319 REVIEW ARTICLE The benefits of statin therapy outweigh their side effects Copyright (c) 2022 Slovenian Medical Journal. This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. The benefits of statin therapy outweigh their side effects Koristi zdravljenja s statini odtehtajo njihove stranske učinke Tadeja Sotler,1 Miran Šebeštjen,1,2 Abstract Statins have been among the most commonly prescribed drugs in more than twenty years. By reducing LDL cholesterol, drugs from this group significantly reduce cardiovascular morbidity and mortality. Statins competitively inhibit the active site of the first and critical rate-limiting enzyme in the mevalonate pathway, HMG-CoA reductase. In addition to the effects on lowering LDL cholesterol, their mechanism of action is also responsible for most of the side effects. However, we do not have reliable data for that statement. The most common side effects, which are also the reason for discontinuing statin treatment, are related to muscle pain. The exact extent of the muscle adverse effects is not known, as we do not have a uniform definition of these side effects. Other side effects include newly onset of type 2 diabetes, hepatotoxicity, haemor- rhagic stroke, and neurological disorders. Despite all these side effects, the benefits of statin treatment far outweigh these side effects. Despite new therapies to lower LDL cholesterol and thus reduce cardiovascular mortality, statin therapy will remain the first choice in both primary and secondary prevention for the next few years. The main drawback of the new therapies is that we do not have enough data on their long-term efficacy and safety. In any case, we should not neglect the economic aspect either, as the cost-effectiveness of statins is much higher compared to new drugs. Izvleček Zdravila iz skupine statinov so v zadnjih več kot 20 letih ena najpogosteje predpisovanih zdravil. Poleg znižanja koncen- tracije holesterola LDL namreč zelo pomembno znižajo srčnožilno obolevnost in umrljivost. Statini kompetitivno zavirajo aktivno mesto reduktaze HMG-CoA prvega in ključnega hitrost omejujočega encima v mevalonatni poti. Ta mehanizem je poleg zmanjšanja vrednosti holesterola LDL najverjetneje odgovoren tudi za večino stranskih učinkov, čeprav za to ni zanesljivih dokazov. Najpogostejši stranski učinki, ki so tudi vzrok za prekinitev zdravljenja, so povezani z mišičnimi bo- lečinami, čeprav natančne razširjenosti ne poznamo, saj ni enotne definicije teh stranskih učinkov. Drugi stranski učinki so še novo nastala sladkorna bolezen tipa 2, hepatotoksičnost, hemoragična možganska kap in nevrološke motnje. Vsem tem stranskim učinkom navkljub je korist zdravljenja s statini mnogo večja od navedenih stranskih učinkov. Kljub novim terapijam za znižanje holesterola LDL in zato zmanjšani srčnožilni umrljivosti bo terapija s statini še naslednjih nekaj let 1 Department of Cardiology, University Medical Centre Ljubljana, Ljubljana, Slovenia 2 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia Correspondence / Korespondenca: Miran Šebeštjen, e: miran.sebestjen@kclj.si Key words: statins; cholesterol; cardiovascular events; adverse effects; toxicity Ključne besede: statini; holesterol; srčnožilni dogodki; stranski učinki; toksičnost Received / Prispelo: 13. 1. 2021 | Accepted / Sprejeto: 18. 1. 2022 Cite as / Citirajte kot: Sotler T, Šebeštjen M. The benefits of statin therapy outweigh their side effects. Zdrav Vestn. 2022;91(7–8):319–31. DOI: https://doi.org/10.6016/ZdravVestn.3217 eng slo element en article-lang 10.6016/ZdravVestn.3217 doi 13.1.2021 date-received 18.1.2022 date-accepted Cardiovascular system Srce in obtočila discipline Review article Pregledni znanstveni članek article-type The benefits of statin therapy outweigh their side effects Koristi zdravljenja s statini odtehtajo njihove stranske učinke article-title The benefits of statin therapy outweigh their side effects Koristi zdravljenja s statini odtehtajo njihove stranske učinke alt-title statins, cholesterol, cardiovascular events, adverse effects, toxicity statini, holesterol, srčnožilni dogodki, stranski učinki, toksičnost kwd-group The authors declare that there are no conflicts of interest present. Avtorji so izjavili, da ne obstajajo nobeni konkurenčni interesi. conflict year volume first month last month first page last page 2022 91 7 8 319 331 name surname aff email Miran Šebeštjen 1,2 miran.sebestjen@kclj.si name surname aff Tadeja Sotler 1 eng slo aff-id Department of Cardiology, University Medical Centre Ljubljana, Ljubljana, Slovenia Klinični oddelek za kardiologijo, Interne klinike, Univerzitetni klinični center Ljubljana, Ljubljana, Slovenija 1 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia Katedra za interno medicino, Medicinska fakulteta, Univerza v Ljubljani, Ljubljana, Slovenija 2 Slovenian Medical Journallovenian Medical Journal 320 CARDIOVASCULAR SYSTEM Zdrav Vestn | July – August 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3217 1 Introduction Statins are one of the most commonly prescribed drugs, reducing cardiovascular morbidity and mortal- ity by lowering LDL cholesterol in both primary and secondary prevention (1). Randomized double-blind studies have shown that lowering LDL cholesterol by 1 mmol/L reduces the relative risk of significant cardiovas- cular events by 22% (2). Despite the widespread use of statins to lower LDL cholesterol and thus also to reduce cardiovascular morbidity and mortality, discontinuation and non-cooperation are very big problems. The reason for this is most often statin-induced muscle symptoms. Other, significantly fewer common causes are diabetes, neurological and neurocognitive effects, and hepato- and nephrotoxicity (3). The patient’s attitude towards the drug depends mainly on their experience and beliefs. Figure 1: Schematic representation of the positive and adverse effects of statins. The numbers shown represent absolute values. Negative beliefs about the drug are an even greater rea- son for non-cooperation than other factors, such as the price of the drug. A study examining the opinions of statin users on social networks has shown that patients are most often concerned because they do not trust drug manufacturers and because they believe statins are harmful or that they do more harm than good (4). The purpose of this review article is to describe both the pos- itive and negative sides of statin therapy and the possible mechanisms of their action (Figure 1, Table 1). 2 Treatment guidelines In the latest ESC/EAS guidelines for the management of dyslipidaemias from 2019, one of the most important ostala prva izbira tako pri primarni kot tudi sekundarni preventivi, saj še ni dovolj podatkov o dolgoročni učinkovitosti in predvsem varnosti novih zdravil. Nikakor pa ne smemo zanemariti niti ekonomskega vidika, saj je stroškovna učinkovitost statinov v primerjavi z novimi zdravili zaenkrat še mnogo večja. 