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Adjunctive Lipid-Lowering Strategies for Patients Needing Additional LDL-C Lowering

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This is part 2 of a 2-part series detailing adjunctive lipid-lowering therapies for patients not reaching recommended low-density lipoprotein cholesterol goals.

Low-density lipoprotein cholesterol (LDL-C) is the principal driver of atherosclerosis and plays a causal role in its pathogenesis.1 Guidelines support the use of maximally tolerated statins as initial therapy for patients requiring LDL-C lowering; however, many patients do not achieve recommended LDL-C goals with statin therapy alone.2 For patients who need additional LDL-C lowering beyond maximally tolerated statins, guidelines recommend the addition of non-statin therapies and diet in high-risk patients not at goal.2-4

Challenges to Achieving LDL-C Goals: Underutilization of Statin Therapy

Unless contraindicated, a statin at a maximally tolerated dose should be the first-line therapy for patients who require pharmacologic treatment to reduce LDL-C.2 However, substantial evidence from real-world registries and administrative claims databases has shown that only approximately half of all high-risk patients with atherosclerotic cardiovascular disease (ASCVD) who should be on a statin were actually receiving statin therapy (Table 1). In addition, a large majority of ASCVD patients were not achieving LDL-C goals on a statin alone, leaving them at residual risk for cardiovascular (CV) events (Table 1). Results from the PINNACLE registry indicated that younger patients (aged 18-64 years), women, and African Americans were less likely to achieve an LDL-C level <70 mg/dL with statin therapy.5

Table 1

Provider inertia often contributes to suboptimal statin utilization, which negatively impacts LDL-C lowering, with many patients not titrated to optimal doses of statin therapy or not prescribed statin therapy. A nationwide analysis, using 2017 to 2018 electronic health record data (Cerner Real World Data) from 384,109 patients with ASCVD, demonstrated that only approximately one-third of adults with ASCVD were receiving a high-intensity statin.6 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.7 In this study, older patients, women, and patients with peripheral artery disease were less likely to be prescribed a high-intensity statin.7

Finally, it has been seen that statin therapy is also underutilized in patients with familial hypercholesterolemia (FH), a genetic cause of elevated cholesterol.8 This is a group of patients characterized by severe hypercholesterolemia (LDL-C >190 md/dL) and who require lipid-lowering therapy (LLT) to achieve LDL-C goals. In a study of patients with FH, approximately 80% of patients were receiving statins (143 out of 184); however, the mean LDL-C for the group was 160.7 mg/dL, well above the target of 100 mg/dL.8

Guideline Recommendations for Adjunctive LLT

Guidelines recommend adjunctive LLT in patients who are not able to reach LDL-C goals despite statin therapy. When adjunctive LLT is needed, several options approved by the US Food and Drug Administration (FDA) have demonstrated efficacy in lowering LDL-C and are recommended in guidelines. Non-statin adjunctive therapies can include ezetimibe, bile acid sequestrants, inclisiran, bempedoic acid, and proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) inhibitors (Figure 1).9,10 The selection of an agent for adjunctive therapy should be based on the required LDL-C reduction and the patient’s risk level (Table 2).2-4

Figure 1
Table 2

Agents for Adjunctive Lipid Lowering

Non-Statin Therapies with Proven CV Outcomes Benefit

PCSK9 inhibitors. PCSK9 inhibitors work by blocking PCSK9, an enzyme which binds to LDL receptors on the surface of hepatocytes. As a result, the number of LDL receptors available to clear LDL-C increases, and LDL-C levels decrease.11,12 Both alirocumab and evolocumab are monoclonal antibodies to PCSK9. Alirocumab was approved by the FDA in April 2015 and is indicated to reduce the risk of myocardial infarction, stroke, and unstable angina requiring hospitalization in adults with established CVD and as an adjunct to diet, alone or in combination with other lipid-lowering therapies, for the treatment of adults with primary hyperlipidemia (including heterozygous FH [HeFH]) to reduce LDL-C.11 When combined with statin therapy, alirocumab typically reduces LDL-C by 48% to 58% beyond reduction from statin therapy.11 Evolocumab, which was approved by the FDA in 2015, is indicated in adults with established CVD to reduce the risk of myocardial infarction, stroke, and coronary revascularization and as an adjunct to diet, alone or in combination with other lipid-lowering therapies, for the treatment of adults with primary hyperlipidemia (including HeFH) to reduce LDL-C.12 When combined with statin therapy, evolocumab reduces LDL-C by an additional 63% to 71% from statin therapy.12

