Lipid Management: Beyond Statins Materials

LIPID MANAGEMENT: BEYOND STATINS

L. Austin Fredrickson, MD, FACP

Dr. Fredrickson is an Assistant Professor of Internal Medicine at the Northeast Ohio Medical University College of Medicine, where he serves as a course director and core teaching faculty. He is board-certified in Internal Medicine and is a practicing general internist.

Topic Overview

While statins are a mainstay of lipid management and are generally safe and well-tolerated, they are not always the ideal choice for some patients. While their role in managing lipids is more limited, non-statin medications may be necessary in certain circumstances, such as when patients cannot take or tolerate statins, when patients do not achieve the intended response from statins, or as additions to statin therapy. Pharmacists should be familiar with non-statin medications, including their indications, mechanisms of action, common and serious side effects, potential drug-drug interactions, and monitoring parameters. Pharmacists should also recognize that nutraceutical therapies exist, with variable evidence for use.

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Universal Activity Number: The ACPE Universal Activity Number assigned to this activity is 

Pharmacist 0669-0000-22-098-H01-P

Pharmacy Technician 0669-0000-22-099-H01-T

Credits: 1 hour of continuing education credit

Type of Activity: Continuing education

Media: Internet Fee Information: $4.99

Estimated time to complete activity: 1 hour, including Course Test and course evaluation

Release Date: December 17, 2022 Expiration Date: December 17, 2025

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1

Target Audience: This educational activity is for pharmacists.

How to Earn Credit: From December 17, 2022, through December 17, 2025, participants must:

Read the “learning objectives” and “author and planning team disclosures;”

Study the section entitled “educational activity;” and

Complete the Course Test and Evaluation form. The Course Test will be graded automatically. Following successful completion of the Course Test with a score of 70% or higher, a statement of participation will be made available immediately. (No partial credit will be given.)

Learning Objectives: Upon completion of this educational activity, participants should be able to:

Describe lipid physiology and non-statin therapy targets

Identify indications, side effect profiles, and monitoring recommendations for lipid-lowering medications

Identify pharmacologic options for patients when statin therapy is intolerable, contraindicated, or subtherapeutic

Disclosures

The following individuals were involved in the development of this activity: L. Austin Fredrickson, MD, FACP, Liz Fredrickson, PharmD, BCPS, and Susan DePasquale, MSN, PMHNP-BC. There are no financial relationships relevant to this activity to report or disclose by any of the individuals involved in the development of this activity.

Introduction

Statins are a mainstay of lipid management and are generally safe and well-tolerated; however, in limited circumstances, they are not always the ideal choice for some patients. Non-statin medications may be necessary for certain circumstances, such as when patients cannot take or tolerate statins because they do not achieve the intended response from statins, or as additions to statin therapy. Pharmacists should be familiar with non-statin medications, including their indications, mechanisms of action, common and serious side effects, potential drug-drug interactions, and monitoring parameters. Pharmacists should also recognize that nutraceutical therapies exist, with variable evidence for use.

Atherosclerotic Cardiovascular Disease

ASCVD, the ubiquitous medical term, stands for atherosclerotic cardiovascular disease, which is a type of heart disease primarily caused by atherosclerosis.1 Atherosclerosis is the result of lipoprotein particle accumulation (excess cholesterol) in the arteries, coupled with an inflammatory process.1,2 Excess cholesterol can be deposited underneath the tunica intima layer of blood vessels by low-density lipoprotein cholesterol (LDL-C). Initially, this develops as a small fatty streak. Over time, however, with increasing lipid deposition, the fatty streak can enlarge to form a more voluminous plaque.1,2 This leads to the narrowing of the arteries and a reduction of blood flow to the heart, brain, and other organs.1,2 As a result, ASCVD can incite many serious health problems, including myocardial infarction, stroke, and peripheral artery disease.1-4 In the United States (US) and worldwide, ASCVD remains a leading cause of death and disability.1,3,4 Atherosclerotic cardiovascular disease results from a combination of risk factors, including hypertension, hypercholesteremia (particularly LDL-C- cholesterol), diabetes, smoking, age (men older than 45 years and women older than 55 years), male gender, and family history.1,2 Additionally, patients who consume diets high in saturated fats and who are physically inactive are also at a higher risk of ASCVD.1,2

