The rate of cholesterol synthesis in the liver is controlled by 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase. Akira Endo, a Japanese scientist, isolated citrinin (1971) and compactin (1973) from culture broths of fungi.7 The compounds showed strong HMG-CoA reductase inhibition.7 In 1978, compactin was first used in a patient at a daily dose of 500 mg and showed excellent results with the serum cholesterol dropping from 1,000 mg/dL to about 700 mg/dL.7 Three years later, compactin was reported to decrease plasma LDL-C level by 29% in patients with heterozygous familial hypercholesterolemia (FH).8 This led to the search for similar compounds. Lovastatin, with a chemical structure very similar to compactin, became the first commercial statin in 1987. It was followed by semisynthetic statins such as simvastatin and pravastatin and synthetic statins such as fluvastatin, atorvastatin, rosuvastatin, and pitavastatin. Atorvastatin and rosuvastatin are the most commonly used statins today.

Statins have become the first-line therapy for reducing the risk of CVD mortality and morbidity as well as for reducing the need for coronary artery revascularization procedures in people who have suboptimal lipid profile, with or without other risk factors.9 Statins are lifesaving as they help primary prevention of CAD by rapidly lowering the LDL-C. Intensive therapy with moderate and high intensity statin can lower LDL-C by 50% or more.10 Even low-intensity statin therapy has been shown to reduce LDL-C levels by about 30%.10 Improvement in lipid profile is known to reduce the risk of CVD.11 Statins have been reported to reduce the incidence of fatal and nonfatal strokes by 31% and 37%, respectively.9 They also have efficacy to lower triglyceride (TG) and very low density lipoproteins (VLDL) levels. In addition, statins reduce platelet aggregation, thrombus formation, inflammation, and C-reactive protein levels, showing pleiotropic effects.1912

Global clinical practice guidelines as well as Korean guidelines from Korean Society for Lipid and Atherosclerosis strongly recommend the use of statins in patients at risk of CVD.112

Approximately 10% to 15% of patients are unable to tolerate statins in the doses required to sufficiently reduce the risk of CVD.1314 The commonest signs and symptoms of statin intolerance are the statin-associated muscle symptoms (SAMSs) occurring in 1% to 10% of patients.15 Other side effects are listed in Table 1. The National Lipid Association Expert Panel on Statin Intolerance defines statin intolerance as a clinical syndrome characterized by the inability to tolerate at least 2 statins, 1 statin at the lowest starting daily dose (rosuvastatin 5 mg, atorvastatin 10 mg, simvastatin 10 mg, lovastatin 20 mg, pravastatin 40 mg, fluvastatin 40 mg, or pitavastatin 2 mg) and another statin at any daily dose due to either objectionable symptoms (real or perceived) or abnormal laboratory values, which are temporally related to statin treatment and reversible upon statin discontinuation, but reproducible by re-challenge with other known determinants being excluded (such as hypothyroidism, interacting drugs, concurrent illnesses, significant changes in physical activity or exercise, and underlying muscle disease).15 In short, before diagnosing a case of statin intolerance, other possible etiologies should first be ruled out and different statins tried at varying doses.14 The universal definition of statin intolerance as the inability to tolerate 2 different statins is applicable to Korean population, yet further investigations are needed to capture its incidence among them.

Although very few patients (<1%) develop serious side effects due to statins, the toxicity of these agents became of great public interest when cerivastatin was withdrawn from the market as a result of deaths from rhabdomyolysis.131617 In this regard, if the side effects still remain intolerable and/or there is over a 10-fold increase in the serum creatinine kinase (CK) level along with an increase in serum creatinine level, it is recommended to discontinue statin therapy.131518

Stain intolerance has been reported as multifactorial and dose-related. Any condition that increases serum statin levels increases the risks of statin intolerance. Such factors include low body mass index, female sex, old age, Asian ethnicity, comorbidity (e.g., hypothyroidism, liver and kidney diseases, and rheumatic diseases), vitamin D deficiency, alcoholism, grapefruit juice consumption (1 qt/day or 0.95 L/day), major surgery or perioperative period, excessive physical activity, history of myopathy while receiving another lipid-lowering therapy, history of CK rise, family history of myopathy, and family history of myopathy while receiving another lipid lowering agent.512131920 The risk is also increased with the use of concomitant medications such as fibrates, cyclosporine, antifungals, macrolide antibiotics, amiodarone, verapamil, and anti-HIV drug-protease inhibitors.5131920

The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine, the Heart Protection Study, and the Prediction of Muscular Risk in Observational Conditions Study showed there are genetic factors associated with statin intolerance.20 Inconsistent association is seen with DNA polymorphism in genes that code for organic anion-transporting polypeptide 1B1, P450 isoenzymes, coenzyme Q, myophosphorylase, carnitine palmitoyl transferase II, myoadenylate deaminase, adenosine triphosphate (ATP)-binding cassette sub-family B member 1, ATP-binding cassette subfamily G member 2, the efflux transporter multidrug resistance protein and serotonin pain receptors.192021

Patients with high risks for CVD should be maintained on a statin-based regimen. Switching to another statin has been found to be efficacious in many patients.5181922 Statins with low risks such as fluvastatin and pravastatin may be used even though they may not be potent enough to reduce the LDL-C to target values in some patients.

