The Role of Non-Statin Lipid-Lowering Therapy in Older Adults with ASCVD

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Cardiovascular Burden in Older Adults

Despite public health initiatives, cardiovascular disease (CVD) remains the leading cause of death in the United States,1-4 especially in older adults.5 The prevalence of CVD increases with age: 60.4% of men and 52.0% of women in the group aged 40 to 59 years have CVD; this jumps to 89.4% and 90.8%, respectively, in adults >80 years of age.6 Advanced age is an established risk factor for atherosclerotic CVD (ASCVD), and according to American College of Cardiology/American Heart Association (ACC/AHA) guidelines, adults aged ≥65 years are considered very high risk for future ASCVD events.7 A 2018 study using the Patient and Provider Assessment of Lipid Management registry determined that patients aged >75 years had substantially higher rates of established ASCVD compared with younger adults (60.9% vs 47.6%; P <.0001).8 The high prevalence of CVD in this population is related to age-related changes, such as increasing oxidative stress,9 myocardial degeneration, and inflammation.10,11

One of the major risk factors for developing CVD is hyperlipidemia.2 Low-density lipoprotein cholesterol (LDL-C) is the most abundant atherogenic lipoprotein in plasma and carries the majority of cholesterol in circulation throughout the body. In addition, 4 other classes of lipoproteins are known to be atherogenic: intermediate-density lipoprotein, very low-density lipoprotein, lipoprotein(a), and chylomicron remnants; whereas high-density lipoprotein cholesterol (HDL-C) is antiatherogenic.12 Atherogenic LDL-C levels increase with age, peaking in men at the age of 50 to 59 years and in women at age 60 to 69 years, thereby also contributing to CVD risk in older adults.13

Development of Atherosclerosis

Endothelial cell dysfunction is the initial step in the pathogenesis of atherosclerosis, which results in compromised barrier integrity.14 This allows for an infiltration and accumulation of LDL particles and other remnant lipid particles in the subendothelial space where they are modified by a variety of mechanisms and engulfed by macrophages and smooth-muscle cells, promoting endothelial cell activation.14 Activation of endothelial cells leads to the migration of additional monocytes and recruitment of immune cells, which, in turn, allows for the gradual creation of foam cells.14 Foam cell accumulation and smooth-muscle cell proliferation results in plaque formation, which may become vulnerable and prone to rupture.14 Plaque rupture results in thrombus formation, which accounts for the majority of clinical events in ASCVD, ie, myocardial infarction, unstable angina, sudden cardiac death, and stroke.14

The development of atherosclerotic plaques increases with increasing LDL-C levels; the higher the LDL-C level, the greater the extent of plaque formation.15,16 Although LDL-C is the key driver in atherosclerosis, plaque formation is accelerated by other risk factors such as age, smoking, high blood pressure, and diabetes.7,17,18 The role of inflammation as a causative factor in the development of atherosclerosis is supported by a growing body of evidence.19 Since the mid-1950s, when LDL-C was first identified as a risk factor for coronary heart disease, there have been numerous epidemiologic studies, genetic studies, and clinical trials that have confirmed the direct correlation of LDL-C with atherosclerotic heart disease.17

Role of Comorbidities in Older Adults

The high prevalence of CVD in older adults is related to a frequent clustering of common risk factors in this population, including dyslipidemia, diabetes, and hypertension, as well as age-related changes in cholesterol metabolism.20 Adults aged 75 to 79 years have a 60% chance of having 2 or more clinically significant comorbid conditions, and the probability increases to ≥75% in adults aged 85 to 89 years.21 Common comorbidities in older adults, including diabetes, hypertension, obesity, and chronic kidney disease (CKD), are associated with inflammation and are known cardiovascular risk factors.22,23 The presence of CKD or type 2 diabetes doubles the risk for cardiovascular events and, when the two are combined, the risk further increases.23 According to the U.S. Renal Data System and the National Health and Nutrition Examination Survey, the prevalence of CVD may be as high as 63% in patients with CKD, compared with 5.8% in people without CKD.24 In addition, cardiovascular events in older adults with type 2 diabetes is a major cause of increased risk of death; the global incidence of CVD in patients with type 2 diabetes is 2 to 3 times higher than in those without type 2 diabetes.25 Peripheral artery disease (PAD) is also associated with an increased risk of ASCVD events, as seen in a retrospective analysis of commercial and Medicare claims data. Colantonio and colleagues evaluated more than 940,000 patients with a diagnosis of PAD, coronary heart disease, or cerebrovascular disease from 2014 to 2017. The ASCVD event rate (per 1000 patient-years) was 42.2 for patients with coronary heart disease (CHD) and 34.7 for patients with PAD. Among patients with both PAD and CHD, the ASCVD event rate was 72.8, and the rate among patients with all 3 conditions was 119.5.26