Lipid Physiology

Cholesterol and triglycerides are hydrophobic (not soluble in water) and thus must be transported through the bloodstream via lipoproteins.5 These lipids are then used for various functions in the body, including as an energy source and to produce steroids or bile acid.6 Lipoproteins are composed of non-polar lipids (cholesterol and triglycerides), phospholipids, free cholesterol, and apolipoproteins.5 There are several different types of lipoproteins, which can be categorized by size, lipid composition, and apolipoproteins.5 The seven types of lipoproteins include chylomicrons, chylomicron remnants, VLDL (very low-density lipoprotein), IDL (intermediate-density lipoproteins), LDL (low- density lipoprotein), HDL (high-density lipoprotein), and Lp(a) (lipoprotein a).5

Very low-density lipoprotein cholesterol (VLDL-C) transports triglycerides.5 When triglycerides are removed from VLDL-C, they become IDL-C. LDL-C results from VLDL-C and IDL. LDL-C carries most cholesterol in the body and is sometimes referred to as "bad" cholesterol.5 Small LDL-C particles are thought to be more pro-atherogenic than large LDL-C particles.5 Conversely, HDL-C is often referred to as "good" cholesterol because it aids in removing excess cholesterol from the blood and is anti-atherogenic.5 Finally, Lp(a) is an LDL-C particle with apolipoprotein (a) attached to Apo B-100 and is considered pro-atherogenic.5 The term LDL has colloquially been interchanged with LDL-C (where “C” denotes the cholesterol carried by LDL particles), but the cholesterol carried by the lipoproteins is primarily discussed here and is denoted with a “-C” after each corresponding lipoprotein.

Dyslipidemia

When an unhealthy imbalance of cholesterol, triglycerides, and lipoproteins occurs, a condition called dyslipidemia results.6 Dyslipidemia is a major risk factor for the development of ASCVD. In evaluating a patient with dyslipidemia, a fasting lipid panel will be used, which measures levels of cholesterol, LDL-C, HDL-C, and triglycerides.6 Six classifications of dyslipidemia (phenotype I, IIa, IIb, III, IV, and V) are generally recognized. These are detailed in Table 1.6

Table 1. Classification of Dyslipidemia (Frederickson Phenotype)

Patient Evaluation

A thorough medical history, lipid panel screening, and use of ASCVD risk calculators can help clinicians determine a patient’s risk of developing ASCVD over a ten-year period.7 Within the 2018 American Heart Association guidelines, this 10-year risk is categorized as low risk (<5%), borderline risk (5 to <7.5%), intermediate risk (7.5 to 20%), and high risk (≥20%).7

Statin Therapy

Statins (HMG-CoA reductase inhibitors) are a mainstay of dyslipidemia treatment and work by inhibiting an enzyme in the liver (HMG-CoA reductase) that is responsible for producing cholesterol.8,9 For patients at lower or borderline risk of developing ASCVD, moderate-intensity statins can be considered with a risk-benefit discussion, including risk enhancers.8 Patients at intermediate risk are recommended to consider treatment with a moderate- to-high intensity statin to reduce LDL-C by 30-49%.8,9 Those considered high

risk should initiate or continue a moderate-to high-intensity statin, with a goal of LDL-C reduction of more than 50%.8 In all of these risk groups, a risk discussion is recommended to take into account patient values, goals, and risk enhancers.8 Lifestyle optimizations are universally recommended.8

Overall, statins have been shown to be effective at lowering LDL-C cholesterol levels and reducing the risk of ASCVD events, including myocardial infarction and stroke.8,9 There are many statins available, including atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin. While statins are efficacious and generally well-tolerated, they may not be an appropriate therapeutic choice in some cases. First, statins may cause unwanted side effects in some individuals, which can preclude the use of these medications. Such side effects include the following:

Allergy or hypersensitivity to statins: Some patients may be allergic to statins or may develop a hypersensitivity reaction to these medications. Symptoms of an allergic reaction can include rash, hives, difficulty breathing, and swelling of the face, lips, tongue, or throat.8

Statin-associated muscle symptoms (SAMS): SAMS include symptoms such as myalgia, myopathy, rhabdomyolysis, and statin- associated myopathy and may occur in 10-25% of patients.8 Risk factors for SAMS include age (with older individuals at higher risk), female sex, low BMI, and heavy exercise.8 Myopathy is dose-dependent and while rhabdomyolysis is a serious effect, it occurs only rarely.8

Statin-induced hepatotoxicity: Statin use can result in elevated hepatic transaminases.8 This may be transient and resolve after therapy is briefly discontinued.8

Statin-associated cognitive dysfunction: This is a rare side effect of statin therapy that may correct by changing the patient from a lipophilic to a hydrophilic statin.8,9

New-onset diabetes: There is a very small but measurable increase in new-onset diabetes after statin initiation in some but not all clinical trials, noted in patients with predisposing factors mostly.8