321 REVIEW ARTICLE The benefits of statin therapy outweigh their side effects Positive effects Adverse effects Statin-induced effects: • reduction of cardiovascular morbidity and mortality; • improvement of endothelial dysfunction; • stabilization of atherosclerotic plaques; • anti-inflammatory effects; • immunomodulatory effects; • antithrombotic effects; • reduction of the risk of dementia; • beneficial effects on bone metabolism. Statin-induced effects: • myalgia; • toxic myopathy; • immune-mediated myopathy; • rhabdomyolysis. Type 2 diabetes. Neurological and neurocognitive effects: • haemorrhagic stroke; • cognitive decline; • peripheral neuropathy; • depression; • confusion and memory loss; • aggressiveness; • personality changes. Hepatotoxicity. Nephrotoxicity. Table 1: Positive and adverse effects of statins. innovations was a change in therapy goals. Target values for lowering LDL cholesterol, which is still the main goal of dyslipidaemia management, are even lower, except in patients at low cardiovascular risk. The recommended reduction in LDL cholesterol level in the group of pa- tients at very high cardiovascular risk is more than 50% or below 1.4 mmol/L, in the high-risk group it is more than 50% or below 1.8 mmol/L, and in the moderate-risk group the target is less than 2.6 mmol/L. Lower LDL cho- lesterol target values therefore also mean higher treat- ment intensity. The guidelines state that statin therapy reduces LDL cholesterol by up to 50% and can be used in combination with other cholesterol-lowering drugs. A 1 mmol/L reduction in LDL cholesterol with statins is associated with a 22% reduction in the incidence of sig- nificant cardiovascular events, a 23% reduction in coro- nary events, a 17% reduction in coronary death, a 17% reduction in stroke incidence, and a 10% reduction in all-cause mortality. The beneficial effects are most pro- nounced in the first year of treatment. The choice of sta- tin depends on the cardiovascular risk and therapy goals of the individual patient, but the response to treatment, associated diseases, and the use of other drugs should al- ways be considered. The guidelines state a strategy for a sequential drug introduction (first high-intensity statin therapy, then ezetimibe, and finally a PCSK9 inhibitor) and mention the possibility of directly adding a PCSK9 inhibitor to statins. If LDL cholesterol target values are not reached at the highest statin dose the patient still tol- erates, a combination with ezetimibe is recommended. Combination with a PCSK9 inhibitor is advised in sec- ondary prevention in patients at very high cardiovascu- lar risk who do not reach LDL cholesterol target values at the highest statin and ezetimibe doses. The guidelines also recommend statins as the first drug of choice to re- duce cardiovascular risk in patients with hypertriglyce- ridaemia, but are not effective in some specific patient groups, such as patients with heart failure and those with haemodialysis (5). The analysis of 19 studies conducted for the US Food and Drug Administration (FDA) included 71,344 pa- tients treated with various statins in primary and sec- ondary prevention over a period of six months to six years. They found that in a group ranging from eight to 286 patients, 72 patients needed to be treated to prevent any cardiovascular event. To prevent one heart attack in groups ranging from 45 to 263 patients, 123 patients had to be treated. One study stated that only 11 patients needed to be treated to prevent one stroke. However, ex- cluding this study, others found that the number of pa- tients needed to be treated to prevent one such event was 263 patients in groups ranging from 92 to 625 patients. All of these studies have shown that diabetes occurred in every 99th subject (6). 3 Mechanism of action of statins The most important effects of statins are lowering LDL cholesterol and thus reducing cardiovascular mor- bidity and mortality. Statins competitively inhibit the ac- tive site of the first and key rate-limiting enzyme of the mevalonate pathway, HMG-CoA reductase. Inhibition of this site prevents access to the substrate, thus inhib- iting the conversion of HMG-CoA to mevalonic acid. In the liver, cholesterol synthesis is reduced, which leads to increased production of microsomal HMG-CoA 322 CARDIOVASCULAR SYSTEM Zdrav Vestn | July – August 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3217 reductase and increased expression of LDL receptors on the cell surface. This leads to an increased removal of LDL from the bloodstream and thus a 20-55% reduction in LDL levels in it. In addition to lowering LDL levels and reducing cardiovascular morbidity and mortality, statins are thought to have additional pleiotropic ef- fects not related to lipids. These include improving en- dothelial function, stabilizing atherosclerotic plaques, anti-inflammatory, immunomodulatory and antithrom- botic effects, effects on bone metabolism, and reduced risk of dementia. Analysis of some studies has shown that statins reduce the risk of cardiovascular events to a greater extent than just by lowering LDL cholesterol lev- els, and that they increase survival even in patients who had had a heart attack and who have normal cholesterol levels (7). There are therefore lipid-dependent and lip- id-independent mechanisms that contribute to the clin- ically beneficial effects of statins. Inhibition of HMG- CoA reductase also reduces the production of non-sterol mevalonate derivatives. The most important non-sterol mevalonate derivatives are farnesyl and geranylgeranyl pyrophosphate, which play a key role in protein pre- nylation and in inhibiting the synthesis of isoprenoid intermediates in the mevalonate pathway (8). Posttrans- lational protein prenylation, which modifies proteins into more hydrophobic molecules, is important for cell signalling, differentiation, growth regulation, and mem- brane transport. Non-sterol mevalonate derivatives are thought to be responsible, among others, for the effect of statins on some key reactions in the coagulation and fibrinolysis cascade (9). The active ingredient of statins is a modified portion of 3,5-dihydroxyglutaric acid, which is structurally sim- ilar to the endogenous substrate, HMG-CoA, and the mevaldyl-CoA transition state intermediate. The ring substituents determine the solubility and pharmacolog- ical properties of the statin (10,11). Atorvastatin, lovas- tatin, simvastatin, and fluvastatin are lipophilic and are metabolized by the cytochrome P450 system. Pravastatin and pitavastatin are hydrophilic and due to this property undergo minimal metabolism in the liver. Rosuvastatin is somewhere in the middle in terms of these properties (12). 4 Statin toxicity The most common toxic effects are statin-associ- ated muscle symptoms (SAMS) (13,14). The exact fre- quency of these side effects is unknown. According to the results of cross-sectional studies, muscle symptoms occur in 10–15% of patients (15-18), and some clinical registries describe as much as 30% incidence of muscle symptoms (14,16). In randomized, double-blind, place- bo-controlled studies, the incidence of these symptoms in 1.5–5% of subjects were definitely underestimated, as patients with a history of statin intolerance were exclud- ed from these studies before randomization or during the induction period (14,15,19,20). However, it is also difficult to determine the exact incidence, as there is no single definition for muscle symptoms. Other side ef- fects of statin therapy include the onset of type 2 dia- betes, neurological and cognitive effects, hepatotoxicity, impaired renal function, and other less common side effects (21). Statin toxicity is thought to be a result of inhibition of the HMG-CoA reductase enzyme, direct cellular and subcellular effects, or a combination of both (22). Other possible causes include genetic factors, interactions with other drugs, vitamin D levels, and other metabolic or im- mune effects (15). Regardless of the mechanism, the end result is a change in the bioavailability and activity of the drug (23). The main predisposing factors are age due to the likely presence of several other diseases (renal or he- patic dysfunction), concomitant use of other drugs that may affect statin function, decreased body weight, and cognitive impairment (17). The only side effects clearly demonstrated in randomized double-blind studies were, in addition to haemorrhagic stroke, muscle symptoms and type 2 diabetes. However, the absolute risk of these side effects is small compared to the absolute benefits of statin therapy (Table 2). 