Statin Intolerance

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Giosiana Bosco	--	2470	2023-04-14 17:15:28	\|
2	Update references	Sirius Huang	Meta information modification	2470	2023-04-17 03:31:27	\|

This entry is adapted from the peer-reviewed paper 10.3390/jcm12062444

Statins are the cornerstone of lipid-lowering therapies effective for cardiovascular risk reduction. Although they are generally well tolerated, statin intolerance (SI) is frequent in clinical practice, and it is usually related to the onset of muscle symptoms, which are defined under the acronym SAMS (Statin-Associated Muscle Side Effects). These side effects are responsible for statin treatment discontinuation that results in increased cardiovascular risk.

statin intolerance non-statin lipid lowering therapy LDL-C target therapeutic adherence cardiovascular risk reduction

1. Introduction

Atherosclerotic cardiovascular disease (ASCVD) is the worldwide leading cause of morbidity and mortality, and an increased low-density lipoprotein cholesterol (LDL-C) plasma level has been considered the causal factor of atherosclerosis progression ^[1]. However, mendelian randomization studies as well as randomized controlled clinical trials and systematic meta-analyses demonstrated that a low LDL-C plasma level was associated with a low cardiovascular risk that was more pronounced if an early and durable LDL-C reduction was observed ^[2].

Statin therapy is considered the first LDL-C lowering strategy able to reduce the cholesterol synthesis by inhibiting 3-hydroxy-3-methylglutaryl CoA (HMGCoA) reductase; thus, liver cholesterol depletion leads to low-density lipoprotein receptor (LDLR) upregulation on the hepatocyte surface and to an increased uptake of circulating LDL-C ^[3]. According to their solubility, statins are classified as lipophilic (simvastatin, atorvastatin, lovastatin, fluvastatin and pitavastatin) or hydrophilic (rosuvastatin and pravastatin); moreover, based on the lipid-lowering efficacy, researchers recognize low-intensity (<30% LDL-C reduction, fluvastatin 20–40 mg, lovastatin 20 mg, pravastatin 20 mg, simvastatin 10 mg), moderate-intensity (30–49% LDL-C reduction, fluvastatin XL 80 mg, lovastatin 40 mg, pravastatin 40 mg, simvastatin 20–40 mg, atorvastatin 10–20 mg, rosuvastatin 5–10 mg) or high-intensity (≥50% LDL-C reduction, atorvastatin 40–80 mg, rosuvastatin 20–40 mg) statin therapies ^[4]. Thus, in the era of personalized medicine the choice of statin dosage depends on cardiovascular risk level as well as the baseline LDL-C level to achieve the recommended LDL-C target ^[5].

Although statin therapy is generally well tolerated, side effects as well as treatment discontinuation have been reported in clinical practice ^[6]; moreover, it was shown that an impaired statin therapy adherence was associated with LDL-C off target and ASCVD risk increase ^[7].

Statin Associated Muscle Symptoms (SAMS) are the most frequent side effects causing statin discontinuation. SAMS have several causes, firstly a negative drucebo effect where damage expectation results from perceived side effects while these symptoms are probably not related to statin mechanism. It is essential to evaluate and properly identify any statin intolerance (SI, partial or complete) to manage statin intake better and choose the appropriate therapeutic strategy for LDL-C reduction. In this context, it was previously showed that non-statin lipid lowering therapies such as ezetimibe or proprotein convertase subtilisin/kexin-type 9 inhibitors (PCSK9-i) were able to reduce LDL-C and ASCVD risk ^[8]^[9]; moreover, PCSK9 RNA silencing (siRNA) as well as ATP citrate lyase inhibitor (ACLY) have recently shown a significant LDL-C decrease ^[10]^[11].

2. Definition and Clinical Manifestations of SI

Over the years, several SI definitions have been proposed to better identify this condition in clinical practice; recently, the National Lipid Association (NLA) provided an updated and accurate SI definition to ameliorate its identification and management ^[12]. According to the NLA scientific statement, SI is defined as one or more statin related adverse effect that resolves or improves after statin dosage reduction or discontinuation and can be classified as complete inability to tolerate any dose of statins or partial intolerance that is defined as the inability to tolerate the needed dosage to achieve LDL-C target. SI is considered if at least two statins have been assumed where one of them is at the lowest approved daily dosage ^[12]. Statin associated side effects (SASE) include a broad spectrum of clinical manifestations such as myalgia, myopathy, rhabdomyolysis, statin induced autoimmune myopathy, newly diagnosed diabetes, liver injury, renal injury, hemorrhagic stroke, cognitive impairment, cataract, cancer and tendon injury (Table 1).