Another mode of using a statin-based therapy is to reduce the dose of the medication. Long-acting statins may be given either at reduced doses or at reduced frequency (1–3 times a week).1823 Rosuvastatin with a half-life of 19 hours and atorvastatin with a half-life of 11–24 hours are particularly useful in this approach.

A non-statin therapy may be tried if the patient does not tolerate any statin or when statins used at maximal tolerable dose fail to reduce the LDL-C to the target level. The most commonly used non-statin lipid-lowering agent is ezetimibe. When used as a monotherapy or in combination with a low-risk statin, it causes a 15% to 20% decrease in LDL-C.24 Being an intestinal agent with no systemic effects, it is not likely to worsen the myalgia. Recently, it has also been shown to reduce the risk of CV events.25 Bile acid sequestrants (BAS) reduce CV events and may be tried together with ezetimibe to produce better lipid control.24 However, BAS is often discontinued due to high (40%–60%) rates of gastrointestinal side effects.24 Colesevelam, a BAS with fewer side effects, leads to better adherence to therapy. Fibrates primarily decrease TG and increase high-density lipoprotein cholesterol (HDL-C) levels; the decrease in LDL-C is less marked. In recent meta-analysis, fibrates failed to show clinical benefit when added on statin therapy.242627 Niacin lowers LDL-C by about 20%. Up to 25% of the patients may discontinue niacin due to its side effects such as flushing and it is rarely used in Korea. It does not show substantial CV benefits.2428

Clinicians, therefore, often consider ezetimibe as the first choice for non–statin-based lipid-lowering therapy. It may be followed by a combination of BAS or fibrates with ezetimibe. But Korean doctors prescribed fish oil frequently with statins, which has no proven benefits by far.

If both the risk for CVD and the LDL-C level are high despite drug therapy at maximal tolerable doses, LDL apheresis can be tried.29 It is used mainly for treating patients with severe dyslipidemia like FH and may be used to lower the dose of statins.

Different dietary modifications have been used to decrease LDL-C levels. These include the use of low saturated fat diets, avoidance of trans fatty acids, and the use of viscous fibers and foods with plant sterols and stanols to decrease LDL-C levels.1229 Though red yeast rice is used to lower LDL-C in statin-intolerant patients, its safety and efficacy have not been proved.29 However, the European Atherosclerosis Society consensus panel believes that the portfolio diet, containing plant sterols, soya protein, viscous fibers, and nuts, can be used either alone or with pharmacologic therapies to lower LDL-C.5 Other therapies such as ubiquinone (Coenzyme Q10 [CoQ10]) and vitamin D supplementation also improve statin tolerability but those supplementation is not essentially needed.529

The gain of function mutations for PCSK9 gene has been linked to high cholesterol levels. The most promising approach to PCSK9 inhibition is the use of monoclonal antibodies (mAbs) targeting PCSK9. The 2 PCSK9-inhibiting mAbs approved so far in the United States, Europe, and Japan are alirocumab and evolocumab.243031 Both these drugs produce a large reduction in LDL-C.3233

In healthy volunteers with baseline LDL-C >100 mg/dL, just a single dose of alirocumab (50, 100, 150, and 250 mg) administered subcutaneously or intravenously reduced the LDL-C by up to 65 percentage points compared to a placebo.34 Alirocumab, with all doses, showed similar LDL-C response irrespective of whether there was FH or non-FH and whether the patients were on atorvastatin or on diet alone within 2 weeks of maximal LDL-C lowering efficacy.3435