Statin-associated immune-mediated necrotizing myopathy (IMNM): This results from the development of antibodies against the HMG-CoA reductase enzyme itself.8

Second, statins are contraindicated in certain patient populations, diseases, and with certain other medications:

Pregnancy: Statins are relatively contraindicated during pregnancy, due to the risk of harm to the developing fetus because of effects on fetal cholesterol synthesis which is needed for organogenesis of the central nervous system and other tissues.8,9

Breastfeeding: Statins are also contraindicated for use during breastfeeding due to their effects on cholesterol synthesis in the infant.8,9

Active or chronic muscle disorders: Statins can cause muscle damage in rare cases, so they may be avoided in patients with active or chronic muscle disorders at higher risk of SAMS.8,9

Hepatotoxicity: Statin use should be avoided in patients with liver toxicity or fulminant hepatic failure. They are often safely tolerated in chronic, stable liver disease.8,9

Drug-drug interactions: Statins have the potential to interact with numerous medications at various levels of severity. Three statins— atorvastatin, lovastatin, and simvastatin—are metabolized primarily by CYP3A4.8 When these medications are administered with CYP3A4 inhibitors such as amiodarone, amlodipine, ciprofloxacin, and diltiazem, patients need to be closely monitored.8 Fluvastatin and rosuvastatin are metabolized by CYP2C9 and drug interactions can occur with

medications such as amiodarone, fluconazole, and metronidazole.8 Table 2 details some important drug-drug interactions.8

Table 2. Statin Drug-Drug Interactions

A third consideration is some patients may experience suboptimal outcomes despite adherence to statin therapy. For patients with clinical ASCVD whose LDL-C levels remain≥70 mg/mL on maximally tolerated statin therapy, add-on therapy may be required.7 Some patients who are considered very high-risk will require medications such as ezetimibe alongside maximally tolerated statin therapy to lower LDL-C levels even further.7 Finally, there are a subset of patients with non-LDL-C dyslipidemias, including hypertriglyceridemia, low HDL-C, and apolipoprotein disorders who may require non-statin therapies for their individual lipoprotein imbalances.7

Non-Statin Therapies

There are numerous medications other than statins used as lipid- lowering agents. Table 3 includes a list of these medications with general dosing recommendations.10-23 Table 4 provides the associated changes in lipoprotein levels associated with these agents.24 These medications will be discussed in further detail below.

Table 3. Non-Statin Therapy Dosing

Table 4. Change in Lipoprotein Values for Non-Statin Drugs

Ezetimibe

Ezetimibe works by inhibiting the absorption of cholesterol at the brush border of the small intestine.17,25 This inhibition results in decreased delivery of cholesterol to the liver, reduced hepatic cholesterol stores, and increased removal of cholesterol from the blood as a result.17 Ezetimibe decreases levels of total cholesterol, LDL-C, ApoB, and triglycerides and increases levels of HDL-C.17 Together, these changes are considered to be anti-atherogenic. Within the IMPROVE-IT trial, the addition of ezetimibe to simvastatin therapy for patients with acute coronary syndrome whose LDL-C levels were less than 125 mg/dL conferred a significant reduction in the absolute risk of recurrent cardiovascular events of 2 percentage points and a 6% reduction in relative risk.25

Ezetimibe is indicated for patients with homozygous familial hypercholesteremia in combination with a statin, for patients with homozygous sitosterolemia as adjunctive therapy, and for patients with primary hyperlipidemia as adjunctive therapy to diet and a statin or as monotherapy if statins are not tolerable or resulting in suboptimal LDL-C reduction.17

While ezetimibe is generally well-tolerated, it has side effects with which pharmacists should be familiar. First, the use of ezetimibe can increase serum transaminases and possible hepatotoxicity can occur.17 This risk is higher when ezetimibe is used concurrently with statin therapy.17 This effect is not dose-related and may be delayed up to ten months after starting therapy.17 A second major consideration is muscle-related side effects. The use of ezetimibe as monotherapy or in combination with a statin may cause various muscle-related effects, including myalgia, myopathy, and rhabdomyolysis, much like with SAMS.17 Most of the time, these symptoms will develop within two weeks of starting the medication.17

Various medications interact with ezetimibe, and pharmacists should check for such interactions to ensure the safe use of this medication. The use of ezetimibe with fibric acid derivatives can lead to potential ezetimibe toxicity and the combination should be avoided (category X interaction).17 Taking ezetimibe with bile acid sequestrants (category D interaction) can lead to decreased absorption of ezetimibe, and ezetimibe should be administered at least 2 hours before or 4 hours after any bile acid sequestrant.17

