAD), acute coronary syn- the sensitivity of the search strategy. dromes (ACS), diabetes mellitus (DM), stroke, hyperten- The main inclusion criterion was data from studies, sion, and chronic kidney disease (CKD) (with or without trials, and meta-analyses on the association between statin coexistent dyslipidemia) [4]. The decrease in CV mortality intolerance and CVD and on statin intolerance and use of incidence worldwide has been attributed to the lowering of alternative therapies. Two authors (AMP and RVG) cholesterol to prevent CAD and total CV disease (CVD) examined every article separately, also investigating [5]. A 21% decrease in CVD mortality and morbidity reviews, case studies, and experimental studies. Any doubt (stroke and fatal coronary events) can be achieved by or issues were resolved by discussion with a third party lowering low-density lipoprotein cholesterol (LDL-C) by (MB). 1.0 mmol/l (38.7 mg/dl) [6]. The beneficial role of statins in primary and secondary prevention [7–9] is among the 2.2 Epidemiology and Definition of Statin most intensively studied issues in modern medicine. The Intolerance Cholesterol Treatment Trialists (CTT) collaboration demonstrated a 12% reduction in all-cause mortality per Although statins are the mainstay of lipid-lowering treat- mmol/l reduction in LDL-C and corresponding significant ment, as many as 20% of individuals with a clinical indi- reductions in myocardial infarction (MI) or coronary death cation for statin therapy are unable to take a daily statin (23%), the need for coronary revascularization (24%), and because of some degree of intolerance [19], and 40–75% of in fatal or non-fatal stroke (17%) after 5 years of statin patients discontinue their statin therapy within 1–2 years therapy [10]. after initiation [18]. Statins are generally safe and well tolerated, but not all The definition of statin intolerance (Table 1) is a ques- patients are able to use a statin. Statin intolerance is most tion of great interest and debate [20]. Intolerance (partial or frequently attributed to muscle-related adverse events complete) should be defined as an inability to tolerate a [11–14]. Statin discontinuation rates remain high, even suitable dose of a statin required for a given patient’s CV among patients with coronary heart disease (CHD) (over risk (e.g., intolerance of atorvastatin 40–80 mg or rosu- 50% after 1 year) [15, 16]. Unfortunately, statin non-ad- vastatin 20–40 mg by a patient with ACS). Intolerance can herence correlates highly with risk for acute CV events, become clinically apparent with a variety of clinical increasing the risk for recurrent MI and CHD [17, 18]. This adverse effects that significantly impair organ function and/ narrative review discusses the definition, diagnosis, and or quality of life after intake of any statin at any dose management of statin intolerance as well as novel treat- (complete intolerance) with or without associated labora- ment approaches that might be considered. tory abnormality (increase in creatine kinase [CK]), or can manifest with temporal associations between symptoms and the onset of therapy or increased dose (partial intol- 2 Methods erance) (usually within 3–6 months). Discontinuation or dose reduction of the drug (statin dechallenge) or 2.1 Search Strategy replacement with another statin can result in remission of symptoms and confirms a diagnosis of statin intolerance We searched electronic databases (MEDLINE [1990–30 [20]. According to Mancini et al. [21], about 70–80% of April 2017], Embase, and SCOPUS [1993–30 April 2017], statin-treated patients are tolerant to treatment, and DARE [1993–30 April 2017]) and Web of Science Core 20–30% are suspected to be statin intolerant. These authors Collection (up to 30 April 2017), and abstracts from also note that a certain diagnosis of statin intolerance is national and international meetings. Where necessary, the found in about 5–6% of patients [21]. According to an relevant authors were contacted to obtain further data. The evaluation by Banach and colleagues [14, 18], a step-by- main search terms were\statins intolerance[ OR\statin- step approach (very careful physical examination of the associated side effects[ OR \statin-related side effects[ patient, assessing patient history and risk for drug inter- OR \statin-induced side effects[ OR \statin-associated/ actions, and exclusion of all possible risk factors and related symptoms[ OR \statin associated muscle symp- conditions that might increase the risk of statin intolerance, toms[ OR SAMS OR\statin-associated/related myalgia[ including the so-called ‘‘nocebo effect’’—psychologically OR \statin associated/related myopathy[ AND \new- conditioned symptoms as a result of expectations due to onset diabetes[ OR NOD AND \management[ OR \al- achieved knowledge of drug-related side effects) yields a ternative therapy[ OR \alternate-day therapy[ OR \nu- diagnosis of complete statin intolerance in only 2–3% of traceuticals[ OR \non-statin drugs[ AND patients. \cardiovascular disease[ OR CVD OR \CV event[ OR Management of Statin Intolerance in 2018 159 Table 1 Definitions of statin intolerance Society Definition of statin intolerance Year References National Lipid Association ‘‘Inability to tolerate at least two statins: one statin at the lowest starting daily dose and another 2014 [22] (NLA) statin at any daily dose, due to either objectionable symptoms (real or perceived) or abnormal laboratory determinations, which are temporally related to statin treatment and reversible upon statin discontinuation’’ International Lipid Expert ‘‘Inability to tolerate at least two statins: one statin at the lowest starting daily dose and another 2014 [23] Panel (ILEP) statin at any daily dose, due to either objectionable symptoms (real or perceived) or abnormal laboratory determinations, which are temporally related to statin treatment and reversible upon statin discontinuation. The resolution of symptoms or changes in biomarkers or even significant improvement with dose reduction or withdrawal of treatment; symptoms or changes in biomarkers are not attributable to predispositions (drug–drug interactions and recognized conditions), increasing the risk of statin intolerance’’ European Atherosclerosis ‘‘The assessment of statin-associated muscle symptoms (SAMS) includes the nature of muscle 2015 [24] Society (EAS) symptoms, increased creatine kinase levels and their temporal association with initiation of therapy with statin, and statin therapy suspension and rechallenge’’ Canadian Consensus ‘‘A clinical syndrome, not caused by drug interactions or risk factors for untreated intolerance 2016 [25] Working Group and characterized by significant symptoms and/or biomarker abnormalities that prevent the long-term use and adherence to statins documented by challenge/dechallenge/rechallenge, where appropriate, using at least two statins, including atorvastatin and rosuvastatin, and that leads to failure of maintenance of therapeutic goals, as defined by