An LDL-Lowering Therapy for Primary and Secondary Prevention of CVD
This article was sponsored by Esperion Therapeutics, Inc.
INTRODUCTION
Cardiovascular disease (CVD) is an important health concern. National Health and Nutrition Examination Survey (NHANES) data from 2017 to 2020 revealed a high prevalence of CVD in 48.6% of adults at least 20 years old in the US, accounting for 127.9 million people in 2020.1 This prevalence tends to increase with age, which emphasizes the age-related risks of CVD.1 Furthermore, the relationship between low-density lipoprotein cholesterol (LDL-C) levels and atherosclerotic CVD (ASCVD) is well established. Outcomes of animal research, genetic investigations, epidemiologic studies, and randomized controlled trials have consistently demonstrated that elevated levels of LDL-C significantly contribute to the development of ASCVD.2 This association highlights the importance of monitoring and managing LDL-C levels when addressing the risk of CVD.
SUBOPTIMAL ATTAINMENT OF RECOMMENDED LDL-C LEVELS
According to American College of Cardiology/American Heart Association guidelines for primary prevention of ASCVD, statins are recommended as the first-line therapy for treating patients with high LDL-C levels (≥ 190 mg/ dL), those with diabetes mellitus who are 40 to 75 years old, and patients who have a sufficient ASCVD risk.3 Despite the widespread use of statin therapy, many patients fail to achieve their recommended cholesterol management levels.4
Wong and colleagues evaluated 2011 to 2012 NHANES data to determine how many patients reported using statin therapy and achieved recommended LDL-C levels specified by the National Lipid Association.5 In total, 1677 patients between the ages of 40 and 75 years were evaluated; they represented over 62 million adults who were eligible for statin therapy (age ≥ 21 years: ASCVD or LDL-C levels ≥ 190 mg/dL; age 40-75 years: with diabetes or with ≥ 7.5% 10-year ASCVD risk [primary prevention group]). Patients with an LDL-C level greater than 190 mg/ dL showed the highest rate of not achieving recommended LDL-C levels (98.0%). Among those with ASCVD, 79.7% of patients did not achieve their recommended LDL-C levels. In the primary prevention group, 46.8% of patients did not reach recommended LDL-C levels using statins alone. According to the results, the researchers predicted that 18.4 million patients taking statin therapy in the US are not reaching their recommended LDL-C levels.5
Various factors influence whether patients reach their recommended LDL-C levels, such as discontinuation,6,7 nonadherence,6-8 high baseline LDL-C levels,9 differences in patient responses to statin therapy,10 and unwillingness or inability to take a statin.11 In light of these challenges, there is a recognized need for additional lipid-lowering therapies (LLTs) that complement first-line options.12,13 Patients on maximally tolerated statins who are not able to achieve recommended LDL-C levels should be given a nonstatin LLT.14 However, use of nonstatin LLTs as an adjunct to statins remains low in high-risk patients.13
BEMPEDOIC ACID AS A NONSTATIN LLT
Esperion Therapeutics, Inc. has 2 products containing bempedoic acid (BA), a fixed-dose combination, NEXLIZET® (bempedoic acid and ezetimibe) 180 mg/10 mg and NEXLETOL® (bempedoic acid) 180 mg. The BA component of NEXLIZET and NEXLETOL are indicated as of March 22, 2024, to reduce the risk of myocardial infarction (MI) and coronary revascularization in adults who are unable to take recommended statin therapy (including those not taking a statin) with established CVD or at high risk for a CVD event but without established CVD.15
As an adjunct to diet, BA (NEXLETOL) is indicated in combination with other LDL-C–lowering therapies, or alone when concomitant LDL-C-lowering therapy is not possible, to reduce LDL-C in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH). BA and ezetimibe (NEXLIZET) is indicated alone or in combination with other LDL-C–lowering therapies to reduce LDL-C in adults with primary hyperlipidemia, incuding HeFH.15
NEXLIZET and NEXLETOL are contraindicated in patients with a prior hypersensitivity to BA or ezetimibe (EZE) or any of the excipients. Serious hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria have been reported.15