Common adverse events in clinical trials occurring in more than 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.11,12 PCSK9 inhibitors require administration by subcutaneous (SC) injection. Alirocumab is administered 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.11 In adults with established CVD, evolocumab starting dose is 140 mg SC every 2 weeks or 420 mg SC monthly. An important limitation to the use of PCSK9 inhibitors is the high cost of therapy.12

CV outcomes trials have demonstrated the effectiveness of alirocumab and evolocumab when used in conjunction with statins in reducing CV risk. The ODYSSEY OUTCOMES trial evaluated alirocumab versus placebo in patients who had been diagnosed with acute coronary syndrome during the previous 12 months.11 All patients were receiving maximally tolerated statin therapy. Over the median follow-up duration of 33 months, the time to first occurrence of the primary composite end point (coronary heart disease death, nonfatal myocardial infarction, fatal and nonfatal ischemic stroke, or unstable angina requiring hospitalization) was significantly lower in patients receiving alirocumab (9.5% vs 11.1%) compared with placebo (hazard ratio [HR], 0.85; P <.001).12 The FOURIER trial was a randomized controlled evaluation of evolocumab versus placebo in patients with LDL-C ≥70 mg/dL who were receiving statin therapy. Mean LDL-C with evolocumab decreased from 92 mg/dL at baseline to 26 mg/dL after 48 weeks of treatment.12 Evolocumab significantly reduced time to occurrence of the primary composite end point (CV death, myocardial infarction, stroke, coronary revascularization, hospitalization for unstable angina) compared with placebo: 9.8% versus 11.3% (HR, 0.85; P <.0001). Results were consistent across key subgroups.12

Non-Statin Therapies That Have Not Established CV Outcomes Benefit

Ezetimibe. Ezetimibe binds directly to Niemann-Pick C1-Like 1 protein and reduces LDL-C by inhibiting the absorption of cholesterol.13 Ezetimibe prevents transportation of dietary cholesterol, decreases the amount of cholesterol delivered to the liver, upregulates hepatic LDL receptors, and inhibits cholesterol absorption in the small intestine.14,15 Ezetimibe is indicated for monotherapy as an adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL-C, apolipoprotein B, and non–high-density-lipoprotein cholesterol in patients with primary hyperlipidemia (HeFH and nonfamilial) and in combination therapy with a statin or fenofibrate.13 The recommended dose of ezetimibe is 10 mg daily. Ezetimibe in combination with statin therapy is contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases.13 As monotherapy, ezetimibe typically reduces LDL-C by 18%.13 When combined with statins, ezetimibe reduced LDL-C by 12% to 15% beyond reduction from statin therapy.13 Ezetimibe is an efficacious adjunct option; however, it may not provide adequate lipid lowering in patients needing extensive additional LDL-C lowering.16

Bile acid sequestrants. Bile acid sequestrants lower LDL-C to a modest degree by increasing LDL-C clearance from the blood, resulting in decreased serum LDL-C levels.17 In the United States, 3 bile acid sequestrants are available in an oral formulation: cholestyramine, colesevelam, and colestipol.17 These agents may reduce LDL-C concentrations by 15% to 30% in a dose-dependent manner if agents are tolerated at maximum doses.17 The impact of bile acid sequestrants on CV outcomes has not been determined. Common adverse events with all 3 agents include constipation, dyspepsia, bloating, nausea, and vomiting. Bile acid sequestrants are not absorbed in the gastrointestinal tract but bind to fat-soluble vitamins, hormones, or medications in the intestine.17

Bempedoic acid. Bempedoic acid is an adenosine triphosphate citrate lyase (ACL) inhibitor FDA approved in February 2020 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.18 The effect of bempedoic acid on CV morbidity and mortality has not been determined. Bempedoic acid lowers LDL-C by inhibiting cholesterol synthesis in the liver. ACL is an enzyme upstream of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase in the cholesterol biosynthesis pathway. ESP15228 is the active metabolite of bempedoic acid, and they both require coenzyme A (CoA) activation by very long-chain acyl CoA synthetase 1, which is primarily expressed in the liver, to ETC-1002-CoA and ESP15228-CoA, respectively. ETC-1002-CoA inhibits ACL, which results in decreased cholesterol synthesis in the liver and upregulation of LDL-C receptors, which lowers LDL-C in the blood.18 ACL is a different enzyme in the cholesterol biosynthesis pathway than the primary target of statins (HMG-CoA); the activity of these 2 enzymes occurs at different steps in the pathway, and they are independently regulated.1,19