Table 1. Side effects associated with statin intake and their frequency adapted from Grundy et al. (2019) ^[13].

Statin-Associated Side Effects (SASE)	Frequency
Statin-Associated Muscle Symptom (SAMS)
- Myalgia: feeling of weakness or symmetrical soreness in proximal muscles (normal CK)	Infrequent (1–5%) in RCTs; frequent (5–10%) in observational studies and in clinical practice
- Myopathy: unexplained muscle pain or weakness or both	Rare
- Rhabdomyolysis: Severe form of myopathy requiring hospitalization and associated with renal failure and myoglobinuria (CK > 40 ULN)	Rare
- Statin-associated autoimmune myopathy: myopathy characterized by the presence of anti-HMGCoAR antibodies and incomplete resolution of pain symptoms	Rare
New onset diabetes mellitus	It depends on population. Frequency increases in the presence of diabetes mellitus risk factors, such as BMI ≥ 30, fasting blood glucose ≥ 100, metabolic syndrome, HbA1c ≥ 6%
Hepatic injury
- Increase of transaminases 3xULN	Infrequent
- Liver failure	Rare
Central nervous system
- Cognitive deterioration	Rare
Cancer	No clear association
Kidney disease	No clear association
Cataract	No clear association
Tendon rupture	No clear association
Haemorrhagic stroke	No clear association
Interstitial lung disease	No clear association
Hypogonadism	No clear association

Abbreviations: BMI = body mass index, CK = creatine kinase, HbA1c = glycosylated hemoglobin, HMGCoAR = 3-Hydroxy-3-Methylglutaryl-CoA Reductase, RCTs = randomized controlled trials, ULN = upper limits of normal.

It is estimated that in clinical practice almost 10% of patients discontinue statins due to SASE or the fear of its development; among SASE, the most frequently observed disorder as well as the main reason for statin discontinuation is the onset of statin associated muscle symptoms (SAMS) ^[14]. SAMS include myalgia that is defined as a feeling of weakness or symmetrical soreness in proximal muscles without creatine kinase (CK) increase, myopathy that is considered an unexplained muscle pain or weakness associated with an increase in creatine kinase (CK) concentration > 10 times the upper limit of normal (ULN) and finally rhabdomyolysis that is described as a severe form of myopathy with markedly elevated CK levels (often >40 times the ULN) requiring hospitalization and associated with acute renal failure; however, these clinical conditions disappear after statin therapy discontinuation. In a low percentage of SAMS, it is reported that the statin-associated autoimmune myopathy (SAAM) is characterized by the presence of proximal muscle weakness and significantly elevated CPK levels (often >10 times the ULN) that do not improve with statin cessation; HMGCoA-reductase antibody testing is used for confirming the diagnosis. SAAM could have an early onset, but usually it appears after several years of statin therapy with an incidence of 2–3 per 100,000 patients treated with statins.

A recent meta-analysis from randomized clinical trials showed that the difference of myalgia incidence due to statins or placebo was <1% ^[15]; this finding suggests that the onset of muscle disorders during statin therapy may be at least attributable to a negative drucebo effect, where damage expectation results in perceived side effects that may not be related to the drug ^[16]. The available data on the statin related negative drucebo effect suggest adopting a statin intolerance prevention system program useful to reduce the probability of an erroneous SAMS diagnosis. To improve long term statin adherence, patients should be informed about the LDL-C lowering efficacy and the cardiovascular benefit of statin therapy; moreover, patients should be advised about the real likelihood of statin related adverse events. Furthermore, in patients with a family history of statin intolerance or a high risk of statin intolerance (for example in cases of hepatic/renal impairment, polypharmacotherapy, etc.), a suitable statin regimen should be considered to avoid side effect occurrence ^[7]. It is needed for clinicians to monitor patients after statin prescription. In this context, a frequent follow-up should be scheduled in order to evaluate the efficacy of treatment, the adherence to therapy and the onset of adverse effects. Patient participation in decision-making with the continuous education is critical to overcome the negative drucebo effect and to avoid a suboptimal lipid-lowering therapy.