Patients on ezetimibe therapy should have a baseline lipid profile completed, and a fasting lipid profile rechecked between 4 and 12 weeks after starting therapy and then every 3 to 12 months.17 LFTs can be checked if deemed reasonable by the prescribing physician.17 Patients should also be monitored for signs and symptoms of myopathy.17

Evolocumab and Alirocumab

Evolocumab and alirocumab are human monoclonal antibodies classified as PCSK9 inhibitors.10,16 PCSK9 (proprotein convertase subtilisin/kexin type 9) binds low-density lipoprotein receptors (LDLR) on the surface of hepatocytes, which promotes the degradation of LDLR within the liver.10 PCSK9 inhibitors function by inhibiting PCKS9 from binding to LDLR.10 This increases the number of LDL receptors available to clear LDL from circulation, lowering LDL levels.10

Evolocumab is used to treat homozygous familial hypercholesteremia as an adjunct therapy to other LDL-C-lowering treatments.10,16 It is also used to manage primary hyperlipidemia as an adjunct to diet, either alone or in combination with other lipid-lowering medications.10,16 Finally, it is indicated in the prevention of cardiovascular events in patients with cardiovascular disease to reduce the risk of myocardial infarction, stroke, and coronary revascularization.10,16 Alirocumab is indicated for the treatment of homozygous familial hypercholesteremia, and primary hyperlipidemia. Alirocumab can reduce the risk of myocardial infarction, stroke, and unstable angina requiring hospitalization in patients with established cardiovascular disease.16

Use of evolocumab is associated with side effects that include hypersensitivity reactions (angioedema and urticaria).10 Patients may also develop a delayed rash or maculopapular exanthem.10 Delayed injection-site reactions are common, with bruising, skin erythema, nasopharyngitis, and flu- like symptoms the most reported symptoms.10 Alirocumab is also associated with local injection site reactions.16 In 1.2% of individuals who take alirocumab, drug-neutralizing antibodies may be seen.16 There is also a less than 1% risk of neurocognitive changes.16 In the FOURIER trial, this was noted in 0 of 1974 patients.16,26

Monitoring parameters for evolocumab and alirocumab include checking a lipid profile before starting treatment, rechecking lipids 4 to 12 weeks after starting therapy, and maintenance checks every 3 to 12 months to monitor clinical response.10,16 Patients should be assessed for signs of hypersensitivity and local injection site reactions.10,16

Inclisiran

Inclisiran is categorized as an antilipemic small interfering ribonucleic acid (siRNA) agent.21 This medication uses the RNA interference mechanism within liver cells to break down mRNA for PCSK9.21 By doing so, it increases the recycling and expression of LDL-C receptors on the surface of hepatocytes,

which subsequently increases the uptake of LDL-C and lowers levels within the circulation.21

Inclisiran can be used as an adjunct to diet and maximally tolerated statin therapy for the treatment of heterozygous familial hypercholesterolemia.21 It is also indicated for the secondary prevention of cardiovascular events as an adjunct to diet and maximally tolerated statin therapy.21

Side effects of inclisiran therapy include the development of antibodies, local injection site reactions, arthralgia, and bronchitis.21 Patients taking inclisiran should have a lipid profile checked prior to starting treatment, with a recheck 4 to 12 weeks later and maintenance checks every 3 to 12 months.21

Omega-3 Fatty Acids

Omega-3 fatty acids act by reducing the hepatic production of low- density lipoproteins that are rich in triglycerides.20,23 In the REDUCE-IT trial, patients with known ASCVD or diabetes mellitus and one other risk factor who had LDL-C controlled on statins but uncontrolled triglycerides (135-500mg/dL) were given icosapent ethyl, a proprietary and highly purified eicosapentaenoic acid (EPA).27 Results showed ASCVD events decreased by 25% and the overall incidence of MI for IPE vs. placebo was significant at 8.6% vs. 12.0%.27

Side effects of omega-3 fatty acids include gastrointestinal disturbances.15 The incidence is lower at doses less than 3 grams a day compared to doses of 4 or more grams per day.23 A “fishy taste” is a common complaint associated with the use of these medications and commonly affects patient adherence.23 To mitigate this, pharmacists can recommend patients freeze the capsules, switch formulations, consume the medication with a fatty meal, or take it at a different time of day.23 Patients who take omega-3 fatty acids should have triglycerides and LDL-C monitored at baseline and then periodically.23