The efficacy and safety of BA when used for LDL-C lowering was investigated in 2 multicenter, randomized, double-blind, placebo-controlled trials (CLEAR Wisdom [NCT02991118] and CLEAR Harmony [NCT02666664]) that included 3009 adult patients with HeFH or established CVD who were on maximally tolerated statin therapy.16 The difference between the BA and placebo groups in mean percent change in LDL-C from baseline to week 12 was -18% (95% CI, -20 to -16%; P < .001).15
The efficacy and safety of BA 180 mg and EZE 10 mg fixed-dose combination (BA + EZE) compared with placebo, EZE 10 mg alone, and BA 180 mg alone in 301 patients with HeFH, established CVD, or multiple risk factors for CVD on maximally tolerated statin therapy was studied in the 053 Trial (NCT03337308). At week 12, BA + EZE significantly lowered the mean LDL-C as compared with the effects of placebo (-38%; 95% CI, -47% to -30%; P < .001).17,18
CLEAR Outcomes Trial
The CLEAR Outcomes trial (NCT02993406) (N = 13,970) was performed to determine whether long-term BA treatment reduces the risk of major adverse CV events (a 4-component composite of death from CV causes, nonfatal MI, nonfatal stroke, or coronary revascularization [MACE-4])19 in patients with, or at high risk for, CVD compared with placebo.19
The study was a randomized, double-blind, placebo-controlled, event-driven trial of patients who were unable to take recommended statin therapy, including no statin; these individuals were primary prevention patients (those at high risk for a CVD event, but without CVD) or secondary prevention patients (with established CVD). Patients were randomized 1:1 to receive either oral BA 180 mg per day (n = 6992) or placebo (n = 6978), alone or as an add-on to other background LLTs. Background therapy could include low-intensity statin dosages. The groups were followed for a median duration of 3.4 years. Notably, 48% and 17% of the study population identified as female and Hispanic or Latino ethnicity, respectively.19
The primary composite end point (ie, MACE-4) occurred in 819 (11.7%) patients in the BA group vs in 927 (13.3%) patients in the placebo group (hazard ratio, 0.87; 95% CI, 0.79-0.96; P = .004).19 As secondary efficacy end points, the study reported a reduction in the incidence of a 3-component composite of CV death, nonfatal stroke, nonfatal MI (MACE-3), nonfatal MI, and coronary revascularization in the BA group compared with the placebo group (Table).19,20 There was no statistically significant difference in the reduction of nonfatal stroke and risk of CV death compared to placebo.19
In CLEAR Outcomes, adverse events (AEs) led to treatment discontinuation in 11% of BA-treated patients and 10% of placebo-treated patients. The most common AEs in the CV outcomes trial for BA, at an incidence of ≥ 2% and 0.5% greater than placebo, were hyperuricemia, renal impairment, anemia, elevated liver enzymes, muscle spasms, gout, and cholelithiasis.15
INDICATION
NEXLIZET (bempedoic acid and ezetimibe) and NEXLETOL (bempedoic acid) are indicated:
- The bempedoic acid component of NEXLIZET and NEXLETOL is indicated to reduce the risk of myocardial infarction and coronary revascularization in adults who are unable to take recommended statin therapy (including those not taking a statin) with:
- established cardiovascular disease (CVD), or
- at high risk for a CVD event but without established CVD.
- As an adjunct to diet:
- NEXLIZET, alone or in combination with other LDL-C lowering therapies, to reduce LDL-C in adults with primary hyperlipidemia, including HeFH.
- NEXLETOL, in combination with other LDL-C lowering therapies, or alone when concomitant LDL-C lowering therapy is not possible, to reduce LDL-C in adults with primary hyperlipidemia, including HeFH.
IMPORTANT SAFETY INFORMATION
Hyperuricemia: Bempedoic acid, a component of NEXLIZET and NEXLETOL, may increase blood uric acid levels, which may lead to gout. Hyperuricemia may occur early in treatment and persist throughout treatment, returning to baseline following discontinuation of treatment. Assess uric acid levels periodically as clinically indicated. Monitor for signs and symptoms of hyperuricemia, and initiate treatment with urate-lowering drugs as appropriate.
