Genetics of Vascular Pathologies

### **Chapter 4**

## Familial Hypercholesterolemia: Three "under" (Understood, Underdiagnosed, and Undertreated) Disease

*Vladimir O. Konstantinov*

### **Abstract**

Familial hypercholesterolemia (FH) is one of the most prevalent genetic disorders leading to premature atherosclerosis and coronary heart disease. The main cause of FH is a mutation in the LDL-receptor gene that leads to loss of function of these receptors causing high levels of blood cholesterol. The diagnosis of FH is not very easy. Wide screenings are needed to reveal high levels of LDL cholesterol among "healthy" population. If the patient has MI or stroke at an early age, high levels of LDL cholesterol, and tendon xanthomas, the diagnosis of FH becomes much more clear. Genetic testing is a gold standard in the diagnosis of FH. There are several factors, influencing the time course of FH. Smoking males with low levels of HDL cholesterol have an extremely higher risk of death than nonsmoking females with high HDL cholesterol. Management of FH includes low cholesterol diet, statin and ezetimibe treatment, PCSK inhibitors, and LDL aphaeresis. Early and effective treatment influences much the prognosis in FH patients.

**Keywords:** prevalence of familial hypercholesterolemia (FH), diagnosis of FH, the time course of FH, treatment of FH

### **1. Introduction**

Familial hypercholesterolemia (FH) is one of the most frequent inherited disorders caused mainly by a mutation of the gene encoding the low density lipoprotein receptor (LDLR). High concentrations of LDL result in uptake of LDL by extracellular matrix, including that of the arterial wall leading to premature atherosclerosis and coronary artery disease (CAD). CAD develops early with symptoms often manifesting in men in the fourth or fifth decade and women about 10 years later. Approximately 5% of all cases of premature myocardial infarction (MI) occur in patients with heterozygous FH [1, 2]. Before the development of statin therapy, at least 50% of FH male patients experienced MI by the age of 60. In homozygotes, symptomatic CAD can occur in childhood, and very few survive past the age of 30.

Brown and Goldstein are indisputably the fathers of FH. In 1972, they attributed the disorder to defective HMG-CoA reductase [3]. But, a year later they recognized that the main cause of the disease was the mutation in the LDLR gene [4]. The extremely rare homozygote with FH has two mutant alleles at the LDLR locus,

leaving a person with an absolute or nearly absolute inability to clear LDL from circulation [1]. Brown and Goldstein initially described homozygous FH (HoFH) as a condition in which an individual inherits a single and same mutation in the LDLR from each parent. Now we recognize this condition as "simple HoFH" [5]. Actually, this is a very rare event. Far more frequently, HoFH is a result of inheritance of two different pathogenic mutations in the same gene that is referred to as a "compound heterozygote." Another type of HoFH is when an individual inherits a mutation of one gene (e.g., LDLR) from one of the parents and different gene (e.g., *apoB* or *PCSK9*) from another. This type of HoFH is a "double heterozygote." It is important to know that the term "heterozygote" is used here to describe homozygote patients.

Heterozygotes with FH possess one normal allele, giving them approximately one half of the normal receptor activity. Actually, LDLR also contributes to the clearance of VLDL remnants from the plasma, so a deficiency of LDLR may lead to some accumulation of remnant lipoproteins as well.

Additionally, mutations of other genes such as *apoB*, *PCSK9*, and so on are now recognized to also cause FH [6–8].

The prevalence of heterozygous FH (HeFH) is about 1/200 [9] and HoFH— 1/160,000 [10, 11]. Therefore, HeFH is a very frequent disorder, and it is more common than type 1 diabetes mellitus. Unfortunately, the diagnosis of FH is often unrecognized, leaving such individuals and members of their families undertreated and of greater risk of consequences of lifelong LDL-C elevations. Nevertheless, the prevalence of FH may differ greatly in different populations. For example, in French Canadians, South African Afrikaners, Ashkenazi Jews, or Christian Lebanese, which are the so-called founder populations, the prevalence of FH can be as high as 1/67 [12, 13]. So, it is important to "know your audience" and be on the lookout for such individuals in daily clinical practice.

### **2. Discussion**

The diagnosis of FH is simple and complicated at the same time. First of all patients with FH should have a very high LDL (>95% for age/gender matched controls) with typically normal TG and HDL. For patients with HoFH, LDL is >500 mg/dl (13 mmol/l) when untreated and >300 mg/dl (7.7 mmol/l)—on lipid-lowering therapy (LLT) [14–16]. The cut point for HeFH in adult had similarly been >190 mg/dl (5 mmol/l). Recent genotyping studies showed great difference in LDL levels among FH patients. To date, the lowest LDL level in untreated FH patient was 170 mg/dl (4.4 mmol/l) [9]. Still, there is no question that the higher the LDL-C, the more aggressive the vascular disease.

The second thing is that patients should have a family history of premature atherosclerotic cardiovascular disease (ASCVD), very high cholesterol, or both. Premature ASCVD in a patient is often a clue to FH. In fact, 20% of all myocardial infarctions (MI) in people under the age of 45 are a consequence of FH [17, 18].

The third thing is that the expected response to lipid-lowering therapy is often blunted in FH patients, and their LDL levels are falling less robustly than would normally be anticipated. This occurs because standard medications such as statins and ezetimibe are concentrated on LDLR upregulation. As these receptors by definition defective, their upregulation is less effective at internalizing LDL from plasma.

Physical signs of FH depend greatly on type of the mutation, age, gender, and other factors.

This is an example of one of our FH patient, a 26-year-old woman, who had tendon xanthomas at the age of 1. She have been examined in different clinics (mainly, dermatological), but the diagnosis of FH was suspected only at the age *Familial Hypercholesterolemia: Three "under" (Understood, Underdiagnosed, and Undertreated… DOI: http://dx.doi.org/10.5772/intechopen.93042*

of 10 when concentration of total cholesterol was measured (total cholesterol level = 21 mmol/l) (**Figure 1**).

Unfortunately, LLT (statins, ezetimibe, and LDL-apheresis) has been started in this patient only at the age of 19. She represents positive stress-echo test, and coronary angiography reveals 50% stenosis of the right coronary artery. A 50% stenosis of both common carotid arteries according to an ultrasound was also revealed. At present time, this patient receives 80 mg of atorvastatin, 10 mg of ezetimibe, and LDL-apheresis procedures (each 2 weeks). She also takes part in a randomized placebo-controlled international clinical study on a new *PCSK9* inhibitor—Inclisiran.

You can see a pedigree of this patient in **Figure 2**. It is seen that the index patient (marked with red arrow) with very high cholesterol level has two still young

### **Figure 1.**

*Corneal arcus (both the eyes) and tendon xanthomas (hands, Achilles tendon, elbow, and knee) in a 26-yearold woman with FH.*

**Figure 2.** *Pedigree of a 26-year-old female (23 at entry).*

parents without clinical signs of ASCVD, but having high total cholesterol levels (9.5–12.2 mmol/l). Parents of proband are divorced, and both of them have new families. The father's daughter from the second marriage who is 11 years of age has also high cholesterol level (8.5 mmol/l). It is seen that the grandfather of the proband died at the age of 54 of acute myocardial infarction (MI).

This patient has undoubtedly homozygous FH phenotype due to a very high cholesterol level, premature atherosclerosis, tendon xanthomas, family history of hypercholesterolemia, and premature ASCVD. Nevertheless, it was interesting to perform genetic testing in this family.

This test was performed in Health-In-Code genetic laboratory (Spain) using Next Generation Sequencing (NGS). Patient specimen (blood) was subjected to automated genomic DNA purification (QIAsymphony SP®, Qiagen). Library preparation was carried out using the Agilent SureSelect library preparation kit for Illumina paired-end multiplexed sequencing according to the manufacturer's instructions. Enrichment of regions of interest was performed using a SureSelect probe kit (Agilent) that selectively captures the coding regions and adjacent intronic areas of the selected genes. After cluster generation, captured DNA was sequenced on the Illumina HiSeq 1500 platform. Sequencing data analysis was done using a proprietary bioinformatics pipeline that includes sample demultiplexing as well as all the steps necessary to obtain a report of annotated variants together with their coverage and corresponding quality parameters.

The design of the custom capture library includes the following six genes related to familial hypercholesterolemia: *APOB, APOE, LDLR, LDLRAP1, PCSK9*, and *SLCO1B1.*

The genes included in this test have been selected on a clinical basis according to their relation to a particular phenotype and classified on the basis of evidence supporting this association into priority, secondary, and candidate genes.

Probes were designed to adequately cover all coding exons and 10 base pairs (bp) of flanking intronic sequences; therefore, this test is unable to identify genetic variants located in intronic zones far from splice sites or UTR regions.

**Analysis of SNVs and INDELs:** This test can identify single-nucleotide variants (SNVs) and insertions/deletions (INDELs) of up to 20 bp. Genetic variants are reported following the Human Genome Variation Society (HGVS) recommendations (www.hgvs.org).

Genetic variants that are selected because of their potential association with the patient's phenotype or constitute relevant incidental findings are reported in the main table of the report on the first page. Please note that a variant's pathogenicity may be subject to change as new scientific evidence appears.

**Confirmation studies:** Variants included in the main table meeting the conditions below are confirmed by orthogonal testing:


Similarly, low-coverage regions in priority genes that may be of clinical interest are resequenced by the Sanger method.

**Analysis of CNVs:** Health-In-Code has developed an alternative bioinformatics pipeline that is also able to identify gross insertions/deletions affecting one or more exons of a gene/s included in the panel (CNVs: copy number variations). This complementary analysis is possible when bioinformatics data are adequate (evaluable CNVs) and may not be available in all studies (nonevaluable CNVs).

**CNV confirmation studies:** Variants identified using this technique will be confirmed by an adequate alternative method.

**Analytical specifications of the test:** Both analytical sensitivity and specificity of this test are greater than 99% for single-nucleotide variants (SNVs) and insertions/deletions (INDELs) of ≤20 bp.

Average coverage values of the tested gene/s and other quality parameters specific to this patient's study are detailed in each study report.

**Technical limitations that can be in any study report:** Despite the high sensitivity and specificity of this test, some genotyping errors may occur in specific situations:


This study is usually not able to identify the phase (same/different alleles) of more than one variant affecting the same gene. This limitation should be considered in cases of recessive disorders, which occur only when both alleles are mutated.

**Unequivocal traceability:** Health-In-Code developed in-house software NextLIMS that efficiently identifies and tracks samples in the laboratory and allows to unequivocally trace the steps a sample has already gone through.

As you can see in **Figure 3**, two different mutations in the LDLR gene were revealed. First mutation (Val806Glyfs\*11) has been previously described and was also found in the mother of proband. Second mutation (Asp569Val) was a new one


### **Figure 3.**

*Results of genetic testing in a 26-year-old female, performed in Health-In-Code genetic laboratory (Spain).*

(never described in the literature previously). The same mutation was found in a father's daughter from the second marriage. Therefore, in case that each variant affects a different copy of the gene (we call this condition as compound heterozygote), the expected phenotype is homozygous familial hypercholesterolemia.

This clinical case shows difficulties in the diagnosis of FH despite of the presence of obvious facts that actually led to the late onset of LLT and marked atherosclerotic lesions of coronary and carotid arteries in a young patient.

Another patient is a female, 42 years of age with high total cholesterol level (11–12 mmol/l) known for 10 years with no signs of ASCVD. Stress test is negative, intima-media thickness of carotid arteries is 0.8 mm, and no tendon xanthomas or corneal arcus.

It is seen that the father of the proband died at the age of 56 of MI, her aunt at the age of 69 has high cholesterol and angina pectoris, and her cousin at the age of 45 has high cholesterol and underwent CABG (**Figures 4** and **5**).

This clinical case is an example of mutation of *apoB* gene that also leads to hypercholesterolemia. Familial ligand defective apolipoprotein B (FDB) was first described in 1986 by Vega and Grundy [19]. In lipoprotein kinetic studies, it was observed that LDL from some donors was cleared more slowly from circulation in individuals with normal LDL receptor function. Genomic DNA analysis revealed a point mutation in Apo B: CGG-to-CAG mutation at the codon for amino acid 3500 resulting in an arginine to glutamine substitution. The prevalence of this disorder is unknown but is estimated to be 5–10% that seen in FH. Hypercholesterolemia in FDB is usually less severe than in FH. Patients with FDB do respond to statin drug therapy, probably reflecting increased removal of Apo E-containing remnant particles through upregulated hepatic LDL receptors. Our patient was treated with rosuvastatin 40 mg/day + ezetimibe 10 mg/day. Her total cholesterol is 4.9 mmol/l; LDL cholesterol is 2.3 mmol/l; HDL cholesterol is 1.8 mmol/l; and TG is 1.6 mmol/l. *Familial Hypercholesterolemia: Three "under" (Understood, Underdiagnosed, and Undertreated… DOI: http://dx.doi.org/10.5772/intechopen.93042*

### **Figure 4.**

*Pedigree of a 42-year-old woman with high cholesterol level.*


### **Figure 5.**

*Results of genetic testing in a 42-year-old woman with high cholesterol level.*

Physical signs of FH can occur but not needed for the diagnosis. Extensor tendon xanthomas, typically affecting the Achilles or the hands, could appear at the age of 20 and may be present in 70% of older patients. Because xanthomas are subtle, careful examination of the dorsal hand tendons and Achilles tendon is required for their detection. Thus, it is important to always examine the Achilles tendon when performing physical exam. Xanthelasma (cutaneous xanthomas on the palpebra) is common in patients with FH after the age of 30; however, it is not specific for FH. With regard to corneal arcus, it does not have to be circumferential. In fact, it often starts in the superior and inferior aspects of the cornea where the blood supply is greatest. Also, a corneal arcus in someone under 45 years of age is pathognomic for FH [20]. It is important to recognize that because of the prevalent use of lipid-lowering therapy xanthomas, and other clinical signs of FH are uncommon findings nowadays.

Although most FH specialists diagnose FH on clinical grounds, three systems are also available: Make Early Diagnosis to Prevent Early Death (MEDPED), the Dutch Lipid Clinic Network (DLCN), and Simon Broom. Each has its own pros and cons, and none is essential to make the diagnosis. Nevertheless, it is useful to utilize them in clinical practice.

As it is clear from **Table 1**, if a patient has LDL-C level ≥8.5 mmol/l and premature coronary artery or cerebral artery disease, he/she already has more than eight points that means definite FH. It is important to know that if a person has positive results of genetic testing, he/she has only eight points and it is not enough to make a diagnose of definite FH.

Once the diagnosis of FH has been made, he/she is dubbed the proband or the index case. As FH is an autosomal dominant disorder, and early diagnosis and treatment dramatically reduce the risk of future ASCVD events, it is important for physicians to identify other members of the family. Screening relatives of the proband is called "cascade screening."

There are two methods of cascade screening, active and passive. Passive screening employs the index case as the messenger to inform the other family members and recommend further testing. Passive screening is usually not very successful. In contradistinction, active cascade screening—a system in which clinicians rather than patients seek out affected family members—is extraordinarily effective.


*\* Premature = <55 years in men; <60 years in women.*

*LDL-C, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor;* apoB*, apolipoprotein B;*  PCSK9*, proprotein convertase subtilisin/kexin type 9.*

### **Table 1.**

*Dutch Lipid Clinic Network Score for FH [21–23].*

### *Familial Hypercholesterolemia: Three "under" (Understood, Underdiagnosed, and Undertreated… DOI: http://dx.doi.org/10.5772/intechopen.93042*

It was successfully performed in the Netherlands. This active cascade screening system sets the bar for the world, identifying nearly 75% of the Netherland's FH population and adding eight additional FH patients for every single-index case identified [9].