The coexistence of multiple health conditions in older adults can make management of these conditions very complex when taking into consideration potential drug–drug interactions and increased risk of adverse drug effects.27 In addition, increasing pill burden (polypharmacy) and the complexity of multiple medication regimens can negatively impact the likelihood that patients will take medications as instructed.28 Cognitive impairment in older adults may also lead to poor medication adherence or the patient may require assistance to ensure the treatment regimen is being followed appropriately.29 Other contributors to nonadherence in these patients may include lack of understanding of medication instructions or new instructions, living alone, and the use of potentially inappropriate medications.29

Guidelines, Risk Stratification, and LDL-C Treatment Targets

Based on the presence of major risk factors, including comorbidities and a calculated 10-year risk score, patients are categorized from low to very high risk or extreme risk by their level of risk for future ASCVD events.30 LDL-C targets and lipid-lowering therapy recommendations are tailored to each risk group. Guidelines from ACC/AHA and the American Association of Clinical Endocrinologists and the American College of Endocrinology (AACE/ACE) vary somewhat in their characterization of risk categories, treatment targets, and recommendations; however, all groups recommend more aggressive LDL-C goals with increasing cardiovascular risk.7,30 As evidence on the role of LDL-C in atherosclerosis has increased, guidelines have evolved over the past 20 years to continually lower LDL-C treatment goals in patients with established ASCVD (Table 1).7,30-34

Table 1

Treatment Recommendations and LDL-C Goals. A 2020 consensus statement from the AACE/ACE on the management of dyslipidemia and prevention of CVD defined 5 risk categories (Table 2).30 These guidelines recommend specific LDL-C target goals for each risk category, with more aggressive goals for lipid-lowering therapy as ASCVD risk increases.30 AHA/ACC risk categories and initial recommendations are described in Table 37; both guidelines emphasize statin use as the backbone of LDL-C management.

Table 2
Table 3

Guideline-Recommended Statin Therapy in Older Adults with ASCVD

Given the high prevalence of CVD and the coexistence of other age-related risk factors, secondary prevention with statin therapy is important to avoid further cardiovascular events and related morbidity and mortality.35 Substantial clinical trial evidence supports the use of statin therapy to reduce the risk of major adverse cardiovascular events in older adults with ASCVD, from a 24% reduction (relative risk, 0.76) in events per 38 mg/dL LDL-C reduction in adults 65 to 70 years of age to 13% reduction (relative risk, 0.87) in those >75 years.36 Unless contraindicated, a statin at the highest tolerated dose should be used as initial treatment for lipid lowering in patients with ASCVD, including patients aged >75 years (Table 4).7

Table 4

However, despite guideline recommendations to use a statin at the highest tolerated dose, many older patients are not titrated to an optimal statin dose or are not prescribed a statin at all. A nationwide analysis, using 2017 to 2018 electronic health record data (Cerner Real World Data) from 384,109 patients with ASCVD, demonstrated that only 36% of adults with ASCVD received a high-intensity statin.37 When stratified by age, 41% of patients aged <55 years, 42.4% of those aged 55 to 64 years, 37.3% of those aged 65 to 74 years, and 28.0% of those ≥75 years were on high-intensity statin therapy.37 In addition, 35.2% of patients <55 years, 27.1% of those aged 55 to 64 years, 26.4% of those aged 65 to 74 years, and 29.0% of patients aged ≥75 years with ASCVD were not receiving any statin therapy.37 Similarly, a retrospective cohort study evaluating statin use in 601,934 patients with ASCVD using pharmacy and medical claims data from commercial health plans from 2018 to 2019 showed that 49.9% of patients were not on any statin therapy and only 22.5% were on a high-intensity statin; older patients, female patients, and those with PAD were less likely to be on a high-intensity statin.38