Bempedoic Acid

Bempedoic acid is a newer antilipemic medication approved by the FDA in February of 2020.11 It inhibits de novo hepatocyte cholesterol biosynthesis and acts as an inhibitor of adenosine triphosphate citrate lyase (ACL), an enzyme upstream of HMG-CoA reductase.11 Bempedoic acid is indicated for lowering LDL-C after diet and maximally tolerated statin therapy for hereditary familial hyperlipidemias or ASCVD.11 It is adjunctive therapy to diet and maximally tolerated statin therapy for patients requiring additional LDL-C lowering.11 Trials have demonstrated bempedoic acid may result in a 15-25% reduction in LDL-C.11

Bempedoic acid is associated with hyperuricemia, tendon ruptures, and rare increases in creatinine kinase, creatinine, and LFTs.11 Its use is contraindicated with simvastatin at doses greater than 20 mg/day and pravastatin at doses greater than 40 mg/day.11 It is also contraindicated in pregnancy.11 After starting bempedoic therapy, patients should have lipid levels checked within 8 to 12 weeks.11 They should also be monitored for signs and symptoms of hyperuricemia and have uric acid levels checked as needed.11 Additionally, signs and symptoms of tendon rupture (joint pain, swelling, inflammation) should also be monitored.11

Evinacumab

Evinacumab is an inhibitor of angiopoietin-like protein 3 and was approved in 2019 for refractory hypercholesterolemia with homozygous familial hypercholesterolemia.15 It is used as adjunctive therapy to other LDL- C-lowering medications.15 This intravenous medication is a recombinant human monoclonal antibody that binds to and inhibits angiopoietin-like protein 3 (ANGPTL3)- a protein produced by the liver that blocks lipoprotein lipase.15 Because lipoprotein lipase breaks down triglycerides, inhibiting ANGPTL3 will decrease triglyceride levels.15 This medicine also promotes VLDL processing and clearance upstream of LDL formation, which decreases LDL-C.15

Patients on this medication may experience hypersensitivity reactions, including anaphylaxis.15 Other side effects include nasopharyngitis, abdominal pain, and dizziness.15 The possibility of pregnancy should be ruled out prior to initiating a patient on this medication.15 LDL-C should be assessed as clinically needed for patients on evinacumab therapy.15 They should also be monitored for signs and symptoms of hypersensitivity reactions.15

Bile Acid Sequestrants

Bile acid sequestrant medications include cholestyramine, colestipol, and colesevelam.12-14 These agents bind with bile acids in the intestine, forming insoluble complexes that are eventually eliminated via feces.12-14 Increasing the elimination of bile acids results in a lowering of serum cholesterol levels, as there is less resorption of cholesterol returned to the liver.12-14 Bile acid sequestrants have an additive effect with statins and niacin, and may separately be used off-label to treat diarrhea that is associated with bile acid malabsorption.12-14 They are used less commonly than other antilipemic agents, given they are less effective and less tolerable.

Side effects of bile acid sequestrants include increases in triglycerides and nausea, bloating, and constipation.12-14 They are associated with many drug interactions, including warfarin, fat-soluble vitamins, and ezetimibe. It is important for patients to take bile acid sequestrants either 1 hour before or four hours after taking other medications.12-14

Patients should have lipid profiles checked between 4 and 12 weeks after starting therapy and then every 3 to 12 months after.12-14

Niacin

Niacin is an antilipemic agent that undergoes bioconversions which eventually result in nicotinamide adenine dinucleotide (NAD+) and NADH.22 While the mechanism by which niacin affects lipoproteins is not fully understood, it may upregulate lipoprotein lipase and inhibit VLDL synthesis and secretion.22 Niacin increases HDL-C levels and lowers total cholesterol,

apolipoprotein B, triglycerides, VLDL-C, LDL-C, and lipoprotein a.22 There is a lack of clinical evidence that niacin improves patient outcomes.

Overall, niacin has low tolerability. Side effects include flushing (benign cutaneous vasodilation) which may be seen in 80% of patients who take this medication.22 Patients can take aspirin or NSAIDS to mitigate these prostaglandin-mediated effects.22 Other effects include increased insulin resistance and decreased glucose tolerance, which may worsen diabetes.22 Niacin has been shown to elevate uric acid levels, worsen gout, and cause kidney stones. 22 Patients may experience GI upset, including nausea and abdominal pain.22 Additionally, niacin can increase LFTs and cause pruritus.22 Finally dry skin and acanthosis nigricans may occur with use.22