national guidelines’’ The definition of statin intolerance has evolved over the therapeutic goals, as defined by national guidelines’’ [25]. years. In late 2014, the National Lipid Association (NLA) This is the most complete and a very pragmatic definition defined this syndrome as an inability to tolerate at least two of complete statin intolerance. The explicit inclusion of statins—one statin at the lowest starting daily dose and references to national guidelines and objectives in a defi- another statin at any daily dose—due to either objection- nition of statin intolerance has the intent to ensure that the able symptoms (real or perceived) or abnormal laboratory practical effort is justified for patients, colleagues, regula- determinations that are temporally related to statin treat- tory authorities, and taxpayers [25, 26]. ment and reversible upon statin discontinuation [22]. In addition to this, the International Lipid Expert Panel 2.3 Symptoms and Biomarkers of Statin Intolerance (ILEP) definition included the resolution of symptoms or changes in biomarkers or even significant improvement 2.3.1 Symptoms of Statin Intolerance with dose reduction or withdrawal of treatment; symptoms or changes in biomarkers are not attributable to predispo- The patient’s subjective assessment of the perceived risks sitions (drug–drug interactions and recognized conditions), and disadvantages compared with the benefits of therapy is increasing the risk of statin intolerance [23]. The European important for an effective approach to statin intolerance. Atherosclerosis Society (EAS) consensus paper suggested Most cases of statin intolerance are related to patient a more clinically oriented definition and recommended that complaints; suspension of therapy due to laboratory the assessment of statin-associated muscle symptoms abnormalities is much less common. Statin intolerance is (SAMS) include the nature of muscle symptoms, increased not simply the occurrence of symptoms in general, but CK levels and their temporal association with initiation of rather the symptoms that are perceived as unaccept- statin therapy, and statin therapy suspension and rechal- able [27]. Identifying true cases of statin intolerance is, lenge [24]. In 2016, the Canadian Consensus Working therefore, of great practical importance in order to avoid Group update defined statin intolerance as ‘‘a clinical unnecessary suspension of statin therapy by patients who syndrome, not caused by drug interactions or risk factors would otherwise benefit from them [27]. However, for untreated intolerance and characterized by significant assessing the probability that negative symptoms are cau- symptoms and/or biomarker abnormalities that prevent the sally related to statins is often difficult. Symptoms (more long-term use and adherence to statins documented by than 75%) are more likely to be attributable to statins if challenge/dechallenge/rechallenge, where appropriate, they appear within the first 3 months of statin therapy and using at least two statins, including atorvastatin and rosu- if they improve after suspension and reoccur after rein- vastatin, and that leads to failure of maintenance of troduction [28, 36]. Statins have specific adverse effects 160 P. P. Toth et al. (myalgias 3–5%; myopathy 0.1–0.2%; new-onset diabetes estimation of CV risk and treatment of adverse event risks [NOD] 9–27%, and hepatotoxicity, usually \1%) [27] when nonpharmacological therapy is not effective [35]. demonstrable or not from abnormal blood markers, SAMS, including myalgia—ranging from mild to severe including muscle (e.g., CK) or liver function studies in intensity—muscle stiffness and tenderness, cramps, and (hepatic transaminases—mainly alanine aminotransferase loss of muscle strength [23, 37], are by far the most [ALT]) [27]. For the latter, it is worth emphasizing that in common adverse effects and one of the most important fact there is no confirmed link between statin therapy and reasons for discontinuing statin therapy. The prevalence of liver damage, and most of the current guidelines and SAMS is around 3–5% in randomized controlled trials consensus papers recommend measuring transaminases including patients with dyslipidemia [38] and up to 20% in only before statin therapy initiation and during treatment if observational studies [39, 40], although the EAS consensus symptoms develop [14]. paper reported a SAMS prevalence as high as 29% [24]. The main adverse reactions due to statins include PRIMO (Prediction of Muscular Risk in Observational myalgia, myotoxicity, and NOD [28, 29]. The risk of conditions), a survey conducted in general medicine clinics developing NOD depends on the presence of prediabetes in France, showed that 10.5% of patients receiving statins (insulin resistance, carbohydrate metabolism disorders), the reported muscle symptoms, though the prevalence varied number of metabolic syndrome components (overweight, with individual statins (fluvastatin had the lowest rate of elevated blood pressure, high triglycerides, low high-den- SAMS, whereas simvastatin had the highest) [41]. The sity lipoprotein cholesterol [HDL-C], and hyperglycemia), USAGE (Understanding Statin Use in America and Gaps in and the duration and intensity of statin therapy. As the Education) study investigated current and former statin number of metabolic syndrome components increases, so users via an internet-based survey and showed that SAMS does the risk for NOD in statin-treated patients [30]. In occurred in 60% of current and 25% of former users and general, one must treat approximately 1000 patients that SAMS were the primary reason for treatment discon- annually to see one new case of NOD on low-dose statin tinuation [42]. Finally, data from the STOMP (Effect of therapy, or 500 patients per year to see one new case on Statins on Skeletal Muscle Function and Performance) moderate- to high-dose statin therapy [31]. However, tak- study, a randomized, double-blind, placebo-controlled trial, ing into account the available data, it is clear that the indicated that myalgia occurred in 9.4% of patients benefits associated with statin therapy outweigh the risk of receiving atorvastatin but also in 4.6% of subjects receiving NOD (for patients at high and very high CV risk, the placebo, for an overall incidence of statin-at- number needed to treat [NNT] vs. the number needed to tributable SAMS of * 5% [43]. harm [NNH] is [3–5 times higher) [32–35]. The NLA Task Force on Statin Safety (updated in 2014) In the JUPITER primary prevention trial, the CV and [44] classified the clinical presentation of SAMS as four mortality benefits of statin therapy exceeded the diabetes distinct entities: (1) myalgia, (2) myopathy, (3) myositis, hazard, including among those at higher risk for developing and (4) myonecrosis (including rhabdomyolysis). Myalgia diabetes. During a follow-up period of up to 5 years, a total is defined as muscle pain or flu-like symptoms (heaviness, of 86 vascular events or deaths were