Adherence to therapy is also a concern among high-risk older patients. In a retrospective cohort analysis of 347,104 statin users with ASCVD who were treated within the Veterans Affairs Health System between January 2013 and April 2014, adults aged ≥75 years were less likely to be adherent to statin therapy compared with adults aged 65 to 74 years.39 Another systematic review of 82 studies, including >3 million patients aged >65 years, demonstrated poor short- and long-term adherence to statins among older adults. In patients taking statins for secondary prevention, 1-year adherence was lower among individuals aged >75 years compared with those aged 65 to 75: 62.6% of patients aged 65 to 75 years were adherent versus 58.3% of those aged >75 years (P <.0001).40 From a pooled analysis of statin use for primary and secondary prevention in this study, it was seen that 59.9%, 59.6%, 55.3%, 35.9%, 35.7%, and 28.4% of older statin users were adherent at 6 months and 2, 3, 4, 5, and ≥10 years, respectively.40

Women are another patient group that has historically been underrepresented in statin trials and undertreated with statin therapy, often receiving less-aggressive lipid management than that received by men, even among older adults. Gender differences in statin use have been observed in the Patient and Provider Assessment of Lipid Management registry, a nationwide registry of outpatients with or at risk for ASCVD.41 Of the 5693 participants, women eligible for AHA/ACC guideline–recommended statin therapy were less likely to have been prescribed any statin than were men (67% vs 78.4%; P <.001) and less likely to be prescribed a statin at guideline-recommended dose intensity (36.7% vs 45.2%; P <.001). Women were also more likely to report never having been offered statin therapy, declining statin therapy, or discontinuing statin therapy.41

Statin Intolerance in Older Adults. More than 30 years of evidence, beginning in 1987 with the Food and Drug Administration (FDA) approval of lovastatin, has shown that statins are safe and well-tolerated by the majority of patients. However, in clinical practice, some patients are unable to take maximum-intensity statin therapy, either because of contraindications (eg, active hepatic disease, pregnancy) or adverse effects of statin therapy, with the most common being skeletal muscle-related symptoms, such as soreness, cramps, stiffness, or weakness.42 The development of more severe myopathy leading to rhabdomyolysis is rare but requires discontinuation of statin therapy.30 Statin intolerance may occur in 5% to >20% of statin-treated patients.30 Older patients may be more susceptible to adverse effects of statin therapy due to age-related factors such as low body mass index from cardiac cachexia or sarcopenia.43 In addition, age-related physiologic changes can alter drug pharmacokinetics and pharmacodynamics, which can increase the risk of adverse effects by increasing drug concentrations.43 As such, statin intolerance may be more common in older patients, warranting either lower intensity statin therapy or the addition of a non-statin medication in order to achieve LDL-C goals.43 The National Lipid Association (NLA) Scientific Statement on Statin Intolerance recommends that patients who are intolerant to statin therapy try another statin medication, a reduced dose, or an alternate dosing regimen to attempt to find a tolerable regimen. However, in patients at high and very high risk with statin intolerance, the NLA statement recommends the consideration of a non-statin therapy while attempting to identify a maximally tolerated statin.42

Role of Adjunct Lipid-Lowering Agents

Many patients are not able to achieve recommended LDL-C goals with statin therapy alone. As such, the use of non-statin adjunct therapy may fill the gap for when additional LDL-C lowering is required and in patients with documented statin intolerance. Both the ACC/AHA 2018 guidelines and the AACE/ACE consensus statement recommend adjunct treatment options for additional lipid lowering in high-risk patients not at goal.7,30 The recently updated 2022 ACC expert consensus decision pathway (ECDP) statement provides practical guidance for providers and patients on the use of newer non-statin therapies in lipid management.44 Given the clinical benefit of LDL-C lowering demonstrated in clinical studies, the ACC ECDP recommends that non-statin adjunct therapy should be considered for adults with ASCVD at very high risk who have LDL-C levels ≥55 mg/dL on statin therapy.44 Non-statin therapies include ezetimibe, bile acid sequestrants, inclisiran, bempedoic acid (which do not as yet have proven cardiovascular outcomes benefit),45 and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.44 These classes of non-statin therapies reduce LDL-C via various mechanisms of action (Figure 1).46 In addition, the ACC ECDP recommends consideration of patient, lifestyle, and treatment factors when determining an appropriate adjunct intervention.44