The time course of FH depends on a lot of genetic and environmental factors. Previously, we have identified mutations of the LDLR gene in 45 families in St. Petersburg [24]. Our aim was to follow the development of dyslipidemia in children of probands with verified mutations of the LDLR gene as these children were growing up, to compare severity of atherosclerotic complications in patients with different LDLR gene mutations, and to compare atherosclerotic disease progress in males and females with FH. We were following probands with FH and their available relatives with LDLR gene mutations, including children, during 10 years. In all patients, total blood plasma cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol were monitored, and clinical manifestations of ASCVD were documented.

As it is seen in **Table 2**, there were 26 original mutations of the LDLR gene, and 7 were not original but revealed in different families. Due to high heterogeneity of FH-causing mutation in St. Petersburg, we failed to establish interrelations between type of LDLR gene mutation and severity of atherosclerosis manifestation. As a rule, complications of coronary artery disease (CAD) were found less commonly and tend to be less severe in females rather than in males (**Table 3**).

As you can see in **Table 3**, CAD was revealed in three-fourth of males with LDLR gene mutations and only in half of females. Thus, mean age of healthy persons was 34 ± 3.1 years in males and 41 ± 2.6 years in females. Mean age of patients with CAD clinical manifestations was 45 ± 1.9 and 53 ± 2.9, respectively. Otherwise, males suffer from atherosclerotic complications more frequently and much earlier than females. Apparently, females are defended of ASCVD anyway in cases of FH. Some authors explain this by protective function of estrogens. Not infrequently, this protection still remains in the menopause period. To our mind, this protective effect could be explained by the level of HDL cholesterol. Thus, we followed up a mother and her two daughters with genetically verified diagnosis of FH. Mother and her younger daughter had severe clinical manifestations of CAD, while older daughter had no clinical manifestations of ASCVD and did not take LLT. LDL levels did not differ


### **Table 2.**

*Number of probands and their relatives with LDLR gene mutations.*


### **Table 3.**

*Number of males and females with the LDLR gene mutations, their age, and the presence of coronary heart disease.*


### **Table 4.**

*LDL/HDL ratio in the three groups of patients with LDLR gene mutations.*

greatly in the members of this family (326 mg/dl—mother, 322 mg/dl—younger daughter (24-year-old), 277 mg/dl—older daughter (30-year-old)), while HDL-C was 44 mg/dl and 49 mg/dl in the first two woman and 65 mg/dl—in the third.

We divided patients with LDLR gene mutations into three groups (**Table 4**). 1 with progressive CAD, 2 with stable disease, 3 without clinical manifestation of CAD and measured LDL/HDL ratio.

It is seen that high level of HDL is the only one proved lipid factor preventing atherosclerosis development in patients with genetically verified familial hypercholesterolemia.

### **3. Conclusion**

Management of FH must always begin with therapeutic lifestyle changes (TLC); therefore, TLC is the foundation of all ASCVD prevention [25]. A healthful diet limited in saturated fats and simple sugars, daily aerobic exercise, avoidance of tobacco and alcohol, maintenance of an optimal blood pressure and weight, and reduction of stress are all important. The mainstay of therapy in FH is to lower the LDL-C as much and as soon as possible. One must remember that all patients with FH are considered high cardiovascular risk, and for this reason, formal risk stratification with Framingham or Score systems is never advised when guiding treatment. According to the European Guidelines, the goal of lipid-lowering therapy is <1.4 mmol/l if the patient has CAD, diabetes mellitus or >50% stenosis of carotid or peripheral arteries, and <1.8 mmol/l—without clinical manifestations of ASCVD [26]. It is recommended in adult patients to use high intensive statin therapy (atorvastatin 80 mg or rosuvastatin 40 mg). In cases where the goal is not achieved on statin therapy, it is recommended to add ezetimibe 10 mg. If the goal is not achieved, you should think about adding *PCSK9* inhibitors (alirocumab 75/150 mg each 2 weeks, evolocumab 140 mg each 2 weeks or 420 mg once a month).

Drug therapy in children with FH should be started at the age of 8–10 years. The LDL-C goal is <4.0 mmol/l (8–10 years) and <3.5 mmol/l (10 years and more). Treatment should be started with statins. In case of homozygous FH when LDL-C levels are more than 13 mmol/l and ASCVD appears in childhood, the treatment should be started from a maximal doses of statins with the addition of ezetimibe and evolocumab (in children >12 years). In severe cases of HoFH, extracorporeal methods of treatment (LDL apheresis, HELP, etc.) are recommended.

Despite of the fact that pathogenesis and clinical manifestations of FH are well understood, this disease still remains underdiagnosed and undertreated. All FH patients are to be considered high risk. Some, however, are unfortunately even higher risk than rest. It depends on age, gender, or some biochemical and environmental risk and antirisk factors. Early diagnosis and management of FH can significantly improve lifespan and quality of life in these patients.

*Familial Hypercholesterolemia: Three "under" (Understood, Underdiagnosed, and Undertreated… DOI: http://dx.doi.org/10.5772/intechopen.93042*

### **Author details**

Vladimir O. Konstantinov Department of Internal Medicine and Cardiology, Metchnikov North-West State Medical University, Saint-Petersburg, Russian Federation

\*Address all correspondence to: atherosclerosis@mail.ru

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, et al., editors. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill; 2001. pp. 2863-2913

[2] Bredie SJ, Kiemeney LA, de Haan AF, et al. Inherited susceptibility determines the distribution of dense low-density lipoprotein subfraction profiles in familial combined hyperlipidemia. American Journal of Human Genetics. 1996;**58**:812-822

[3] Goldstein JL, Brown MS. Familial hypercholesterolemia: Identification of a defect in the regulation of 3-hydroxy-3methylglutaril coenzyme A reductase activity associated with overproduction of cholesterol. Proceedings of the National Academy of Sciences of the United States of America. 1973;**70**(10):2804-2808

[4] Brown MS, Goldstein GL. Familial hypercholesterolemia: Defective binding of lipoproteins to cultured fibroblasts associated with impaired regulation of 3-hydroxy-3-methylglutaril coenzyme A reductase activity. Proceedings of the National Academy of Sciences of the United States of America. 1974;**71**(3):788-792

[5] Cuchel M et al. Homozygous familial hypercholesterolemia: New insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolemia of the European Atherosclerosis Society. European Heart Journal. 2014;**35**(32):2146-2157

[6] Boren J et al. The molecular mechanism for the genetic disorder familial defective apolipoprotein B100. The Journal of Biological Chemistry. 2001;**276**(12):9214-9218

[7] Whitfield AJ et al. Lipid disorders and mutations in the APOB gene. Clinical Chemistry. 2004;**50**(10):1725-1732

[8] Horton JD, Cohen JC, Hobbs HH. Molecular biology of PCSK9: Its role in LDL metabolism. Trends in Biochemical Sciences. 2007;**32**(2):71-77

[9] Sjouke B et al. Homozygous autosomal dominant hypercholesterolemia in the Netherlands: Prevalence, genotypephenotype relationship, and clinical outcome. European Heart Journal. 2015;**36**(9):560-565

[10] Vishwanath R, Hemphill LC. Familial hypercholesterolemia and estimation of US patients eligible for low-density lipoprotein apheresis after maximally tolerated lipid-lowering therapy. Journal of Clinical Lipidology. 2014;**8**(1):18-28

[11] Walzer S et al. Homozygous familial hypercholesterolemia (HoFH) in Germany: An epidemiological survey. Clinicoecon Outcomes Research. 2013;**5**:189-192

[12] Seftel HC et al. Prevalence of familial hypercholesterolemia in Johannesburg Jews. American Journal of Medical Genetics. 1989;**34**(4):545-547

[13] Zakharova FM, Damgaard D, Mandelshtam MY, Golubkov VI, et al. Familial hypercholesterolemia in St-Petersburg: The known and novel mutations found in the low-density lipoprotein receptor gene in Russia. BMC Medical Genetics. 2005;**8**:6-6

[14] Marais AD et al. A dosetitration and comparative study of rosuvastatin and atorvastatin in patients with homozygous familial hypercholesterolemia. Atherosclerosis. 2008;**197**(1):400-406

[15] Raal FJ, Santos RD. Homozygous familial hypercholesterolemia:

*Familial Hypercholesterolemia: Three "under" (Understood, Underdiagnosed, and Undertreated… DOI: http://dx.doi.org/10.5772/intechopen.93042*

Current perspectives on diagnosis and treatment. Atherosclerosis. 2012;**223**(2):262-268

[16] Kolansky DM et al. Longitudinal evaluation and assessment of cardiovascular disease in patients with homozygous familial hypercholesterolemia. The American Journal of Cardiology. 2008;**102**(11):1438-1443

[17] Goldstein JL et al. Hyperlipidemia and coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. The Journal of Clinical Investigation. 1973;**52**(7):1544-1568

[18] Neefjes LA et al. Accelerated subclinical coronary atherosclerosis in patients with familial hypercholesterolemia. Atherosclerosis. 2011;**219**(2):721-727

[19] Vega GL, Grundy SM. In vivo evidence for reduced binding of low density lipoproteins to receptors as a cause of primary moderate hypercholesterolemia. The Journal of Clinical Investigation. 1986;**78**:1410-1414

[20] Zech LA, Hoeg GM. Correlating corneal arcus with atherosclerosis in familial hypercholesterolemia. Lipids in Health and Disease. 2008;**7**:7

[21] Austin MA, Hutter CM, Zimmern RL, Humphries SE. Genetic causes of monogenic heterozygous familial hypercholesterolemia: A HuGE prevalence review. American Journal of Epidemiology. 2004;**160**:407-420

[22] Haase A, Goldberg AC. Identification of people with heterozygous familial hypercholesterolemia. Current Opinion in Lipidology. 2012;**23**:282-289

[23] Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial

hypercholesterolemia is underdiagnosed and undertreated in the general population: Guidance for clinicians to prevent coronary heart disease: Consensus statement of the European Atherosclerosis Society. European Heart Journal. 2013;**34**:3478-3490a

[24] Lipovetsky BM, Mandelshtam MY, Konstantinov VO. Clinico-genetical peculiarities of probands with familial hypercholesterolemia and members of their families, observed during 10 years and more. Atherosclerosis and Dyslipidemias. 2015;**1**:41-46. Russian

[25] Eckel RH et al. AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology. 2013, 2014;**63**(25PtB):2960-2984

[26] Mach F, Baigent C, Catapano AL, et al. ESC/EAS Guidelines for the management of dyslipidemias: Lipid modification to reduce cardiovascular risk. European Heart Journal. 2020;**41**(1):111-188

Section 3

## A Therapeutic Approach to Vascular Pathologies

## **Chapter 5** Statin Therapy in Children

*Bhuvana Sunil and Ambika Pallikunnath Ashraf*

### **Abstract**

Landmark studies such as the Bogalusa Heart study, Pathobiological Determinants of Atherosclerosis in Youth study, and Muscatine and Young Finns studies established that the atherosclerotic process begins in childhood. Early precursors of atherosclerosis may increase risk of cardiovascular morbidity in adulthood. Followup studies of children with familial homozygous hypercholesterolemia showed that initiation of statin therapy slowed the progression of carotid intima-media thickness and reduced cardiovascular disease risk. Despite the growing evidence on the efficacy of statins and a rising prevalence of dyslipidemia, there are concerns regarding long-term safety and efficacy. Moreover, data on statin use in children with secondary dyslipidemia are sparse. This chapter provides a comprehensive review of the current state of literature on the indications, contraindications, efficacy and safety data on the use of statins in pediatric dyslipidemia.

**Keywords:** pediatric dyslipidemia, HMG Co-A reductase inhibitors, low-density lipoprotein cholesterol, cardiovascular risk factors

### **1. Introduction**

Cardiovascular disease (CVD) is the leading cause of mortality in the United States [1]. Atherosclerosis, a silent precursor of CVD has its origins from early in childhood [2, 3]. Some dyslipidemias such as familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCH) are highly prevalent clinically silent disorders. Elevated lipid levels in childhood track well into adulthood [4]. In 2011, the National Heart, Lung, and Blood Institute (NHLBI) convened an expert panel on Cardiovascular Health and Risk Reduction in Children and Adolescents, which recommended for universal lipid screening in the pediatric population [5]. The universal lipid screening leads to identification of a large number of children with previously unrecognized dyslipidemia. Statins are one of the most potent classes of lipid lowering medications for CV risk reduction. This chapter describes the current screening and management guidelines, efficacy and adverse effects of statin therapy in pediatric dyslipidemia.

### **1.1 Mechanism of action of statins**

The primary mechanism of action of statins is inhibition of the enzyme-3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This is a ratelimiting step in the biosynthesis of cholesterol. Reduced intrahepatic cholesterol leads to decreased VLDL assembly. The hepatocyte cholesterol depletion leads to upregulation of sterol regulatory binding element proteins (SREBPs), the nuclear transcription factors that regulate LDL receptors (LDL-R). Upregulation of LDL-R on the surface of the hepatocyte in turn results in increased uptake and degradation of low-density lipoprotein cholesterol (LDL) [6]. They reduce the secretion of apoB, which affects the rate at which HMG CoA reductase is available to synthesize cholesterol again [7].

Statins induce inhibition of the Rho-signaling pathway, activate peroxisome proliferator-activated receptor alpha (PPARα) and improve HDL levels by increased production of apoA-I, the major apolipoprotein of HDL [8, 9]. Decrease in isoprenylation of signaling molecules, such as Ras, Rho, and Rac, leads to the modulation of various signaling pathways. By inhibiting mevalonic acid synthesis, statins prevent the synthesis of isoprenoid intermediates farnesyl pyrophosphate and geranyl geranylpyrophosphate [10]. It has been long established that a proinflammatory environment is necessary for plaque progression and advancement of atherosclerosis, and these intermediates are known to have a pro-inflammatory effect. Statins can inhibit posttranslational modification of Ras and Rho, which regulate cell proliferation, differentiation, apoptosis, and the cytoskeletal modifications [11]. Statins have also been proposed to be beneficial to prevent progression of atherosclerosis by their pleiotropic effect [12]. Experimental models have suggested reduction in T-cell clustering with the use of statins, thereby proposing an immunomodulatory effect [13].

### **1.2 Risk factors and medical conditions**

**Table 1** lists the medical risk factors and conditions to be considered while screening for dyslipidemia as defined by the Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. The terminology from this table will be used throughout the chapter.

### **1.3 Current screening recommendations for pediatric dyslipidemia**

Although the atherosclerotic process begins in childhood, most pediatric lipid disorders do not have any obvious clinical manifestations [2, 3]. Screening based on family history alone can miss up to 30–60% dyslipidemias [5, 14]. In higher risk

**Positive family history**: parent, grandparent, aunt, uncle, sibling with any of these before the age 55 Y in a male or 65 Y in a female: myocardial infarction, stroke, angina, coronary artery bypass, stent, angioplasty, sudden cardiac death, parent with total cholesterol >240 mg/dL


*Abbreviations: BP, blood pressure; BMI, body mass index.*

*Adapted from Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents, National Heart, Lung, and Blood Institute 2011.*

### **Table 1.**

*Cardiovascular risk factors and high-risk medical conditions.*

### *Statin Therapy in Children DOI: http://dx.doi.org/10.5772/intechopen.91367*

adult patients, especially those with disorders such as FH, statin therapy has been retrospectively associated with reducing risk of major cardiovascular events [15]. In the absence of clear history or physical examination findings, recognition of children with lipid disorders needs universal screening. The United States NHLBI, the American Academy of Pediatrics and the American Heart Association have all endorsed selective risk based screening and universal screening [5, 16, 17]. International Organizations such as the European Atherosclerosis Society recommend selective and cascade screening [18]. In contrast, the United States Preventive Services Task Force (USPSTF) concluded that current evidence is insufficient to assess the benefits or harms of screening for lipid disorders in children and adolescents, even though it acknowledges the importance of early identification of dyslipidemias [19]. For many CV risk factors like dyslipidemia, hypertension, and obesity, it is difficult to conduct large, long-term studies because of the time, cost and expected difficulties in study adherence. Recently, relatively long term follow up studies indicated that the initiation of statin therapy during childhood in patients with FH slowed the progression of carotid intima-media thickness and reduced the risk of cardiovascular disease in adulthood [20].