avoided, with no NOD tenderness, stiffness, aches or cramps) with normal CK diagnosed in patients with no major diabetes risk factors levels [44]. It is very important to know which muscle (CV events - 39%, p = 0.0001; no increase of diabetes, aches are typically associated with SAMS. Based on the p = 0.99), and 93 vascular events or deaths were avoided proposal by the NLA, the SAMS Clinical Index (SAMS- for every 54 NOD cases diagnosed in patients with one or CI) score, recently updated by Rosenson et al. [45], pro- more factors for diabetes development (CV events - 39%, vides the greatest score (3 points) for the typical large p = 0.0001; increase in diabetes 28%, p = 0.01). More- muscle symmetric (e.g., bilateral) aches, 2 points for over, statin therapy was associated with a time to NOD of bilateral aches of the smaller distal or proximal muscula- only 5.4 weeks compared with placebo [36]. To reduce the ture, and 1 point for asymmetric, non-uniform symptoms risk of NOD while receiving statin therapy, patients should [44]. In the STOMP study [43], subjects who reported be advised to exercise, reduce caloric intake, lose weight, myalgia while taking statins reported predominantly leg and stop smoking, all interventions that should be under- symptoms (hip flexor, quadriceps, hamstring, and/or calf taken in any case. aches; quadriceps or calf cramps; and/or quadriceps, Statin therapy should be continued in patients with hamstring, and/or calf fatigue), whereas those receiving NOD. In such cases, patient management includes a placebo reported more diverse symptoms such as whole- hypoglycemic diet, loss of excessive body weight, and body fatigue and groin pain [43, 44]. The SAMS-CI score prescription of antidiabetic drugs, if appropriate [34]. The might be a very useful tool with which to confirm statin- approach to lipid lowering in overweight or obese primary related myalgia and to exclude the nocebo effect. prevention patients is to introduce statins after careful Management of Statin Intolerance in 2018 161 Myopathy with muscle weakness (not attributed to pain) diagnostic yield is low and not cost effective [11]. Statin- can occur with normal or elevated CK [29]. Factors pre- associated liver abnormalities (aminotransferase levels) are disposing to the development of myopathy include age rare, mild, dose-related, and not related to reduction in [75 years, female sex, renal and hepatic dysfunction, LDL-C. Thus, drug- and dose-specific effects are more hypothyroidism, alcohol abuse, excessive physical exer- important determinants of liver and muscle toxicity than tion, genetic susceptibility, perioperative period, and con- magnitude of LDL-C lowering [52, 53]. They are also current use of drugs inhibiting the metabolism of statins, usually temporary, and it is possible to return to baseline such as clarithromycin, erythromycin, azole antifungals, levels after 2–4 weeks [52, 53]. Persistent elevation of diltiazem, verapamil, amiodarone, fibrates (particularly ALT more than three times the upper limit of normal gemfibrozil), cyclosporin, clopidogrel, sulfonamides, and (ULN) were observed in B 1% of patients treated with red yeast rice [23, 34, 37]. It has been also observed that statins. These are dose related, with rates of \0.5% for low levels of vitamin D and coenzyme Q10 (CoQ10) might moderate-dose rosuvastatin and at all doses, and slightly increase the risk of statin intolerance; however, available higher rates (about 1%) with atorvastatin or simvastatin data do not yet enable recommendations on their supple- 80 mg [52]. ALT elevations often improve even when mentation to prevent SAMS [46, 47]. Myopathy is a gen- statin therapy is continued. The incidence of liver failure is eral term encompassing all forms of muscle disease, the same among statin-treated patients as in the general including toxic disorders as well as acquired and herita- population not treated with statins [54]. Finally, it is worth ble metabolic disorders. The term does not necessarily remembering that the use of statins prevents about 33% of connote symptoms or any degree of CK elevation. Muscle major CVD events when compared with placebo, and sta- biopsy also suggests some myopathic statin-induced tins may cause serious liver disease in 1/1,000,000 (NNH is abnormalities that may be present in the context of normal 1 million). Between 10 and 30% of patients do not receive CK levels [43]. statins because of fear of hepatotoxicity [14, 23]. Myositis with muscle inflammation is associated with Other early markers also might predict and diagnose other symptoms (e.g., tenderness to palpation), CK eleva- statin intolerance [11]. One such biomarker being consid- tion, and leukocyte infiltration into muscle tissue. ered, at least in in vitro experiments, is lactate dehydro- Myonecrosis is always associated with muscle injury and genase, but its clinical utility in cases of statin-induced elevation of serum CK [29]. The most serious, and fortu- myopathy has not been validated [56]. A study that treated nately very rare, form of myonecrosis is rhabdomyolysis rats with drugs that are highly toxic to myocytes (carba- (1.6 per 100,000 patient-years), in which muscle break- mate acetylcholinesterase inhibitor; isoproterenol, a syn- down is responsible for a massive release of CK and thetic catecholamine), but not with statins, identified fatty myoglobin, with resulting myoglobinuria and acute renal acid binding protein 3 (FABP3) and myosin light chain 1 failure [29]. However, rhabdomyolysis currently occurs (MLC1) as biomarkers of skeletal muscle toxicity based on principally in cases of genetic predisposition as well as the specific tissue distribution of these proteins [55, 56]. drug–drug interactions [48]. According to the EAS con- Burch et al. [57] evaluated skeletal muscle troponin I sensus paper on SAMS, it is important to remember the (sTnI), myosin light chain 3 (MYL3 [S3]), CK isoform M cut-off point value of 4, above which muscle symptoms (CKM), and FABP3 compared with CK in the monitoring seem to be more attributable to statin therapy [24]. of drug-induced skeletal muscle injury. sTnI, MYL3, CKM, and FABP3 all outperformed CK and/or added value 2.3.2 Biomarkers of Statin Intolerance for the diagnosis of drug-induced novel skeletal muscle injury (i.e., myocyte degeneration/necrosis) [57]. In addi- New biomarkers for statin-induced myopathy are emerg- tion, when used in conjunction with CK, sTnI, MYL3, ing. Unfortunately, most cannot be commonly used CKM, and FABP3 individually and collectively improved because of complexities in methodology and costs, and diagnostic sensitivity and specificity, as well as diagnostic their sensitivity and specificity still need to be defined [11]. certainty, for novel skeletal muscle injury and responded in The most widely used serum marker is the serum CK level a sensitive manner to low levels of novel skeletal muscle [49], but its exclusive use as a diagnostic marker is inad- injury degeneration/necrosis in rats. CKM