Figure 1

Adjunctive Lipid-Lowering Therapy: Non-Statin Therapies with Proven Cardiovascular Benefit

PCSK9 Inhibitor Monoclonal Antibodies. PCSK9 promotes hepatic LDL-receptor degradation through extracellular binding of PCSK9 to the LDL receptor, followed by intracellular lysosomal degradation. As a result, the number of LDL receptors on the cell surface declines and levels of LDL-C in the blood rise.17,47 Currently, 2 PCSK9 inhibitor monoclonal antibodies are available in the United States: alirocumab, which was FDA approved in April 2021, and evolocumab, which was FDA approved in 2015.

Alirocumab is approved as an adjunct to diet, alone or in combination with other lipid-lowering therapies (eg, statins, ezetimibe), for the treatment of adults with primary hyperlipidemia (including heterozygous familial hypercholesterolemia [HeFH] and homozygous familial hypercholesterolemia [HoFH]) to reduce LDL-C, and it is approved to reduce the risk of myocardial infarction, stroke, and unstable angina requiring hospitalization in adults with established CVD.48 When combined with statin therapy, alirocumab typically reduces LDL-C by 48% to 58% compared with placebo.48

Evolocumab is approved for reducing the risk of myocardial infarction, stroke, and coronary revascularization in adults with established CVD; as an adjunct to diet, alone or in combination with other lipid-lowering therapies (eg, statins, ezetimibe) for the treatment of adults with primary hyperlipidemia (including HeFH) to reduce LDL-C; and as an adjunct to diet and other lipid-lowering therapies (eg, statins, ezetimibe, LDL apheresis) in patients with HoFH who require additional lowering of LDL-C.49 When combined with statin therapy, evolocumab reduces LDL-C by an additional 63% to 71% compared with placebo.49

Alirocumab and evolocumab require frequent self-injection. Alirocumab is administered subcutaneously (SC) in the thigh, abdomen, or upper arm every 2 weeks starting at 75 mg, which may be increased to a maximum of 150 mg every 2 weeks. Alternatively, 300 mg SC every 4 weeks may be used as a starting dose for less frequent injections.48 In adults with established CVD, evolocumab starting dose is 140 mg SC every 2 weeks or 420 mg SC monthly.49 Common adverse events in clinical trials occurring in >5% of patients and more frequently than placebo include injection-site reactions, nasopharyngitis, influenza, upper respiratory tract infection, back pain, diabetes mellitus, noncardiac chest pain, and myalgia.48,49 PCSK9 inhibitors are generally well-tolerated and efficacious, but an important limitation to their use is the high cost of therapy.30

Improved cardiovascular outcomes have been seen with PCSK9 inhibitors in the FOURIER and ODYSSEY OUTCOMES trials. The FOURIER trial evaluated cardiovascular outcomes with evolocumab in patients aged 40 to 85 years with ASCVD who were receiving statin therapy.50 Patients were randomly assigned to receive either evolocumab or placebo. LDL-C was reduced by a mean of 56 mg/dL with the addition of evolocumab; after 2.2 years of follow-up, the composite primary end point (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization) occurred in 9.8% of patients in the evolocumab group versus 11.3% of patients in the placebo group (hazard ratio, 0.85; P <.001).50

The ODYSSEY OUTCOMES trial evaluated cardiovascular outcomes with alirocumab versus placebo in patients aged ≥40 years with acute coronary syndrome within the past 12 months on maximally tolerated statin therapy.51 In the placebo group, LDL-C increased an average of 4 mg/dL after 12 months whereas LDL-C decreased by a mean of 44 mg/dL in the alirocumab group. After a median follow-up of 2.8 years, the primary end point (a composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) occurred in 9.5% of the alirocumab group versus 11.1% of the placebo group (hazard ratio, 0.85; P <.001).51