Niacin should not be used in patients who become pregnant.22 It should be used cautiously in patients with diabetes, gout, or unstable angina.22 It may increase myopathy with simvastatin more so than other statins.22 Diabetic patients who take niacin should monitor their blood glucose levels.22 If niacin is taken with a statin, CPK, and serum potassium levels should be monitored periodically, and LFTs should be measured pre-treatment and then every 6 to 12 weeks for the first year. 22 Uric acid levels can be monitored in patients who are predisposed to gout.22

Fibrates

Fibric acid antilipemic agents include fenofibrate and gemfibrozil.18,19 Fenofibrate and gemfibrozil are agonists for PPAR-alpha, downregulate apoprotein C and upregulate the synthesis of a fatty acid transport protein and lipoprotein lipase.18,19 This leads to an increase in the breakdown of VLDL and the elimination of triglycerides.18,19 These agents reduce VLDL-C levels and total triglyceride levels by 30 to 60%.18,19 They may also increase HDL-C levels.18,19

Major side effects of fibrates include GI symptoms.18 Rarely, patients may experience rash, arrhythmias, hypokalemia, or rhabdomyolysis.18 Gemfibrozil may cause myopathies, especially when used in combination with

statins.19 Other side effects include minor increases in liver transaminases (seen in 5% of patients) and an increased risk of cholesterol gallstones (gemfibrozil-associated cholelithiasis).18,19

Fibrate use is associated with some drug interactions. They can potentiate the action of oral anticoagulants (like warfarin).18,19 When used in combination with statins, they increase the risk of rhabdomyolysis.18,19 Their use is contraindicated in hepatic disease, renal disease, and pregnancy. Gemfibrozil should be used cautiously with statins, if at all.19

Monitoring for fibrates includes lipid profiles periodically, LFTs at baseline and then periodically, kidney function in those with kidney impairment, and signs and symptoms of myalgia, myopathy, and rhabdomyolysis.18,19

Economic Considerations

The cost of these alternative lipid-lowering therapies should be taken into consideration when determining a patient’s treatment regimen. Compared with statin therapy for secondary prevention, PCSK9 inhibitors have incremental cost-effectiveness ratios from $141,700 - $450,000 per quality- adjusted life-year (QALY) added, at mid-2018 list prices.7 None of the published models report “good value” (<$50,000 per QALY added). Virtually all indicate “low value” (≥$150,000 per QALY added).7 Generally, the older and generic medications are more affordable than the newer, biologic agents.

Nutraceutical Alternatives

Nutraceutical medications may play a role in the care of patients who are statin intolerant, which is now referred to as having statin-associated adverse events. These natural agents target low-density lipoprotein cholesterol targets that are not reached with either tolerable statin and/or non-statin therapies. Per the literature, these agents may be recommended for use in high-risk or very high-risk patients with complete statin intolerance who have not reached LDL-C target levels with non-statin therapy.28 In these

cases, nutraceutical agents as monotherapy or in combination with other lipid- lowering therapies can be considered.28 These may also be useful in high-risk or very high-risk patients with partial statin intolerance who have not reached LDL-C targets with tolerable statin therapy and/or non-statin therapy.28 Finally, nutraceutical therapies can be considered in patients with statin intolerance and high cholesterol levels (and other risk factors with intermediate cardiovascular risk who have not reached LDL-C targets.28

Red yeast rice is one nutraceutical alternative therapy. The dose is 1,200 to 4,800 mg a day.28 Its use is associated with a decrease of LDL-C between 15 and 25%.28 Red yeast rice may cause side effects like those of statins due to the content of monacolin K within the product.28 A second option is bergamot (citrus begamia). The evidence for use of bergamot is not as strong as for red yeast rice.29 The dose of bergamot is 500 to 1500 mg daily, with expected decreases in LDL-C levels between 15 and 25%.28 There are no major safety concerns with the use of this product.28 A third option is soy products. There is also little available evidence for use of soy products compared to red yeast rice.28 The daily dose when used is 25 to 100 g.28 Expected decreases if LDL-C levels of 6 to 10%.28 Soy products may interfere with thyroid function and fertility.28 Further, they can lead to decreased absorption of calcium, magnesium, copper, iron, and zinc.28 Pharmacists should thoroughly review available information and evidence pertaining to these alternative therapies before recommending them to patients or prescribers. A review of potential drug-drug and drug-food interactions should also be completed.

Summary

Atherosclerotic cardiovascular disease is a type of heart disease that is primarily caused by atherosclerosis. Atherosclerosis is the result of lipoprotein particle accumulation (excess cholesterol) in the arteries, coupled with an inflammatory process.