5 Statin-associated muscle symptoms Muscle symptoms are by definition muscle pain, tension or muscle weakness together with an increase in creatinine kinase (CK) concentration to at least ten times the upper limit of normal (24). The most severe form of muscle damage is rhabdomyolysis, which can also lead to acute renal failure or exacerbation of chronic renal failure mainly due to increased concentrations of myoglobin in the blood (25). Myopathies are rare in patients without associated diseases, although the relative risk of muscle pain is high (25). However, the absolute risk is very small, occurring in one patient per 10,000 patients treated for one year, while the incidence of rhabdomyolysis is two to three patients per 100,000 patients treated for one year (26). From a clinical point of view, muscle symptoms can be divided into four groups: rhabdomyolysis with a high concentration of CK (> 100 times the upper limit of normal (ULN)), myoglobinuria and renal impairment; 323 REVIEW ARTICLE The benefits of statin therapy outweigh their side effects Legend: CI – confidence interval; HPS – Heart Protection Study; JUPITER – Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin trial; CHD – coronary heart disease; MI – myocardial infarction; PAD – peripheral artery disease; PROSPER – Prospective Study of Pravastatin in the Elderly at Risk; SEARCH – Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine; SPARCL – Stroke Prevention by Aggressive Reduction in Cholesterol Levels; CD – cardiovascular disease; TIA – transient ischaemic attack. Study (reference) Subjects (age) Intervention Impact on cardiovascular events (ratio of prospects (95% CI)) Muscle symptoms (% of patients) Diabetes Neurological side effects SEARCH (25) 12,064 survivors of MI (ages 18–80) 80 mg simvastatin daily versus 20 mg simvastatin daily Coronary events (0.94 (0.88–1.01)) stroke (0.85 (0.60–1.21)) myopathy 53 (1%) versus two (0.03%) not studied haemorrhagic stroke (odds ratio (0.91 CI (0.77–1.09)) HPS (26) 20,536 patients with CHD, PAD or diabetes (ages 40–80) 40 mg simvastatin daily versus placebo Coronary events (0.73 (0.76–0.97)) stroke (0.75 (0.66–0.85)) myalgia 32.9% versus 33.2% not studied haemorrhagic stroke 51 (0.5%) versus 53 (0.5%) JUPITER (33) 17,802 healthy subjects 20 mg rosuvastatin daily versus placebo MI (0.46 (0.30– 0.70)) stroke (0.52 (0.34–0.97)) total mortality (0.80 (0.67–0.97)) muscle weakness or pain 1421 (16%) versus 1375 (15.4%) newly discovered 270 (3%) versus 216 (2.4%) not studied SPARCL (56) 4,731 patients who had had a stroke or TIA 80 mg atorvastatin daily versus placebo Stroke (0.97 (0.66–0.95)) significant coronary event 81 (3.4%) versus 120 (5.1%) myalgia 129 (5.5%) versus 141 (6.0%) myopathy 0.3% in both groups not studied haemorrhagic stroke 55 (2.3%) versus 33 (1.4%) PROSPER (57,58,59) 5,804 patients with a history of CD or risk factors (70–82 years) 40 mg pravastatin daily versus placebo death due to CHD and MI (0.81 (0.96–0.94)) stroke (0.96 (0.79–1.16)) myalgia 36 (1.2%) versus 32 (1.1%) not studied no differences between the groups Table 2: Overview of the most important research on the effect of statins on cardiovascular events and the most common side effects. myalgia or mild increase in CK (< five-fold ULN); self-limiting toxic statin myopathy (CK values between 10 and 100 ULN); myositis or immune-mediated necro- tising myopathy with HMG-CoA reductase antibodies and CK values between 10 and 100 times ULN (27). Regardless of the definition, muscle symptoms usu- ally manifest as symmetrical weakness of large proximal muscles primarily of the lower limbs. Symptoms occur at rest or shortly after physical activity and usually occur within one month after starting treatment or after in- creasing the dose (15,22). Phenotypically, seven progres- sively inferior, statin-associated myotoxic phenotypes were proposed. They begin with asymptomatic CK el- evation and include tolerable and intolerable myalgia, myopathy, severe myopathy, rhabdomyolysis, and im- mune-mediated necrotizing myositis (28). Due to the ability to nonselectively diffuse into the ex- trahepatic tissues such as skeletal muscle, muscle symp- toms are more common in lipophilic statins such as sim- vastatin, atorvastatin, and lovastatin (15,21). In contrast, hydrophilic statins, which are represented by pravastatin and fluvastatin, have a lower ability to penetrate mus- cles and therefore a lower risk of muscle symptoms (15). Up to 60% of muscle symptoms are associated with the 324 CARDIOVASCULAR SYSTEM Zdrav Vestn | July – August 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3217 concomitant use of statins with drugs metabolized by the same hepatic cytochrome P450 (22). Some believe that the greatest risk for muscle symptoms is previous myopathy with another statin, treatment with high-dose statins, a history of unexplained seizures or elevated CK values in personal history, a family history of muscle symptoms with lipid-lowering therapy, and untreated hypothyroidism (29). Other risk factors include female gender, age over 80, impaired liver or kidney function, alcoholism, consumption of grapefruit juice, vitamin D deficiency, low body mass index, and excessive physical activity. The SEARCH study (30) reported more than 10 times more myopathies in patients treated with 80 mg simvastatin daily than those treated with 20 mg daily, and the Heart Protection Study (HPS) reported one case per 1,000 or 10,000 patients treated with 40 mg daily for one year (31). Therefore, prescribing the highest doses in all patients is no longer recommended. Regulatory data- bases also contain a large number of reports of muscle symptoms at high doses of atorvastatin, but these data are very biased and the absolute risk of muscle symp- toms even at the highest dose is actually very low (32). In the HPS study comparing 40 mg simvastatin dai- ly with placebo, there was a relative risk for any form of myalgia of 0.99 (95% confidence interval, 0.95–1.03) regardless of creatinine kinase, while the relative risk of myalgia in patients with creatine kinase levels was more than four times the upper limit of normal, 1.7 (95% con- fidence interval, 0.9–3.1). In patients whose creatinine kinase levels were increased more than 10-fold above the upper limit of normal, the relative risk was 2.5 (95% con- fidence interval, 0.8-8.0) (31). Vitamin D deficiency has been independently associ- ated with muscle weakness and severe myopathy. There is a hypothesis that vitamin D deficiency may exacerbate statin-induced myopathy. In vitamin D deficiency, CY- P3A4 is directed to the hydroxylation pathway of vitamin D, which reduces the amount of this metabolite available for statin metabolism, which could increase statin tox- icity. Ahmed et al. investigated the association between low vitamin D levels and myalgia in patients receiving statins and the regulation of myalgia with vitamin D re- placement while patients continued to receive statins. Patients with vitamin D deficiency were treated with 50,000 units of ergocalciferol per week for 12 weeks. Pa- tients with myalgia receiving statins were found to have lower serum vitamin D levels than patients without my- algia receiving statins. Vitamin D replacement improved muscle symptoms in 92% of patients who were receiv- ing statins and had myalgia and concomitant vitamin D deficiency (33). Calcium plays a key role in the contraction and relax- ation of skeletal muscle, so it is one of the important fac- tors in the formation of SAMS, which includes muscle spasms and cramps. The main pump that allows calcium to be re-absorbed into the sarcoplasmic reticulum is the sarco-endoplasmic reticulum calcium ATPase (SERCA). When SERCA activity was observed in statin users, ac- tivity was found to be 30% higher in asymptomatic statin users than in subjects not receiving statin; however, there was no difference between statin users with or without symptoms (34). Increased SERCA activity may impair calcium homeostasis and does not occur as a compen- satory mechanism, and its content in skeletal muscle has been shown to decrease after five weeks of endurance training. Therefore, if increased SERCA activity contrib- utes to impaired calcium homeostasis, as shown in statin users, physical activity could benefit such patients (35). Coenzyme Q10 (CoQ10) is a fat-soluble vitamin-like substance that, when reduced to ubiquinol, protects cells against free radical-induced oxidative stress and is in- volved in the electron transport in the respiratory chain. Several studies have found that plasma concentrations of coenzyme Q10 are reduced in statin users. Coenzyme Q10 replacement has therefore been suggested for the treatment of SAMS. However, studies have shown that despite the effective increase in serum concentrations of coenzyme Q10, SAMS occurred as often when coen- zyme Q10 was replaced as when it was not. Here, too, the occurrence of SAMS has been shown to be multifactori- al and unlikely to be related solely to the effect of statins on coenzyme Q10 (36,37). 