Non-Statin Therapies That Have Not Established Cardiovascular Benefit

Ezetimibe. Ezetimibe is a cholesterol absorption inhibitor that directly binds to Nieman Pick C1 like 1 protein and prevents the transportation of dietary cholesterol from the gut lumen to intestinal enterocytes, resulting in decreased amounts of cholesterol delivered to the liver and an upregulation of hepatic LDL receptors.52,53 Ezetimibe also inhibits cholesterol absorption in the small intestine. Ezetimibe is approved as monotherapy as an adjunct to diet for the reduction of elevated total cholesterol, LDL-C, apolipoprotein B, and non–HDL-C in patients with primary hyperlipidemia (HeFH and nonfamilial).45 It is also approved for combination therapy with a statin or fenofibrate.45 The standard dose of 10 mg/day lowers LDL-C by approximately 18% as monotherapy45 and an additional 12% to 17% when combined with statin therapy30; however, ezetimibe may not provide sufficient lipid lowering in patients needing extensive additional LDL-C lowering.45 Ezetimibe is generally well-tolerated30 but is contraindicated in combination with a statin in patients with active liver disease or unexplained persistent elevations in serum transaminases.45

The IMPROVE-IT trial evaluated patients aged ≥50 years with recent acute coronary syndrome receiving ezetimibe plus statin therapy versus statin monotherapy. The primary end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, or nonfatal stroke.54 During a 6-year follow-up, patients in the ezetimibe plus statin group had a mean LDL-C of 53.7 mg/dL versus 69.5 mg/dL in the statin monotherapy group. At 7 years, the rate of the primary end point was 32.7% in the ezetimibe plus statin group and 34.7% in the statin only group (hazard ratio, 0.936; P = .016).54

Bile Acid Sequestrants. Bile acid sequestrants increase LDL-C clearance from the blood, resulting in decreased serum LDL-C levels.55 Currently, 3 oral bile acid sequestrants are available in the United States: cholestyramine, colesevelam, and colestipol. Cholestyramine is associated with mild serum aminotransferase and alkaline phosphatase elevations, which can be resolved by stopping therapy. Common adverse events with these agents include constipation, dyspepsia, bloating, nausea, and vomiting, and more commonly occur with larger doses and in patients aged >65 years.55 Bile acid sequestrants are not absorbed in the gastrointestinal tract but bind to fat-soluble vitamins, hormones, or medications in the intestine. If tolerated at maximum doses, these agents may reduce LDL-C concentrations by 15% to 30%.55,56

Bempedoic Acid. Bempedoic acid is an adenosine triphosphate-citrate lyase (ACL) inhibitor indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with HeFH or established ASCVD who require additional lowering of LDL-C (approved by the FDA in February 2020).57 The effect of bempedoic acid on cardiovascular morbidity and mortality has not been determined. Bempedoic acid lowers LDL-C by inhibition of cholesterol synthesis in the liver. ACL is an enzyme upstream of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase in the cholesterol biosynthesis pathway. Bempedoic acid and its active metabolite, ESP15228, require coenzyme A (CoA) activation by very long-chain acyl-CoA synthetase 1 (ACSVL1) to ETC-1002-CoA and ESP15228-CoA, respectively. ACSVL1 is expressed primarily in the liver. Inhibition of ACL by ETC-1002-CoA results in decreased cholesterol synthesis in the liver and lowers LDL-C in the blood via upregulation of LDL receptors.57 The target of bempedoic acid, ACL, is a different enzyme in the cholesterol biosynthesis pathway than the primary target of statins; the activity of these 2 enzymes occurs at different steps in the pathway, and they are independently regulated.58

The recommended dosage of bempedoic acid, in combination with maximally tolerated statin therapy and diet, is 180 mg administered orally once daily.57 The effect of bempedoic acid on cardiovascular morbidity and mortality has not been determined. Bempedoic acid is also available in a fixed-dose combination tablet containing 180 mg of bempedoic acid and 10 mg of ezetimibe and indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with HeFH or established ASCVD who require additional lowering of LDL-C.59 The effect of bempedoic acid and ezetimibe on cardiovascular morbidity and mortality has not been determined.

