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Introduction

Cardiovascular (CV) disease has been the leading cause of death in the United States (U.S.) for decades.¹ Managing dyslipidemia, specifically with medications that lower low-density lipoprotein cholesterol (LDL-C), is an evidence-based treatment strategy to reduce risk of CV disease and events. The prevalence of lipid-lowering medication use among adults in the U.S. age 20 years of age and older is estimated to be 15.5% (based on data from 2007 to 2010).² Among lipid-lowering medications used in the U.S., statin medications are the primary agents used to treat patients with dyslipidemia. Moreover, newer drug therapies and new evidence about non-statin drug therapies may increase the overall use of lipid-lowering medications.

Some patients are at high risk for atherosclerotic cardiovascular disease (ASCVD) despite "normal" cholesterol values. These patients are candidates for statin therapy. Furthermore, prescribing statin medications in patients with a history of ASCVD or patients considered high risk for CV disease (e.g., patients with diabetes) has been used as a clinic metric to benchmark and compare quality among health care organizations.

Implementation of evidence-based treatments for dyslipidemia is a clinical activity that can involve pharmacists. Pharmacists increasingly provide clinical care for patients with ASCVD or who have elevated CV risk. Evidence demonstrates that pharmacy intervention programs improve control and treatment of patients with dyslipidemia.^3-6 Moreover, a pharmacist-managed CV risk reduction service that implements statin therapy in ASCVD patients has been shown to reduce CV events and mortality compared with patients not receiving this service.⁷ Pharmacists must be knowledgeable about recommended treatment approaches for dyslipidemia, different lipid-lowering medications, and treatment among special populations including those at high risk for CV events.

EVIDENCE-BASED GUIDELINES AND EXPERT RECOMMENDATIONS

Historically, the National Cholesterol Education Program (NCEP) has published an evidence-based guideline for the management of dyslipidemia. The latest version of the NCEP guideline, the Adult Treatment Panel III (ATP 3), was published in 2001 with a focused update published in 2004.^8,9 The ATP 3 had continued to recommend a traditional treatment approach that was similar in concept to previous NCEP guidelines.¹⁰ Within this approach, patients are treated to a specific LDL-C goal (primary target of therapy) based on risk factors for and evidence of cardiac disease or cardiac disease equivalents. For patients with fasting triglycerides greater than 200 mg/dL, the guideline emphasized treating to a specific non-high-density lipoprotein cholesterol (non-HDL-C) goal as the secondary target. In general, patients with evidence of cardiac disease or those with higher CV risk were assigned lower LDL-C goals (and non-HDL-C when applicable).

The National Heart Lung and Blood Institute (NHLBI) sponsored the NCEP guideline. Despite plans and work to update the ATP 3 guideline and publish an ATP 4 guideline, NHLBI decided not to release an ATP 4 guideline. Instead they gave their evidence-based review of literature to the American College of Cardiology/American Heart Association (ACC/AHA), which translated this information into an evidence-based guideline.¹¹ The ACC/AHA guideline recommends robust changes in the overall management approach for dyslipidemia based on randomized clinical trials from the evidence-based review. These new recommendations deviate from traditional LDL-C targets but rather treat with statins of fixed intensity based upon a calculated risk for CV events. This has resulted in significant debate and disagreement among the medical community, as many clinicians have questioned this change in the overall approach to managing dyslipidemias. To highlight this point, the inaugural National Lipid Association (NLA) recommendations, published in 2014, contradict the disregard for LDL-C targets by supporting a treatment approach that is fundamentally similar to the traditional NCEP guideline.

ACC/AHA Guideline

The ACC/AHA guideline recommends statin-based therapy as proven treatment approaches for patients falling into 1 of 4 statin benefit groups (see Figure 1).¹¹ When statin therapy is recommended for patients in 1 of these 4 groups, therapy is recommended as either moderate-intensity or high-intensity (see Table 1), with statin intensity based on average strength in lowering LDL-C. Statin benefit groups were determined based on an evidence-based review of high-quality randomized controlled trials. Specifically, the clinical trials considered in this evidence-based guideline were trials that had demonstrated clear reductions in CV events among a wide variety of patient populations.¹¹ It is important to note that nearly all of these clinical trials compared a fixed dose of a statin to either placebo or a fixed dose of a different statin. Hence, this was the guideline justification for adopting a fixed-intensity approach rather than to treat to an LDL-C goal specifically.