6 Statins and diabetes The incidence of new-onset type 2 diabetes with sta- tin therapy is higher in patients with pre-existing risk factors such as increased body mass index, higher levels of glycated haemoglobin and impaired glucose tolerance. No differences have been observed between hydrophilic and lipophilic statins, but it appears to be more common in elderly patients and those taking high doses of statins (15). The exact mechanisms by which statins trigger type 2 diabetes are unknown, but there may be direct and indirect effects, including effects on body weight, adipocyte differentiation, blood glucose homeostasis via gluconeogenesis and insulin signalling pathway, changes in concentration and activity of adiponectin and leptin as well as with impaired β-cell function (17,38-40). In understanding the effect of statins on the development of diabetes, it would be helpful to know whether the risk 325 REVIEW ARTICLE The benefits of statin therapy outweigh their side effects of developing diabetes during statin therapy is related to the specific action of statins, that is, the inhibition of HMG-CoA reductase, or due to other statin effects. In 18 studies involving 12,725 patients, they found an average LDL cholesterol reduction of 0.89 mmol/L, while the risk of developing diabetes increased by 10% compared to the control group. These studies included all statins currently on the market, except rosuvastatin. It has been calculated that the risk of developing statin-in- duced diabetes was 0.1% per year, and that the reduction in cardiovascular events was 0.42% per year (41). Despite the increased risk of developing diabetes with statin therapy, the benefit of reducing significant coronary events outweighs the potential side effects. In the JUPITER study (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluat- ing Rosuvastatin trial), which included 17,802 patients without known cardiovascular disease, glycated haemo- globin was slightly higher than placebo after two years of use in the group receiving rosuvastatin (5.9 versus 5.8), which was statistically significant (42,43). There was also a quarter more newly diagnosed diabetes, which was al- so statistically significant (3.0% vs. 2.4%). Meta-analyses have shown that a standard dose of a statin increases the risk of developing type 2 diabetes by 10%, and higher doses, including rosuvastatin 20 mg used in the JUPI- TER study, by a further 10% (44,45). Type 2 diabetes usually occurs soon after starting statin therapy, and the risk does not increase with continued treatment. Diabe- tes usually occurs in patients with already expressed risk factors such as increased body mass index, increased levels of glycated haemoglobin, or impaired glucose tol- erance (42,46,47). A retrospective study of 12,725 patients with type 2 diabetes compared for 3 years the HbA1c levels at six- month intervals between patients who had been treated with statin in the past and patients who did not receive statins but were starting insulin therapy. In the first six months, patients who had received statins in the past had a 0.26% decrease in HbA1c, and the decrease was 0.34% in patients who were not receiving statins. A sim- ilar and statistically significant change between HbA1c values was seen even after 12 months. There was a de- crease of 0.29% in patients who had received statins in the past and a decrease of 0.37% in patients who were not receiving statins. Patients who had received statins in the past had higher HbA1c levels after three years. A conclusion was made that patients with type 2 diabetes treated with insulin who had received statins in the past experienced a decrease in insulin sensitivity, making in- sulin treatment less effective in lowering HbA1c (48). The clinical significance of the increase in the inci- dence of type 2 diabetes with statin therapy is not entire- ly clear, as the reduction in cardiovascular morbidity and mortality significantly exceeds the increase in morbidity and mortality associated with diabetes. The incidence of new-onset diabetes in primary prevention is around 1% per year (44), which is around 10–20 new diabetics per 10,000 statin-taking patients per year. If the assump- tion, that this is associated with a doubling of the risk of cardiovascular disease is made (same as in the case of spontaneous diabetes) (49), then 10,000 patients in primary prevention with a 5 to 10% risk in five years of treatment would have five to ten cardiovascular events. Despite this side effect, lowering LDL cholesterol by 1 to 2 mmol/L in the same patient population prevents 150 to 300 identical events, despite the potentially detrimen- tal effect of new-onset diabetes (50-52). 7 Hepatotoxicity Statin therapy may result in a mild increase in trans- aminases, which rarely presents a clinically significant hepatic impairment. Elevations in transaminases occur in approximately 3% of patients, usually within the first year of initiation of therapy, and resolve spontaneously despite continued statin use (53-55). Hepatotoxicity is most likely a feature of all statins and is associated with an increase in their dose (56,57). An increase in transaminases alone, but without an increase in bilirubin, is not unequivocally associated with clinically or pathologically significant hepatocyte damage (58). An even bigger problem is the fact that there is no uniform definition of drug-induced liver in- jury (DILI). The exact mechanism of action of DILI is unknown, but in vitro models have shown dose- and time-depen- dent mitochondrial dysfunction due to statins. In mito- chondria, there is thought to be a significant increase in mitochondrial superoxide, which is one of the important cytotoxic and signalling mediators in mitochondrial or hepatic injury. Another important reason for statin-in- duced hepatotoxicity is that statins cause apoptosis. Cerivastatin was withdrawn from the market in 2001 due to DILI. Other possible mechanisms of hepatotoxicity are inhibition of respiratory chain enzymes, mitochon- drial membrane depolarization, and release of calcium ions (59). The incidence of statin-induced liver injury is higher when using statins at maximum doses with other lipid-lowering drugs such as fibrates, other hep- atotoxic drugs, or drugs with similar enzyme pathways, or when used in the elderly and people with significant 326 CARDIOVASCULAR SYSTEM Zdrav Vestn | July – August 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3217 liver or kidney injury (59). Drug-induced liver injury is relatively rare, with elevated levels of biomarkers of liver injury such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), total serum bilirubin, and alkaline phosphatase (ALP) being observed (38). Therefore, active monitor- ing of liver tests in asymptomatic patients is not recom- mended in this context. Elevated liver enzymes can be misleading given the actual extent of liver injury. Despite elevated liver enzymes, hepatic adverse reactions are ra- re. Action is required when symptoms of hepatotoxicity such as fatigue, weakness, loss of appetite, yellowing of the skin or eyes, and dark urine occur (60). A meta-anal- ysis of 135 randomized controlled trials of 246,000 pa- tients receiving atorvastatin, lovastatin, and simvastatin showed that 50% of patients were at increased risk for el- evated transaminases compared with placebo. However, there was only a slight increase in values, which did not necessarily mean serious adverse reactions for the liver and usually stabilized over time (61). Statin-induced liv- er abnormalities have therefore not been demonstrated and are equally common in statin-treated patients and placebo-treated patients. Monitoring of liver enzymes is required when liver dysfunction is present or statins are combined with other hepatotoxic drugs. It is important not to reduce or discontinue statin therapy if liver test values remain below three times the upper limit of nor- mal (62). 