Screening can be performed either with a fasting or non-fasting serum lipid profile. The triglyceride (TG) levels are the most affected component of the lipid profile by non-fasting status. The LDL and non-HDL (TC-HDL) are mostly unaffected by the non-fasting status and can therefore be used for screening purposes [21, 22]. Cholesterol and LDL tend to increase until 2 years and plateau until adolescence. A 10–20% reduction of TC and LDL occurs in both normal children as well as children with genetic dyslipidemias during puberty, and can result in false negatives during this time [23]. Therefore, it is important to universally screen for lipid disorders between ages 9–11 Y and repeat between ages 17–19 Y. **Table 2** depicts lipid values very by age, according National Cholesterol Education Program (NCEP) Expert Panel on Cholesterol Levels in Children.

Up to 12 months, no routine screening of lipid profiles is recommended in infancy. Between 2 and 8 Y and 12 and 16 Y, a fasting lipid profile (FLP) is recommended if there is a positive family history, if the child has a moderate or high-risk medical condition or a high risk factor. Between 9 and 11 Y and 17 and 21 Y, universal screening is recommended. If on a non-fasting sample, the non-HDL ≥ 145 mg/dL or HDL < 40 mg/dL, it is recommended to repeat an FLP twice within 2 weeks to 3 months and average the results. Values to address on the FLP


*Abbreviations: TC, total cholesterol; LDL, low-density lipoprotein cholesterol; HDL, high-density lipoprotein cholesterol; TG, triglyceride.*

*Values from the National Cholesterol Education Program [24]. All fasting values in mg/dL. To convert to SI units, divide total cholesterol, LDL, HDL, and non-HDL by 38.6, and for TG, divide by 88.6. High and borderline-high values are indicative of approximately the 95th and 75th percentiles for age.*

### **Table 2.** *Lipid values by age.*

after averaging the results include LDL ≥ 130 mg/dL, non-HDL ≥ 145 mg/dL, HDL < 40 mg/dL, TG ≥ 100 mg/dL if <10 years; ≥ 130 mg/dL if ≥10 years [5].

### **1.4 Diagnostic considerations in pediatric dyslipidemia**

Dyslipidemia could be primary or secondary. Primary lipid disorders include monogenic conditions like FH or familial hypertriglyceridemia. Some genetic dyslipidemias like FCH do not have a recognized genetic defect yet, and have variable degrees of dyslipidemia and varying patterns of increase of TG and LDL within the same family. Obesity can exacerbate the expression of dyslipidemia in children with this underlying genotype. Lipid disorders could also be secondary to the underlying untreated medical conditions. Some considerations include diabetes mellitus, hypothyroidism, hypercortisolism, metabolic syndrome, growth hormone deficiency, pregnancy, drug and medication use, acute and chronic hepatitis, nephrotic syndrome, chronic kidney disease etc. [25–31].

After ruling out secondary dyslipidemias, primary dyslipidemias are to be considered. Primary lipid disorders can be broadly categorized by the predominantly affected component of the lipid profile. **Table 3** depicts patterns of inheritance, predominant affected lipoprotein and prevalence in the more commonly encountered primary dyslipidemias. Of these conditions, the most prevalent conditions are heterozygous FH (HeFH 1:300) and FCH (1:100).

### **1.5 Lifestyle management of dyslipidemia**

Dietary management and lifestyle changes are the cornerstone of therapy for many secondary dyslipidemias. A registered dietitian nutritionist is central to implementing lifestyle changes, trained to assess the child's nutritional status and make practical modifications to facilitate behavioral changes. In children and adolescents with obesity, moderate, gradual weight reduction has been shown to improve dyslipidemia and decrease insulin resistance.

The NCEP has proposed a stepwise dietary regulation for children with elevated LDL levels. For all children more than 1 year of age and older, the Cardiovascular Health Integrated Lifestyle Diet (CHILD)-1 diet is the first step (Step 1 diet); this constitutes total fat (25–30% of total daily calories), saturated fat (8–10% of daily kcal/estimated energy requirements), avoiding trans-fat, <300 mg/day from cholesterol, dietary fiber (14 g/1000 kcal), fat-free unflavored milk, limiting sodium intake and sweetened juice (no added sugar) <120 mL/day. Polyunsaturated fatty acids up to 10% of daily calories, and monounsaturated fatty acid intake of 10–15% of daily caloric intake is recommended [5].

If the CHILD-1 modifications do not show the desired lipid changes within 3 months of initiation, the next step is to advance to the CHILD-2 diet (Step 2 diet), which further restricts saturated fat. The CHILD-2 diet consists of 25–30% of total calories from fat, <7% from saturated fat, <10% from monounsaturated fat, and avoiding trans-fat. The CHILD-2 diet specific for LDL lowering (CHILD-2-LDL) also recommends use of fiber supplementation and plant stanols/sterols: plant sterol and stanol esters up to 2 g/day, water-soluble fiber psyllium, dose of 6 g/day (2–12 years) and 12 g/day (>12 years). The CHILD 2 diet specific to TG lowering (CHILD-2-TG) recommends decreasing sugar and sugar-sweetened beverages, replacing simple with complex carbohydrates, and increasing dietary fish to increase omega-3 fatty acid intake [5].

The expert panel also recommends at least 1 h of moderate-to vigorous physical activity every day of the week, with vigorous, intense physical activity on at least 3


*Abbreviations: TC, total cholesterol; LDL, low density lipoprotein cholesterol; HDL, high density lipoprotein cholesterol; TG, triglyceride; AD, autosomal dominant; AR, autosomal recessive; LDL-R, LDL receptor; PCSK9, proprotein convertase subtilisin/kexin type 9; apoB, apolipoprotein; ABCG, ATP-binding cassette sub-family G member; LIPA, lysosomal acid lipase type A; LPL, lipoprotein lipase;* GPIHBP1*, glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1;* LCAT*, lecithin cholesterol acyl transferase.*

### **Table 3.**

*Characteristic features of primary dyslipidemias.*

of these days in agreement with the 2008 Physical Activity Guidelines for Americans from the U.S. [5].

### **1.6 Laboratory evaluations prior to statin therapy**

Suggested serum testing prior to initiation of statin therapy include testing to rule out secondary causes of dyslipidemia—serum albumin, blood glucose level or hemoglobin A1C, renal function tests, serum thyroid-stimulating hormone, free T4 concentration, and a pregnancy screen. These tests are to be done as deemed clinically necessary. Liver function studies, serum creatinine kinase (CK) levels are useful to obtain at baseline to monitor for future potential adverse effects.

### **1.7 Indications for statin therapy in pediatrics**

Children with average LDL-C ≥ 190 mg/dL have a high likelihood of FH and almost certainly require pharmacotherapy, as diet and exercise modifications can maximally reduce lipids by 10–20% [32]. Fasting TG level of ≥500 mg/dL (which may indicate postprandial elevations to >1000 mg/dL and risk of pancreatitis) are also best referred and managed by a lipid specialist. Referral may ultimately be required if LDL levels remain elevated beyond ≥160 mg/dL despite 6 months of lifestyle interventions. Once the lipid profile has been repeated within a 2 week to 3-month period, the following average values currently are recommended to start statin therapy concomitantly with diet and lifestyle modifications.

In children <10 years of age:


In children ≥10 years:


### **1.8 Expected effects of statin therapy**

Aside from PCSK9 inhibitors, statins are the most potent class of lipid lowering agents. The expected effects of statin therapy on TC and LDL levels are dependent on their potency and dosing. Most statins have a mild effect on increasing HDL by 2–5%, and on decreasing TG levels by up to 40%. **Table 4** outlines the starting dosing, properties and potency by expected effects on LDL reduction of some of the commonly used statins in pediatrics. Although the statins with longer half-lives inhibit the enzyme for a longer time, even with statins that have a shorter half-life are effective at reducing the LDL levels because they reduce overall serum levels of lipoproteins with a half-life of approximately 2–3 days. For this reason, all statins can be administered in once a day dosing. The general principal behind statin therapy in pediatrics is to use the lowest effective doses of a statin. Currently, the maximum daily dose studied in pediatrics is for 40 mg of lovastatin, pravastatin, and simvastatin; 20 mg of atorvastatin and rosuvastatin; and 80 mg of fluvastatin.


### **Table 4.**

*Starting doses and properties of statin drug therapy.*

In the United States, pravastatin and pitavastatin have FDA approval for children age ≥ 8 years with HeFH. Lovastatin, simvastatin, fluvastatin, atorvastatin and rosuvastatin have been approved for children ≥10 years with FH. At the higher prescribed doses, atorvastatin and rosuvastatin are more potent than the other approved medications [33]. Key randomized clinical trials for each of these statins in the order of approval for pediatric use are summarized in **Table 5**.

### **1.9 Special considerations for high-risk conditions**

As diabetes is considered a CV risk factor, intensive lipid management is suggested for these patients. In addition to maintaining the best glycemic control possible, the American Diabetes Association recommends starting treatment with statins for LDL ≥ 160 mg/dL and considering treatment for LDL ≥ 130 mg/dL with additional risk factors basing the treatment decision on the child's complete CVD risk profile, including assessment of blood pressure, family history, and smoking status with a goal of lowering LDL to under 100 mg/dL [48].

In nephrotic syndrome, chronic kidney disease and polycystic ovarian syndrome as well LDL ≥ 160 mg/dL maybe a threshold for initiating statin treatment in addition to adequate mediation therapy for the underlying condition, lifestyle and diet therapy. In Kawasaki disease, patients >2 years old without persistent coronary artery abnormalities should undergo lipid screening 1 year after the acute phase, and if normal, universal screening can be considered. Patients with coronary artery aneurysms should undergo annual screening and treated for levels ≥160 mg/dL.

### **1.10 Challenges in pediatric dosing**

Thus far, statins are only available in pill form. With the exception of simvastatin oral suspension, other liquid preparations or flavoring are not readily available which maybe an issue for children with sensory issues or difficulty swallowing a pill. A disintegrating formulation of simvastatin is available, and this may be helpful in younger children. Although compounding the medication at local pharmacies is an option, several logistical issues limit this accessibility. Some of the extended release preparations such as Lovastatin and fluvastatin are rarely used in children, and should not be crushed. Fluvastatin is available as a capsule but the contents are not to be separated per manufacturer's instructions.



### **Table5.**

*Prominent pediatric clinical trials with lipid lowering effects of statins.*

### *Statin Therapy in Children DOI: http://dx.doi.org/10.5772/intechopen.91367*

### **1.11 Considerations for statin bioavailability**

### *1.11.1 Factors affecting absorption*

Recently, ontogenic and genetic factors have been described as potential variables influencing systemic availability of statins [49]. As statins are orally delivered, the gastric milieu and intestinal transport can have effects on the efficacy, and may have population and individual level variability in efficacy. Influx transport proteins such as OATP1A2 and OATP2B1, which are pH dependent, are shown to have an effect at the level of the enterocyte for absorption of statins [50]. Variations in MRP2 (*ABCC2* c.1446C>G), an efflux transporter has been shown to decrease the bioavailability of pravastatin [51]. Co-ingesting statins with food has also shown to have some variability in bioavailability that affects some statins more than others. For instance, absorption of fluvastatin, pravastatin and rosuvastatin is delayed when taken with food [52–55]. In contrast, package inserts of lovastatin state that levels are lower when administered under fasting conditions. Timing of food intake appears to have no effect on simvastatin.

Timing of administration has also shown to have some effect on bioavailability. This is due to multiple factors including diurnal cholesterol biosynthesis peak at nighttime and early morning and possibly the difference in gastric emptying, absorption and distribution. Reduction in both peak concentration as well as overall area under the curve (AUC) distribution have been described with evening administration of pravastatin and atorvastatin [56, 57]. Fluvastatin concentrations have been reportedly higher when dosed in the evening [58] while rosuvastatin remained unaffected [59]. Although statins are best given in the evening to coincide with the peak cholesterol biosynthesis at night, and the long-acting statins, atorvastatin and rosuvastatin, may be given any time, in clinical practice, the difference in efficacy in relation to the timing is negligible.

As with most oral medications, first pass metabolism is another factor with the potential to influence bioavailability and toxicity. Depending upon the statin, when the enterocyte is the level at which first-pass occurs, the bioavailability may be reduced, reducing toxicity but overall efficacy as well. If the first pass occurs at the level of the liver, since the hepatocytes are the primary target for the statins, a more favorable risk profile is potentially created. If the hepatocytes have more primary exposure, reduction in systemic availability and increased hepatic exposure should lead to lesser adverse effects while enhancing action at the target organ level, creating a more favorable safety profile [60].

### *1.11.2 Factors affecting metabolism*

Of the multiple cytochromes that have been shown to have *in-vitro* capacity of metabolizing statins, CYP3A4 has been the most important, especially for simvastatin, lovastatin, and atorvastatin [61, 62]. Rosuvastatin is able to strongly inhibit CYP2C9 activity [63]. Clinically, the co-administration of CYP3A4 inhibitors like clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal, grapefruit, etc. can lead to significant elevations in statin levels, and have the risk of higher toxicity. Inducers of CYP3A4 including phenobarbital, phenytoin, rifampicin, St. John's Wort and glucocorticoids can reduce the bioavailability of statins [64].

While considering drug interactions, concomitant administration of other lipid lowering therapy has to be kept in mind, especially for treatment of conditions such as FCH. For instance, gemfibrozil, which is used to lower TG levels, can engage with the OATP1B1-mediated transport of the statin into the hepatocyte and gut

cells. It can also catalyze glucuronidation. The net effect is these interactions are a higher concentration of systemic statin level and a greater risk of adverse effects [62, 65].

### *1.11.3 Factors affecting elimination*

Elimination can be significantly impacted by half-lives as mentioned in **Table 4**. Some statins including atorvastatin and simvastatin undergo conjugation while pravastatin, rosuvastatin, and pitavastatin do not undergo extensive conjugation. Biliary excretion of the UGT-conjugated statins occurs through—multidrug resistance 1 (MDR1; *ABCB1*), multidrug resistance-associated protein 2 (MRP2; *ABCC2*), breast cancer resistance protein (BCRP; *ABCG2*), bile salt exporting pump (BSEP; *ABCB11*) [60]. Although these efflux transporters have had *in vitro* effects, the *in vivo* effects of variants of these transporters are not well studied. Renal clearance is less significant than the biliary elimination of statins [55, 66, 67]. Of the statins, pravastatin is the most renally cleared at around 20% [68].

### **1.12 Adverse effects of statin therapy**

Of all the classes of lipid lowering medications, statins are best tolerated with least reported adverse events [69]. The safety profile of statins has been well studied in adults. Most studies studying the safety and efficacy of statins are in children with FH. The most commonly reported side effects including muscle related adverse events and hepatic transaminase occur relatively infrequently. When statin treatment was starting to be recommended as young as 8 years of age, there were fair concerns about the effects on cognition, growth and development, metabolic rate with potential for decades of exposure to this medication.

Multiple studies have shown no adverse effects of statins on growth and sexual maturation [70]. In addressing the overall safety profile of statins, a recent metaanalysis showed that statin treatment was effective for treating FH, with a good short-term safety profile [69]. The 10- and 20-year follow-up studies on the use of statins in pediatric dyslipidemias did not report significant serious adverse events [20, 71]. There is a dearth of large long-term randomized controlled trials to establish the long-term safety issues of statins.