Figure 1. American College of Cardiology/American Heart Association Guidelines for Treatment of Blood Cholesterol11

Table 1. Statin Intensity as Defined in ACC/AHA Guidelines11

The 4 statin benefit groups comprise patients requiring benefit from both primary and secondary prevention from statins. They are categorized as individuals with:

1. ASCVD
2. Baseline LDL-C greater than or equal to 190 mg/dL
3. Age 40-75 years with diabetes and LDL-C of 70-189 mg/dL
4. Age 40-75 years without diabetes with LDL-C of 70-189 mg/dL, and estimated 10-year ASCVD risk of greater than or equal to 7.5%

Each recommendation within these statin benefit groups is supported by both a class of recommendation (COR) and level of evidence (LOE). The COR is I, IIa, or IIb (based on degree of benefit outweighing risk), and the LOE is A, B, or C (based on quality of supporting clinical trials) with I and A having the strongest support.

The ACC/AHA guideline includes a new risk scoring tool that estimates future risk of ASCVD. This new risk estimator is the ACC/AHA Guideline on the Assessment of Cardiovascular Risk's focus, which was published concurrently with the cholesterol guidelines.¹² This new risk estimator is named the "Pooled Cohort Equations" and calculates a patient's estimated 10-year risk of developing ASCVD, which includes coronary heart disease and symptomatic carotid artery disease. Predicting ASCVD risk is needed for 2 of the statin benefit groups to identify which patients would most benefit from primary prevention with statins (groups 3 and 4) and dosing intensity (group 3). The previous NCEP guideline had used the Framingham Risk Score (FRS) to determine a patient's cardiovascular risk. However, the FRS only predicts risk of "hard" coronary heart disease (clinical evidence of angina, myocardial infarction, and coronary death), while the Pooled Cohort Equations comprehensively evaluate additional forms of ASCVD such as fatal and nonfatal stroke.

The ACC/AHA guideline emphasized statin therapy as the only lipid-lowering drug class shown to demonstrate reductions clearly in CV events. Moderate- or high-intensity statin regimens are defined by the average ability of a certain statin at a specific dose, assuming medication adherence, to reduce LDL-C (Table 1). The ACC/AHA guideline mentions low-intensity statin regimens, but in general, does not recommend them unless extenuating circumstances (such as drug interactions or previous intolerance to a higher intensity statin) are present. This guideline does not recommend nonstatin therapies (i.e., ezetimibe, bile acid sequestrants, fibrates, niacin, omega-3 fatty acids) for routine use. They are reserved for patients with baseline LDL-C values of 190 mg/dL or higher in combination with maximal statin therapy; in patients who cannot tolerate recommended statin therapy regimens; or for other extenuating circumstances such as severe hypertriglyceridemia.

Of note, since the time the ACC/AHA guideline was published, the IMPROVE-IT trial demonstrated that ezetimibe in combination with moderate-intensity statin therapy further reduces risk of CV events in patients with ASCVD compared with moderate-intensity statin therapy alone.¹³ Hence at present time, in the ASCVD population, ezetimibe is the only nonstatin therapy proven to reduce CV events.

NLA Recommendations

The NLA published recommendations for patient-centered management of dyslipidemia in 2014.¹⁴ In contrast to the ACC/AHA treatment approach, the NLA advocates treating patients to specific LDL-C and non-HDL-C targets. Similar to the NCEP ATP 3, the NLA recommends LDL-C as the primary target of therapy (see Table 2). However, NLA recommendations include non-HDL-C as the co-primary target of therapy. These recommendations also state that clinicians should target non-HDL-C ahead of LDL-C, which is vastly different than the NCEP ATP 3. Furthermore, the NLA recommendations identify apolipoprotein B (Apo B) as a therapy target, but only as an optional secondary target. The NLA's recommendations were not formulated and ranked according to an evidence-based scoring structure, and represent expert opinion in most cases.