showed the equate and non-specific because high serum levels are not strongest correlation (r = 0.47, p\0.0001), followed by always associated with myopathy [50]. CK levels can be FABP3 (r = 0.52, p\0.0001), MYL3 (r = 0.48, elevated by exercise in a dose-independent manner [29] p\0.0001), sTnI (r = 0.47, p\0.0001), aspartate and by drug interactions, genetic variants, CoQ10 defi- transaminase (AST; r = 0.46, p\0.0001), and CK ciency, and vitamin D deficiency [51]. (r = 0.32, p\0.0001) [57]. These findings support the Routine liver function analyses are no longer recom- suggestion that sTnI, MYL3, CKM, and FABP3 are suit- mended in the management of statin therapy because the able for voluntary use, in conjunction with CK, in 162 P. P. Toth et al. regulatory safety studies in rats to monitor drug-induced day post-MI, median CRP was significantly higher in the skeletal muscle injury and for the potential translational use group from whom statins had been withdrawn. of these exploratory biomarkers in early clinical trials to Complete statin intolerance, which requires statin dis- ensure patient safety [57]. Dobkin [58] suggested the continuation, affects \5% of patients with statin intoler- functional evaluation of hip-flexor and abductor perfor- ance symptoms [23, 25]. Numerous approaches to mance (because it occurred independently of CK levels). maintaining statin persistence have been published Wu et al. [59] proposed the evaluation of the kinetics of [24, 25, 29, 34]. Therefore, we would especially like to recovery exercise phosphocreatine by means of phosphorus focus on combination therapy for patients not able to tol- magnetic resonance spectroscopy ( P-MRS). In this study, erate suitable statin doses. Briefly, we can always consider patients were treated for 4 weeks with statin therapy and step-by-step reduction of the dose (dechallenge) and were shown to have a prolonged metabolic recovery time intermittent dosages (alternate-day therapy). We know this in the calf despite no change in serum CK levels [59]. does not significantly influence the magnitude of LDL-C Unfortunately, several drawbacks are associated with these reduction for rosuvastatin and atorvastatin [66]. The muscle-specific markers: rapid clearance, dependence of lipophilicity and hydrophilicity of statins seems to be renal dysfunction, heterogeneous response depending on important, and changing from a hydrophilic to a lipophilic the type of myotoxicants in general, and the difficulty and statin may be of some benefit in the SAMS setting [23, 24]. high costs of measurements [11, 60]. We have also observed that both statin groups had the same Laaksonen et al. [61] proposed lipidomic evaluation of effects concerning efficacy and safety in patients with ACS plasma muscle gene profiles, which helped to identify [67]. Hydrophilic statins (rosuvastatin and pravastatin) several sensitive biomarkers of metabolic alterations seem to cause fewer statin intolerance symptoms, and this induced in skeletal muscle by high-dose statin regimens is especially important for elderly patients [23] (Table 2). (increased expression of arachidonic acid 5-lipoxygenase activating protein, phospholipase C, numerous species of 2.4 Alternative Drug Treatment phosphatidylethanolamine, selective pools of long-chain triglycerides, and phosphocholine ether). However, such The use of lipid-lowering therapy in clinical practice has complex genomic and combined lipidomic analyses are become progressively more challenging because exagger- very difficult to perform and, above all, to interpret rou- ated patient concerns over side effects and potential toxi- tinely in clinical practice. Two microRNAs (miRNAs; city can lead to poor adherence to statin therapy or 133a/b and 499-5p) were evaluated as potential biomarkers discontinuation [15, 22] despite the highly established of tissue damage because of their long half-lives in serum. benefits of LDL-C reduction [68, 69]. The use of ezetimibe The serum levels of miR-133a/b were reported as sensitive monotherapy is still limited (due to US FDA recommen- and specific markers of cardiac and skeletal muscle toxicity dations in the USA as well as restricted reimbursement in [62]; miR-499-5p might serve as a biomarker for statin- Europe, leading to use in \5–10% of the patients who enhanced muscle injury during exercise because it was require it according to guideline recommendations) [13], increased in the plasma of runners after a marathon and and use of the monoclonal antibodies directed against increased when muscle contraction was combined with proprotein convertase subtilisin kexin type 9 (PCSK9) exposure to statins [63]. Further studies are still necessary tends to be severely restricted by managed care formula- to confirm the specificity and sensitivity of innovative ries. Statin monotherapy or statin combination therapy with biomarkers in statin-treated patients. other currently available drugs do not all have the same capacity to induce appropriate reductions in LDL-C in 2.3.3 Statin Intolerance Management patients at high CV risk [70]. Therefore, there is a clinical need for new therapies, alone or in combination with cur- Probably the most important issue in the management of rent drugs (Table 2), to lower LDL-C. patients with statin intolerance/SAMS is the need to con- Bempedoic acid (ETC-1002) has a unique mechanism of tinue statin therapy. It is especially critical for patients with action (adenosine triphosphate-citrate lyase inhibition) high and very high CV risk, as therapy discontinuation for [71, 72]. The efficacy of combination therapy with statins 4–6 weeks might cause atheroma plaque instability [64] and bempedoic acid has been evaluated in a randomized and increases the risk of CV events [17]. A further aspect to controlled trial (NCT02072161) [73]. A total of 134 consider is inflammation. Sposito et al. [65] assessed the patients who had been treated with one of a series of statin existence of a rebound inflammatory effect after statin regimens (atorvastatin 10 or 20 mg; simvastatin 5, 10, or withdrawal in the acute phase of MI. At baseline, statin 20 mg; rosuvastatin 5 or 10 mg; or pravastatin 10, 20, or users presented with a lower C-reactive protein (CRP) than 40 mg) for at least 3 months before the trial began were patients not receiving a statin before the MI. By the fifth randomized to bempedoic acid 120 or 180 mg or placebo Management of Statin Intolerance in 2018 163 Table 2 Therapeutic possibilities for the treatment of statin-intolerant patients and their influence on low-density lipoprotein cholesterol levels Agent Subjects Dose Duration LDL-C levels References BA with low-dose statins 134 120 mg/day 12 weeks - 17.3 ± 4.0% [73] hypercholesterolemic (p\0.01) pts 180 mg/day - 24.3 ± 4.2% (p\0.001) PL - 4.2 ± 4.2% BA 56 240 mg/day vs. PL 8 weeks - 28.7% (p\0.001) [74] hypercholesterolemic (increase pts by 60 mg q2w) BA with or without EZE 177 120 mg/day 12 weeks -27.5 ± 1.3 mg/dl [75] hypercholesterolemic (p = 