CLEAR Outcomes Primary Prevention Subgroup Analysis
Methods: A prespecified, exploratory analysis of CLEAR Outcomes participants enrolled for primary prevention was performed. Of the 4206 primary prevention patients (30% of the total trial population), 2100 were randomized to BA and 2106 to placebo.21 Primary prevention was defined as meeting 1 or more of the following inclusion criteria: Reynolds risk score above 30% or SCORE risk above 7.5% over 10 years, type 1 or 2 diabetes in women older than 65 years or men older than 60 years, or a coronary artery calcium score greater than 400 Agatston units at any time in the past.21,22 The occurrence of MACE-4 was 5.3% in the BA group (111 patients) vs 7.6% in the placebo group (161 patients) (relative risk reduction, 32%; number needed to treat, 43; HR, 0.68; 95% CI, 0.53-0.87) (Figure).21
Limitations: This is a secondary analysis of a subpopulation in a larger randomized trial. Such hypothesis-generating analyses can result in false-positive findings due to the testing of multiple subgroups and may represent the play of chance. The sample size represented a fraction of the total enrolled population, and the number of events was smaller, resulting in wider confidence intervals. The inclusion of patients who reported an inability to tolerate statins resulted in a high mean baseline LDL-C level. The effects of cholesterol lowering on CV events in populations with lower pretreatment LDL-C levels was not studied. The trial selected patients using specific criteria for a high level of risk of a first cardiac event. Whether outcomes would be similar in patients identified using other criteria for increased risk remains uncertain.20
IMPORTANT SAFETY INFORMATION (continued)
Tendon Rupture: Bempedoic acid, a component of NEXLIZET and NEXLETOL, is associated with an increased risk of tendon rupture or injury. Tendon rupture may occur more frequently in patients over 60 years of age, in those taking corticosteroid or fluoroquinolone drugs, in patients with renal failure, and in patients with previous tendon disorders. Discontinue NEXLIZET (bempedoic acid and ezetimibe) or NEXLETOL (bempedoic acid) at the first sign of tendon rupture. Consider alternative therapy in patients who have a history of tendon disorders or tendon rupture.
The most common adverse reactions in the primary hyperlipidemia trials of bempedoic acid, a component of NEXLIZET and NEXLETOL, in ≥2% of patients and greater than placebo were upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, pain in extremity, anemia, and elevated liver enzymes.
Adverse reactions reported in ≥2% of patients treated with ezetimibe (a component of NEXLIZET) and at an incidence greater than placebo in clinical trials were upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity, fatigue, and influenza.
CONCLUSION
Once-daily BA plays an important role in addressing the challenge of treating elevated LDL-C levels, a key contributor to CVD. Based on the CLEAR Outcomes data, BA is the only LDL-C–lowering nonstatin that is FDA-approved to reduce the risk of MI and coronary revascularization in primary prevention and secondary prevention patients.
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IMPORTANT SAFETY INFORMATION (continued)
In the primary hyperlipidemia trials of NEXLIZET, the most commonly reported adverse reactions (incidence ≥3% and greater than placebo) observed with NEXLIZET, but not observed in clinical trials of bempedoic acid or ezetimibe, were urinary tract infection, nasopharyngitis, and constipation.
The most common adverse reactions in the cardiovascular outcomes trial for bempedoic acid, a component of NEXLIZET and NEXLETOL, at an incidence of ≥2% and 0.5% greater than placebo were hyperuricemia, renal impairment, anemia, elevated liver enzymes, muscle spasms, gout, and cholelithiasis.
Concomitant use of NEXLIZET (bempedoic acid and ezetimibe) or NEXLETOL (bempedoic acid) with greater than 20 mg of simvastatin or 40 mg of pravastatin should be avoided due to the potential for increased risk of simvastatin- or pravastatin-related myopathy.
Discontinue NEXLIZET or NEXLETOL when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus. Because of the potential for serious adverse reactions in a breast-fed infant, breastfeeding is not recommended during treatment with NEXLIZET or NEXLETOL.
Report pregnancies to Esperion Therapeutics, Inc. Adverse Event reporting line at 1-833-377-7633.
Please see Full Prescribing Information for NEXLETOL and NEXLIZET.
REFERENCES
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