8 Neurological disorders The most important and most common neurologi- cal disorder is intracerebral haemorrhage. Other neu- rological disorders for which we have somewhat less data are cognitive decline, peripheral neuropathy, de- pression, confusion, and memory loss, aggression, and personality changes (21). In observational studies, cho- lesterol levels were negatively associated with haemor- rhagic stroke, especially in patients with elevated arterial blood pressure (63-65). In a randomized, double-blind SPARCL study of 4,731 patients who recovered from cerebrovascular disease, atorvastatin 80 mg statistically significantly reduced ischaemic cerebrovascular events by 21%, but also resulted in a significant increase in hae- morrhagic events by 40% (66). When these results are combined with other results from other studies from the CTT meta-analysis (1), the risk of a haemorrhagic car- diovascular event increases by 21% when LDL choles- terol is reduced by 1 mmol/L. However, the reduction in the risk of all cerebrovascular events with statin therapy is greater than the risk of haemorrhagic stroke (52,66). Ribe et al. conducted the largest study to date on the association between statin use and the risk of cerebral haemorrhage in patients who have already had a stroke. More than 55,000 patients were included who started statin therapy after their first intracerebral haemorrhage or ischaemic stroke. They found that the risk of cerebral haemorrhage was similar in patients treated with statins and in those who did not receive statins, regardless of the type of stroke. However, in the subgroup of patients who have previously suffered an ischaemic stroke, the risk is even lower. It was also found that many patients receiving statins start treatment with other drugs after a stroke, which could have a significant effect on the risk of stroke (67). Regarding the risk of haemorrhagic transformation, a retrospective study was performed comparing patients previously treated with statins, patients who started sta- tin therapy within 3 days after ischaemic stroke, and with patients who were not receiving statins. They found that statin therapy was not associated with early haem- orrhagic complications and that statin therapy had not previously affected the treatment of ischaemic stroke with thrombolysis. Early introduction of statins after ischaemic stroke is also not associated with an increased risk of intracerebral haemorrhage (68). The role of statins in the development of peripheral neuropathy has not yet been clearly demonstrated, and changes in the integrity of cell membranes of neurons, whose important building block is cholesterol, have been described as a possible mechanism. Statins could also af- fect energy use in neurons by inhibiting coenzyme Q10 (69). According to studies conducted so far, treatment with statins could cause changes in peripheral nerves. But in most cases, these changes do not cause clinically significant symptoms (70). Cognitive functions during statin therapy were close- ly monitored in the PROSPER study, which included 5,804 patients aged 72 to 80 years (71-73). Cognitive function was found to be unaffected by treatment with 40 mg pravastatin. Potential memory impairment was closely monitored in the Heart Protection Study (HPS), which followed 20,536 patients taking 40 mg simvastatin daily or placebo for 5 years. It turned out that there were no differences between the groups (31). It is not entirely clear whether these disorders are caused by the direct action of statins, as the blood-brain barrier selectively permeates so that the brain is self-reli- ant in endogenous cholesterol synthesis (38). Lipophilic statins are thought to pose a higher risk due to a greater chance of permeating the blood-brain barrier, but these effects are not necessarily specific for statins, but may 327 REVIEW ARTICLE The benefits of statin therapy outweigh their side effects be due to low cholesterol (10). Lower serum lipid levels could adversely affect the formation of cell membranes of neurons, myelin sheaths, and nerve synapses. When less cholesterol is available for neurons, this can contrib- ute to a decrease in serotonin activity through decreased receptor expression, which can result in behavioural changes and psychiatric adverse effects (72). 9 Other statin-related side effects Other statin-related side effects include: cataracts, gastrointestinal disorders, urogenital disorders, gynae- comastia, and reproductive disorders. Most are thought to result from reduced formation of intermediates and end products of the mevalonate pathway. Thyroid diseas- es that are not thought to be statin-related may contrib- ute to statin intolerance, especially in muscle symptoms (17). Meta-analyses have not shown significant effects of statins or lower cholesterol levels using statin on cataract development or prevention. In vitro studies have shown that atorvastatin promotes phagocytosis and reduces inflammation in the retinal pigment epithelium, which may protect against age-related macular degeneration (74). Statins could be associated with lowering androgen as they inhibit the formation of the substrate required for local synthesis. One study found an increased risk of gynaecomastia during statin therapy (75). 10 Timing of statin administration Due to the different half-lives of statins, especially those with a short half-life, the effect is highly depen- dent on the time of ingestion. Cholesterol biosynthe- sis changes during the day, peaking between midnight and five o’clock in the morning, so the action of statins during this time can greatly affect the patient’s lipid pro- file. Statins with a short half-life, such as simvastatin, pravastatin, lovastatin, and fluvastatin, should be taken by patients in the evening for best results. Statins with longer half-lives, such as atorvastatin and rosuvastatin are not affected by the timing of administration (76,77). However, there are no data on whether the time of inges- tion and concomitant consumption of food affects the occurrence and severity of side effects. 11 Drug interactions Interactions between different drugs occur when previous or concomitant administration of one drug changes the pharmacokinetics or pharmacodynamics of the other drug and therefore the effects of the drugs are different than would be expected from each indi- vidual drug. This may lead to a change in the effective- ness or toxicity of one or both drugs. Their effect may be additive, synergistic, or antagonistic, and there may be changes in the absorption, distribution, metabolism, or excretion of the drug. The most clinically important drug interactions are pharmacokinetic and are often due to the induction or inhibition of enzymes and transport- ers involved in drug metabolism. Most statins undergo microsomal metabolism by the CYP450 isoenzymes and are recognized by transporters in the liver, intestine, and kidney (78). Some genetic variants may contribute to statin toxicity by mutations in genes with the transcrip- tion for proteins that regulate pharmacokinetics (recep- tors, transporters and enzymes) and pharmacodynam- ics of statins (muscle enzymes) (17). Genetic variants in CYP450 enzyme activity may affect statin interactions with other drugs, while genetic variants in membrane transporters may affect hepatic uptake, circulating con- centration, and peripheral tissue exposure (38). The most common drugs that may interact with statins are glucocorticoids, antipsychotics, HIV prote- ase inhibitors, azoles, immunosuppressants, macrolides, calcium channel blockers, and drugs that affect lipids such as gemfibrozil. Additional reactions can also be caused by alcohol, opioids, and cocaine (22). 