As concerns the pediatric population, it was shown that the risk of statin treatment associated adverse event was lower in children than in adults. Two possible explanations may be considered. Firstly, in children a low statin dose is usually considered as starting therapy; moreover, the pediatric population has generally less frequent comorbidities that could increase drug to drug interactions and SAMS risk. Of note, the prevalence of adverse events was similar between children receiving statins or placebo. If adverse events occur, they are nonserious and reversible events and principally include the liver toxicity, SAMS, teratogenic effects and drug-to-drug interaction. Despite the reported safety and efficacy, many children with lipid disorders are not on statin therapy; in this context, it is extremely important to early identify and manage children with lipid abnormalities in order to prevent their future cardiovascular risk ^[17].

However, the prevalence of statin intolerance is higher in clinical practice than in RCTs, and it is probably due to the use of non-unique terminology of SAMS description or the lack of standardized measurements for SAMS detection. Thus, in order to determine how likely muscle symptoms are attributable to statins, the NLA Statin Muscle Safety Task Force performed the Statin-Associated Clinical Index of Muscle Symptoms (SAMS-CI) ^[18]. The SAMS-CI includes four separate items: the first regards the location and patterns of muscle symptoms, and the others focus on the timing of symptoms relative to starting, stopping (dechallenge) and rechallenging with statins.

In this context, in order to optimize the lipid lowering therapy in subjects with muscle symptoms, SAMS-CI could be useful for the detection of statin-related muscle disorders, and thus a personalized lipid lowering therapy approach could be adopted ^[19]. Several endogenous and exogenous factors have been identified to promote the onset of SAMS (Table 2).

Table 2. Endogenous and exogenous risk factors predisposing SAMS adopted from Gulizia et al. 2017 ^[20].

Endogenous Risk Factors	Exogenous Risk Factor
Elderly	Intensive physical activity
Female sex	High intensity statin therapy
Asian ethnicity	Alcohol abuse
Positive history of muscle and/or joint pain	Drug abuse
Inflammatory or metabolic neuromuscular disease - Spinobulbar muscular atrophy - Alpha 1 4 glucosidase deficiency - Carnitine palmitoyl transferase II deficiency - Dermatomyositis - Myotonic dystrophy types I and II - Malignant hyperthermia - Mcardle’s disease - Myasthenia gravis - Recurrent myoglobinuria - Mitochondrial myopathy - Necrotizing myopathy - Inclusion body myositis - Peripheral neuropathy - Polymyositis - Amyotrophic lateral sclerosis	Drug interactions - Nicotinic acid - Amiodarone - Azoles - Antipsychotic drugs - Immunosuppressive drugs (cyclosporine) - Fibrates (gemfibrozil) - Protease inhibitors - Macrolides - Nefazodone - Verapamil - Warfarin
Positive history of increased CK (especially if CK > 10 ULN)	Grapefruit or blueberry juice consumption (>1 L/day)
Positive family history of myopathy	Unregulated supplements (e.g., red yeast rice, pleurotus mushrooms, etc.).
Induced myopathy by statins or other hypolipidemic drugs	Surgical procedures
Low body mass index
Severe kidney failure (III-IV stage KDOQI)
Acute or decompensated hepatopathy
Hypertension/heart failure (secondary to kidney disease)
Untreated or undertreated hypothyroidism
Diabetes mellitus
Acute infection
Biliary obstruction
Major trauma with increased metabolic demand
Vitamin D deficiency
Genetic polymorphisms - Cytochrome P isoenzymes - Lipin-1 mutations - ABC transporter polymorphism - RYR gene variant - SLCO1B1 gene variant

Abbreviations: ABC = ATP-binding cassette, CK = creatine kinase; KDOQI = kidney disease outcome quality initiative, RYR = ryanodine receptor, SAMS = statin-associated muscle symptoms, SLCO1B1 = solute carrier organic anion transporter family member 1B1, ULN = upper limits of normal.