The efficacy of bempedoic acid was studied in 2 randomized, double-blind, placebo-controlled trials that enrolled 3009 adults with HeFH or established ASCVD who were on maximally tolerated statin therapy. When added to diet and maximally tolerated statin therapy, the difference between bempedoic acid and placebo in mean change in LDL-C from baseline to week 12 was -18% in one study and -17% in the second study.57 The fixed-dose combination of bempedoic acid/ezetimibe was studied in a single, randomized, double-blind, placebo-controlled parallel group trial that enrolled 301 patients with HeFH, established ASCVD, or multiple risk factors for CVD on maximally tolerated statin therapy. The difference between bempedoic acid/ezetimibe and placebo in mean change in LDL-C from baseline to week 12 was -38% when added to diet and maximally tolerated statin therapy.59 The efficacy of bempedoic acid/ezetimibe fixed-dose combination in patients with multiple risk factors for CVD has not been established.

Elevations in serum uric acid have occurred with bempedoic acid; uric acid levels should be assessed periodically as clinically indicated,57 and treatment with urate-lowering drugs may be used as appropriate. Tendon rupture has also occurred with bempedoic acid, and it should be discontinued at the first sign of tendon rupture. Bempedoic acid should be avoided in patients who have a history of tendon disorders or tendon rupture.57 The most common (incidence ≥2% and greater than placebo) adverse reactions observed with bempedoic acid were upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, pain in extremity, anemia, and elevated liver enzymes.57 The most common (incidence ≥ 2% and greater than placebo) adverse reactions observed with the fixed-dose combination of bempedoic acid/ezetimibe were upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, pain in extremity, anemia, elevated liver enzymes, diarrhea, arthralgia, sinusitis, fatigue, and influenza.59 Bempedoic acid shares a metabolic pathway with statins and should be avoided in patients receiving simvastatin >20 mg or pravastatin >40 mg to avoid increased risk of myopathy.57 Please see additional Important Safety Information at the end of this article.

The effect of bempedoic acid alone or in combination with ezetimibe on cardiovascular outcomes has not been established; however, a large, placebo-controlled study is currently ongoing to evaluate the effect of bempedoic acid on cardiovascular outcomes. Results from this study are anticipated in 2023.60,61

Small Interfering RNA PCSK9 Inhibitor. Inclisiran, which was FDA approved in December 2021, is a small interfering RNA that also inhibits PCSK9 but acts differently than the monoclonal antibodies by directing the catalytic breakdown of messenger RNA for PCSK9.62 In the ORION-10 trial, which evaluated inclisiran in patients with ASCVD taking statins, inclisiran reduced LDL-C by 49% to 56% beyond reduction with statin therapy.62

Inclisiran recommended dosing is 284 mg SC administered by a clinician on day 1, day 90, and then every 6 months, in combination with maximally tolerated statin therapy.62 Common adverse events in clinical trials (≥3%) with inclisiran include injection site reaction, arthralgia, urinary tract infection, diarrhea, bronchitis, pain in extremity, and dyspnea.62 An outcomes trial assessing the effect of inclisiran on major adverse cardiovascular events is currently in progress; however, results are not expected until 2026 or 2027.63

Conclusions

The burden of CVD is very high in older adults. With advancing age, patients often experience an increase in cardiovascular risk factors, including elevated LDL-C levels contributing to atherogenesis and complex cardiometabolic comorbidities. Clinical guidelines recommend that statin therapy be initiated in older adults with ASCVD, even in patients aged >75 years. Despite evidence-based guidelines, this is a population that is often underrepresented in clinical trials and undertreated with statin therapy. In addition, lipid management in older adults can be complicated by the presence of comorbid conditions, polypharmacy, and other age-related factors. Poor adherence to statin therapy and adverse events can also be challenging when managing an older patient population. Even with maximally tolerated statin therapy, some patients still require additional lipid lowering. When additional LDL-C lowering is required, new and existing non-statin adjunct therapies can contribute to LDL-C goal attainment.

INDICATION

Bempedoic acid and bempedoic acid/ezetimibe are indicated as adjuncts to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C.

Limitations of Use: The effect of bempedoic acid and bempedoic acid/ezetimibe on cardiovascular morbidity and mortality has not been determined.