The recommended dosage of bempedoic acid, in combination with maximally tolerated statin therapy and diet, is 180 mg administered orally once daily.18 Bempedoic acid is also available in a fixed-dose combination tablet containing 180 mg of bempedoic acid and 10 mg of ezetimibe.20 This combination was approved by the FDA in February 2020 and is 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.20 The effect of bempedoic acid and ezetimibe on CV 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.18 When added to diet and maximally tolerated statin therapy, the difference between bempedoic acid and placebo in mean percent change in LDL-C from baseline to week 12 was -18% in one study and -17% in the second study.18

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 percent change in LDL-C from baseline to week 12 was -38% when added to diet and maximally tolerated statin therapy.20 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, and uric acid levels should be assessed periodically as clinically indicated. Monitor for signs and symptoms of hyperuricemia, and initiate treatment with urate-lowering drugs as appropriate.18 Tendon rupture has also occurred with bempedoic acid, and it should be discontinued at the first sign of tendon rupture. Avoid bempedoic acid in patients who have a history of tendon disorders or tendon rupture.18 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. 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.18 The most common (≥2% in patients and greater than placebo) adverse reactions observed in patients treated with ezetimibe were upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity, fatigue, and influenza.20 The most commonly reported adverse reactions with bempedoic acid/ezetimibe (≥3% and greater than placebo) not observed in clinical trials of bempedoic acid or ezetimibe were urinary tract infection, nasopharyngitis, and constipation.20 Bempedoic acid shares a metabolic pathway with statins and should be avoided in patients receiving >20 mg of simvastatin or >40 mg of pravastatin to avoid increased risk of myopathy.18 Please see additional Important Safety Information at the end of this article.

siRNA PCSK9 inhibitor. Inclisiran is a double-stranded small interfering ribonucleic acid (siRNA) that also inhibits PCSK9 but acts in ways unlike the monocloncal antibodies. In hepatocytes, inclisiran directs the catalytic breakdown of mRNA for PCSK9 and increases LDL-C receptor recycling and expression on the hepatocyte cell surface, thereby increasing LDL-C uptake and lowering LDL-C in circulation.21 Inclisiran was approved by the FDA in December 2021 and is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with HeFH or clinical ASCVD who require additional lowering of LDL-C.21

The ORION-10 trial, which evaluated inclisiran in patients with ASCVD who were also receiving statins, showed that inclisiran reduced LDL-C by 49% to 56% beyond reduction with statin therapy.21 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.21 Common adverse events in clinical trials (≥3%) with inclisiran include injection-site reaction, arthralgia, urinary tract infection, diarrhea, bronchitis, pain in extremity, and dyspnea.21 An outcomes trial assessing the effect of inclisiran on major adverse CV events is currently in progress; however, results are not expected until 2026.22

Barriers to LLT and Strategies to Overcome

Clinical Inertia

Despite the availability of several non-statin adjunct therapies with varied mechanisms of actions, patients with ASCVD often do not have their LLT intensified, despite not being at their goal LDL-C. In the GOULD registry, only 17.1% of ASCVD patients had their LLT intensified during a 2-year period, even though 68.3% remained at LDL-C >70 mg/dL.23 In patients with LDL-C levels >100 mg/dL, LLT intensification occurred in only 22.4%. Among these patients, statin dosage was intensified in 6.4%, ezetimibe was added in 6.8%, and a PCSK9 inhibitor was added in 6.3% of patients.23 Similarly, in patients with an LDL-C between 70 mg/dL and 99 mg/dL, 14.4% had LLT intensification. Among this population, 6.3% had statin intensification, 4.5% had ezetimibe added to statin therapy, and a PCSK9 inhibitor was added in only 2.2% of patients.23