0.0008) pts 180 mg/day - 30.1 ± 1.3 mg/dl (p\0.0001) EZE 10 mg/day - 21.2 ± 1.3 mg/dl (p\0.0001) 120 mg ? EZE 10 mg/day - 43.1 ± 2.6 mg/dl (p\0.0001) 180 mg ? EZE 10 mg/day - 47.7 ± 2.8 mg/dl (p\0.0001) BA 12,600 statin-intolerant 180 mg/day 6 years Ongoing [76] pts expected ATO 60 10 mg/day 6 weeks 100 ± 25 mg/dl [129] hypercholesterolemic (p = 0.3) pts 20 mg/alternate day 68 ± 28 mg/dl (p\1.0) 20 mg/day 96 ± 41 mg/dl (p\1.0) ROS 45 20 mg/alternate day 6 weeks - 40.9% (p\0.0001) [130] hypercholesterolemic 10 mg/day - 78.5% (p\0.0001) pts ATO 61 20 mg/alternate day 3 months - 95 ± 31 mg/dl [131] hypercholesterolemic (p\0.05) pts 20 mg/day - 94 ± 28 mg/dl (p\0.05) ROS 37 dyslipidemic pts 10 mg/alternate day 6 weeks -57 ± 1.2 mg/dl [132] (p\0.01) 10 mg/day - 60 ± 1.0 mg/dl (p\0.01) PRA 104 dyslipidemic pts Half-dose alternate days vs. daily 4 months 113 ± 21 mg/dl [133] (p\0.04) 104 ± 24 mg/dl (p\0.04) ATO 54 10 mg/day 6 weeks No statistically [134] hypercholesterolemic significant differences 10 mg/alternate day pts between the three 20 mg/alternate day groups regarding total or a percentage ATO 40 20 mg/alternate day 12 weeks No statistically [135] hypercholesterolemic significant differences 20 mg/day pts between the two groups ATO 60 pts with CAD 10 mg/alternate day 6 weeks 105 ± 26 mg/dl [136] (p\0.008) 10 mg/day 88 ± 21 mg/dl (p\0.008) 164 P. P. Toth et al. Table 2 continued Agent Subjects Dose Duration LDL-C levels References FLU 23 40 mg/alternate day 6 weeks 144 ± 21 mg/dl [137] hypercholesterolemic (p\0.05) pts 20 mg/day 138 ± 19 mg/dl (p\0.05) ROS 80 pts with primary 10 mg/alternate day 8 weeks 105.07 ± 26.30 mg/dl [138] hypercholesterolemia (p\0.001) 10 mg/day 94.10 ± 40.16 mg/dl (p\0.001) ATO 100 dyslipidemic pts 10 mg/alternate day 3 months 73.6 ± 14.71 mg/dl [139] (p\0.0001) 10 mg/day 93.79 ± 17.48 mg/dl (p\0.0001) ATO 141 pts with Alternate day vs. daily 12 weeks Alternate-day dosing of [140] dyslipidemia or CAD ATO was inferior to daily dosing in maintaining the NCEP-ATP III goal EZE 432 pts with primary 5 mg/day 12 weeks - 15.7% (p\0.01) [141] hypercholesterolemia 10 mg/day - 18.5% (p\0.01) EZE ? statins 769 pts with primary Statin ? EZE 10 mg/day 8 weeks - 25.1% (p\0.001) [142] hypercholesterolemia Statin ? PL - 3.7% (p\0.001) EZE ? SIM 720 pts with FH SIM ? EZE 10 mg/day 24 months 141.3 ± 52.6 mg/dl [143] (p\0.01) EZE ? SIM 1128 pts with EZE/SIM 10/20 mg/day 6 weeks - 49.6% (p\0.001) [144] hypercholesterolemia EZE/SIM 10/40 mg/day - 53.9% (p\0.001) and metabolic syndrome EZE ? ROS 239 pts with high risk EZE/ROS 10/40 mg/day 6 weeks - 70% (p\0.001) [145] of CHD ROS 40 mg - 56% (p\0.001) PCSK9 inhibitor EVO 1117 primary 140 mg vs. PL 10 weeks 66–75% (p\0.001) [83] with moderate- and hypercholesterolemia 420 mg vs. PL 12 weeks 63–65% (p\0.001) high- intensity statins and mixed dyslipidemia pts PCSK9 inhibitor EVO 1359 dyslipidemic pts 70 mg q2w ? statin or EZE 12 weeks - 40.20% (p\0.001) [86] with statin or EZE 105 mg q2w ? statin or EZE - 52.86% (p\0.001) 140 mg q2w ? statin or EZE - 59.26% (p\0.001) 280 mg q4w ? statin or EZE - 42.55% (p\0.001) 350 mg q4w ? statin or EZE - 47.00% (p\0.001) 420 mg q4w or EZE - 52.66% (p\0.001) PCSK9 inhibitor EVO 511 pts with 420 mg/month 24 weeks - 102.9 mg/dl [88] with statin uncontrolled LDL-C (p\0.001) and history of intolerance to two or more statins PCSK9 inhibitor ALI 361 pts at moderate to ALI 75 mg q2w 24 weeks -102.9 mg/dl [96] with EZE high CV risk with (p\0.001) statin intolerance EZE 10 mg - 31.2 mg/dl (p\0.001) Inclisiran with statin 501 pts at high CVD Single dose of 200–500 mg/day 180 days 27.9–41.9% after a [98] risk with elevated or double dose of single dose LDL-C 100–300 mg/day 35.5–52.6% after two doses (for both p\0.001) Management of Statin Intolerance in 2018 165 Table 2 continued Agent Subjects Dose Duration LDL-C levels References Red yeast rice DS 83 pts in dietary 2.4 g/day red yeast rice 12 weeks From 4.47 ± 0.70 to [99] treatment 3.49 ± 0.70 (p\0.05) Plant extracts (red yeast 39 pts with moderate Red yeast rice 166.67 mg (0.4% 16 weeks - 14.1% (p\0.001) [102] rice, sugar cane-derived hypercholesterolemia monacolin K), sugar cane policosanols, and extract 3.70 mg (90% artichoke leaf extracts) policosanols–octacosanol 60%), artichoke leaf dry extract 200 mg (5–6% chlorogenic acid) daily Natural nutraceuticals 933 dyslipidemic pts 1 tablet/day associated with diet 16 weeks - 23.5% (p\0.001) [103] (red yeast, policosanol, and berberine) Nutraceutical 30 pts with moderate Berberine 500 mg, policosanols 8 weeks - 21.1% (p\0.001) [104] combination (red yeast CV risk 10 mg, folic acid 0.2 mg, rice extract, berberine, CoQ10 2.0 mg, astaxanthin policosanol, 0.5 mg daily astaxanthin, CoQ10, folic acid) Acid ethyl ester 702 statin-treated pts 4 or 2 g/day 12 weeks - 6.2% (p = 0.0067) [112] (AMR101) Chokeberry flavonoid 44 pts after MI 85 mg tid of chokeberry flavonoid 6 weeks Ox-LDL levels - 29% [114] extract extract (Aronia melanocarpa E.) (p\0.000) Spirulina 312 pts 1–10 g/day 2–12 months - 41.32 mg/dl [116] (p\0.001) BER vs. EZE 228 pts with primary Berberine 500 mg, policosanol 6 months - 31.7% (p\0.001) [146] hypercholesterolemia 10 mg, red yeast rice 200 mg EZE 10 mg/day - 25.4% (p\0.001) AEs adverse events, ALI alirocumab, ATO atorvastatin,BA bempedoic acid, BER berberine, CAD coronary artery disease, CHD coronary heart disease, CoQ10 coenzyme Q10, CV cardiovascular, CVD cardiovascular disease, DS dietary supplement, EVO evolocumab, EZE ezetimibe, FH familial hypercholesterolemia, FLU fluvastatin, LDL-C low-density lipoprotein cholesterol, MI myocardial infarction, NCEP-ATP III National Cholesterol Education Program Adult Treatment Panel III, ND not defined, Ox-LDL oxidized low-density lipoprotein, PCSK9 proprotein convertase subtilisin/kexin type 9, PL placebo, PRA pravastatin, pts patients, qxw every x weeks, ROS rosuvastatin, SIM simvastatin, tid three times daily [73]. LDL-C was reduced significantly with bempedoic not adequately managed with statins [77–79]. Evolocumab acid 120 or 180 mg daily, respectively, compared with and alirocumab have recently received marketing autho- placebo: - 17.3 ± 4.0% (p\0.01) and - 24.3 ± 4.2% rization in the EU and the USA [79]. The approved indi- (p\0.001) [73]. Thompson et al. [74] conducted a multi- cations for evolocumab are (1) adults with primary center, double-blind, 8-week trial in a group of patients hypercholesterolemia (heterozygous familial hypercholes- intolerant to at least one statin and reported that ETC-1002 terolemia [HeFH] and non-familial), unable to achieve was effective at reducing LDL-C (by almost 29%) and was LDL-C goals with the maximum tolerated dose of a statin well tolerated in patients with SAMS. A recent phase IIb or alone or in combination with other lipid-lowering ther- trial in which patients with and without statin intolerance apies in patients who are intolerant to statins, or for whom received daily treatment with ETC-1002 120 or 180 mg a statin is contraindicated; (2) adults and adolescents aged alone or with ezetimibe confirmed these results. These C 12 years with homozygous familial hypercholestero- treatments reduced LDL-C more than did ezetimibe alone laemia (HoFH) in combination with other lipid-lowering and had a similar tolerability profile [75]. It is worth therapies [80]. Alirocumab is approved for adults with mentioning that a new phase III trial (NCT02993406) primary hypercholesterolemia (HeFH and non-familial) or investigating whether treatment with bempedoic acid ver- mixed dyslipidemia, in patients unable to achieve their sus placebo decreases the risk of CV events in 12,600 LDL-C goals with maximum tolerated dose of a statin or, statin-intolerant patients has commenced [76] (Table 2). alone or in combination with other lipid-lowering thera- PCSK9 monoclonal antibodies constitute a breakthrough pies, in patients who are intolerant to statins or for whom a for statin-intolerant patients or those in whom LDL-C is statin is contraindicated [81]. 