The NLA's specific recommended lipid goals are based on patient-specific risk for ASCVD. Individual risk is based on criteria that includes past medical history, patient characteristics, major ASCVD risk factors, risk indicators, and quantitative assessment of risk (in certain patients).^14,15 Table 3 provides the NLA criteria for ASCVD risk assessment. This risk assessment requires identification of major ASCVD risk factors and/or risk indicators (see Table 4). For patients who are considered high or very high risk, the NLA recommends implementing drug therapy when a patient's non-HDL-C or LDL-C are above their determined goal. However, for patients considered low or moderate risk, drug therapy is recommended at threshold values that are higher than a patient's specific goal value.^14,15

The NLA recommendations are similar to the ACC/AHA guideline with regard to strongly endorsing the use of moderate- to high-intensity statin therapy. However, because of the recommendation for specific lipid goals, the NLA recommendations identify a more expanded role for the use of nonstatin drugs in combination with statins, to achieve lipid targets. This recommendation is highlighted for treating patients considered high or very high risk. Detailed additional guidance for patients with familial hypercholesterolemia or severe hypertriglyceridemia is provided in the NLA recommendations.

Table 2. National Lipid Association Recommendations—Treatment Goals14

Table 3. National Lipid Association Criteria for ASCVD Risk Assessment14

Table 4. Major ASCVD Risk Factors and National Lipid Association—Identified Risk Indicators14

ACC/AHA versus NLA

The ACC/AHA guideline and the NLA recommendations outline dyslipidemia management strategies that have similarities and differences. Both strongly advocate for statin drug use, and emphasize the concept that patients with clinical ASCVD and other high risk criteria need aggressive lipid management. However, the ACC/AHA recommendation for fixed-intensity statin therapy is in sharp contrast to NLA recommendations to treat to a target LDL-C. Of note, the NLA published general recommendations for the management of dyslipidemia in their Part 1 publication, and made additional recommendations on special populations in their Part 2 publication in January 2016.¹⁵

Because of the lack of harmonization between the guidelines, physicians may be confused about which approach to use. On one hand, the ACC/AHA guideline are based on randomized evidence, in line with the Health and Medicine Division of the National Academies (formerly the Institute of Medicine) standards for trustworthy clinical practice guidelines.¹⁶ Clinicians who follow ACC/AHA guideline recommendations for therapy can appreciate and consider the COR and LOE for a specific recommendation when implementing clinical decisions. In contrast, clinicians who follow NLA recommendations must recognize that recommendations from this document represent expert opinion including other forms of evidence (such as observational cohort studies). Adopting this approach requires a more tailored approach, similar to previous NCEP guidelines. Worthy of mention is that many NLA authors had significant conflicts of interests with the pharmaceutical manufacturers or companies that perform advanced lipid tests, which could have influenced their expert opinion.

Recommendations from Other Organizations

Shortly before the ACC/AHA guideline was in press, the International Atherosclerosis Society (IAS) published a position paper online in 2013 providing global recommendations for dyslipidemia management.¹⁷ The IAS recommends LDL-C as the major therapy target, and non-HDL-C as the alternate therapy target. Specifically, for patients with clinical ASCVD (i.e., secondary prevention patients) the IAS recommends an LDL-C target of less than 70 mg/dL and a non-HDL-C target of less than 100 mg/dL. For patients without ASCVD (i.e., primary prevention), the recommended LDL-C and non-HDL-C targets are less than 100 mg/dL and less than130 mg/dL, respectively. These recommendations are similar to the NLA recommendations but do not rank the level of evidence supporting their lipid targets.

The American Diabetes Association (ADA) publishes annually standards of care for patients with diabetes that include evidence-based recommendations for lipid management.¹⁸ The ADA recommendations align closely with the ACC/AHA guideline.¹¹ The ADA recommends moderate- or high-intensity statin therapy for patients with diabetes. Consideration of patient's specific risk factors, similar to the NLA recommendations, is included, but specific lipid targets or goals are not.

LIPID-LOWERING PHARMACOTHERAPY

Table 5 describes several different lipid-lowering medications. Medications that are used primarily to lower LDL-C include statins, ezetimibe, bile acid sequestrants, and the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors. The fibric acid derivatives and omega-3 fatty acid agents are used to lower very elevated triglycerides (TGs). Niacin, however, has mixed effects and may be used for lowering LDL-C or TGs.