Strategies to overcome clinical inertia. Strategies to overcome clinical inertia in lipid management include increasing the implementation of evidence-based guidelines to change clinical practice. The GOULD registry found that clinical sites with lipid management protocols were more likely to intensify LLT (P <.001) and get patients to LDL <70 mg/dL (P <.001) compared with sites without lipid management protocols; likewise, sites where the lead physician was a cardiologist and believed the appropriate therapeutic goal for patients with ASCVD to be LDL-C <70 mg/dL were more likely to intensify LLT.23 A systematic review by Groenhof and colleagues investigated the benefit of computerized decision support systems (CDSS) on CV risk management. CDSS can be used for reminders for risk factor assessment, evaluation of risk factor levels, and for recommending evidence-based treatment strategies as part of lipid management protocols; CDSS functionalities can include drug alerts, laboratory test ordering, and treatment advice. The researchers identified 3 studies that investigated the effect of CDSS on lipid control in CV patients and 6 studies on lipid control in patients with type 2 diabetes.24 Design, characteristics, and desired clinical outcomes varied substantially among the trials. Of the 2 studies that reported on lipid goal attainment in CV patients, no significant difference was noted with CDSS versus usual care, whereas a significant difference was noted with CDSS versus usual care in patients with type 2 diabetes.24 Technical development, consistent use, and reporting of CDSS is still growing; however, it holds promise in helping clinicians integrate evidence-based guidelines into practice.

An important factor in overcoming inertia in lipid management may also be the lack of an active Centers for Medicare & Medicaid Services or National Committee for Quality Assurance Healthcare Effectiveness Data and Information Set quality measure for LDL-C control.25,26 Currently, the only relevant measures are related to the utilization of statins for the prevention and treatment of CVD. Although the current quality measures may not be a reason why patients are not intensified beyond statin therapy alone, it stands to reason that additional interventions would be implemented across health systems if a measure were to be added reflecting the proportion of patients achieving LDL-C control.


Adherence and treatment discontinuation remain concerns when patients are receiving chronic LLT, as almost half of patients with CV conditions do not take medications as prescribed. Adherence is usually defined using medication possession ratio (MPR) or as the proportion of days covered (PDC), both of which measure the number of doses dispensed in relation to the days in a dispensing period where 100% reflects perfect adherence.27

A retrospective study using a claims database of a large health insurer for patients hospitalized for myocardial infarction or atherosclerotic disease investigated adherence to statin therapy and angiotensin-converting enzyme inhibitor therapy in 4015 patients post–myocardial infarction and 12,976 patients with atherosclerotic disease. In the myocardial infarction cohort, 57% of patients had a PDC <80%, and 26% of patients were taking less than half of their prescribed doses (PDC <40%).28 Similarly, 66% of patients with atherosclerotic disease had a PDC <80%, and 28% had a PDC <40%.28 Fewer major adverse CV events during the follow-up period were observed for adherent patients (PDC ≥80%) compared with those only partially adherent (PDC ≥40% to ≤79%).28

Researchers conducted a retrospective cohort study of 347,104 adults within the Veterans Affairs Health System between 2013 and 2014 and evaluated statin adherence in patients with ASCVD, reporting higher adherence in this population (mean MPR 87.7% over a 12-month period).29 Factors associated with lower adherence included high-intensity statin use (vs moderate-intensity statin use), women (vs men), all minority groups (vs non-Hispanic white patients), and younger and older patients (vs patients aged 65-74 years).29 Mean LDL-C values were lower in adherent patients: 77.2 mg/dL for MPR ≥90% versus 92.1 mg/dL for MPR <50%.29 After adjusting for adherence to other CV medications and patient characteristics, a significant association was observed between low statin adherence and mortality.29

Initiatives to improve adherence. Given the importance of medication adherence to improved clinical outcomes, there have been many multifaceted and multidisciplinary strategies aimed at improving adherence.27,30-34 Several systematic reviews have investigated many of these strategies, including digital technology interventions, pharmacist counseling, and financial incentives, with studies showing generally positive or varied results.