12 Statins and grapefruit juice Since the incidental discovery of interactions of grapefruit juice with certain drugs in 1989, interac- tions with about 85 drugs, including statins, have been identified. The main compounds in grapefruit juice that cause statin interactions are furanocoumarin bergamot- tin and its derivative 6’,7’-dihydroxybergamottin. The compounds inactivate CYP3A4, a key enzyme in the metabolism of some statins. Studies have shown that the concentration of this enzyme in the gastrointestinal tract is reduced by 50% within four hours after drinking grapefruit juice. Inactivation of CYP3A4 in the gastro- intestinal tract affects presystemic metabolism of statins and thus increases their systemic availability. This effect occurs only with statins metabolized by CYP3A4, name- ly lovastatin, simvastatin, and atorvastatin. Fluvastatin, rosuvastatin, and pravastatin are unaffected as they are metabolized by other enzymes. The effect of grapefruit juice on statins drops to 10% of the maximum value 24 hours after drinking it, which means that the half-life of the effect of grapefruit juice is seven to eight hours. For statins with relatively short half-lives, such as sim- vastatin and lovastatin, drinking grapefruit juice in the 328 CARDIOVASCULAR SYSTEM Zdrav Vestn | July – August 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3217 evening when patients also take statin means half the ef- fect of drinking juice in the morning (79). 13 »Nocebo« effect The placebo effect is the beneficial effect on health that results from positive expectations during treatment. In contrast, the nocebo effect is the detrimental effect on health resulting from negative expectations during treatment. The effects of nocebo and placebo on statin therapy were investigated in three randomized studies: ASCOT, ODYSSEY ALTERNATIVE, and GAUSS-3. The results have demonstrated the effect of nocebo in the placebo groups and have shown that about 20% of patients receiving atorvastatin were in fact intolerant of it (80). In two large studies, the development of SAMS was observed in patients with statin intolerance. Patients were divided into two groups, one receiving PCSK9 inhibitors and the other ezetimibe. The mechanism of action of both drugs is different from the mechanism of action of statins, so apart from the nocebo effect, no other explanation has been found for the occurrence of this side effect (81,82). After discontinuation of statin therapy until symp- toms have resolved, the time of resuming treatment is crucial for the long-term reduction of the risk of ath- erosclerotic cardiovascular disease. More than 70% of patients who discontinued treatment due to adverse re- actions are expected to reattempt statin therapy. Such patients are offered the option of re-initiating treatment with the same statin dose, possibly at less frequent in- tervals (e.g. every other day), at a lower dose, or with a different statin. If symptoms persist for more than two months after discontinuing statin therapy, other causes should be assessed (hypothyroidism, rheumatic diseas- es, etc.) (80). 14 Conclusion The true prevalence of statin intolerance is still not fully understood, but discontinuation of treatment and non-cooperation are a major clinical problem. There are many mechanisms to explain statin toxicity and intoler- ance, and a major obstacle to detecting these patients is the lack of a clear definition and, above all, a biochem- ical marker to identify or even predict which patients will develop intolerance or toxicity. However, the vast majority of statin side effects cannot be attributed to just one factor, but to the intertwining of the various mech- anisms previously described. Given the relatively high effect on reducing cardiovascular morbidity and mor- tality and the very low absolute risk of side effects, as well as their cost-effectiveness, statins are likely to be the first drug of choice for the treatment of dyslipidae- mia for at least some time. However, further research is needed to find one or more biochemical markers to help us identify patients more likely to have side effects. On the other hand, of course, we need alternative solutions that will enable the treatment of patients with proven adverse effects, which are, nevertheless, rare. Despite the fact that there are drugs that reduce the effect of PC- SK9 with antibodies and its synthesis, statins in patients with elevated LDL cholesterol in both primary and sec- ondary prevention are likely to remain the first choice for some time. There is still insufficient data on the long- term efficacy and safety of new drugs. Conflict of interest None declared. Acknowledgment We, the authors, would like to thank Katja Bizilj, Bachelor’s degree in Slovene language and literature and dr. Christopher Berrie for the language review. The image was prepared with the MindtheGraph software (https://mindthegraph.com/). List of Abbreviations ALP = alkaline phosphatase ALT = alanine aminotransferase ASCOT = Anglo-Scandinavian Cardiac Outcomes Trial AST = aspartate aminotransferase CK = creatine kinase CTT = Cholesterol Treatment Trialists CYP3A4 = cytochrome P450 3A4 CYP450 = cytochrome P450 DILI = drug induced liver injury EAS = European Atherosclerosis Society ESC = European Society of Cardiology FDA = Food and Drug Administration GAUSS-3 = Goal Achievement After Utilizing an An- ti-PCSK9 Antibody in Statin Intolerant Subjects 3 GGT = gamma-glutamyl transferase HIV = human immunodeficiency virus HMG-CoA = hydroxymethylglutaryl-coenzyme A HPS = Heart Protection Study IDL = intermediate-density lipoprotein JUPITER = Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvasta- tin trial LDL = low-density lipoprotein 329 REVIEW ARTICLE The benefits of statin therapy outweigh their side effects References 1. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al.; Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366(9493):1267-78. DOI: 10.1016/S0140-6736(05)67394-1 PMID: 16214597 2. Silverman MG, Ference BA, Im K, Wiviott SD, Giugliano RP, Grundy SM, et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis. JAMA. 2016;316(12):1289-97. DOI: 10.1001/ jama.2016.13985 PMID: 27673306 3. Ward NC, Watts GF, Eckel RH. Statin Toxicity. Circ Res. 2019;124(2):328-50. DOI: 10.1161/CIRCRESAHA.118.312782 PMID: 30653440 4. Golder S, O’Connor K, Hennessy S, Gross R, Gonzalez-Hernandez G. Assessment of Beliefs and Attitudes About Statins Posted on Twitter: A Qualitative Study. JAMA Netw Open. 2020;3(6):e208953. DOI: 10.1001/ jamanetworkopen.2020.8953 PMID: 32584408 5. 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. Eur Heart J. 2020;41(1):111- 88. DOI: 10.1093/eurheartj/ehz455 PMID: 31504418 6. Chou R, Dana T, Blazina I, Daeges M, Jeanne TL. Statins for prevention of cardiovascular disease in adults: evidence report and systematic review for the US preventive services task force. JAMA. 2016;316(19):2008-24. DOI: 10.1001/jama.2015.15629 PMID: 27838722 7. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335(14):1001-9. DOI: 10.1056/NEJM199610033351401 PMID: 8801446 8. Stickney JT, Buss JE. Murine guanylate-binding protein: incomplete geranylgeranyl isoprenoid modification of an interferon-gamma- inducible guanosine triphosphate-binding protein. Mol Biol Cell. 2000;11(7):2191-200. DOI: 10.1091/mbc.11.7.2191 PMID: 10888661 9. Bellosta S, Ferri N, Bernini F, Paoletti R, Corsini A. Non-lipid-related effects of statins. Ann Med. 2000;32(3):164-76. DOI: 10.3109/07853890008998823 PMID: 10821323 10. Fong CW. Statins in therapy: understanding their hydrophilicity, lipophilicity, binding to 3-hydroxy-3-methylglutaryl-CoA reductase, ability to cross the blood brain barrier and metabolic stability based on electrostatic molecular orbital studies. Eur J Med Chem. 2014;85:661-74. DOI: 10.1016/j.ejmech.2014.08.037 PMID: 25128668 11. Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. 