Statins have been shown to be effective at lowering LDL-C cholesterol levels and reducing the risk of ASCVD events. While statins are efficacious and

generally well-tolerated, they may not be an appropriate therapeutic choice in some cases. Statins may cause unwanted side effects in some individuals, which can preclude the use of these medications. Non-statin therapies are useful when goals are not met on maximally tolerated statin therapy.

Through their cellular mechanisms of action, non-statin therapies can be utilized effectively and safely. When combining non-statin drugs together or with statin medications, potential interactions, and contraindications should be kept in mind, e.g., gemfibrozil should be used cautiously with statins, if at all.

Pharmacists should recognize that natural options also exist with variable evidence to support their uses. Armed with this arsenal of information, pharmacists will be equipped to further lower ASCVD risk and ultimately improve patient outcomes.

Course Test

Which of the following is true regarding statin therapy?

Those who have mild reactions to statins can be safely reassessed and rechallenged

They are safe to use during pregnancy

They have been found to cause cancer

They work by activating lipoprotein lipase and raising HDL-C

In patients with clinical ASCVD who do not achieve ≥50% reduction in LDL-C levels and whose LDL-C levels remain ≥70 mg/dL, what medication is recommended as add-on therapy?

Fenofibrate

Inclisiran

Ezetimibe

Alirocumab

Which class of medications is recommended to add for very high- risk patients whose LDL-C remains uncontrolled on maximally tolerated statin therapy and ezetimibe?

Fatty acid

Bile acid sequestrants

Bempedoic acid

PCSK9 inhibitors

Which class of medications works by blocking intestinal and biliary cholesterol absorption, thereby decreasing LDL-C levels?

Ezetimibe

Fibrates

PCSK9 inhibitors

Niacin

Which of the following statements is most accurate regarding PCSK9 inhibitors?

They are relatively inexpensive

The most common reaction is hyperuricemia

They theoretically may increase hepatitis C infectivity by downregulating HCV receptors in the liver

They work by blocking bile acid reuptake by hepatocytes

Which of the following medications has been shown to decrease ASCVD events by 25%?

Icosapent ethyl

Gemfibrozil

Alirocumab

Niacin

Which of the following statements is most accurate regarding bile acid sequestrants?

They cause diarrhea and pruritus

They downregulate LDL receptors, increasing LDL-C levels

Other medications should be taken separately from them, at least 1-2 hours prior or 4 hours afterward

They are safe to mix with warfarin and require no extra monitoring when coadministered

A patient on high-dose simvastatin was started on an unknown pill to further lower LDL-C but subsequently arrived in the emergency department with severe rhabdomyolysis.        was most likely prescribed, leading to severe rhabdomyolysis.

Gemfibrozil

Niacin

Ezetimibe

Inclisiran

Of the available nutraceutical options, which has been shown to reduce LDL-C the most at maximal dosages?

Red yeast rice

Soy

Fish oils

Peppercorn

A patient on statin therapy starts ezetimibe. Which of the following should be monitored at least annually?

Hepatitis C RNA levels

Creatinine kinase

Lipid panel

Uric acid

References

The National Heart, Lung, and Blood Institute. Arteriosclerosis. What is Arteriosclerosis? NHLBI. 2022. https://www.nhlbi.nih.gov/health/atherosclerosis. Accessed February 11, 2023.

Bergheanu SC, Bodde MC, Jukema JW. Pathophysiology and treatment of atherosclerosis: Current view and future perspective on lipoprotein modification treatment. Neth Heart J. 2017;25(4):231-242. doi:10.1007/s12471-017-0959-2

Adhikary D, Barman S, Ranjan R, Stone H. A Systematic Review of Major Cardiovascular Risk Factors: A Growing Global Health Concern. Cureus. 2022;14(10):e30119. Published 2022 Oct 10. doi:10.7759/cureus.30119

Barquera S, Pedroza-Tobías A, Medina C, et al. Global Overview of the Epidemiology of Atherosclerotic Cardiovascular Disease. Arch Med Res. 2015;46(5):328-338. doi:10.1016/j.arcmed.2015.06.006

Feingold K. Introduction to Lipids and Lipoproteins. Endotext [Internet]. 2021. MDText.com, Inc.

Dixon DL, Riche DM, Kelly MS. Dyslipidemia. In: DiPiro JT, Yee GC, Michael Posey LL, Haines ST, Nolin TD, Ellingrod VL. eds. DiPiro: Pharmacotherapy A Pathophysiologic Approach, 12e. McGraw Hill; 2021.