### *1.12.1 Rhabdomyolysis/myopathy*

Lipophilic statins are more prone to causing myopathy as they attain greater intramuscular concentrations compared to hydrophilic statins. Pravastatin and rosuvastatin are hydrophilic, others are lipophilic. However, fluvastatin, a lipophilic statin has reportedly lower side muscle-related side effects. Non-specific muscle aches and weakness has been described with all the statins. An extensive systematic review on statin safety in adults determined rhabdomyolysis to be rare at 3 per 100,000 person-years for atorvastatin, simvastatin, lovastatin, pravastatin, and fluvastatin [72]. In children, three large systematic reviews did not find any difference between the statin group and control group for rhabdomyolysis (CK levels increased 10 fold from upper limit of normal) [69, 73, 74]. *Clinically important rhabdomyolysis* is evidence of muscle cell destruction or enzyme leakage, regardless of the CK level, considered to be causally related to a change in renal function. In practice, when CK levels are up trending and elevated to >10 upper limit of normal, with or without co-existent myoglobinuria and/or renal injury, it is recommended to stop the statin [75]. Given that this is a rare side effect, common causes including exercise, cold exposure, trauma, seizures, hypothyroidism, recent infections/myositis, autoimmune etiologies etc. need to be considered. Therapy can be commenced, preferably with a different statin when the CK levels normalize.

Statin induced myopathy is exceedingly rare in children with FH. In adults, myopathy, which includes myalgia and an increase in serum CK levels, occurs in approximately 0.1–1% of patients using statins. The risk factors associated with this are concomitant renal insufficiency, hepatic dysfunction, hypothyroidism, polypharmacy and intake of CYP3A4 inhibitors [76]. Of the reported cases, a coexistent polymorphism in SLCO1B1 resulting in decreased transport of statins into the hepatocytes, thereby increasing systemic toxicity was discovered, especially with lipophilic statins like simvastatin. Statin induced myopathy was 4.5 and 16.9 times more likely in heterozygote and homozygote carriers with this polymorphism [77].

### *1.12.2 Hepatic dysfunction*

This is a rare side effect in statins, and in adult studies, the overall incidence of persistent transaminase elevation is considered to be about 0.5–3%. The Scandinavian Simvastatin Survival Study as well as the Heart Protection Study Collaboration group, as well as the Air Force/Texas Coronary Atherosclerosis Prevention Study, which were large randomized trials that studied simvastatin and lovastatin in large populations did not find significant differences in persistent hepatic transaminases between statin and placebo therapy in adults [78–80]. In children, three large systematic reviews did not find any difference between the statin group and control group for incidence of transaminitis (over 3-fold increase in alanine transferase or aspartate aminotransferase) [69, 73, 74].

Previously, patients receiving statins routinely measured liver function studies for monitoring transaminase elevation. In 2012, the FDA withdrew this requirement, and in practice, liver enzymes are measured as clinically needed. The examiner should inform the patient/parent to report symptoms of jaundice, malaise and fatigue as a sign of potential hepatotoxicity. In practice, if transaminase levels are found to be greater than 3 times the baseline either in symptomatic patients or during routine evaluation, the test should be repeated and other etiologies ruled out as well, given the rare incidence. During the work up process, one should consider discontinuation or dose reduction based on the presentation. Currently, the benefit of statin therapy far outweighs the risk of liver- and muscle-related adverse events.

### *1.12.3 Teratogenicity/need for contraception*

Traditionally, animal studies have shown the potential of teratogenicity with statins due to disruption of cholesterol synthesis [81, 82]. Human studies in this regard are lacking, and the data we have so far is derived mostly from small cohort studies and case reports [83]. Contrastingly, some cohort studies did not find a significant teratogenic effect from maternal use of statins in the first trimester [84]. A meta-analysis of 6 controlled studies including a total of 618 women failed to find an increase in the risk of birth defects [85]. Many of these studies, however, were small, short term and insufficiently powered, making it difficult to generalize the results. At this time, women of childbearing age, as well as pubertal girls should be advised about concerns of teratogenicity with statin use in pregnancy, and counseled on the importance of concomitant contraceptive use.

### *1.12.4 Risk of type 2 diabetes mellitus (T2DM)*

One of the concerning long-term side effects of statin treatment in children has been the higher risk of developing T2DM. A meta-analysis of RCTs in 91,000

*Statin Therapy in Children DOI: http://dx.doi.org/10.5772/intechopen.91367*

adult patients showed that statin therapy was associated with a 9% increase in the incidence of T2DM. Although there was a slightly increased risk of development of diabetes, the absolute risk as well as the comparative risk when measured against risk of coronary risk reduction was low [86]. In contrast, other studies in patients with FH treated with statins did not show a higher risk [87]. In pediatrics, the available data have been mostly reassuring, with two large 10- and 20-year followup studies not showing a significant increase in the incidence of T2DM when compared to the general population incidence [20, 71].

### *1.12.5 Concerns for non-specific effects on reduced cholesterol synthesis*

Cholesterol is utilized by ubiquitously, and has a number of biological functions in other cells in the body; therefore, many non-hepatic cells also are capable of synthesizing LDL-R for uptake of cholesterol. Cholesterol is a precursor for both steroid and sex hormones. However, the use of statins has not been associated with adverse effects on the production of hormones that depend on normal sterol level availability, for instance, the adrenal hormones [74]. Fetal and neonatal cholesterol levels are lower, suggesting that an optimal homeostatic mechanism exists in which even during periods of high metabolic demand, lower levels of cholesterol are sufficient to support normal biological function [88]. Although some variations in dehydroepiandrosterone sulfate (DHEAS) and luteinizing hormone (LH) levels are reported in the literature, these differences were too small to have clinical relevance, given that the studied children did not have any growth or pubertal abnormalities [74].

### **2. Conclusions**

Pediatric dyslipidemia could be due to monogenic, secondary or polygenic causes. Fatty plaques, the precursors of atherosclerosis and exposure to cardiovascular risk factors begin in childhood and progress into adulthood. All children with dyslipidemia benefit from diet and lifestyle modifications but the effect is limited in children with markedly elevated LDL levels. Statins are first line pharmacotherapeutic agents for elevated LDL concentrations with a favorable safety profile and robust short-term data with benefits outweighing the risks. Long-term data are needed in children to better understand the safety and efficacy of these medications.

### **Conflict of interest**

The authors declare no conflict of interest.


### **Appendices and nomenclature**


### **Author details**

Bhuvana Sunil and Ambika Pallikunnath Ashraf \* Department of Pediatrics, Division of Endocrinology, University of Alabama, Birmingham, USA

\*Address all correspondence to: aashraf@peds.uab.edu

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Benjamin EJ, Muntner P, Bittencourt MS. Heart disease and stroke statistics-2019 update: A report from the American Heart Association. Circulation. 2019;**139**(10):e56-e528

[2] Freedman DS, Khan LK, Dietz WH, Srinivasan SR, Berenson GS. Relationship of childhood obesity to coronary heart disease risk factors in adulthood: The Bogalusa Heart Study. Pediatrics. 2001;**108**(3):712-718

[3] McGill HC Jr, McMahan CA, Gidding SS. Preventing heart disease in the 21st century: Implications of the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study. Circulation. 2008;**117**(9):1216-1227

[4] Webber LS, Srinivasan SR, Wattigney WA, Berenson GS. Tracking of serum lipids and lipoproteins from childhood to adulthood. The Bogalusa Heart Study. American Journal of Epidemiology. 1991;**133**(9):884-899

[5] FOR EPOIG, CHILDREN RRI. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: Summary report. Pediatrics. 2011;**128**(Suppl 5):S213

[6] Brown M, Goldstein J. A receptormediated pathway for cholesterol homeostasis. Science. 1986;**232**(4746): 34-47

[7] Ness GC, Chambers CM, Lopez D. Atorvastatin action involves diminished recovery of hepatic HMG-CoA reductase activity. Journal of Lipid Research. 1998;**39**(1):75-84

[8] Schaefer J, Schweer H, Ikewaki K, Stracke H, Seyberth H, Kaffarnik H, et al. Metabolic basis of high density lipoproteins and apolipoprotein AI increase by HMG-CoA reductase inhibition in healthy subjects and a patient with coronary artery disease. Atherosclerosis. 1999;**144**(1):177-184

[9] Martin G, Duez H, Blanquart C, Berezowski V, Poulain P, Fruchart J-C, et al. Statin-induced inhibition of the rho-signaling pathway activates PPARα and induces HDL apoA-I. The Journal of Clinical Investigation. 2001;**107**(11): 1423-1432

[10] Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature. 1990;**343**(6257):425

[11] Cho K-J, Hill MM, Chigurupati S, Du G, Parton RG, Hancock JF. Therapeutic levels of the hydroxmethylglutaryl-coenzyme A reductase inhibitor lovastatin activate ras signaling via phospholipase D2. Molecular and Cellular Biology. 2011; **31**(6):1110-1120

[12] Labos C, Brophy JM, Smith GD, Sniderman AD, Thanassoulis G. Evaluation of the pleiotropic effects of statins. Arteriosclerosis, Thrombosis, and Vascular Biology. 2018;**38**(1):262-265

[13] Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nature Medicine. 2000;**6**(12):1399

[14] Ritchie SK, Murphy EC, Ice C, Cottrell LA, Minor V, Elliott E, et al. Universal versus targeted blood cholesterol screening among youth: The CARDIAC project. Pediatrics. 2010; **126**(2):260-265

[15] Versmissen J, Oosterveer DM, Yazdanpanah M, Defesche JC, Basart DC, Liem AH, et al. Efficacy of statins in familial hypercholesterolaemia: A long term cohort study. BMJ. 2008;**337**:a2423

[16] American Academy of Pediatrics endorsement: Screen all children ages 9–11 for cholesterol. AAP News. 2011: E111111-1

[17] Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ ABC/ACPM/ADA/AGS/APhA/ASPC/ NLA/PCNA Guideline on the Management of Blood Cholesterol: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;**139**(25): e1082-ee143

[18] Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). European Heart Journal. 2020; **41**(1):111-188

[19] Bibbins-Domingo K, Grossman DC, Curry SJ, Davidson KW, Epling JW, García FA, et al. Screening for lipid disorders in children and adolescents: US Preventive Services Task Force recommendation statement. Journal of the American Medical Association. 2016;**316**(6):625-633

[20] Luirink IK, Wiegman A, Kusters DM, Hof MH, Groothoff JW, de Groot E, et al. 20-year follow-up of statins in children with familial hypercholesterolemia. New England Journal of Medicine. 2019;**381**(16): 1547-1556

[21] Nordestgaard BG, Langsted A, Mora S, Kolovou G, Baum H, Bruckert E, et al. Fasting is not routinely required for determination of a lipid profile: Clinical and laboratory implications including flagging at desirable concentration cut-points—A joint consensus statement from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine.

European Heart Journal. 2016;**37**(25): 1944-1958

[22] Doran B, Guo Y, Xu J, Weintraub H, Mora S, Maron DJ, et al. Prognostic value of fasting versus nonfasting lowdensity lipoprotein cholesterol levels on long-term mortality: Insight from the National Health and Nutrition Examination Survey III (NHANES-III). Circulation. 2014;**130**(7):546-553

[23] Eissa MA, Mihalopoulos NL, Holubkov R, Dai S, Labarthe DR. Changes in fasting lipids during puberty. The Journal of Pediatrics. 2016; **170**:199-205

[24] National Cholesterol Education Program (NCEP): Highlights of the report of the expert panel on blood cholesterol levels in children and adolescents. Pediatrics. 1992;**89**(3): 495-501

[25] Cook S, Kavey REW. Dyslipidemia and pediatric obesity. Pediatric Clinics. 2011;**58**(6):1363-1373

[26] Saland JM, Ginsberg H, Fisher EA. Dyslipidemia in pediatric renal disease: Epidemiology, pathophysiology, and management. Current Opinion in Pediatrics. 2002;**14**(2):197-204

[27] Gabriela Brenta M, Fretes O. Dyslipidemias and hypothyroidism. Pediatric Endocrinology Reviews (PER). 2014;**11**(4):390-399. PMID: 24988692

[28] Arnaldi G, Scandali VM, Trementino L, Cardinaletti M, Appolloni G, Boscaro M. Pathophysiology of dyslipidemia in Cushing's syndrome. Neuroendocrinology. 2010;**92**(Suppl 1):86-90

[29] Lanes R, Soros A, Gunczler P, Paoli M, Carrillo E, Villaroel O, et al. Growth hormone deficiency, low levels of adiponectin, and unfavorable plasma lipid and lipoproteins. The Journal of Pediatrics. 2006;**149**(3):324-329

*Statin Therapy in Children DOI: http://dx.doi.org/10.5772/intechopen.91367*

[30] Wild R, Weedin EA, Wilson D. Dyslipidemia in pregnancy. Cardiology Clinics. 2015;**33**(2):209-215

[31] Henkin Y, Como JA, Oberman A. Secondary dyslipidemia: Inadvertent effects of drugs in clinical practice. Journal of the American Medical Association. 1992;**267**(7):961-968

[32] Yu-Poth S, Zhao G, Etherton T, Naglak M, Jonnalagadda S, Kris-Etherton PM. Effects of the National Cholesterol Education Program's Step I and Step II dietary intervention programs on cardiovascular disease risk factors: A meta-analysis. The American Journal of Clinical Nutrition. 1999; **69**(4):632-646

[33] Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR\* Trial). American Journal of Cardiology. 2003;**92**(2): 152-160

[34] McCrindle BW, Ose L, Marais AD. Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: A multicenter, randomized, placebo-controlled trial. The Journal of Pediatrics. 2003;**143**(1): 74-80

[35] Gandelman K, Glue P, Laskey R, Jones J, LaBadie R, Ose L. An eight-week trial investigating the efficacy and tolerability of atorvastatin for children and adolescents with heterozygous familial hypercholesterolemia. Pediatric Cardiology. 2011;**32**(4):433-441

[36] Canas JA, Ross JL, Taboada MV, Sikes KM, Damaso LC, Hossain J, et al. A randomized, double blind, placebocontrolled pilot trial of the safety and efficacy of atorvastatin in children with elevated low-density lipoprotein

cholesterol (LDL-C) and type 1 diabetes. Pediatric Diabetes. 2015;**16**(2):79-89

[37] Langslet G, Breazna A, Drogari E. A 3-year study of atorvastatin in children and adolescents with heterozygous familial hypercholesterolemia. Journal of Clinical Lipidology. 2016;**10**(5): 1153-62.e3

[38] Van Der Graaf A, Nierman MC, Firth JC, Wolmarans KH, Marais AD, De Groot E. Efficacy and safety of fluvastatin in children and adolescents with heterozygous familial hypercholesterolaemia. Acta Paediatrica. 2006;**95**(11):1461-1466

[39] Lambert M, Lupien P-J, Gagné C, Lévy E, Blaichman S, Langlois S, et al. Treatment of familial hypercholesterolemia in children and adolescents: Effect of lovastatin. Pediatrics. 1996;**97**(5): 619-628

[40] Stein EA, Illingworth DR, Kwiterovich J, Peter O, Liacouras CA, Siimes MA, et al. Efficacy and safety of lovastatin in adolescent males with heterozygous familial hypercholesterolemia A randomized controlled trial. Journal of the American Medical Association. 1999;**281**(2):137-144

[41] Clauss SB, Holmes KW, Hopkins P, Stein E, Cho M, Tate A, et al. Efficacy and safety of lovastatin therapy in adolescent girls with heterozygous familial hypercholesterolemia. Pediatrics. 2005;**116**(3):682-688

[42] Knipscheer H, Boelen C, Kastelein J, Van Diermen D, Groenemeijer B, Van Den Ende A, et al. Short-term efficacy and safety of pravastatin in 72 children with familial hypercholesterolemia. Pediatric Research. 1996;**39**(5):867