In the ODYSSEY ALTERNATIVE randomized trial comprised of statin-intolerant patients with primary hypercholesterolemia, alirocumab induced greater LDL-C reductions than ezetimibe.36 In the intent-to-treat population, alirocumab (75 mg or 150 mg every 2 weeks) reduced mean LDL-C level by 45% compared with 14.6% in the ezetimibe (10 mg/day) group (mean difference, −30.4; p<0.0001) at 24 weeks. Alirocumab group (n=52, 41.9%) achieved the LDL-C goal of <70 mg/dL or <100 mg/dL (based on the CV risk) than in the ezetimibe group (n=5, 4.4%).36 In the Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects (GAUSS) phase 2 trial, evolocumab was administered to 160 statin-intolerant patients.37 Subcutaneous administration of the evolocumab was associated with dose-dependent LDL-C reductions of about 41% with 280 mg to about 51% with 350 mg and about 63% with 420 mg evolocumab plus 10 mg ezetimibe.37 In the GAUSS-3 trial in statin-intolerant patients, in comparison to oral ezetimibe 10 mg daily, subcutaneous evolocumab 420 mg monthly reduced LDL-C to significantly lower levels after 24 weeks.38 The Durable Effect of PCSK9 Antibody Compared with Placebo Study showed that evolocumab (420 mg every 4 weeks) reduced the LDL-C by an additional 55% to 60% in patients on background lipid-lowering therapy with diet alone or diet plus atorvastatin 10 mg daily, atorvastatin 80 mg daily, or atorvastatin 80 mg plus 10 mg ezetimibe for 4–12 weeks.39 Long-term tolerability and adherence was also good.39 In a large phase 3 study of alirocumab (150 mg subcutaneously every 2 weeks), involving 2,341 patients at high risk for CVD, alirocumab was added to statin therapy at the maximum tolerated dose.40 In the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects Elevated Risk study, 27,564 patients received subcutaneous evolocumab (140 mg every 2 weeks or 420 mg monthly) or placebo in addition to statin therapy.41 PCSK9 inhibition lowered the LDL-C by 59% from a median of 92 to 30 mg/dL, and CVD risks reduced significantly.

Thus, PCSK9 inhibition with either alirocumab or evolocumab has been proven to lower LDL-C levels even in statin-intolerant patients to a greater extent than did changing over to a different statin, increasing the dose of statins, or adding ezetimibe. This new category of drugs is expected to be a potential treatment option in reducing CVD risks for statin-intolerant patients.

Lomitapide is a microsomal TG transfer protein inhibitor used as an adjunct to other lipid-lowering therapies in patients with homozygous FH. It reduces LDL-C by up to 40% and can be used along with lipid apheresis for an additive effect.4243 However, still the concern is on the increase of hepatosteatosis in human clinical trials.

Mipomersen, a second-generation antisense oligonucleotide, inhibits the synthesis of apolipoprotein B and lowers LDL-C in high-risk statin-intolerant patients. In phase 3 studies, it reduced LDL-C by up to 36% in homozygous FH.42 It is used as an adjunct to other lipid-lowering therapies.

Several therapies are being studied for widespread use in non-FH and heterozygous FH. Newer PCSK9 inhibitors being studied for these indications include mAbs (LY3015014 and RG7652 in phase 2), the adnectin (BMS-962476, in phase 1), and the small interfering RNA (ALN-PCS/inclisiran).44 Results from the phase 2 ORION-1 study recently showed that inclisiran lowered LDL-C levels in patients with high CV risk and elevated LDL-C levels.45 Genetic mutations leading to cholesteryl ester transfer protein (CETP) deficiency are associated with increases in HDL-C. This led to speculation that CETP inhibitors may reduce the risk of CVD. CETP inhibitors in clinical development show variable effects with increases in HDL-C, varying from 35% to over 150% and LDL-C reduction being minimal to about 45%.44 Trials with torcetrapib and dalcetrapib have been terminated as torcetrapib showed an increase in CVD events while dalcetrapib did not improve CVD events compared to placebo.44 A phase 2 study of TA-8995 showed significant LDL-C reductions after 12 weeks on various monotherapy doses or in combination with statins and currently is being studied in a phase 3 trial.44 Another CETP inhibitor, anacetrapib was reported to have lower incidence of major coronary events than placebo in patients with atherosclerotic vascular disease and receiving intensive statin therapy.46 Furthermore, clinical development of evacetrapib was terminated based on the safety observations in an interim analysis.47

ETC-1002 is an oral agent that directly inhibits hepatic ATP citrate lyase and leads to decrease in de novo cholesterol synthesis and increased expression of LDL receptors. It reduces LDL-C by up to 30% when administered as a monotherapy, and the reduction increases up to 43% and 48% for 120 mg and 180 mg of ETC-1002 plus ezetimibe, respectively.48

A new niacin-related compound, CAT-2054, has been tried in healthy volunteers. It was well tolerated with no flushing reports at doses ≤500 mg/dL.44 The drug is planned to enter phase 2 studies. Another niacin-related compound, ARI-3037MO, caused statistically significant mean decreases in renormalization groups of 56.7% and increases in HDL-C of 7.7% in healthy volunteers at a 6 g daily dose without causing flushing, itching, or other dermatological changes.44 The extent of its effect on the LDL-C level of dyslipidemic population is yet to be determined.