Table 5. Lipid-Lowering Medications

Statins

Stains are the drug class with the best evidence to support reducing both LDL-C and risk of CV events. All guidelines universally endorse statins as the primary lipid-lowering drugs for most patients.^11,14,17,18 All statins are available generically, except for pitavastatin and rosuvastatin (which loses patent exclusivity in 2016). Most statins should be administered in the evening to inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase maximally. However, atorvastatin, pitavastatin and rosuvastatin can be administered at any time due to their long half-lives.

Adverse effects

Most patients who are treated with statin therapy tolerate treatment well. But, in some cases "statin intolerance" has been described. The prevalence of statin intolerance is unknown, but has been estimated to be up to 10%.¹⁹ The ACC/AHA guideline does not define statin intolerance. The NLA defines statin intolerance as a clinical syndrome characterized by the inability to tolerate at least 2 statins, 1 statin at the lowest starting daily dose and another statin at any daily dose.¹⁹ Both ACC/AHA and NLA recommend alternative drug therapy in patients unable to tolerate statin therapy.^11,14 However, physicians should try multiple statins at different doses before deeming a patient statin intolerant.

Managing statin-associated adverse effects is important because statin therapy, in conjunction with lifestyle modifications, is the preferred evidence-based strategy to lower risk of CV events. The NLA published comprehensive reviews on statin safety.^19,20 The 2014 review addresses statin-associated muscle toxicity, liver toxicity, cognitive changes, diabetes, and drug interactions.^19,20 The ACC/AHA guideline also provides recommendations for monitoring and managing statin safety issues.¹¹

Cognitive Effects - FDA issued a warning about mild impaired cognition with statin therapy several years ago stating that these events are reversible.²¹ Cognitive changes can include memory loss, forgetfulness, and confusion. While onset varies, symptoms are reported to be reversible within a few weeks of stopping statin therapy. While FDA implies that these adverse effects can occur with all statins, the 2014 NLA report states that most published case reports of cognitive adverse effects are with simvastatin and atorvastatin, which are both lipophilic.²² Reducing the statin dose, stopping the statin, or rechallenge with a hydrophilic statin (e.g., pravastatin or rosuvastatin) are all possible treatment options for patients complaining of cognitive adverse effects.²² However, evidence supporting a causal relationship between statins and cognitive impairment is poor, and systematic evidence-based reviews do not support an association.^23,24 The NLA concluded that there is insufficient evidence implicating statin-related negative cognitive effects.²² The AHA/ACC guideline is similar and recommends evaluating all potential sources of cognitive deficits in statin therapy patients who complain of cognitive adverse effects.¹¹

New-Onset Diabetes - Statin therapy has been associated with a dose-dependent, yet modest 10% to 12% increase in risk of developing type 2 diabetes.^25-28 This warning has been added to statin product labeling. However, this risk of new-onset diabetes is offset by the 25% to 35% reduction in CV events. The Cholesterol Treatment Trialist data estimate that treating 255 patients with statin therapy for 4 years would result in 1 case of new-onset diabetes but would prevent death or nonfatal myocardial infarction in 5.4 patients.^29,30 Because the benefit from statin therapy outweighs the risk of potential diabetes development, the NLA, ACC/AHA, and ADA all recommend statin therapy.^11,18,29

Muscle Complaints - The most common statin-associated adverse effects are muscle complaints including muscle pain, cramping, and sometimes soreness. The 2014 NLA statin report provides a categorization and classification system that describes and defines each of the statin-associated muscle complaints.³¹ According to the NLA, there are 5 types of muscle complaints: (1) myalgia, (2) myopathy, (3) myositis, (4) myonecrosis, and (5) myonecrosis with myoglobinuria or acute renal failure (clinical rhabdomyolysis).³¹

Myalgia is unexplained muscle discomfort. It can be described by patients as aches, soreness, stiffness, tenderness, or cramping around exercise.³⁰ Myalgia is accompanied by normal creatine kinase (CK) serum values. Myopathy is weakness not attributable to pain and not associated with elevated CK serum values. Myositis is any degree of muscle inflammation, with myonecrosis being present if there is an elevated serum CK value (mild myonecrosis is a 3-fold or more increase in CK, moderate is a 10-fold or more increase in CK, severe is a 50-fold or greater increase in CK).³⁰ Myonecrosis with myoglobinuria or acute renal failure with an increase in serum creatinine of 0.5 mg/dL or more is clinical rhabdomyolysis. The NLA estimates that myalgia occur in 1% to 5% of statin treated patients in clinical trials, but up to 11% to 29% in observational cohorts.³¹ Clinical rhabdomyolysis is considered very rare, yet is the most serious adverse effect.³¹