[43] Avis HJ, Hutten BA, Gagné C, Langslet G, McCrindle BW, Wiegman A, et al. Efficacy and safety of rosuvastatin therapy for children with familial hypercholesterolemia. Journal

of the American College of Cardiology. 2010;**55**(11):1121-1126

[44] Braamskamp MJ, Langslet G, McCrindle BW, Cassiman D, Francis GA, Gagné C, et al. Efficacy and safety of rosuvastatin therapy in children and adolescents with familial hypercholesterolemia: Results from the CHARON study. Journal of Clinical Lipidology. 2015; **9**(6):741-750

[45] Stein EA, Dann EJ, Wiegman A, Skovby F, Gaudet D, Sokal E, et al. Efficacy of rosuvastatin in children with homozygous familial hypercholesterolemia and association with underlying genetic mutations. Journal of the American College of Cardiology. 2017; **70**(9):1162-1170

[46] de Jongh S, Lilien MR, Jos op't Roodt J, Stroes ES, Bakker HD, Kastelein JJ. Early statin therapy restores endothelial function in children with familial hypercholesterolemia. Journal of the American College of Cardiology. 2002;**40**(12):2117-2121

[47] García-de-la-Puente S, Arredondo-García JL, Gutiérrez-Castrellón P, Bojorquez-Ochoa A, Maya ER, Pérez-Martínez MDP. Efficacy of simvastatin in children with hyperlipidemia secondary to kidney disorders. Pediatric Nephrology. 2009;**24**(6):1205-1210

[48] Association AD. 12. Children and adolescents: Standards of medical care in diabetes—2018. Diabetes Care. 2018; **41**(Supplement 1):S126-S136

[49] Wagner J, Leeder JS. Pediatric pharmacogenomics: A systematic assessment of ontogeny and genetic variation to guide the design of statin studies in children. Pediatric Clinics. 2012;**59**(5):1017-1037

[50] Nozawa T, Imai K, Nezu J, Tsuji A, Tamai I. Functional characterization of pH-sensitive organic anion transporting polypeptide OATP-B in human. The Journal of Pharmacology and Experimental Therapeutics. 2004; **308**(2):438-445

[51] Shirasaka Y, Suzuki K, Nakanishi T, Tamai I. Intestinal absorption of HMG-CoA reductase inhibitor pravastatin mediated by organic anion transporting polypeptide. Pharmaceutical Research. 2010;**27**(10):2141-2149

[52] Pan HY, DeVault AR, Brescia D, Willard DA, McGovern ME, Whigan DB, et al. Effect of food on pravastatin pharmacokinetics and pharmacodynamics. International Journal of Clinical Pharmacology, Therapy, and Toxicology. 1993;**31**(6): 291-294

[53] Radulovic LL, Cilla DD, Posvar EL, Sedman AJ, Whitfield LR. Effect of food on the bioavailability of atorvastatin, an HMG-CoA reductase inhibitor. Journal of Clinical Pharmacology. 1995;**35**(10): 990-994

[54] Shang D, Deng S, Yao Z, Wang Z, Ni X, Zhang M, et al. The effect of food on the pharmacokinetic properties and bioequivalence of two formulations of pitavastatin calcium in healthy Chinese male subjects. Xenobiotica. 2016;**46**(1): 34-39

[55] Smith HT, Jokubaitis LA, Troendle AJ, Hwang DS, Robinson WT. Pharmacokinetics of fluvastatin and specific drug interactions. American Journal of Hypertension. 1993;**6**(11 Pt 2):375s-382s

[56] Triscari J, Rossi L, Pan HY. Chronokinetics of pravastatin administered in the PM compared with AM dosing. American Journal of Therapeutics. 1995;**2**(4): 265-268

[57] Cilla DD Jr, Gibson DM, Whitfield LR, Sedman AJ. Pharmacodynamic effects and

### *Statin Therapy in Children DOI: http://dx.doi.org/10.5772/intechopen.91367*

pharmacokinetics of atorvastatin after administration to normocholesterolemic subjects in the morning and evening. Journal of Clinical Pharmacology. 1996; **36**(7):604-609

[58] Fauler G, Abletshauser C, Erwa W, Loser R, Witschital K, Marz W. Timeof-intake (morning versus evening) of extended-release fluvastatin in hyperlipemic patients is without influence on the pharmacodynamics (mevalonic acid excretion) and pharmacokinetics. International Journal of Clinical Pharmacology and Therapeutics. 2007;**45**(6): 328-334

[59] Martin PD, Mitchell PD, Schneck DW. Pharmacodynamic effects and pharmacokinetics of a new HMG-CoA reductase inhibitor, rosuvastatin, after morning or evening administration in healthy volunteers. British Journal of Clinical Pharmacology. 2002;**54**(5): 472-477

[60] Wagner J, Abdel-Rahman SM. Pediatric statin administration: Navigating a frontier with limited data. Journal of Pediatric Pharmacology and Therapeutics. 2016;**21**(5):380-403

[61] Prueksaritanont T, Ma B, Yu N. The human hepatic metabolism of simvastatin hydroxy acid is mediated primarily by CYP3A, and not CYP2D6. British Journal of Clinical Pharmacology. 2003;**56**(1):120-124

[62] Prueksaritanont T, Gorham LM, Ma B, Liu L, Yu X, Zhao JJ, et al. In vitro metabolism of simvastatin in humans [SBT]identification of metabolizing enzymes and effect of the drug on hepatic P450s. Drug Metabolism and Disposition. 1997;**25**(10):1191-1199

[63] Sakaeda T, Fujino H, Komoto C, Kakumoto M, Jin JS, Iwaki K, et al. Effects of acid and lactone forms of eight HMG-CoA reductase inhibitors on CYP-mediated metabolism and MDR1mediated transport. Pharmaceutical Research. 2006;**23**(3):506-512

[64] Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: Mechanisms and clinical relevance. Clinical Pharmacology and Therapeutics. 2006; **80**(6):565-581

[65] Shitara Y, Hirano M, Sato H, Sugiyama Y. Gemfibrozil and its glucuronide inhibit the organic anion transporting polypeptide 2 (OATP2/ OATP1B1: SLC21A6)-mediated hepatic uptake and CYP2C8-mediated metabolism of cerivastatin: Analysis of the mechanism of the clinically relevant drug-drug interaction between cerivastatin and gemfibrozil. Journal of Pharmacology and Experimental Therapeutics. 2004;**311**(1):228-236

[66] Stern RH, Yang BB, Horton M, Moore S, Abel RB, Olson SC. Renal dysfunction does not alter the pharmacokinetics or LDLholesterol reduction of atorvastatin. Journal of Clinical Pharmacology. 1997;**37**(9): 816-819

[67] Martin PD, Warwick MJ, Dane AL, Hill SJ, Giles PB, Phillips PJ, et al. Metabolism, excretion, and pharmacokinetics of rosuvastatin in healthy adult male volunteers. Clinical Therapeutics. 2003;**25**(11):2822-2835

[68] Everett DW, Chando TJ, Didonato GC, Singhvi SM, Pan HY, Weinstein SH. Biotransformation of pravastatin sodium in humans. Drug Metabolism and Disposition. 1991; **19**(4):740-748

[69] Vuorio A, Kuoppala J, Kovanen PT, Humphries SE, Tonstad S, Wiegman A, et al. Statins for children with familial hypercholesterolemia. Cochrane Database of Systematic Reviews. 2017;**7**

[70] Humphries SE, Cooper J, Dale P, Ramaswami U. The UK paediatric

familial hypercholesterolaemia register: Statin-related safety and 1-year growth data. Journal of Clinical Lipidology. 2018;**12**(1):25-32

[71] Kusters DM, Avis HJ, de Groot E, Wijburg FA, Kastelein JJ, Wiegman A, et al. Ten-year follow-up after initiation of statin therapy in children with familial hypercholesterolemia. Journal of the American Medical Association. 2014;**312**(10):1055-1057

[72] Law M, Rudnicka AR. Statin safety: A systematic review. The American Journal of Cardiology. 2006;**97**(8):S52- S60

[73] Arambepola C, Farmer AJ, Perera R, Neil HA. Statin treatment for children and adolescents with heterozygous familial hypercholesterolaemia: A systematic review and meta-analysis. Atherosclerosis. 2007;**195**(2):339-347

[74] Avis HJ, Vissers MN, Stein EA, Wijburg FA, Trip MD, Kastelein JJ, et al. A systematic review and meta-analysis of statin therapy in children with familial hypercholesterolemia. Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;**27**(8):1803-1810

[75] Thompson PD, Clarkson PM, Rosenson RS. An assessment of statin safety by muscle experts. American Journal of Cardiology. 2006;**97**(8a): 69c-76c

[76] Rosenson RS. Current overview of statin-induced myopathy. The American Journal of Medicine. 2004; **116**(6):408-416

[77] Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, et al. SLCO1B1 variants and statin-induced myopathy—A genomewide study. The New England Journal of Medicine. 2008;**359**(8):789-799

[78] Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: Results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. Journal of the American Medical Association. 1998; **279**(20):1615-1622

[79] Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;**344**(8934):1383-1389

[80] MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised placebo-controlled trial. Lancet. 2002;**360**(9326):7-22

[81] Edison RJ, Muenke M. Mechanistic and epidemiologic considerations in the evaluation of adverse birth outcomes following gestational exposure to statins. American Journal of Medical Genetics Part A. 2004;**131**(3):287-298

[82] Godfrey LM, Erramouspe J, Cleveland KW. Teratogenic risk of statins in pregnancy. Annals of Pharmacotherapy. 2012;**46**(10): 1419-1424

[83] Edison RJ, Muenke M. Central nervous system and limb anomalies in case reports of first-trimester statin exposure. The New England Journal of Medicine. 2004;**350**(15):1579-1582

[84] Bateman BT, Hernandez-Diaz S, Fischer MA, Seely EW, Ecker JL, Franklin JM, et al. Statins and congenital malformations: Cohort study. BMJ: British Medical Journal. 2015;**350**:h1035

[85] Zarek J, Koren G. The fetal safety of statins: A systematic review and metaanalysis. Journal of Obstetrics and Gynaecology Canada. 2014;**36**(6): 506-509

[86] Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ,

*Statin Therapy in Children DOI: http://dx.doi.org/10.5772/intechopen.91367*

et al. Statins and risk of incident diabetes: A collaborative meta-analysis of randomised statin trials. The Lancet. 2010;**375**(9716):735-742

[87] Besseling J, Kastelein JJ, Defesche JC, Hutten BA, Hovingh GK. Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus. Journal of the American Medical Association. 2015; **313**(10):1029-1036

[88] Woollett L, Heubi JE. Fetal and neonatal cholesterol metabolism. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, Dungan K, Grossman A, et al., editors. Endotext. South Dartmouth (MA): MDText.com, Inc.; 2000

### **Chapter 6**

## Pharmacokinetic Aspects of Statins

*Lucía Cid-Conde and José López-Castro*

### **Abstract**

Statins are the most used therapeutic group in the treatment of hypercholesterolemia and reduce the risk of cardiovascular events and mortality. Long prescription periods and their pharmacokinetic characteristics increase the possibility of interactions, especially at the metabolism level. Simvastatin, lovastatin, and atorvastatin are metabolized by CYP3A4 isoenzymes, so they will have more significant interactions than fluvastatin, pitavastatin, and rosuvastatin that require CYP2C9. The main interactions are with macrolides, azole antifungals, antiretrovirals, platelet antiaggregants, anticoagulants, oral antidiabetics, calcium channel blockers, immunosuppressants, and other hypolipidemic agents, among others. A review of all medications that are taken by patients treated with statins should be performed at each medical consultation and during all healthcare transitions.

**Keywords:** drug interactions, metabolism, isoenzymes CYP3A4, rhabdomyolysis, hypolipidemic drugs

### **1. Introduction**

As a consequence of the variability in their origin, statins have notable differences; however, their pharmacodynamic similarities allow them to be grouped together for study. As for the mechanism of action, its effects and the clinical consequences of its use, there is an important group congruence already well known.

Nowadays, seven statins are commonly used: lovastatin (first licensed in 1987), simvastatin (1988), pravastatin (1991), fluvastatin (1994), atorvastatin (1997), rosuvastatin, and pitavastatin (2003). Cerivastatin, approved in 1998, was subsequently withdrawn from the world market due to a high risk of rhabdomyolysis.

They are the most therapeutic group used in the treatment of hypercholesterolemia and most have been shown to reduce the risk of events and cardiovascular mortality; however, the long prescription periods of these drugs and their pharmacokinetic characteristics increase the possibility of drug interactions [1].

### **2. Statins pharmacokinetics**

### **2.1 Absorption**

The interaction of statins at the level of absorption can translate into a decrease in the absorption of the drug by a change in pH, a variation in the speed of intestinal motility or the formation of complexes and/or chelates.

All currently marketed statins are absorbed orally in a variable range (between 30% for lovastatin and 35% for pravastatin), so the influence of intake at the time of administration is very important to achieve an effect adequate therapeutic [2].

The absorption of a drug can be reduced, delayed, or increased by food consumption, as they share many physiological mechanisms and coincide with numerous organs. This is why the medication schedule is so important in these drugs. In general, all statins reduce their absorption in the presence of food so that their administration is usually at night, before bedtime, and without food, although there are some exceptions. When pravastatin is administered with food, its bioavailability is reduced by approximately 35% compared to that obtained in its administration before meals. This bioavailability reduction is also observed for fluvastatin, both water soluble, so it is recommended to space its administration with respect to meals at least 4 hours. As for atorvastatin, it seems that a meal with a medium fat content may slightly reduce its absorption, while with simvastatin, it does not seem that this fact is relevant. Unlike the previous ones, the administration of lovastatin after a meal increases its plasma concentration by 50% compared to the fasting state. Therefore, it is recommended that lovastatin be taken with food. As for the most recent statins, rosuvastatin and pitavastatin, rosuvastatin has an absorption in which plasma concentrations are reached at approximately 5 hours after oral administration. The total bioavailability is approximately 20%. Rosuvastatin, unlike its group mates, can be taken at any time of the day, its absorption being the same with both food and without food.

Likewise, pitavastatin is widely absorbed by 80%, without interacting with food. There is no accumulation due to repeat multiple doses; therefore, the single dose is accepted.

### **2.2 Distribution**

Plasma protein binding is variable, but in general, it is very high. Except for 50% of pravastatin, all are above 95%. The tissue distribution is wide, crossing the blood-brain and placental barriers, even passing into breast milk. No clinically important interactions have been described by displacement of statins from their binding to plasma proteins. However, the fact that statins could be displaced by another drug is a fact that must always be taken into consideration and studied to discover a possible case.

The hepatic specificity of these drugs is determined by their degree of lipophilicity and by the presence of organic anion transport proteins (OATPs) that allow more hydrophilic statins such as pitavastatin, pravastatin, and rosuvastatin to enter the hepatocyte. The lipophilic statins (atorvastatin, fluvastatin, lovastatin, and simvastatin) can enter directly in cells. On the other hand, some statins can inhibit P-glycoprotein (multidrug resistance protein), a drug-carrying protein in the cell, so they could lead to drug interactions. Lovastatin and simvastatin are ingested as lipophilic lactone prodrugs, whereas other statins are administered as active acid forms.

### **2.3 Metabolism**

Statins are metabolized by CYP450 isoenzymes, with the exception of pravastatin, which is metabolized in the cellular cytosol by sulfation. In addition, they present gastrointestinal and hepatic first-pass metabolism. There are differences in metabolism with respect to gender and age, but not enough to modify the doses in the absence of other pathologies (**Table 1**).


### **Table 1.**

*Common P-gp substrates, inhibitors, and inducers associated with the CYP450 enzymes affecting statin metabolism [42].*

CYP450 metabolizes a high percentage of drugs, especially the CYP3A4 isoenzyme (about 36%). The main factors that affect the metabolism by this route are enzyme induction, enzyme inhibition, and genetic polymorphisms.