A systematic review using data from randomized controlled trials from electronic databases investigated whether app-based interventions can help improve medication adherence in CVD. The researchers evaluated 16 trials published between 2014 and 2020 and found that in 9 trials, medication adherence rates significantly improved compared with controls; a meta-analysis of 6 studies that reported continuous data showed a significant overall effect in favor of app-based interventions.30 Another systematic review and meta-analysis of randomized trials measured the effectiveness of digital technology (mobile phones, Internet, software applications, and wearables) interventions on behavior changes, including adherence, in patients with CVD.31 In 25 identified studies, digital interventions included telerehabilitation, telemonitoring, and online coaching and included behavioral change constructs such as goal setting, record keeping, social engagement, support, rewards and incentives, and self-management. Standard text messaging targeted only at medication adherence did not show a significant effect (P = 0.11); however, programs that used standard text messaging to target medication adherence plus additional behavioral outcomes (physical inactivity, diet, smoking, alcohol intake) were significantly effective with use of digital intervention compared to usual care (P = .02).31

Pharmacist counseling is also an important intervention that may help improve adherence in patients with CVD. One retrospective study of 1102 patients new to statin therapy demonstrated that patients who participated in 2 brief face-to-face counseling sessions with a community pharmacist at the initiation of statin therapy subsequently demonstrated significantly greater medication adherence and persistence than those who did not receive counseling.32 Likewise, an open-label, prospective, randomized trial showed that face-to-face educational counseling by community-based pharmacists had a positive impact at 6 months on statin discontinuation (discontinuation rate of 11% vs 16% in the control group; HR, 0.66; 95% confidence interval [CI], 0.46-0.96; P = .026), although the MPR did not differ between the groups (99.5% intervention group vs 99.2% control group).34 Finally, the effectiveness of tailored phone consultations with a pharmacist for mail-order pharmacy patients was evaluated in a randomized, parallel group, controlled trial of 677 patients receiving ≥1 oral medication for type 2 diabetes or lipid lowering. At 6 months, 10.6% of the intervention group were nonadherent (<90% of the medication taken in the past 7 days) versus 19.6% in the control group (95% CI, 1.11-2.15; P = .01).33

Some data suggest that financial incentives may improve adherence, including a randomized clinical trial that showed the impact of financial incentives on achievement of LDL-C goal.35 The trial included 4 groups: a control group, which received no financial incentives; a group in which patients could receive incentives; a group in which physicians could receive incentives; or a group in which patients and physicians could receive shared incentives. Only those in the shared incentives group achieved a significant 12-month LDL-C reduction (P = .002) compared with the control group.35 LDL-C reduction at 12 months was 33.6 mg/dL in the shared incentives group (from a baseline of 160.1 mg/dL) and 25.1 mg/dL in the control group (from a baseline of 161.5 mg/dL).35

A core component of many of these interventions is familiarity with the reasons for nonadherence, which can then be mitigated with patient education and counseling on disease management.27 For example, in the PALM registry, 617 patients had declined or discontinued a statin and the most common reasons identified were fear of side effects (37%) and experiencing perceived side effects (60%). Other reasons for statin discontinuation were preference for diet and exercise, dislike of taking medication, and a belief that statin therapy is not needed.27

Addressing patient-specific concerns, closing patients’ educational gaps, and getting patients involved in their own healthcare may be the most effective way to improve adherence.36 Patients with ASCVD are largely unaware of their own level of CV risk, the reasons for LLT, their most recent LDL-C level, and their targets for treatment. Arnold and colleagues published a study in 2021 based on GOULD registry data that included 5006 US outpatients with ASCVD and 113 physician providers. All patients were using a PCSK9 inhibitor or had suboptimal LDL-C control. The study showed that only 28% of patients correctly understood the reason they were taking lipid-lowering medication. Most (68%) did not know their most recent LDL-C level, and 69% did not know their LDL-C goal.36 Among the physicians, 66% indicated that the primary factor influencing nonadherence was that patients lacked an understanding of the importance and effectiveness of statins.36 Addressing the substantial educational gap among patients and providing patient-centric education in plain language to stress the importance of achieving desired LDL-C levels can mitigate patient hesitancies.27 Education may also aid in improving a patient’s resistance to intensifying LLT and prompt important conversations with providers.27

Implications for Payers

The costs associated with CVD in the United States are astronomical. Estimated expenditures for direct costs of CVD were $226.2 billion in 2017 and 2018, according to the US Agency for Healthcare Research and Quality (Figure 2).37 Indirect costs, ie, lost productivity and mortality, were estimated at $151.8 billion, for a combined cost of $378.0 billion.37