Hypothyroidism and potential drug-drug interactions can increase the risk of statin-associated muscle complaints.³¹ Other possible risk factors may include acute and chronic physical activity, and low vitamin D serum concentrations.^32-35

Management strategies for addressing statin-associated muscle complaints include reducing the dose, holding doses, and rechallenging with a different statin. The AHA/ACC recommends stopping statin therapy when muscle symptoms arise and if muscle complaints are severe, evaluating for rhabdomyolysis. The ACC/AHA provides limited guidance on rechallenge, but does state that if muscle complaints are mild to moderate, then stopping statin and attempting a rechallenge once symptoms resolve is reasonable.¹¹ Rechallenge is recommended with the same statin, at the same or lower dose, and if not tolerated, then a low dose of an alternative statin can be tried.¹⁰ The NLA suggests stopping statin therapy for 2-4 weeks in any patient with intolerable symptoms, evidence of muscle weakness, or mild/moderate/severe myonecrosis.³¹ If symptoms resolve, NLA recommends a rechallenge with a different statin (at lowest recommended daily dose), or another statin. Studies have shown that rechallenge is successful in 70% to 80% of patients.³⁶ If symptoms return upon rechallenge, the NLA recommends using a statin with a long half-life (i.e., rosuvastatin or atorvastatin), but not dosing on a daily basis.³¹ A work-up for alternative etiologies is recommended if symptoms reappear after rechallenge or continue after initial discontinuation.³¹

Ezetimibe

Ezetimibe is used exclusively to lower LDL-C without effects on other lipid parameters. It is a very well tolerated agent that provides modest LDL-C lowering and no potential for major drug-drug interactions.

Of all the available nonstatins, only ezetimibe has been shown to reduce the risk of CV events when used in combination with a statin. The IMPROVE-IT trial was a large randomized, placebo-controlled, outcome study that enrolled more than 18,000 patients. It demonstrated a reduction in CV events with ezetimibe in combination with simvastatin 40 mg versus simvastatin 40 mg monotherapy in secondary prevention patients with ASCVD (recent acute coronary syndrome). After almost 5 years of treatment, the incidence of CV events was 32.7% in the ezetimibe with simvastatin therapy and 34.7% with simvastatin monotherapy (p = 0.016), a relative risk reduction of 6%.¹³ This study was unavailable when the ACC/AHA guideline and the NLA recommendations were published.

IMPROVE-IT provides the only evidence demonstrating reductions in CV events with statin-nonstatin combination therapy, but it did not examine high-intensity statin therapy (i.e., atorvastatin or rosuvastatin) with ezetimibe. Because the ACC/AHA guideline recommends high-intensity treatment, IMPROVE-IT's impact for those already on such high-intensity therapy may be limited. Nevertheless, of the available nonstatin agents, ezetimibe has accrued the most evidence and has a prominent role in combination with statin therapy, especially for patients who cannot tolerate high-intensity statin therapy, or who fail to have adequate LDL-C lowering despite statin therapy.

Bile Acid Sequestrants

Bile acid sequestrants are the only lipid-lowering drugs that are not systemically absorbed.. These agents are specifically used for LDL-C lowering, and should ideally be used in combination with a statin drug. While these agents do not have any known systemic adverse effects, because they are not absorbed, many patients experience gastrointestinal adverse effects (mostly bloating, cramping, and constipation). Moreover, these drugs decrease absorption of other drugs when administered concurrently, though this is less of an issue with colesevelam. Other less common adverse effects include decreased absorption of fat-soluble vitamins and increased triglycerides.

PCSK9 Inhibitors

The newest lipid-lowering agents are PCSK9 inhibitors. These agents have a unique mechanism of action and are bioengineered monoclonal antibodies. In contrast to other common lipid-lowering medications, these 2 agents (alirocumab and evolocumab) are subcutaneous injections that are administered every 2 weeks. Because they are monoclonal antibodies, they are very expensive agents and are available through specialty pharmacies. The primary adverse effects patients may experience are injection site reactions, nasopharyngitis, and influenza. Otherwise, they are relatively well tolerated.^37,38,39

The PCSK9 inhibitors can reduce LDL-C up to 72%.³⁷ Clinical trials available with both PCSK9 inhibitors have mostly been in combination with statin therapy or other lipid-lowering drugs (i.e., ezetimibe). However, some data support PKSD9 inhibitor use as an alternative to a statin in patients who cannot tolerate statin therapy. Regardless, PCSK9 inhibitors' primary role is in very high risk patients with ASCVD or with very high baseline LDL-C values (patients with familial hypercholesterolemia [FH]).