*Enzymatic inducer* is that medication that stimulates the synthesis and/or activity of a CYP450 isoenzyme, usually CYP3A4. This produces a stimulation of the metabolism of both the inducing drug itself (self-induction) and the drug administered concomitantly, in this case the statin, so it would reduce more rapidly its plasma concentrations. A reduction in plasma concentrations results in a lower effect of the hypolipemiant drug. In the case of having to administer the two medications, it would be necessary to perform blood concentration tests and, if necessary, increase the dose of statin. The most frequent enzyme inducers are rifampicin, rifabutin, phenobarbital, carbamazepine, phenytoin, nevirapine, efavirenz, troglitiazone, polyglitazone, or St. John's wort (Hipérico).

*Enzymatic inhibitor* is that medication that, administered together with the statin, inhibits a CYP450 isoenzyme. This produces a decrease in statin metabolism, increasing its plasma concentrations, and can cause adverse effects. The most potent and frequent enzyme inhibitors are protease inhibitors such as ritonavir (potent antiretroviral used precisely because of its inhibitory role in potentiation pharmacokinetics) and some macrolides such as erythromycin, proton pump inhibitors such as omeprazole, azole antifungals such as ketoconazole or itraconazole, or the juice of Grapefruit, among many others.

The metabolites can be hydroxylated, omega or beta-oxidized, methylated, or glucuronized derivatives, whose pharmacological activity is highly variable.

Therefore, the spectrum of clinical effectiveness is wide, from lovastatin or simvastatin, which are really pharmacologically inactive lactones and that carry out their pharmacological activity through their metabolites, to fluvastatin, which has practically inactive metabolites.

Simvastatin and lovastatin undergo significant CYP3A4 metabolism and atorvastatin undergoes a lesser amount as one of its minor metabolic pathways. This is in contrast to fluvastatin, pitavastatin, and rosuvastatin, which require CYP2C9. Because CYP3A4 is the most common enzyme involved in drug metabolism, simvastatin and lovastatin will have more interactions that will likely require intervention [2].

Thus, state-of-the-art statins, rosuvastatin and pitavastatin, are minimally metabolized by CYP450 isoenzymes and by P-glycoprotein. This causes them to have a lower probability of interactions. Pitavastatin, on the other hand, has minimal hepatic metabolism due to the first step (enterohepatic circulation). It is practically not metabolized; it is mainly eliminated by bile route; and its renal excretion as an active drug is minimal (less than 2%). The main metabolic pathway of pitavastatin is lactonization/glucuronidation. Rosuvastatin is also not metabolized by cytochrome CYP3A4; it uses CYP2C9 and CYP2C19 but it does so in a very low percentage [3].

P-glycoprotein (P-gp) is responsible for the intestinal and biliary elimination of some of the statins such as pravastatin or atorvastatin.

### **2.4 Excretion**

The amount of statin that is excreted in its unchanged form through renal elimination is small. The overall dependence of statin metabolites on renal elimination is modest, with pravastatin being the highest at 20% and atorvastatin being the lowest at <2%.

Fluvastatin, lovastatin, pravastatin, and simvastatin have a relatively short halflife (less than 5 hours). These medications are optimally dosed at night or given as an extended-release formulation to maximize the effect (fluvastatin or lovastatin). By contrast, pitavastatin (12 hours), atorvastatin (14 hours), and rosuvastatin (between 15 and 30 hours) have longer half-lives and can be dosed at any time of the day.

Statins are also excreted into bile and feces as a means of drug elimination. This excretion is facilitated by OATPs. Similar to CYP450, there are several subtypes of OATP that can affect the elimination of rosuvastatin and pitavastatin [2].

The drug interactions with statins may sometimes be attributable to decreased drug excretion, especially in patients with impaired glomerular filtration rate, and are related to the extent the statin is renally excreted. This potential issue is limited with atorvastatin, which has the least amount of renal excretion (<2%), but may be a consideration for other statins that have a higher degree of renal excretion (pitavastatin, pravastatin, rosuvastatin, simvastatin) (**Table 2**).


### **Table 2.** *Pharmacokinetic properties of statins [2].*

### **3. Interactions**

The long prescription periods of these drugs and their pharmacokinetic characteristics already exposed, increase the possibility of drug interactions. The most frequent adverse effects are headache, gastrointestinal discomfort, cramps, and asymptomatic elevation of transaminases, among others. The most important safety problem is myopathy, which can progress to rhabdomyolysis and death of the patient (**Table 3**).

### **3.1 Drug-drug interactions**

HMG-CoA reductase inhibitors have different pharmacokinetic profiles, which may affect potential drug interactions.

### *3.1.1 Antiplatelet agents*

There is controversy between the interaction of clopidogrel with statins motivated mainly by differences in the design and method of the studies.

So, no effect of atorvastatin or any statin on antiplatelet activity of single dose of clopidogrel found in prospective study of 25 patients taking atorvastatin, 25 patients taking other statin, and 25 patients taking no statin [4].

This administration of CYP3A4-metabolized statins in clopidogrel treated patients does not induce any changes in the conversion of clopidogrel into its active thiol form and therefore neither has a quantitatively nor clinically relevant influence on clopidogrel efficacy [5].

Several randomized clinical trials (RCTs) compare the results of patients in whom clopidogrel was associated and a statin metabolized by CYP3A4 (atorvastatin, lovastatin, simvastatin); with those treated with statins not metabolized by CYP3A4 (fluvastatin and pravastatin). Patients treated with atorvastatin had similar rates of bleeding and complications, without any interaction being checked [6]. In other trials, the inhibition of platelet aggregation was similar when fluvastatin, pravastatin, or atorvastatin was associated with clopidogrel [7].

In a cohort study conducted in 10,491 patients who were prescribed clopidogrel, when comparing 43.5% of the patients who were associated with atorvastatin, with whom a non-CYP3A4 statin was associated, or with the group that did not receive statin, there was no increase in possible side effects [8].

A clinical trial of 50 patients comparing the association of clopidogrel-acetylsalicylic acid with that of atorvastatin-clopidogrel, after a "bypass" of the coronary artery, shows that the combination with atorvastatin further increased platelet inhibition and, consequently, the antiaggregant effect would be greater than the association with acetylsalicylic acid [9].

Clinical trials have evaluated pharmacokinetic interactions of ticagrelor coadministered with atorvastatin, simvastatin, or lovastatin. They have shown an increase in Cmax (maximum concentration) and AUC (area under the curve) of atorvastatin, simvastatin, or lovastatin as a result of CYP3A4 inhibition by ticagrelor. However, these changes were not statistically significant [10]. The dose of simvastatin and lovastatin should not exceed 40 mg daily when prescribed with ticagrelor. There were no clinically significant interactions when ticagrelor is used in combination with pravastatin, fluvastatin, pitavastatin, or rosuvastatin, and no dosing restrictions were needed. No clinically significant drug interactions have been reported with prasugrel in combination with statins.


### **Table 3.**

*Statin interactions [7, 8, 13, 23, 25, 37, 39].*

### *3.1.2 Anticoagulants*

The warfarin and statin interaction information is limited; however, the case reports show a possible effect on coagulation, especially with fluvastatin or rosuvastatin [11] (for its potent inhibitory effect on CYP2C9) and lovastatin (possibly due to the displacement of protein binding). Other statins, except pravastatin, could have interactions, by inhibition of warfarin or acenocoumarol metabolism, or by displacement of protein binding.

Several studies neither have demonstrated significant interaction between warfarin-pitavastatin [12] and warfarin-atorvastatin [13], nor have shown clinically significant drug interactions with statins and new anticoagulants such as dabigatran, apixaban, rivaroxaban, and edoxaban.

The use of statins with warfarin as combination therapy is useful when clinically indicated. It is advisable to monitor the international normalized ratio (INR) more closely when a statin is started or changed in dose. The impact on the INR appears lowest for pitavastatin and atorvastatin [14].

### *3.1.3 Oral antidiabetics*

It has been shown that statins and metformin reduce inflammation and oxidative stress. These results show an additional cardioprotective effect, as a direct action mechanism or through its pleiotropic effects. That is why patients with type II diabetes mellitus often take metformin and statins together to control the risk of cardiovascular disease and glucose metabolism. Metformin shows beneficial effects on both dyslipidemia and glycemic control and it has been shown to reduce the risk of cardiovascular disease. While statins can have an additional beneficial effect on the risk of cardiovascular disease, the combined treatment with both medications seems be a good therapeutic option [15].

The prescription of statins and dipeptidyl peptidase 4 (DPP-4) inhibitors is becoming common in patients with type 2 diabetes mellitus and hyperlipidemia. Several mechanisms have been proposed to describe the interaction between the two, ranging from the effects of sitagliptin on renal excretion of statins to interaction at the level of liver metabolism [16]. A case report of simvastatin-induced rhabdomyolysis in the presence of sitagliptin proposed that the nephrotoxicity of sitagliptin led to reduced renal excretion of simvastatin [17].

However, a clinical trial that studied the effects of sitagliptin on the pharmacokinetics of simvastatin in 12 healthy human subjects aged 18–45 years, both male and female, showed no effect on simvastatin metabolism [18]. The authors did not recommend dose adjustment, when simvastatin was coadministered with sitagliptin. Similarly, another study in 10 patients found no effects of the use of simvastatin on the pharmacokinetics of sitagliptin, and no dose adjustment was recommended for any of the drugs [19].

In a case report of rhabdomyolysis induced by lovastatin and sitagliptin, the authors suggested an interaction between statin and sitagliptin at the CYP3A4 level as the cause. They claimed that because both are metabolized by CYP3A4, when coadministered, they can compete for the same enzyme, resulting in a higher serum statin concentration, which leads to statin-induced rhabdomyolysis [20]. Two other case reports of rhabdomyolysis with atorvastatin and sitagliptin had similar suggestions, indicating that sitagliptin leads to an increase in serum concentration of atorvastatin through its effects on liver metabolism by CYP3A4 rather than on renal excretion. A thorough review of the literature suggests that atorvastatin and sitagliptin are not prone to drug pharmacokinetic interactions, either separately or in a fixed combination of drugs.

Statins that can cause rhabdomyolysis by interaction with sitagliptin are lovastatin, atorvastatin, and simvastatin as they are all metabolized by CYP3A4. This interaction is not described with statins that are not metabolized by CYP3A4 such as pravastatin, rosuvastatin, pitavastatin, and fluvastatin.

When exenatide (10 mcg twice daily) was administered concomitantly with a single dose of lovastatin (40 mg), the values of AUC and Cmax of lovastatin decreased approximately 40 and 28%, respectively, and the Tmax (maximum concentration time required) was delayed about 4 hours. In the 30-week placebo-controlled clinical trials, the concomitant use of exenatide and hydroxymethylglutaryl coenzyme A (HMG CoA) inhibitors was not associated with consistent changes in lipid profiles. Although no dose adjustment is required, possible changes in LDL-C or total cholesterol should be taken into account. The lipid profile should be evaluated regularly. Liraglutide did not modify the general exposure of atorvastatin to a clinically significant degree following the administration of a single dose of 40 mg of atorvastatin; therefore, no dose adjustment of atorvastatin is necessary when administered with liraglutide. There was a 38% decrease in atorvastatin Cmax, and the average Tmax was delayed 1–3 hours with liraglutide [3].

### *3.1.4 Azole antifungals*

Azole antifungals are inhibitors of the CYP3A4 isoenzyme although itraconazole is more potent than fluconazole. When administered concomitantly with statins, a metabolic block can occur with an increase in plasma concentrations of the latter and the possibility of unwanted effects [21].

There are case reports of myopathy and rhabdomyolysis due to the simultaneous use of simvastatin or atorvastatin with itraconazole and fluconazole. A study that evaluated the effect of itraconazole on the pharmacokinetics of lovastatin in 12 healthy volunteers showed an increase in Cmax of 13 times (range 10–23 times) and 20 times in the AUC of the active metabolite of lovastatin [22].

On the other hand, two randomized double-blind, two-phase, cross-sectional studies conducted to evaluate the effect of fluconazole on plasma concentrations of fluvastatin and pravastatin showed an increase in the AUC and Cmax of fluvastatin by 84 and 44%, respectively; while no significant changes in pravastatin levels were documented.

Itraconazole increased by 15 times the AUC and the Cmax of lovastatin; likewise, simvastatin showed a significant increase in the Cmax and AUC of the acid form (β-hydroxy acid) by 17 and 19 times, respectively. Therefore, the concomitant use of lovastatin and simvastatin with itraconazole should be avoided by the potential increase in toxicity on skeletal muscle. On the other hand, the use of itraconazole with fluvastatin or pravastatin did not generate significant changes in the levels of these statins. Similarly, the combination of fluconazole with rosuvastatin generated an increase in the AUC and Cmax of rosuvastatin without clinical relevance [23].

### *3.1.5 Antiretroviral agents (ARV)*

The use of lipid-lowering drugs in patients with HIV/AIDS is increasingly frequent, due to the increase in life expectancy of this group of patients, a situation that is associated with the presentation of other health problems, such as increased cardiovascular risk, accelerated biological aging, chronic inflammatory process, and prolonged exposure to medications ARV [24].

Metabolism of protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) is mainly due to CYP3A4 inhibition. Pravastatin, due to its metabolic mechanism of sulfation, is of choice in patients treated with PI (except darunavir), although in some cases, it may be necessary to increase the dose of

### *Pharmacokinetic Aspects of Statins DOI: http://dx.doi.org/10.5772/intechopen.91910*

pravastatin, for example, with nelfinavir or ritonavir. The use of simvastatin, lovastatin, and atorvastatin (except pravastatin, fluvastatin, and rosuvastatin) should be avoided in patients with PI treatment, especially with ritonavir, atazanavir, saquinavir, or nelfinavir [25]. However, it is necessary to keep in mind that the combination of rosuvastatin with lopinavir/ritonavir caused an increase in the AUC and Cmax of rosuvastatin of 2.1 and 4.7 times, respectively. AUC and Cmax of rosuvastatin were increased by 213 and 600% when atazanavir/ritonavir was administered.

Efavirenz decreased the AUC of atorvastatin, simvastatin, and pravastatin by 43, 58, and 40%, respectively. It is recommended to carry out a closer follow-up and if necessary, adjust the dose of statins [26].

### *3.1.6 Calcium channel blockers*

Non-dihydropyridine calcium antagonists (verapamil and diltiazem) have a significant increase in AUC and Cmax when coadministered with simvastatin, lovastatin, and atorvastatin, due to inhibition of P-gp activity (decreased efflux) or enzymatic inhibition of CYP3A4. Lovastatin increased the AUC and Cmax of verapamil by 62.8 and 32.1%; while verapamil AUC was increased by 42.8% in the presence of atorvastatin. On the other hand, simvastatin increased its AUC and Cmax 2.6 and 4.6 times, respectively, due to the use of verapamil. Additionally, there are reports of cases of rhabdomyolysis due to the combination verapamil, cyclosporine, and simvastatin. Diltiazem can cause an increase in Cmax by 3.6 times and the AUC by 5 times of simvastatin and 3.5 times of lovastatin; effect that is not evident in the case of pravastatin [27]. It should be noted that although the inhibitory effect of diltiazem on simvastatin increases the pharmacological effect of statins, an increased risk of myopathy is also observed. According to the above, there is a report of cases of myopathy and/or rhabdomyolysis with doses equal to and greater than 20 mg of simvastatin or atorvastatin. A dose adjustment is recommended in patients treated with verapamil and simvastatin (maximum 20 mg) or lovastatin (maximum 40 mg). Pravastatin, for which no relevant interactions have been described at the CYP450 level, could be an alternative for patients who need treatment with calcium channel blockers that interfere with CYP3A4.