Grundy SM, Stone NJ, Bailey AL, 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 [published correction appears in Circulation. 2019 Jun 18;139(25):e1182-e1186]. Circulation.

2019;139(25):e1082-e1143. doi:10.1161/CIR.0000000000000625

Li M, Wang X, Li X, et al. Statins for the Primary Prevention of Coronary Heart Disease. Biomed Res Int. 2019;2019:4870350. Published 2019 Jan 29. doi:10.1155/2019/4870350

Lexicomp Online, Lexi-Drugs Online. Simvastatin. Waltham, MA: UpToDate, Inc.; January 4, 2023. https://online.lexi.com. Accessed January 29, 2023.

Lexicomp Online, Lexi-Drugs Online. Alirocumab. Waltham, MA: UpToDate, Inc.; October 10, 2022. https://online.lexi.com. Accessed January 29, 2023.

Lexicomp Online, Lexi-Drugs Online. Bempedoic Acid. Waltham, MA: UpToDate, Inc.; November 22, 2022. https://online.lexi.com. Accessed January 29, 2023.

Lexicomp Online, Lexi-Drugs Online. Cholestyramine. Waltham, MA: UpToDate, Inc.; December 6, 2022. https://online.lexi.com. Accessed January 29, 2023.

Lexicomp Online, Lexi-Drugs Online. Colesevelam. Waltham, MA: UpToDate, Inc.; December 23, 2022. https://online.lexi.com. Accessed January 29, 2023.

Lexicomp Online, Lexi-Drugs Online. Colestipol. Waltham, MA: UpToDate, Inc.; October 14, 2022. https://online.lexi.com. Accessed January 29, 2023.

Lexicomp Online, Lexi-Drugs Online. Evinacumab. Waltham, MA: UpToDate, Inc.; October 10, 2022. https://online.lexi.com. Accessed January 29, 2023.

Lexicomp Online, Lexi-Drugs Online. Evolocumab. Waltham, MA: UpToDate, Inc.; November 11, 2022. https://online.lexi.com. Accessed January 29, 2023.

Lexicomp Online, Lexi-Drugs Online. Ezetimibe. Waltham, MA: UpToDate, Inc.; December 21, 2022. https://online.lexi.com. Accessed January 29, 2023.

Lexicomp Online, Lexi-Drugs Online. Fenofibrate. Waltham, MA: UpToDate, Inc.; January 3, 2023. https://online.lexi.com. Accessed January 29, 2023.

Lexicomp Online, Lexi-Drugs Online. Gemfibrozil. Waltham, MA: UpToDate, Inc.; December 31, 2022. https://online.lexi.com. Accessed January 29, 2023.

Lexicomp Online, Lexi-Drugs Online. Icosapent ethyl. Waltham, MA: UpToDate, Inc.; December 17, 2022. https://online.lexi.com. Accessed January 29, 2023.

Lexicomp Online, Lexi-Drugs Online. Inclisiran. Waltham, MA: UpToDate, Inc.; November 12, 2022. https://online.lexi.com. Accessed January 29, 2023.

Lexicomp Online, Lexi-Drugs Online. Niacin. Waltham, MA: UpToDate, Inc.; December 26, 2022. https://online.lexi.com. Accessed January 29,

2023.

Lexicomp Online, Lexi-Drugs Online. Omega 3 Fatty Acids. Waltham, MA: UpToDate, Inc.; December 17, 2022. https://online.lexi.com. Accessed January 29, 2023.

Rosenson R. Effects of lipid-lowering drugs on serum lipid levels. UpToDate. December 2022. https://www.uptodate.com/contents/statins-actions-side-effects-and- administration. Accessed January 29, 2023.

Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015;372(25):2387-2397. doi:10.1056/NEJMoa1410489

Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713-1722. doi:10.1056/NEJMoa1615664

Bhatt DL, Steg PG, Brinton EA, et al. Rationale and design of REDUCE- IT: Reduction of Cardiovascular Events with Icosapent Ethyl- Intervention Trial. Clin Cardiol. 2017;40(3):138-148. doi:10.1002/clc.22692

Penson PE, Banach M. The Role of Nutraceuticals in the Optimization of Lipid-Lowering Therapy in High-Risk Patients with Dyslipidaemia. Curr Atheroscler Rep. 2020;22(11):67. Published 2020 Sep 18. doi:10.1007/s11883-020-00887-z

Osadnik T, Goławski M, Lewandowski P, et al. A network meta-analysis on the comparative effect of nutraceuticals on lipid profile in adults. Pharmacol Res. 2022;183:106402. doi:10.1016/j.phrs.2022.106402

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