166 P. P. Toth et al. Evolocumab and alirocumab have been studied in therapy). The addition of evolocumab to statin therapy numerous phase II and phase III clinical trials involving (with or without ezetimibe) significantly reduced the pri- high-risk patients, including those with statin intolerance mary endpoint (composite of CV death, MI, stroke, hos- and those with familial hypercholesterolemia (FH) pitalization for unstable angina, or coronary [82–88]. Evolocumab reduces LDL-C by approximately revascularization) and key secondary endpoints (composite 60–65%, influences all other lipid profile parameters, and of CV death, MI, or stroke) of the trial by 15% (hazard has favorable effects on lipoprotein(a) [89–92]. Evolocu- ratio [HR] 0.85; 95% confidence interval [CI] 0.79–0.92; mab is also very well tolerated as monotherapy, added to p\0.001) and 20% (HR 0.80; 95% CI 0.73–0.88; statins, or added to statins plus ezetimibe [82], without p\0.001), respectively [95]. major adverse effects such as myalgia, CK elevations, The available evidence for alirocumab suggests that this NOD [93], or neurocognitive disorders [94]. In a pooled treatment is also (similarly) effective in reducing LDL-C analysis of four phase III studies, the effectiveness and and is well tolerated. The results of the ODYSSEY safety of evolocumab was comparable in patients with or ALTERNATIVE trial in patients with statin intolerance without type 2 DM (T2DM) and did not differ between demonstrated good tolerability and efficacy [96]. The T2DM subgroups [82]. Toth et al. [87] reported a com- ODYSSEY phase III program includes more than 23,000 prehensive safety assessment of evolocumab in 6026 patients and 14 studies with alirocumab alone or in com- patients in 12 phase II and III parent trials with a median bination with other lipid-lowering agents, and as exposure of 2.8 months, and in 4465 of those patients who monotherapy in patients with primary HeFH, non-FH, or continued with a median follow-up of 11.1 months in two statin intolerance [97]. The ODYSSEY OUTCOMES study open-label extension (OLE) trials, demonstrating a favor- is not yet completed (it will likely be presented at the able benefit–risk profile for evolocumab. Overall adverse American College of Cardiology meeting in March 2018) event (AE) rates were similar between evolocumab and and is assessing the CV benefit of alirocumab in 18,600 control groups in the parent trials (51.1 vs. 49.6%) and in patients (at higher risk than in the FOURIER trial), over year 1 of the OLE trials (70.0 vs. 66.0%), as were those for approximately 5 years of follow-up (the mean follow-up serious AEs (SAEs). Elevations of serum transaminases, will be at least 3 years). A subgroup analysis of 2341 bilirubin, and CK were infrequent and similar between patients with and without T2DM in ODYSSEY LONG- groups [87]. Muscle-related AEs were similar between TERM showed that alirocumab effects were also consis- evolocumab and control groups. Neurocognitive AEs were tent, regardless of the clinical history of patients with infrequent and balanced during the double-blind parent T2DM at baseline [97] (Table 2). studies (five events [0.1%] in the evolocumab groups vs. Another approach to PCSK9 inhibition is in develop- six events [0.3%] in the control groups). No neutralizing ment. The ORION-1 (Trial to Evaluate the Effect of ALN- anti-evolocumab antibodies were detected [87]. The PCSSC Treatment on LDL-C) trial found that inclisiran, a GAUSS-3 (Goal Achievement after using an anti-PCSK9 chemically synthesized small interfering RNA designed to antibody Intolerant statins subject-3) trial was a statin target PCSK9 messenger RNA, lowered PCSK9 and LDL- intolerance study that included 511 adult patients with a C levels among patients at high CV risk who had elevated history of intolerance to two or more statins [88]. Patients LDL-C levels [98]. In this trial, over the course of were treated with non-statin therapies (evolocumab vs. 180 days, 501 patients received a single dose of inclisiran ezetimibe). After 2 years, LDL-C levels were significantly 200, 300, or 500 mg or two doses (at days 1 and 90) of more reduced (by 36.1%) in the evolocumab group than in inclisiran 100, 200, or 300 mg [98]. At day 180, inclisiran the ezetimibe group (p\0.001). Muscle symptoms were significantly reduced (p\0.001 vs. placebo) LDL-C levels reported in 28.8% of ezetimibe-treated patients and 20.7% from 27.9 to 41.9% after a single dose and 35.5 to 52.6% of evolocumab-treated patients (p = 0.17) [88]. The after two doses. Two doses of inclisiran 300 mg produced recently published FOURIER (Further Cardiovascular the greatest reduction in LDL cholesterol levels at day 180 Outcomes Research with PCSK9 Inhibition in Subjects (48% of patients had LDL-C \50 mg/dl [\1.3 mmol/l]) with Elevated Risk) trial provided strong evidence on CV [98]. At day 240, PCSK9 and LDL-C levels remained endpoints and additional long-term safety (mean significantly lower than at baseline with all inclisiran reg- 26 months) in 27,564 patients with established CVD (MI, imens. Inclisiran may emerge as an important therapeutic ischemic stroke, or symptomatic peripheral artery disease). option for statin-intolerant patients, as lipid-lowering Patients were randomized to receive either subcutaneous occurs with few serious AEs or symptoms of immune evolocumab 140 mg every 2 weeks, subcutaneous evolo- system activation [98] (Table 2). An advantage of this drug cumab 420 mg every month, or matching placebo injec- is that it can be can be administered every 6 months. tions [95]. All patients were receiving background statin This class of new drugs will be used in the long term, therapy (almost 70% receiving high-intensity statin generally for the rest of the treated patients’ lives. Despite Management of Statin Intolerance in 2018 167 claims that millions of patients with dyslipidemia could devoid of the safety risks associated with synthetic phar- benefit from these PCSK9 inhibitors, these treatments