Dihydropyridine calcium antagonist (amlodipine) produces an increase in the Cmax and AUC of simvastatin and atorvastatin, without significant effects on lipid or blood pressure and combination therapy may be considered [28]. The separate administration of at least 4 hours of simvastatin and amlodipine minimizes the occurrence of this interaction [29, 30].

### *3.1.7 Antiarrhythmic agents*

Amiodarone is an inhibitor of CYP3A4 (irreversibly) and P-gp (reversible), causing interactions when used concomitantly with statins metabolized by CYP450 or substrates of the P-gp. There have been reports of toxicity between amiodarone and statins that are CYP3A4 substrates, particularly simvastatin. Thus, a 75% increase in AUC and Cmax of simvastatin has been demonstrated when coadministered with amiodarone. However, there are no significant pharmacokinetic interactions between amiodarone and pravastatin [31].

Muscle-related toxicity was the most commonly reported adverse event with combination therapy (77%). The percentages of simvastatin and atorvastatin adverse events reported in which amiodarone was concomitantly used were 1.0 and 0.7%, respectively. By contrast, the percentage of pravastatin adverse events in which amiodarone was used was only 0.4%. Patients on simvastatin-amiodarone combination therapy were more likely to be hospitalized and were on a higher statin dose compared with atorvastatin-amiodarone-treated patients. No dose adjustment for rosuvastatin, pravastatin, fluvastatin, and pitavastatin is necessary when coadministered concomitantly with amiodarone.

Additionally, no dose adjustments are recommended for atorvastatin because data suggest that severe interactions with amiodarone are less likely to occur than with other statins metabolized via CYP3A4 (simvastatin and lovastatin). Lovastatin should not exceed 40 mg daily when prescribed in combination with amiodarone and simvastatin, and should be limited to no more than 20 mg daily. On the basis of pharmacokinetic and observational data and adverse events reported in randomized, controlled trials, combination therapy with amiodarone and rosuvastatin, atorvastatin, pitavastatin, fluvastatin, or pravastatin is reasonable.

Coadministration of amiodarone and dronedarone with either lovastatin or simvastatin may be considered. When used in combination with amiodarone, the dose of lovastatin should not exceed 40 mg daily and the dose of simvastatin should not exceed 20 mg daily. There are no known clinically significant interactions between dronedarone and other statins.

Digoxin is not dependent on the CYP450 system because it is not known to induce or inhibit any of these enzymes. Metabolism of digoxin is primary by gut bacteria. In a study that included 24 healthy volunteers, the addition of atorvastatin 80 mg to digoxin resulted in an average increase of 20% in the Cmax of digoxin and an average 15% increase in the AUC of digoxin [32]. However, lower doses of atorvastatin (10 mg) combined with digoxin did not alter the pharmacokinetics of digoxin. Atorvastatin appears to be the only statin that is reported to have this interaction. The mechanism is not fully understood but may be mediated by an impact of atorvastatin on the intestinal secretion of digoxin medicated by the P-gp efflux transporter, resulting in an increased digoxin absorption. The existence of alternatives to atorvastatin, such as fluvastatin, pravastatin, and rosuvastatin, which do not affect P-gp, may be of choice in patients treated with digoxin.

### *3.1.8 Immunosuppressants*

The combination of statins with calcineurin inhibitors (cyclosporine and tacrolimus), due to its inhibitory effect of CYP3A4, inhibitor of OATPB1 and be substrates of P-gp, could cause an increase in serum statin levels and the risk of myopathy and rhabdomyolysis, especially at high doses of statins.

There are reports of cases of rhabdomyolysis with different statins, except fluvastatin and, to a lesser extent, pravastatin. In the case of simvastatin, AUC increases up to 20 times and the effect is enhanced by the use of other CYP3A4 enzymatic inhibitors. On the other hand, in the case of atorvastatin, cases of rhabdomyolysis present without alterations the pharmacokinetics of cyclosporine. Cyclosporine is associated with an increase in AUC and Cmax of rosuvastatin by 7.1 and 10.6 times, respectively.

There is evidence of the safety and effectiveness of fluvastatin in transplant patients treated with cyclosporine. This effect could be due to the fact that fluvastatin, compared to other statins, has a shorter elimination half-life, a greater capacity for protein binding and less circulating active metabolites. In the case of pravastatin, this drug does not accumulate significantly in plasma in patients receiving immunosuppression with cyclosporine, and with rosuvastatin, cyclosporine increased the AUC of this statin by 7.1 times.

Limited data exist on tacrolimus and statin interactions. One open-label evaluation of 13 healthy volunteers suggested that after 4 days of therapy with atorvastatin 40 mg daily, 2 doses of tacrolimus had no impact on the atorvastatin pharmacokinetics [33].

### *Pharmacokinetic Aspects of Statins DOI: http://dx.doi.org/10.5772/intechopen.91910*

In case reports, the use of sirolimus in combination with statins has been associated with muscle-related toxicity, including rhabdomyolysis. Only one randomized, open-label, three-way crossover, single-dose study in 24 healthy volunteers has suggested that everolimus had no effect on the AUC of atorvastatin 20 mg or pravastatin 20 mg [34].

The combination therapy of cyclosporine, tacrolimus, everolimus or sirolimus with lovastatin, simvastatin, and pitavastatin is potentially harmful and should be avoided. The combination of cyclosporine, tacrolimus, everolimus, or sirolimus with daily dose of fluvastatin, pravastatin and rosuvastatin may be considered and should be limited to 40, 20, and 5 mg daily, respectively. The dose of atorvastatin >10 mg daily when coadministered with cyclosporine, tacrolimus, everolimus, or sirolimus is not recommended without close monitoring of creatinine kinase and signs or symptoms of muscle-related toxicity. The combination of fluvastatinrapamycin has been linked to the appearance of rhabdomyolysis.

### *3.1.9 Macrolides*

Macrolides, especially clarithromycin, erythromycin, and telithromycin, are the most potent inhibitors of the CYP3A4 isoenzyme, followed by the weak inhibitor, roxithromycin, and finally, azithromycin. CYP3A4 is an isoenzyme that metabolizes simvastatin, lovastatin, and atorvastatin, which increases their plasma concentrations and the risk of myotoxicity. Rosuvastatin, fluvastatin, and pravastatin are not significantly affected by this interaction. Of all macrolides, azithromycin can be used with statins. Erythromycin increased the Cmax of simvastatin (in its lactone form) by 3.4 times, the AUC by 6.2 times and its acid-hydroxy acid form by 3.9 times. Erythromycin increased Cmax and AUC of atorvastatin by 37.7 and 32.5%, respectively. The effect is attributed to decreased metabolism of statins, inhibition of intestinal P-gp, and decreased bile secretion.

In general, case reports of rhabdomyolysis are available due to the interaction between simvastatin and clarithromycin, between lovastatin and erythromycin, and between clarithromycin and azithromycin [35]. A study that evaluated the effect of azithromycin and clarithromycin on the pharmacokinetics of atorvastatin showed that clarithromycin increases AUC and Cmax by 82 and 56%, respectively; meanwhile, there were no significant changes with azithromycin.

### *3.1.10 Interactions between lipid lowering agents*

Some patients may require the combination of several lipid lowering agents, the statin-fibrate association being the most common. However, the greater hypolipidemic effect is accompanied by an increased risk of myopathy, especially with gemfibrozil, due to its inhibitory effect on glucuronidation of statins, increasing the concentrations of the latter.

Gemfibrozil increases the AUC of simvastatin by 35% and the AUC of simvastatin in its acid form by 135% and of lovastatin acid by 280%. Therefore, there is a report of cases of rhabdomyolysis and kidney disease, due to the combination of gemfibrozil with simvastatin, atorvastatin, and lovastatin.

In addition, gemfibrozil increases the AUC of rosuvastatin by 1.88 times and its Cmax by 2.21 times [36]. Gemfibrozil had only a modest effect when administered with pitavastatin in 24 subjects with an increase of 45% in the AUC [37]. Metabolism is only a minor pathway for pitavastatin via CYP2C9, which is unaffected by gemfibrozil. Fluvastatin transport in hepatocytes via the OATP transporters is potently inhibited by gemfibrozil [38]. However, in at least 1 study of 17 subjects, no significant difference was observed in the AUC and Cmax in a comparison of the gemfibrozil-fluvastatin combination and gemfibrozil alone.

Related to this interaction, it is important to note that fenofibrate is considered more suitable than gemfibrozil, which is supported in studies showing the absence of interaction of fenofibrate with pravastatin, simvastatin, and atorvastatin.

However, fenofibrate may increase rosuvastatin plasma levels and there is a case report of renal failure in a patient taking this combination.

The combination of gemfibrozil with lovastatin, pravastatin, and simvastatin is potentially harmful and should be avoided. Although gemfibrozil interacts with atorvastatin, pitavastatin, and rosuvastatin, the result is only a minor increase in statin concentrations, and the combination may be considered if clinically indicated. Fluvastatin may be used in combination with gemfibrozil without any specific dose limitations, and this particular statin does not interact with gemfibrozil.

Combination therapy with fenofibrate/fenofibric acid and any statin is reasonable when clinically indicated.

Ezetimibe is well tolerated and does not interact with fluvastatin, lovastatin, rosuvastatin, or simvastatin. However, cases of myopathy have been reported in patients due to the combination ezetimibe and atorvastatin.

### *3.1.11 Antidepressants*

Although coadministration of statins and antidepressants is likely, given the association between depression and many chronic diseases, the prevalence of clinically relevant interactions between them is not well-documented.

With the exception of atorvastatin and fluvastatin, which inhibit the activity of CYP3A4 and CYP2C9, respectively, most statins do not appear to be inhibitors or inducers of the main drug metabolizing enzymes. On the other hand, some antidepressants act as inhibitors of several CYPs and, therefore, may impair the elimination of statins metabolized through these isoforms. Based on this knowledge, it can be anticipated that concomitant use of nefazodone or fluvoxamine, potent or moderate CYP3A4 inhibitors, respectively, with atorvastatin, lovastatin, or simvastatin should increase the plasma concentrations of these statins.

Statin metabolism may be susceptible to OATP inhibition by imipramine, nortriptyline, and amitriptyline, with a possible increase in drug concentration. Atorvastatin, a CYP3A4 inhibitor, can act on the metabolism of tricyclic antidepressants (excluding nortriptyline). Also, an interaction between imipramine (a P-gp substrate) and statins (P-gp inhibitors) could be hypothesized.

Fluvoxamine is the only moderate CYP3A4 inhibitor, and may be associated with an increased risk of interactions if administered with atorvastatin, lovastatin, and simvastatin. While the potential interaction between fluoxetine and statins has not been investigated in humans, experimental evidence in animal models found that the combination of simvastatin with fluoxetine may enhance anxiolytic and antidepressant properties. Both fluvoxamine and fluoxetine act as moderate inhibitors of CYP2C9 activity and, in theory, can increase plasma concentrations of fluvastatin, which is metabolized primarily through this isoform. However, the magnitude of this interaction would probably be below the threshold of clinical importance. Due to the theoretical risk of a metabolic interaction, lower doses of atorvastatin, lovastatin, and simvastatin may be indicated in patients treated with fluvoxamine. On the other hand, it is unlikely that the pharmacokinetics of pitavastatin and rosuvastatin, minimally metabolized by CYP2C9, may be significantly affected by the coadministration of fluvoxamine and fluoxetine.

In the case of joint administration of selective inhibitors reuptake serotonins (SSRIs) with statins, escitalopram, citalopram, and sertraline appear to be safe with all statins.

### *Pharmacokinetic Aspects of Statins DOI: http://dx.doi.org/10.5772/intechopen.91910*

Coadministration with statins metabolized through CYP3A4 (atorvastatin, simvastatin, and lovastatin) or, to a lesser extent, fluvastatin through CYP2D6, could lead to a potentially competitive inhibition. However, there are no clinical or in vitro studies available on possible interactions between serotonin and norepinephrine reuptake inhibitor (SNRI)/norepinephrine reuptake inhibitor (NRI)/vortioxetine and statins. Venlafaxine and duloxetine have two main metabolic pathways: CYP2D6 and CYP3A4 or CYP2D6 and CYP1A2, respectively.

There are no studies on the coadministration of specific noradrenergic and serotonergic antidepressants (NaSSA), mirtazapine coadministered with statins. According to in vitro studies, mirtazapine is metabolized by CYP1A2, CYP2D6 and, to a lesser extent by CYP3A4 and inhibits CYP2D6 and CYP1A2 with negligible potency. Therefore, there is a low probability of interactions.

With respect to the norepinephrine-dopamine reuptake inhibitor (NDRI), bupropion is a moderate CYP2D6 inhibitor and is metabolized by CYP2D6. Considering the lacking of in vitro and in vivo pharmacokinetics studies and the metabolic pathway of statins, with only fluvastatin metabolized to a lesser extent by CYP2D6 and the high rate of renal excretion (>85%), the intereactions pharmacokinetics are no probable [39].

### *3.1.12 Other drugs*

The joint use of simvastatin with *erlotinib* or *imatinib* has been related to cases of rhabdomyolysis. In addition, imatinib (CYP3A4 inhibitor) increases the AUC of simvastatin 3.5 times [40].

With the concomitant use of simvastatin and *pazopanib*, an increase in the incidence of ALT elevations has been documented, so simvastatin treatment should be discontinued when these alterations are observed. In addition, it cannot be ruled out that pazopanib affects the pharmacokinetics of other statins (atorvastatin, fluvastatin, and rosuvastatin). This potential for interaction and morbidity in cancer patients can be minimized by the use of pravastatin, instead of simvastatin, since this drug is excreted by the kidneys and has no significant metabolism via CYP3A4.

The interaction of *Rifampicin* with pravastatin is contradictory, on the one hand in one study, rifampin increased the AUC of pravastatin by 2 times; while another, in healthy volunteers, showed that rifampicin decreases plasma statin levels by 40%. With atorvastatin, rifampin decreases the AUC of atorvastatin by 80%. In the case of simvastatin, the decrease reaches 87%. On the other hand, with rosuvastatin, the effect was minor and was not considered clinically relevant.

**Cholestyramine:** there is possible reduction of plasma levels of statins, by fixation to the resin in the intestinal lumen and lipid-lowering activity, although clinical practice seems to indicate otherwise. It is recommended to administer the statin 1 hour before or 4 hours after the resin.

**Sildenafil:** there is a report of myopathy with rosuvastatin and a case of rhabdomyolysis with simvastatin.

**Ciprofloxacin (weak CYP3A4 inhibitor):** there is a report of rhabdomyolysis with simvastatin.

**Efalizumab:** there is a case report of rhabdomyolysis with pravastatin.

**Danazol:** it is a moderate androgen receptor agonist and a partial progestogenic agonist. It is able to inhibit the metabolism of some statins by increasing their plasma concentrations. Cases of myopathy and rhabdomyolysis have been described. Likewise, a case of acute pancreatitis was published in an 80-year-old patient treated with this combination of drugs. Although documented cases affect simvastatin and

lovastatin, it is advisable to exercise caution with any statin administered in conjunction with danazol and control the occurrence of muscle symptoms.

**Risperidone and simvastatin:** risperidone inhibits the oxidative metabolism of statin and increases its toxicity with a risk of rhabdomyolysis. Muscle pain and weakness, with increased creatin kinase, have been reported in a patient with simvastatin 30 mg/day, 12 days after taking risperidone 1 mg/24 h.

In patients taking *ranolazine,* the use of statins, whose metabolism is highly dependent on CYP3A4 as simvastatin or lovastatin, should be limited due to the risk of rhabdomyolysis [3].

### **3.2 Drug-food interactions**

There are phytotherapeutic agents that can interact with medications. St. John's wort is a CYP3A4 enzyme inducer, while grapefruit juice is an enzyme inhibitor.