The endogenous factors include gender, age, ethnicity and genetic factors. Gheorghe et al. showed that women are more likely to discontinue statin treatment compared to men (10.9% vs. 6.1%) as well as to take a lower statin dose than recommended (3.6% vs. 2%); these findings could be explained by increasing fear of adverse reactions such as muscle symptoms and hepatic cytolysis. In this context, it is needed to focus on the differences of gender related statin metabolism. Women have a lower muscle mass than men, and so they might be more vulnerable to SAMS; in contrast, they have a higher percentage of fat tissue compared to men with increasing the lipophilic statin distribution volume. Finally, the CYP3A4 enzyme expression is twice higher in women than in men, and thus the SAMS risk could be increased in female subjects by enhancing CYP450 isoform interactions. Taking into consideration these findings, the gender-related statin metabolism might explain why women are more exposed to the risk of statin discontinuation and thus to an increased risk of future cardiovascular events. In this context, it is needed to optimize statin treatment in women to improve their compliance and to achieve the recommended LDL-C targets ^[21].

Moreover, the exogenous factors include alcohol or drug consumption, extreme exercise or concomitant therapies with potential drug-to-drug interactions such as protease inhibitors, azoles, macrolides or immunosuppressants ^[22]^[23]^[24].

While atorvastatin, lovastatin and simvastatin are metabolized primarily by the isoenzyme P3A4 of cytochrome P450 (CYP3A4), the isoenzyme P2C9 (CYP2C9) is responsible for metabolism of fluvastatin, pitavastatin and rosuvastatin. Moreover, pravastatin is the only statin that is not metabolized by the CYP isoenzyme family.

Atorvastatin, simvastatin and lovastatin are mainly involved in drug-to-drug interactions; in this context, cytochrome P3A4 inhibitors such as azole antifungals, immunosuppressive agents and human immune-deficiency virus (HIV) protease inhibitors can greatly increase statin plasma concentration with increasing the risk of statin intolerance. These are drugs widely used in clinical practice, and strong epidemiologic evidence has demonstrated that in autoimmune disorders or in case of HIV infection there is a premature, rapidly processing atherosclerosis development, followed by cardiovascular (CV) complications ^[25]. Moreover, bleeding or prolonged prothrombin time has been reported in patients taking statins metabolized by CYP3A4 concomitantly treated with warfarin ^[26]. In this context, the discontinuation of statin treatment due to drug-to-drug interactions might be associated with an increased risk of CV diseases and all-cause mortality.

The assessment and the correction of modifiable risk factors could reduce the adverse effects of statin therapy.

As concerns glucose homeostasis, the absolute risk of statin-related newly diagnosed diabetes mellitus is about 0.2% per year, although this percentage depends on the population risk, and it could be greater in patients with a family history of diabetes mellitus as well as subjects with pre-diabetes or insulin resistance ^[15].

As regards liver injury, while severe liver toxicity is rare (0.001%), an increase of transaminases > 3 times the ULN is common, but it is usually transient and not associated with hepatopathy; however, this alteration is usually managed by stopping statins and rechecking transaminases after 4–6 weeks ^[26].

Finally, there is no evidence of a causal relationship between statin use and risks of hemorrhagic stroke, cognitive impairment, cataract or cancer ^[27].

3. Statin Intolerance and Cardiovascular Events

While the lipid-lowering effects of statins typically occur within 4 weeks of initiating therapy, the treatment-related cardiovascular benefits are usually observed after at least 2–5 years of continuous therapy ^[28].

Depending on statin doses, it was shown that LDL-C as well as triglycerides (TG) were reduced by 20–60% and 10–30%, respectively ^[29]; moreover, a meta-analysis of randomized clinical trials showed that an LDL-C decrease of 1 mmol/L (39 mg/dL) was associated with 10%, 23% and 17% reductions of all cause-mortality, coronary events and ischemic stroke, respectively ^[30]. On the other hand, Sandoval et al. showed that a poor adherence or discontinuation of statin therapy were linked to increased cardiovascular disease, cerebrovascular events or mortality ^[28].

Finally, Serban et al. found that the cumulative incidence of recurrent myocardial infarction was higher among patients with statin intolerance compared to high adherence statin subjects ^[31].

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Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Giosiana Bosco

Francesco Di Giacomo Barbagallo

Salvatore Spampinato

Lorena Lanzafame

Antonino Di Pino

Salvatore Piro

Francesco Purrello

Roberto Scicali

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Update Date: 17 Apr 2023

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1. Introduction

2. Definition and Clinical Manifestations of SI

3. Statin Intolerance and Cardiovascular Events

References