will macological therapy because it has a combination of low actually meet the health needs of a small population of doses of its active ingredients—low enough not to be patients (at very high CV risk who benefit the most) associated with untoward effects but high enough to exert because of the high costs in all countries in which they are therapeutic effects in combination with other complemen- marketed. tary substances [105]. Armolipid Plus can reduce total cholesterol (11–21%) and LDL-C (15–31%) levels, which 2.5 Alternative Nutraceutical Therapy is equivalent to changes associated with low-dose statins. In patients with mild to moderate hyperlipidemia intolerant It is known that lipid-lowering therapy might not be to statins who do not achieve LDL-C targets with ezetim- enough to completely attenuate the risk of CVD, residual ibe, Armolipid Plus can promote a further 10% reduction risk still exists, and that alternative therapy with in total cholesterol and LDL-C. Moreover, Armolipid nutraceuticals may help improve therapy adherence and Plus offers additional benefits in terms of improvements reduce the risk of patients with statin intolerance [37]. in vascular stiffness, which is an independent predictor of Natural products can be used in combination with a non- CV events [105]. statin (as well as with small doses of synthetic or natural The mechanism of action of policosanol, a mix of eight statins) in subjects with statin intolerance. long-chain aliphatic alcohols derived from the fermentation Monacolins such as policosanols and bergamot inhibit of sugar cane, rice, wheatgerm, or sunflower seeds is not HMG-CoA reductase, and red yeast rice extract (Monascus yet clear [106]. Data on the lipid-lowering effects of purpureus) contains a variety of monacolins [99]. A 2005 policosanols are contradictory. The down-regulation of cell study in 111 Caucasian individuals demonstrated that a HMG-CoA reductase by this formulation has been pro- brand dietary supplement comprising M. purpureus titrated posed [107]. Its lipid-lowering activity might be compa- extract and octacosanols, which contain a low dose of rable to that of statins, and it may be even more effective at niacin, resulted in LDL-C lowering by 20% (p\0.001) and increasing HDL-C and lowering side effects [108]; how- a reduction of triglyceride plasma level by 16% (p\0.01) ever, the data on their actual effectiveness are still con- in patients with moderate hypercholesterolemia with no tradictory [106, 109–111]. Further research is needed to clinically relevant changes in muscle and liver toxicity determine with certainty whether policosanols have bene- markers [100]. LDL-C lowering was similar to that ficial lipid-lowering effects and whether they might have obtained with pravastatin [100]. Red yeast rice used in beneficial effects for patients who are intolerant to statins. combination with plant sterols mimicked the effect of The efficacy of icosapent ethyl (IPE; Vascepa [for- statins and ezetimibe by significantly lowering LDL-C by merly AMR101]; Amarin Pharma Inc., Bedminster, NJ, 33% and total cholesterol by 19% in only 6 weeks of USA) in improving lipid parameters was demonstrated in a nutraceutical therapy [101]. Red yeast rice extract contains 12-week randomized, placebo-controlled trial (ANCHOR) nine varieties of bioactive constituents (monacolins) with that enrolled statin-treated patients at high CV risk with the same formulation as lovastatin. Furthermore, co-ad- well-controlled LDL-C levels and persistently high ministration of leaf extracts and red yeast rice significantly triglyceride levels (C 200 and \500 mg/dl) [112]. Com- reduced LDL-C (21.4%; p\0.001) and total cholesterol pared with placebo, IPE 4 and 2 g daily reduced median (14.1%; p\0.001) after 16 weeks [102]. The combination triglyceride levels from baseline by 21.5% (p\0.0001) and of berberine with red yeast rice significantly improved 10.1% (p = 0.0005), respectively, without increasing different lipid parameters (i.e., lowered total cholesterol, LDL-C levels. The 4-g daily dose decreased LDL-C levels LDL-C, and triglyceride levels [p\0.001 for all] and by 6.2% (p = 0.007) and significantly reduced other lipid increased HDL-C concentration [p\0.001]) after parameters compared with a light liquid paraffin placebo, 16 weeks of treatment [103]. Comparable results were including apolipoprotein B (9.3%; p\0.0001), very low- observed in another clinical trial [104]. This study showed density lipoprotein cholesterol (VLDL-C) (24.4%; results similar to those with pravastatin in subjects with p\0.0001), lipoprotein-associated phospholipase A2 moderate dyslipidemia and metabolic syndrome: the same (19.0%; p\0.0001), and high-sensitivity CRP (hsCRP) combination induced an increase of 4.8% in HDL-C and a (22.0%; p = 0.0005) [112]. One study of IPE in statin- lowering of 21.1% in total cholesterol and 21.1% in LDL-C intolerant patients suggested it might be potentially effec- [104]. In the setting of statin intolerance, Armolipid Plus , tive in this group of patients [113]. a formulation that contains natural substances (red yeast In a double-blind study, Naruszewicz et al. [114] used rice, policosanol, and berberine combined with folic acid, chokeberry extract in 44 patients (11 women and 33 men, astaxanthin, and coQ10) with putative complementary mean age 66 years) who survived an MI and received statin lipid-lowering properties, offers an effective alternative therapy for at least 6 months (80% dose of simvastatin 168 P. P. Toth et al. 40 mg daily) [114]. Subjects were randomized to receive in patients with SAMS, enabling effective reduction of either chokeberry flavonoid extract (Aronia melanocarpa LDL-C and possibly a lower statin dose [120]. Curcumin E.) 85 mg three times daily or placebo for 6 weeks. The may modulate the production of HDL and biomarkers of study extract comprised the following constituents: antho- HDL functionality by increasing apolipoprotein AI (apo- cyanins (about 25%), polymeric procyanidins (about 50%), AI) and lecithin cholesterol acyl transferase (LCAT) and and phenolic acids (about 9%) [114]. Compared with pla- decreasing cholesteryl ester transfer protein (CETP), cebo, flavonoids significantly reduced serum 8-isoprostans paraoxonase-1 (PON1), myeloperoxidase (MPO), and (p\0.000) and oxidized LDL levels (p\0.000) (by 38 and lipoprotein-associated phospholipase A2 (Lp-PLA2) [121]. 