2005;19(1):117- 25. DOI: 10.1111/j.1472-8206.2004.00299.x PMID: 15660968 12. Sirtori CR. The pharmacology of statins. Pharmacol Res. 2014;88:3-11. DOI: 10.1016/j.phrs.2014.03.002 PMID: 24657242 13. Keen HI, Krishnarajah J, Bates TR, Watts GF. Statin myopathy: the fly in the ointment for the prevention of cardiovascular disease in the 21st century? Expert Opin Drug Saf. 2014;13(9):1227-39. DOI: 10.1517/14740338.2014.937422 PMID: 25017015 PCSK-9 = proprotein convertase subtilisin/kexin type 9 PROSPER = Prospective Study of Pravastatin in the El- derly at Risk SAMS = statin-associated muscle symptoms SEARCH = Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine SPARCL = Stroke Prevention by Aggressive Reduction in Cholesterol Levels ULN = upper limit of normal 14. Saxon DR, Eckel RH. Statin intolerance: a literature review and management strategies. Prog Cardiovasc Dis. 2016;59(2):153-64. DOI: 10.1016/j.pcad.2016.07.009 PMID: 27497504 15. Banach M, Rizzo M, Toth PP, Farnier M, Davidson MH, Al-Rasadi K, et al. Statin intolerance - an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Arch Med Sci. 2015;11(1):1-23. DOI: 10.5114/aoms.2015.49807 PMID: 25861286 16. Laufs U, Scharnagl H, März W. Statin intolerance. Curr Opin Lipidol. 2015;26(6):492-501. DOI: 10.1097/MOL.0000000000000236 PMID: 26780003 17. Mancini GB, Baker S, Bergeron J, Fitchett D, Frohlich J, Genest J, et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Consensus Working Group Update (2016). Can J Cardiol. 2016;32(7):S35-65. DOI: 10.1016/j.cjca.2016.01.003 PMID: 27342697 18. Tobert JA, Newman CB. Statin tolerability: in defence of placebo- controlled trials. Eur J Prev Cardiol. 2016;23(8):891-6. DOI: 10.1177/2047487315602861 PMID: 26318980 19. Rosenson RS. Trial designs for statin muscle intolerance. Curr Opin Lipidol. 2017;28(6):488-94. DOI: 10.1097/MOL.0000000000000454 PMID: 28832369 20. Bays H. Statin safety: an overview and assessment of the data—2005. Am J Cardiol. 2006;97(8):6C-26C. DOI: 10.1016/j.amjcard.2005.12.006 PMID: 16581330 21. Bitzur R, Cohen H, Kamari Y, Harats D. Intolerance to statins: mechanisms and management. Diabetes Care. 2013;36:S325-30. DOI: 10.2337/dcS13- 2038 PMID: 23882066 22. Muntean DM, Thompson PD, Catapano AL, Stasiolek M, Fabis J, Muntner P, et al. Statin-associated myopathy and the quest for biomarkers: can we effectively predict statin-associated muscle symptoms? Drug Discov Today. 2017;22(1):85-96. DOI: 10.1016/j.drudis.2016.09.001 PMID: 27634340 23. Gluba-Brzozka A, Franczyk B, Toth PP, Rysz J, Banach M. Molecular mechanisms of statin intolerance. Arch Med Sci. 2016;12(3):645-58. DOI: 10.5114/aoms.2016.59938 PMID: 27279860 24. McKenney JM, Davidson MH, Jacobson TA, Guyton JR; National Lipid Association Statin Safety Assessment Task Force. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol. 2006;97(8):89C-94C. DOI: 10.1016/j. amjcard.2006.02.030 PMID: 16581336 25. Armitage J. The safety of statins in clinical practice. Lancet. 2007;370(9601):1781-90. DOI: 10.1016/S0140-6736(07)60716-8 PMID: 17559928 26. Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol. 2006;97(8):52C-60C. DOI: 10.1016/j.amjcard.2005.12.010 PMID: 16581329 27. Selva-O’Callaghan A, Alvarado-Cardenas M, Pinal-Fernández I, Trallero-Araguás E, Milisenda JC, Martínez MÁ, et al. Statin-induced myalgia and myositis: an update on pathogenesis and clinical recommendations. Expert Rev Clin Immunol. 2018;14(3):215-24. DOI: 10.1080/1744666X.2018.1440206 PMID: 29473763 330 CARDIOVASCULAR SYSTEM Zdrav Vestn | July – August 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3217 28. Alfirevic A, Neely D, Armitage J, Chinoy H, Cooper RG, Laaksonen R, et al. Phenotype standardization for statin-induced myotoxicity. Clin Pharmacol Ther. 2014;96(4):470-6. DOI: 10.1038/clpt.2014.121 PMID: 24897241 29. Bruckert E, Hayem G, Dejager S, Yau C, Bégaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study. Cardiovasc Drugs Ther. 2005;19(6):403-14. DOI: 10.1007/s10557-005-5686-z PMID: 16453090 30. Armitage J, Bowman L, Wallendszus K, Bulbulia R, Rahimi K, Haynes R, et al.; Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet. 2010;376(9753):1658-69. DOI: 10.1016/S0140-6736(10)60310-8 PMID: 21067805 31. Collins R, Armitage J, Parish S, Sleight P, Peto R; Heart Protection Study Collaborative Group. 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. DOI: 10.1016/ S0140-6736(02)09327-3 PMID: 12114036 32. Holbrook A, Wright M, Sung M, Ribic C, Baker S. Statin-associated rhabdomyolysis: is there a dose-response relationship? Can J Cardiol. 2011;27(2):146-51. DOI: 10.1016/j.cjca.2010.12.024 PMID: 21459261 33. Ahmed W, Khan N, Glueck CJ, Pandey S, Wang P, Goldenberg N, et al. Low serum 25 (OH) vitamin D levels (<32 ng/mL) are associated with reversible myositis-myalgia in statin-treated patients. Transl Res. 2009;153(1):11-6. DOI: 10.1016/j.trsl.2008.11.002 PMID: 19100953 34. Allard NA, Schirris TJ, Verheggen RJ, Russel FG, Rodenburg RJ, Smeitink JA, et al. Statins Affect Skeletal Muscle Performance: Evidence for Disturbances in Energy Metabolism. J Clin Endocrinol Metab. 2018;103(1):75-84. DOI: 10.1210/jc.2017-01561 PMID: 29040646 35. Majerczak J, Karasinski J, Zoladz JA. Training induced decrease in oxygen cost of cycling is accompanied by down-regulation of SERCA expression in human vastus lateralis muscle. J Physiol Pharmacol. 2008;59(3):589- 602. PMID: 18953100 36. Banach M, Serban C, Sahebkar A, Ursoniu S, Rysz J, Muntner P, et al.; Lipid and Blood Pressure Meta-analysis Collaboration Group. Effects of coenzyme Q10 on statin-induced myopathy: a meta-analysis of randomized controlled trials. Mayo Clin Proc. 2015;90(1):24-34. DOI: 10.1016/j.mayocp.2014.08.021 PMID: 25440725 37. Taylor BA, Lorson L, White CM, Thompson PD. A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy. Atherosclerosis. 2015;238(2):329-35. DOI: 10.1016/j.atherosclerosis.2014.12.016 PMID: 25545331 38. Mach F, Ray KK, Wiklund O, Corsini A, Catapano AL, Bruckert E, et al.; European Atherosclerosis Society Consensus Panel. Adverse effects of statin therapy: perception vs. the evidence - focus on glucose homeostasis, cognitive, renal and hepatic function, haemorrhagic stroke and cataract. Eur Heart J. 2018;39(27):2526-39. DOI: 10.1093/eurheartj/ ehy182 PMID: 29718253 39. Betteridge DJ, Carmena R. The diabetogenic action of statins - mechanisms and clinical implications. Nat Rev Endocrinol. 2016;12(2):99- 110. DOI: 10.1038/nrendo.2015.194 PMID: 26668119 40. Brault M, Ray J, Gomez YH, Mantzoros CS, Daskalopoulou SS. Statin treatment and new-onset diabetes: a review of proposed mechanisms. Metabolism. 2014;63(6):735-45. DOI: 10.1016/j.metabol.2014.02.014 PMID: 24641882 41. Anyanwagu U, Mamza J, Donnelly R, Idris I. Effects of background statin therapy on glycemic response and cardiovascular events following initiation of insulin therapy in type 2 diabetes: a large UK cohort study. Cardiovasc Diabetol. 2017;16(1):107. DOI: 10.1186/s12933-017-0587-6 PMID: 28830436 42. Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012;380(9841):565-71. DOI: 10.1016/S0140-6736(12)61190-8 PMID: 22883507 43. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Kastelein JJ, et al.; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-207. DOI: 10.1056/NEJMoa0807646 PMID: 18997196 44. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375(9716):735-42. DOI: 10.1016/ S0140-6736(09)61965-6 PMID: 20167359 45. Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD, et al. Risk of incident diabetes with intensive-dose compared with moderate- dose statin therapy: a meta-analysis. JAMA. 2011;305(24):2556-64. DOI: 10.1001/jama.2011.860 PMID: 21693744 46. Waters DD, Ho JE, DeMicco DA, Breazna A, Arsenault BJ, Wun CC, et al. Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials. J Am Coll Cardiol. 2011;57(14):1535-45. DOI: 10.1016/j.jacc.2010.10.047 PMID: 21453832 47. Livingstone SJ, Looker HC, Akbar T, Betteridge DJ, Durrington PN, Hitman GA, et al. Effect of atorvastatin on glycaemia progression in patients with diabetes: an analysis from the Collaborative Atorvastatin in Diabetes Trial (CARDS). Diabetologia. 