Figure 2

Increased implementation of strategies to reduce LDL-C in patients at risk or with established ASCVD is important to reduce further CV risk. Despite the availability of low-cost generic statins, utilization is poor, and for many, statin therapy alone is not sufficient to reach LDL goals.8,9,23 Guideline-recommended intensification of therapy by either increasing the statin dose and/or adding a non-statin adjunctive therapy is warranted in these patients.2,3,38 All of the FDA-approved non-statin LLTs, ie, ezetimibe, PCSK9 inhibitors, bile acid sequestrants, and bempedoic acid, have an acceptable risk/benefit profile when used as adjunctive therapy to maximally tolerated statin and diet when additional LDL-C lowering is warranted. However, financial barriers and administrative burden for prescribing may make access to these agents challenging and contribute to inability to meet LDL-C goals.27 A national survey of 22,521 adults with ASCVD in the Medical Expenditure Panel Survey from the Agency of Healthcare Research and Quality found that the average out-of-pocket cost for patients with ASCVD was $2227 per year, with 45% of direct costs going toward medication, and 13.7% of families with an ASCVD patient experienced a high financial burden, especially in low-income families.39 In addition, the US National Health Interview Survey found that 12.6% of adults with ASCVD reported cost to be a factor for nonadherence: 8.6% reported missing doses, 8.8% reported taking lower-than-prescribed doses, and 10.5% delayed a refill order to save money.40

The administrative burden of prior authorizations for novel non-statin therapies may also be a contributing factor to low rates of therapy intensification. In a retrospective analysis of patients prescribed a PCSK9 inhibitor identified in the Symphony Health Solutions database between 2015 and 2016 (N = 45,029), only 20.8% of patients were approved by their insurer on day 1; in addition, more than half of all patients (52.8%) had their claim rejected and never received the prescription and 34.7% had the claim approved but abandoned (never picked up) the prescription.41 Although the median time between initial submission and approval was 3.9 days, 17% of patients had a wait time of ≥30 days before approval.41 A similar analysis using Symphony Health data of patients prescribed a PCSK9 inhibitor between 2015 and 2017 (N = 139,036) found similar rates of rejection (61%) and abandonment (15%).42 These access challenges can have negative clinical consequences in addition to causing patient and prescriber frustration. Myers and colleagues found that patients with rejected claims for PCSK9 inhibitors had a significantly higher risk of having a major CV event after the initial submission compared with patients with a paid claim (who were approved and received therapy) (HR, 1.10; 95% CI, 1.01-1.19; P = .02), as did patients who abandoned their prescription (HR, 1.12; 95% CI, 1.01-1.24; P = .03).42 When a stricter definition of a paid claim was used, the risk of a major CV event was even greater for patients with a rejected claim and who abandoned their prescription. Efforts to establish policies intended to reform the prior authorization process are underway, with many recent initiatives already in progress. These policy changes aim to streamline prior authorizations with the triplet goals of easing the burden for providers, providing more timely access to care for patients, and ensuring appropriate evidence-based medication selection.43-45


Statins are the backbone to LLT when patients require pharmaceutical intervention for LDL-C lowering. However, statin therapy alone may not be sufficient in getting patients to guideline-recommended target LDL-C goals. Several options are available and recommended by the relevant guidelines, including ezetimibe, PCSK9 inhibitors, bile acid sequestrants, and bempedoic acid, all of which are effective in further reducing LDL-C. Clinical inertia remains a major barrier to appropriate use of non-statin adjunctive therapies, and efforts have been made to address suboptimal LDL-C management. Other barriers that can be detrimental to a patient’s ability to reach LDL-C goals include nonadherence to therapy and financial and access constraints. In those patients for whom adjunctive therapy is indicated, ease of access to prescribed medications can help patients reach guideline-recommended goals and improve overall health. Payers should consider strategies to reduce these barriers, encourage guideline-directed therapy, and increase patient engagement in their own care to provide the best-quality lipid management.


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.


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 accompanying full Prescribing Information for bempedoic acid and bempedoic acid/ezetimibe.


Esperion Therapeutics would like to acknowledge John Welz, MPH, and Abbey Stackpole, PharmD, of Amplity Health for their contributions in developing this article.


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Last modified: January 9, 2023