29%, respectively), as well as hsCRP (p\0.007) and Curcumin is safe to consume, even at dosages of up to monocyte chemoattractant protein-1 (MCP-1) (p\0.001) 8–12 g daily [122]; however, so far, its low bioavailability levels (by 23 and 29%, respectively). In addition, signifi- and efficacy profile in vivo has limited its clinical appli- cant increases in adiponectin (p\0.03) levels and reduc- cation [123]. Further clinical trials with curcumin formu- tions in systolic and diastolic blood pressure, by a mean lations with improved bioavailability are necessary to average of 11 and 7.2 mmHg, respectively, were found examine its effects on lipid metabolism and SAMS [114]. The abovementioned results mean this extract is treatment. potentially beneficial for statin-intolerant patients, but Several nutraceuticals exert lipid-lowering and athero- further studies in these subjects are necessary to defini- protective properties [124–126]. Berberine, curcumin, tively confirm its effectiveness and safety profile. polydatin, n-3 PUFA-enriched fish oil, docosahexaenoic Spirulina is a filamentous, water blue-green microalga acid (DHA)-enriched canola oil, marine n-3 PUFAs, and (Cyanobacterium) [115]. The hypolipemic properties of quercetin-3-O-b-D-glucoside have been identified as able to spirulina have not been conclusively studied. One meta- lower PCSK9 levels, an important regulator of lipid analysis [116] of seven randomized controlled trials metabolism and an efficient target for plasma LDL-C showed a significant effect from supplementation with reduction [127]. In particular, the use of some of these spirulina, with reduced plasma concentrations of total agents is supported by data from human trials in patients cholesterol (- 46.76 mg/dl; p\0.001), LDL-C (- with at least one condition related to the metabolic syn- 41.32 mg/dl; p\0.001), triglycerides (- 44.23 mg/dl; drome, HeFH, or dyslipidemia. Administration of a pill p\0.001), and elevated levels of HDL-C (6.06 mg/dl; containing berberine 500 mg for 6 months reduced LDL-C p = 0.001). The impact of spirulina on plasma concentra- by 10.5% (p\0.0001) in patients with HeFH, an effect the tions of total cholesterol and triglycerides was independent authors suggested was associated with an indirect berber- of administered dose (dose range: 1–10 g/day). Spirulina ine-mediated inhibitory effect on PCSK9 [127]. Xuezhi- contains high levels of antioxidants (e.g., beta-carotene), kang is a cholestin extract that contains a mixture of phycocyanin, microelements (K, Na, Ca, Mg, Fe, Zn), lovastatin (dominant compound), plant sterols, and iso- vitamins (tocopherols), eight necessary amino acids, flavones. Administration of xuezhikang 1200 mg daily for polyunsaturated fatty acids (PUFAs)—especially c-li- 8 weeks increased plasma PCSK9 levels by 34% nolenic acid—and phenolic compounds [117]; however, (p = 0.006) and decreased LDL-C and total cholesterol by the active components responsible for the hypolipidemic 28 and 22% (p = 0.001, p = 0.002), respectively [127]. effects of spirulina are not fully understood. This meta- Enrichment of canola oil with DHA was shown to lower analysis was the first to evaluate the effects of spirulina circulating PCSK9 and triacylglycerol levels by 6%. Fur- supplementation on serum lipid parameters based on the thermore, circulating PCSK9 levels were found to be sig- results from randomized controlled trials, but further well- nificantly and positively associated with LDL-C, designed trials are required to clarify the clinical value of triacylglycerol, and apolipoprotein B (apoB) levels, spirulina supplementation as an add-on to conventional and whereas no association was found between PCSK9 and novel lipid-lowering therapies in patients with HDL-C levels [127]. Consumption of marine n-3 PUFAs dyslipidemia. 2200 mg daily for 12 weeks decreased circulating PCSK9 Curcumin, a natural dietary polyphenol responsible for levels by 11.4 and 9.8% in premenopausal and post- the yellow color of the Indian spice turmeric (Curcuma menopausal women, respectively. In contrast, plasma longa L.), has analgesic, antioxidant [118], and anti-in- LDL-C levels showed no significant changes [127]. flammatory properties relevant to the treatment of SAMS Therefore, some nutraceuticals such as berberine and as it prevents and reduces muscular fatigue, blocks the curcumin are suggested as useful adjuncts to statin therapy inflammatory pathway of the nuclear factor, attenuates because of their inhibition of PCSK9 independent of sterol- muscular atrophy, and improves regeneration of muscle responsive element-binding protein. Nevertheless, evi- fibers after injuries [119]. Since curcumin also has lipid- dence from well-designed randomized controlled trials is modifying properties, it may serve as an additive to therapy required to support the added value of such a combination Management of Statin Intolerance in 2018 169 Open Access This article is distributed under the terms of the in reducing CV events compared with statin monotherapy Creative Commons Attribution-NonCommercial 4.0 International [127] (Table 2). License (http://creativecommons.org/licenses/by-nc/4.0/), which per- mits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons 3 Conclusions license, and indicate if changes were made. Statins are generally safe and very efficacious agents for reducing the burden of atherogenic lipoproteins in serum References and the risk for acute CV events, including MI, stroke, death, and need for revascularization. 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Colantonio LD, Bittner V, Reynolds K, et al. Association of might be considered, especially when other means with serum lipids and coronary heart disease in contemporary which to achieve the LDL-C goal of the therapy are lacking. observational studies. Circulation. 2016;133:256–64. 10. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of However, further studies in patients intolerant to statins are cholesterol-lowering treatment: prospective meta-analysis of necessary to confirm their effectiveness and safety. data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267–78. Compliance with Ethical Standards 11. Muntean DM, Thompson PD, Catapano AL, et al. Statin-asso- ciated myopathy and the quest for biomarkers: can we effec- Funding This review was written independently. The authors did not tively predict statin-associated muscle symptoms? Drug Discov receive financial or professional help with the preparation of the Today. 2017;22:85–96. manuscript. 12. Gluba-Brzozka A, Franczyk B, Toth PP, et al. Molecular mechanisms of statin intolerance. Arch Med Sci. Conflict of interest Maciej Banach has no conflicts of interest that 2016;12:645–58. might be relevant to the contents of this manuscript. Peter P. Toth has 13. Patel J, Martin SS, Banach M. Expert opinion: the therapeutic previously received consulting fees and/or honoraria from AbbVie, challenges faced by statin intolerance. Expert Opin Pharma- Amarin, Amgen, Gemphire, Kowa, Merck, Regeneron, and Sanofi cother. 2016;17:1497–507. and payment for lectures from Amarin, Amgen, Kowa, Merck, 14. Banach M, Rizzo M, Toth PP, et al. Statin intolerance—an Regeneron, and Sanofi. Rosaria Vincenza Giglio, Giuseppa Cas- attempt at a unified definition. Position paper from an Interna- tellino, Angelo Maria Patti, and Dragana Nikolic have participated in tional Lipid Expert Panel. 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American Journal of Cardiovascular DrugsSpringer Journals

Published: Jan 9, 2018

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