Some studies show a decrease in statin concentrations and, therefore, their effectiveness when St. John's wort is administered with rosuvastatin, atorvastatin, or simvastatin. The effect is not observed for pravastatin. It is recommended to avoid grapefruit juice with lovastatin and simvastatin; avoid large quantities of grapefruit just if taking atorvastatin (increases in area-under-the-curve to 2.5-fold have been reported with consumption of ≥750 mL to 1.2 L per day). In the case of lovastatin, grapefruit juice causes a 12-fold increase in Cmax and 15-fold increase in AUC; on the other hand, for the acid form of lovastatin, the increase in Cmax was 4 times, and in AUC, it was 5 times. In the case of orange juice, its administration has been linked to a significant increase of pravastatin AUC in healthy volunteers [2].

Red yeast rice is a popular over-the-counter treatment for hyperlipidemia. Red yeast rice has varying amounts of monacolin K (similar to lovastatin). The products are not standardized and no red yeast rice product should be administered to a patient taking a prescribed statin.

Licorice (*Glycyrrhiza glabra* L., Licorice) in vitro has shown a slight inhibition of CYP3A4 and CYP2D6. Some cases of muscular alteration with increased creatin kinase and, in some cases, rhabdomyolysis have been reported in patients taking high amounts. The risk may increase when associated with drugs that cause muscle toxicity, such as statins, so their combination should be avoided [41].

### **3.3 Influence of genetic variations in the pharmacokinetic profile of the statins**

The activity of the CYP3A4 and CYP2C9 isoenzymes has great interindividual variability as a result of their genetic polymorphism. SLCO1B1 polymorphisms (gene encoding the organic anion transport polypeptide, OATP1B1) can cause variability in statin plasma levels. OATP1B1 affects the hepatic uptake of statins, where statins are going to be metabolized and exert their action at the intracellular level. A reduced activity of OATP1B1 may decrease their efficacy and increase their plasma concentrations, with the consequent risk of muscle toxicity.

Thus, the Genome Wide Association Study (GWAS) studied 300,000 polymorphisms in patients treated with statins and who had presented myopathies in front of a control group with statins and who had not presented myopathies. The conclusions reached were: patients who presented the C521T > C polymorphism of the SLCO1B1 gene (also encoded as SLCO1B1\* 5) should not receive treatment with statins, since they have a high risk of suffering from myalgias or myopathy after a few months of treatment; patients with polymorphisms of the CYP2C9 gene that conditions a poor metabolizer (PM) phenotype of the CYP2C9 enzyme (although they do not present mutations in the SLCO1B1 gene) will eliminate fluvastatin less efficiently and may have myopathies (administration of other types of statins is

### *Pharmacokinetic Aspects of Statins DOI: http://dx.doi.org/10.5772/intechopen.91910*

recommended); simvastatin, atorvastatin, and lovastatin are eliminated by cytochrome CYP3A4 and CYP3A4 polymorphisms that induce poor metabolizers (PM) have not been found, but it must be taken into account that many drugs are potent CYP3A4 inhibitors and a comedication with these statins could induce myopathies due to drug interaction. The application of genetic information to individualize pharmacological treatments to maximize efficacy and avoid adverse events, or pharmacogenetics, is an important component of precision medicine [42].

### **4. Conclusions**

A review of all medications that are treated by patients treated with statins should be performed at each medical consultation and during all healthcare transitions within a health system so that drug interactions can be identified early, evaluated, and properly managed, implementing adjustments of dose, changing to another safer statin or discontinuing when necessary. A thorough understanding of the pharmacokinetics of statins and other concomitantly administered medications is paramount to ensure patient safety.

### **Conflict of interest**

The authors declare no conflict of interest.

### **Author details**

Lucía Cid-Conde1 and José López-Castro2 \*

1 Pharmaceutical Specialist in Hospital Pharmacy, University Hospital Complex of Ourense, Ourense, Spain

2 Internal Medicine Department Hospital Público de Monforte, Lugo, Spain

\*Address all correspondence to: jose.lopez.castro@sergas.es

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Yan MM, Wu SS, Ying YQ, Lu N, Zhong MK. Safety assessment of concurrent statin treatment and evaluation of drug interactions in China. SAGE Open Medicine. 2018;**6**:1-9

[2] Wiggins BS, Saseen JJ, Page RL, Reed BN, Sneed K, Kostis JB, et al. Recommendations for management of clinically significant drug-drug interactions with statins and select agents used in patients with cardiovascular disease. Circulatión. 2016;**134**(21):e468-e495

[3] Kellick KA, Bottorff M, Toth PP. A clinician's guide to statin drug-drug interactions. Journal of Clinical Lipidology. 2014;**8**:S30-S46

[4] Serebruany VL, Midei MG, Malinin AI, Oshrine BR, Lowry DR, Sane DC, et al. Absence of interaction between atorvastatin or other statins and clopidogrel: Results from the interaction study. Archives of Internal Medicine. 2004;**164**(18):2051-2057

[5] Siepmann T, Heinke D, Kepplinger J, Barlinn K, Gehrisch S, Grählert X, et al. Interaction of clopidogrel and statins in secondary prevention after cerebral ischaemia—A randomized, doubleblind, double-dummy crossover study. British Journal of Clinical Pharmacology. 2014;**78**(5):1058-1066

[6] Han YL, Zhang ZL, Li Y, Wang SL, Jing QM, Wang ZL, et al. Comparison on long-term effects of atorvastatin or pravastatin combined with clopidogrel for patients undergoing coronary stenting: A randomized controlled trial. Zhonghua Yi Xue Za Zhi. 2009A;**89**(32): 2240-2244

[7] Wenaweser P, Eshtehardi P, Abrecht L, Zwahlen M, Schmidlin K, Windecker S, et al. A randomised determination of the effect of fluvastatin and atorvastatin on top of dual antiplatelet treatment on

platelet aggregation after implantation of coronary drug-eluting stents. The EFA-trial. Thrombosis and Haemostasis. 2010;**104**(3):554-562

[8] lagojevic A, Delaney JA, Lévesque LE, Dendukuri N, Boivin JF, Brophy JM. Investigation of an interaction between statins and clopidogrel after percutaneous coronary intervention: A cohort study. Pharmacoepidemiology and Drug Safety. 2009;**18**(5):362-369

[9] Tetik S, Ak K, Isbir S,

Eksioglu-Demiralp E, Arsan S, Iqbal O, et al. Clopidogrel provides significantly greater inhibition of platelet activity than aspirin when combined with atorvastatin after coronary artery bypass grafting: A prospective randomized study. Clinical and Applied Thrombosis/ Hemostasis. 2010;**16**(2):189-198

[10] Teng R, Mitchell PD, Butler KA. Pharmacokinetic interaction studies of co-administration of ticagrelor and atorvastatin or simvastatin in healthy volunteers. European Journal of Clinical Pharmacology. 2013;**69**:477-487

[11] Simonson SG, Martin PD, Mitchell PD, Lasseter K, Gibson G, Schneck DW. Effect of rosuvastatin on warfarin pharmacodynamics and pharmacokinetics. Journal of Clinical Pharmacology. 2005;**45**:927-934

[12] Yu CY, Campbell SE, Zhu B, Knadler MP, Small DS, Sponseller CA, et al. Effect of pitavastatin vs. rosuvastatin on international normalized ratio in healthy volunteers on steadystate warfarin. Current Medical Research and Opinion. 2012;**28**:187-194

[13] Stern R, Abel R, Gibson GL, Besserer J. Atorvastatin does not alter the anticoagulant activity of warfarin. Journal of Clinical Pharmacology. 1997;**37**:1062-1064

*Pharmacokinetic Aspects of Statins DOI: http://dx.doi.org/10.5772/intechopen.91910*

[14] Guidoni CM, Camargo HPM, Obreli-Neto PR, Girotto E, Pereira LRL. Study of warfarin utilization in hospitalized patients: Analysis of possible drug interactions. International Journal of Clinical Pharmacy. 2016;**38**: 1048-1051

[15] Van Stee MF, De Graaf AA, Groen AK. Actions of metformin and statins on lipid and glucose metabolism and possible benefit of combination therapy. Cardiovascular Diabetology. 2018;**17**(1):94

[16] Bhome R, Penn H. Rabdomiólisis precipitada por una interacción farmacológica sitagliptina-atorvastatina. Diabetic Medicine. 2012;**29**(5):693-694

[17] Kao DP, Kohrt HE, Kugler J. Insuficiencia renal y rabdomiólisis asociadas con el uso de sitagliptina y simvastatina. Diabetic Medicine. 2008;**25**(10):1229-1230

[18] Bergman AJ, Cote J, Maes A, et al. Efecto de sitagliptina sobre la farmacocinética de simvastatina. Journal of Clinical Pharmacology. 2009;**49**(4):483-488

[19] Cerra M, Luo WL, Li SX, et al. Los efectos de la simvastatina en la farmacocinética de sitagliptina. Journal of Population Therapeutics and Clinical Pharmacology. 2012;**19**(3):e356-e360

[20] DiGregorio RV, Pasikhova Y. Rhabdomyolysis caused by a potential sitagliptin-lovastatin interaction. Pharmacotherapy. 2009;**29**(3):352-356

[21] Eljaaly K, Alshehri S. An updated review of interactions of statins with antibacterial and antifungal agents. Journal of Translational Science. 2017;**3**(3):1-4

[22] Tiessen RG, Lagerwey HJ, Jager GJ, Sprenger HG. Drug interaction caused by communication problems. Rhabdomyolysis due to a combination

of itraconazole and simvastatin. Nederlands Tijdschrift voor Geneeskunde. 2010;**154**:A762

[23] Cooper KJ, Martin PD, Dane AL, Warwick MJ, Schneck DW, Cantarini MV. The effect of fluconazole on the pharmacokinetics of rosuvastatin. European Journal of Clinical Pharmacology. 2002;**58**:527-531

[24] Robert SR, Colantonio LD, Burkholder GA, Chen L, Muntner P. Trends in utilization of statin therapy and contraindicated statin use in HIV--infected adults treated with antiretroviral therapy from 2007 through 2015. Journal of the American Heart Association. 2018;**7**(24):1-18

[25] Giraldo NA, Amariles P, Gutiérrez FJ, Monsalve M, Faus MJ. Interacciones medicamentosas en pacientes infectados con el VIH: aproximación para establecer y evaluar su relevancia clínica: actualización 2009. Farmacia Hospitalaria. 2010;**3**(4):90-93

[26] Gerber JG, Rosenkranz SL, Fichtenbaum CJ, Vega JM, Yang A, Alston BL, et al. AIDS Clinical Trials Group A5108 team. Effect of efavirenz on the pharmacokinetics of simvastatin, atorvastatin, and pravastatin: Results of AIDS Clinical Trials Group 5108 study. Journal of Acquired Immune Deficiency Syndromes. 2005;**39**:307-312

[27] Hu M, Mak VW, Tomlinson B. Simvastatin-induced myopathy, the role of interaction with diltiazem and genetic predisposition. Journal of Clinical Pharmacy and Therapeutics. 2011;**36**:419-425

[28] Nishio S, Watanabe H, Kosuge K, Uchida S, Hayashi H, Ohashi K. Interaction between amlodipine and simvastatin in patients with hypercholesterolemia and hypertension. Hypertension Research. 2005;**28**:223-227

[29] Park CG, Lee H, Choi JW, Lee SJ, Kim SH, Lim HE. Non-concurrent dosing attenuates the pharmacokinetic interaction between amlodipine and simvastatin. International Journal of Clinical Pharmacology and Therapeutics. 2010;**48**:497-503

[30] Zhou Y-T, Yu L-S, Zeng S, Huang Y-W, Xu H-M, Zhou Q . Pharmacokinetic drugdrug interactions between 1,4-dihydropyridine calcium channel blockers and statins: Factors determining interaction strength and relevant clinical risk management. Therapeutics and Clinical Risk Management. 2014;(10):17-26

[31] Becquemont L, Neuvonen M, Verstuyft C, Jaillon P, Letierce A, Neuvonen PJ, et al. Amiodarone interacts with simvastatin but not with pravastatin disposition kinetics. Clinical Pharmacology and Therapeutics. 2007;**81**(5):679-684

[32] Boyd RA, Stern RH, Stewart BH, Wu X, Reyner EL, Zegarac EA, et al. Atorvastatin coadministration may increase digoxin concentrations by inhibition of intestinal P-glycoproteinmediated secretion. Journal of Clinical Pharmacology. 2000;**40**:91-98

[33] Lemahieu WP, Hermann M, Asberg A, Verbeke K, Holdaas H, Vanrenterghem Y, et al. Combined therapy with atorvastatin and calcineurin inhibitors: no interactions with tacrolimus. American Journal of Transplantation. 2005;**5**:2236-2243

[34] Basic-Jukic N, Kes P, Bubic-Filipi L, Vranjican Z. Rhabdomyolysis and acute kidney injury secondary to concomitant use of fluvastatin and rapamycin in a renal transplant recipient. Nephrology, Dialysis, Transplantation. 2010;**25**:2036. author reply 2036-2037

[35] Molden E, Andersson KS. Simvastatin-associated rhabdomyolysis after coadministration of macrolide antibiotics in two patients. Pharmacotherapy. 2007;**27**:603-607

[36] Bergman E, Matsson EM, Hedeland M, Bondesson U, Knutson L, Lennernäs H. Effect of a single gemfibrozil dose on the pharmacokinetics of rosuvastatin in bile and plasma in healthy volunteers. Journal of Clinical Pharmacology. 2010;**50**:1039-1049

[37] Mathew P, Cuddy T, Tracewell WG, Salazar D. An open-label study on the pharmacokinetics (PK) of pitavastatin (NK-104) when administered concomitantly with fenofibrate or gemfibrozil in healthy volunteers. Clinical Pharmacology and Therapeutics. 2004;**75**:33

[38] Noé J, Portmann R, Brun ME, Funk C. Substrate-dependent drugdrug interactions between gemfibrozil, fluvastatin and other organic aniontransporting peptide (OATP) substrates on OATP1B1, OATP2B1, and OATP1B3. Drug Metabolism and Disposition. 2007;**35**:1308-1314

[39] Palleria C, Roberti R, Iannone LF, Tallarico M, Barbieri MA, Vero A, et al. Clinically relevant drug interactions between statins and antidepressants. Journal of Clinical Pharmacy and Therapeutics. 2019. DOI: 10.1111/ jcpt.13058

[40] Weeraputhiran M, Sundermeyer M. Rhabdomyolysis resulting from pharmacologic interaction between erlotinib and simvastatina. Clinical Lung Cancer. 2008;**4**(9):232-234

[41] Vaquero MP, Sánchez Muniz FJ, Jiménez Redondo S, Prats Oliván P, Higueras FJ, Bastida S. Major diet-drug interactions affecting the kinetic characteristics and hypolipidaemic properties of statins. Nutrición Hospitalaria. 2010;**25**(2):193-206

*Pharmacokinetic Aspects of Statins DOI: http://dx.doi.org/10.5772/intechopen.91910*

[42] Maggo SDS, Kennedy MA, Clark DWJ. Clinical implications of pharmacogenetic variation on the effects of statins. Drug Safety. 2011;**34**:1-19

## *Edited by Alaeddin Abukabda, Maria Suciu and Minodora Andor*

This book provides a broad overview of the molecular mechanisms associated with relevant and significant cardiovascular conditions that continue to plague humanity. It also discusses potential and promising therapeutic avenues targeted at addressing these conditions. The overarching goal of this multifaceted work is to entice future and current members of the scientific community to direct their endeavors towards improving our current knowledge of cardiovascular disease conditions and curb their impact on our everyday lives.

Published in London, UK © 2021 IntechOpen © Lars Neumann / iStock

Cardiovascular Risk Factors in Pathology

Cardiovascular Risk Factors

in Pathology

*Edited by Alaeddin Abukabda,* 

*Maria Suciu and Minodora Andor*