2016;59(2):299-306. DOI: 10.1007/s00125-015- 3802-6 PMID: 26577796 48. Scattolini V, Luni C, Zambon A, Galvanin S, Gagliano O, Ciubotaru CD, et al. Simvastatin rapidly and reversibly inhibits insulin secretion in intact single-islet cultures. Diabetes Ther. 2016;7(4):679-93. DOI: 10.1007/ s13300-016-0210-y PMID: 27830474 49. Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E, et al.; Emerging Risk Factors Collaboration. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta- analysis of 102 prospective studies. Lancet. 2010;375(9733):2215-22. DOI: 10.1016/S0140-6736(10)60484-9 PMID: 20609967 50. Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Peto R, et al.; Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371(9607):117- 25. DOI: 10.1016/S0140-6736(08)60104-X PMID: 18191683 51. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al.; Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-81. DOI: 10.1016/S0140-6736(10)61350-5 PMID: 21067804 52. Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, Barnes EH, et al.; Cholesterol Treatment Trialists’ (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380(9841):581-90. DOI: 10.1016/S0140-6736(12)60367- 5 PMID: 22607822 53. Chalasani N. Statins and hepatotoxicity: focus on patients with fatty liver. Hepatology. 2005;41(4):690-5. DOI: 10.1002/hep.20671 PMID: 15789367 54. Bełtowski J, Wójcicka G, Jamroz-Wiśniewska A. Adverse effects of statins - mechanisms and consequences. Curr Drug Saf. 2009;4(3):209-28. DOI: 10.2174/157488609789006949 PMID: 19534648 55. Russo MW, Hoofnagle JH, Gu J, Fontana RJ, Barnhart H, Kleiner DE, et al. Spectrum of statin hepatotoxicity: experience of the drug-induced liver injury network. Hepatology. 2014;60(2):679-86. DOI: 10.1002/hep.27157 PMID: 24700436 56. Kasliwal R, Wilton LV, Cornelius V, Aurich-Barrera B, Shakir SA. Safety profile of rosuvastatin: results of a prescription-event monitoring study of 11,680 patients. Drug Saf. 2007;30(2):157-70. DOI: 10.2165/00002018- 200730020-00005 PMID: 17253880 57. Alsheikh-Ali AA, Maddukuri PV, Han H, Karas RH. Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: insights from large randomized statin trials. J Am Coll Cardiol. 2007;50(5):409-18. DOI: 10.1016/j.jacc.2007.02.073 PMID: 17662392 331 REVIEW ARTICLE The benefits of statin therapy outweigh their side effects 58. Meurer L, Cohen SM. Drug-Induced Liver Injury from Statins. Clin Liver Dis. 2020;24(1):107-19. DOI: 10.1016/j.cld.2019.09.007 PMID: 31753243 59. Karahalil B, Hare E, Koç G, Uslu İ, Şentürk K, Özkan Y. Hepatotoxicity associated with statins. Arh Hig Rada Toksikol. 2017;68(4):254-60. DOI: 10.1515/aiht-2017-68-2994 PMID: 29337684 60. Naci H, Brugts J, Ades T. Comparative tolerability and harms of individual statins: a study-level network meta-analysis of 246 955 participants from 135 randomized, controlled trials. Circ Cardiovasc Qual Outcomes. 2013;6(4):390-9. DOI: 10.1161/CIRCOUTCOMES.111.000071 PMID: 23838105 61. Agarwala A, Kulkarni S, Maddox T. The association of statin therapy with incident diabetes: evidence, mechanisms, and recommendations. Curr Cardiol Rep. 2018;20(7):50. DOI: 10.1007/s11886-018-0995-6 PMID: 29779165 62. Azemawah V, Movahed MR, Centuori P, Penaflor R, Riel PL, Situ S, et al. State of the Art Comprehensive Review of Individual Statins, Their Differences, Pharmacology, and Clinical Implications. Cardiovasc Drugs Ther. 2019;33(5):625-39. DOI: 10.1007/s10557-019-06904-x PMID: 31773344 63. Ebrahim S, Sung J, Song YM, Ferrer RL, Lawlor DA, Davey Smith G. Serum cholesterol, haemorrhagic stroke, ischaemic stroke, and myocardial infarction: korean national health system prospective cohort study. BMJ. 2006;333(7557):22-5. DOI: 10.1136/bmj.38855.610324.80 PMID: 16757495 64. Iso H, Jacobs DR, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med. 1989;320(14):904-10. DOI: 10.1056/NEJM198904063201405 PMID: 2619783 65. Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, Halsey J, et al.; Prospective Studies Collaboration. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet. 2007;370(9602):1829-39. DOI: 10.1016/S0140-6736(07)61778-4 PMID: 18061058 66. Goldstein LB, Amarenco P, Zivin J, Messig M, Altafullah I, Callahan A, et al.; Stroke Prevention by Aggressive Reduction in Cholesterol Levels Investigators. Statin treatment and stroke outcome in the stroke prevention by aggressive reduction in cholesterol levels (SPARCL) trial. Stroke. 2009;40(11):3526-31. DOI: 10.1161/STROKEAHA.109.557330 PMID: 19745172 67. Ribe AR, Vestergaard CH, Vestergaard M, Pedersen HS, Prior A, Lietzen LW, et al. Statins and risk of intracerebral hemorrhage in individuals with a history of stroke. Stroke. 2020;51(4):1111-9. DOI: 10.1161/ STROKEAHA.119.027301 PMID: 32114928 68. Scheitz JF, MacIsaac RL, Abdul-Rahim AH, Siegerink B, Bath PM, Endres M, et al.; VISTA collaboration. Statins and risk of poststroke hemorrhagic complications. Neurology. 2016;86(17):1590-6. DOI: 10.1212/ WNL.0000000000002606 PMID: 27016519 69. Gaist D, García Rodríguez LA, Huerta C, Hallas J, Sindrup SH. Are users of lipid-lowering drugs at increased risk of peripheral neuropathy? Eur J Clin Pharmacol. 2001;56(12):931-3. DOI: 10.1007/s002280000248 PMID: 11317483 70. Özdogan Ö. Peripheral polyneuropathy in patients receiving long-term statin therapy. Turk Kardiyol Dern Ars. 2019;47(7):552-3. PMID: 31582676 71. Houx PJ, Shepherd J, Blauw GJ, Murphy MB, Ford I, Bollen EL, et al. Testing cognitive function in elderly populations: the PROSPER study. PROspective Study of Pravastatin in the Elderly at Risk. J Neurol Neurosurg Psychiatry. 2002;73(4):385-9. DOI: 10.1136/jnnp.73.4.385 PMID: 12235304 72. Leppien E, Mulcahy K, Demler TL, Trigoboff E, Opler L. Effects of statins and cholesterol on patient aggression: is there a connection? Innov Clin Neurosci. 2018;15(3-4):24-7. PMID: 29707423 73. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, et al.; PROSPER study group. PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360(9346):1623- 30. DOI: 10.1016/S0140-6736(02)11600-X PMID: 12457784 74. Tian B, Al-Moujahed A, Bouzika P, Hu Y, Notomi S, Tsoka P, et al. Atorvastatin promotes phagocytosis and attenuates pro-inflammatory response in human retinal pigment epithelial cells. Sci Rep. 2017;7(1):2329. DOI: 10.1038/s41598-017-02407-7 PMID: 28539592 75. Skeldon SC, Carleton B, Brophy JM, Sodhi M, Etminan M. Statin medications and the risk of gynecomastia. Clin Endocrinol (Oxf). 2018;89(4):470-3. DOI: 10.1111/cen.13794 PMID: 29923212 76. Awad K, Banach M. The optimal time of day for statin administration: a review of current evidence. Curr Opin Lipidol. 2018;29(4):340-5. DOI: 10.1097/MOL.0000000000000524 PMID: 29771699 77. Awad K, Serban MC, Penson P, Mikhailidis DP, Toth PP, Jones SR, et al.; Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group. Effects of morning vs evening statin administration on lipid profile: A systematic review and meta-analysis. J Clin Lipidol. 2017;11(4):972-985. e9. DOI: 10.1016/j.jacl.2017.06.001 PMID: 28826569 78. Bellosta S, Corsini A. Statin drug interactions and related adverse reactions: an update. Expert Opin Drug Saf. 2018;17(1):25-37. DOI: 10.1080/14740338.2018.1394455 PMID: 29058944 79. Lee JW, Morris JK, Wald NJ. Grapefruit juice and statins. Am J Med. 2016;129(1):26-9. DOI: 10.1016/j.amjmed.2015.07.036 PMID: 26299317 80. Robinson JG. New insights into managing symptoms during statin therapy. Prog Cardiovasc Dis. 2019;62(5):390-4. DOI: 10.1016/j. pcad.2019.10.005 PMID: 31669768 81. Sullivan D, Olsson AG, Scott R, Kim JB, Xue A, Gebski V, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA. 2012;308(23):2497-506. DOI: 10.1001/jama.2012.25790 PMID: 23128163 82. Moriarty PM, Thompson PD, Cannon CP, Guyton JR, Bergeron J, Zieve FJ, et al.; ODYSSEY ALTERNATIVE Investigators. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol. 2015;9(6):758-69. DOI: 10.1016/j.jacl.2015.08.006 PMID: 26687696