IMPORTANT SAFETY INFORMATION

Contraindications: Bempedoic acid has no contraindications. Bempedoic acid/ezetimibe is contraindicated in patients with a known hypersensitivity to ezetimibe tablets. Hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria have been reported with ezetimibe.

Warnings and Precautions: Hyperuricemia: Bempedoic acid, a component of bempedoic acid and bempedoic acid/ezetimibe, may increase blood uric acid levels. Hyperuricemia may occur early in treatment and persist throughout treatment, and may lead to the development of gout, especially in patients with a history of gout. Assess uric acid levels periodically as clinically indicated. Monitor for signs and symptoms of hyperuricemia, and initiate treatment with urate-lowering drugs as appropriate.

Tendon Rupture: Bempedoic acid is associated with an increased risk of tendon rupture or injury. In clinical trials, tendon rupture occurred in 0.5% of patients treated with bempedoic acid versus 0% of patients treated with placebo, and involved the rotator cuff (the shoulder), biceps tendon, or Achilles tendon. Tendon rupture occurred within weeks to months of starting bempedoic acid. Tendon rupture may occur more frequently in patients over 60 years of age, patients taking corticosteroid or fluoroquinolone drugs, patients with renal failure, and patients with previous tendon disorders. Discontinue bempedoic acid and bempedoic acid/ezetimibe at the first sign of tendon rupture. Avoid bempedoic acid and bempedoic acid/ezetimibe in patients who have a history of tendon disorders or tendon rupture.

Adverse Reactions: In bempedoic acid clinical trials, the most commonly reported adverse reactions were upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, pain in extremity, anemia, and elevated liver enzymes. Reactions reported less frequently, but still more often than with placebo, included benign prostatic hyperplasia and atrial fibrillation. In the bempedoic acid/ezetimibe clinical trial, the most commonly reported adverse reactions observed with bempedoic acid/ezetimibe, but not observed in clinical trials of bempedoic acid or ezetimibe, a component of bempedoic acid/ezetimibe, and occurring more frequently than with placebo, were urinary tract infection, nasopharyngitis, and constipation.

Adverse reactions reported in clinical trials of ezetimibe, and occurring at an incidence greater than with placebo, included upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity, fatigue, and influenza. Other adverse reactions reported in postmarketing use of ezetimibe included hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria; erythema multiforme; myalgia; elevated creatine phosphokinase; myopathy/rhabdomyolysis; elevations in liver transaminases; hepatitis; abdominal pain; thrombocytopenia; pancreatitis; nausea; dizziness; paresthesia; depression; headache; cholelithiasis; cholecystitis.

Drug Interactions: Simvastatin and Pravastatin: Concomitant use with bempedoic acid results in increased concentrations and increased risk of simvastatin or pravastatin-related myopathy. Use of either bempedoic acid and bempedoic acid/ezetimibe with greater than 20 mg of simvastatin or 40 mg of pravastatin should be avoided.

Cyclosporine: Caution should be exercised when using bempedoic acid/ezetimibe and cyclosporine concomitantly due to increased exposure to both ezetimibe and cyclosporine. Monitor cyclosporine concentrations in patients receiving bempedoic acid/ezetimibe and cyclosporine. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the benefits of alterations in lipid levels provided by bempedoic acid/ezetimibe.

Fibrates: Coadministration of bempedoic acid/ezetimibe with fibrates other than fenofibrate is not recommended. Fenofibrate and ezetimibe may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected in a patient receiving bempedoic acid/ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered.

Cholestyramine: Concomitant use of bempedoic acid/ezetimibe and cholestyramine decreases ezetimibe concentration. This may result in a reduction of efficacy. Administer bempedoic acid/ezetimibe either at least 2 hours before, or at least 4 hours after, bile acid sequestrants.

Lactation and Pregnancy: It is not recommended that bempedoic acid or bempedoic acid/ezetimibe be taken during breastfeeding. Discontinue bempedoic acid or bempedoic acid/ezetimibe when pregnancy is recognized, unless the benefits of therapy outweigh the potential risks to the fetus. Based on the mechanism of action of bempedoic acid, bempedoic acid and bempedoic acid/ezetimibe may cause fetal harm.

Please see enclosed full Prescribing Information for Nexlizet and Nexletol.

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