The FDA-approved indication for alirocumab and evolocumab is as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or ASCVD who require additional LDL-C lowering. Evolocumab is also indicated for homozygous familial hypercholesterolemia (HoFH). This role may continue to evolve with extended clinical experience and with additional clinical trials evaluated reductions in CV events.^38,39

Other Agents

Other lipid-lowering agents, such as niacin, fibric acid derivatives, and omega-3 fatty acids, are primarily used for patients with very elevated TGs. These agents are summarized in Table 5. The primary health risk associated with very high TGs is pancreatitis. However, patients typically will not experience pancreatitis unless TG exceeds 1000 mg/dL. Moreover, most guidelines do not recommend treating with a triglyceride-lowering drug unless fasting TGs are 500 mg/dL or greater.

Two other agents, mipomersen and lomitapide (not listed in Table 5), are rarely used and indicated only for HoFH patients.

SPECIAL POPULATIONS

Children and Adolescents

In the general pediatric population, including children and adolescents, primary risk reduction approaches to prevent abnormalities that may expedite the development of early atherosclerosis include promoting healthy lifestyles and behavior modification.

Considering the increasing risk of obesity among pediatric patients, promotion of healthy lifestyles is a public health issue. However, certain pediatric patients are high risk for ASCVD. These include patients with HoFH in whom ASCVD is evident in the first and second decades of life.^40,41,42

Previous NCEP guidelines recommended cholesterol screening in patients aged 2-19, but only for select pediatric patients.^32,42 These select pediatric patients included those with parents known to have very elevated total cholesterol (greater than 240 mg/dL). However, in 2011, the NHLBI published guidelines for cardiovascular health and risk reduction in children and adolescents.⁴³ These newer guidelines recommend lipid screening in pediatric patients starting as early as 2 years of age for high-risk pediatric patients, and universal screening at age 9.⁴³ In these guidelines, pediatric patients with Kawasaki disease who have regressed coronary aneurysms, chronic inflammatory disease (systemic lupus erythematosus, juvenile rheumatoid arthritis), HIV infection, or nephrotic syndrome are considered at moderate CV risk. Pediatric patients with diabetes mellitus (type 1 or 2), chronic kidney disease/end-stage renal disease/post-renal transplant, post-orthotopic heart transplant, or Kawasaki disease with current aneurysms are considered high CV risk.

The goal of LDL-C-lowering therapy in pediatric patients is to decrease LDL-C to less than 130 mg/dL (the 95th percentile).⁴⁴ Comprehensive modalities, such as weight management, glucose control in diabetes, blood pressure control in hypertension, and LDL-C lowering, are recommended. Although the long-term benefits of treating dyslipidemia in pediatric patients have not been fully studied, the management approach is similar to that employed in adult patients. For example, reducing LDL-C to goal values, or achieving at a 50% reduction from baseline, is the primary treatment target in pediatric patients with FH.⁴⁵ Treating severe hypertriglyceridemia is also recommended, with specific triglyceride lowering drug therapy recommended when triglycerides elevations are greater than 500 mg/dL.⁴⁴

When lifestyle modification is ineffective, lipid-lowering drug therapy should be considered. It is important to note that lipid-lowering drug therapies have been studied in pediatric patients primarily with either HoFH or HeFH. Although many agents are approved for use in pediatric patients, their labeling addresses the specific ages for which they are approved, and doses (see Table 6). Primary lipid-lowering drugs for pediatric patients include statins, with pravastatin being approved for use at age 8 years, ezetimibe, and bile acid sequestrants (specifically colesevelam and cholestyramine).

Table 6. Lipid-Lowering Drug Therapies in Pediatric Patientsa

Older Patients

As age increases, risk of ASCVD similarly increases. Moreover, advanced age (45 years and older for men, 55 years and older for women) is considered a major independent risk factor for ASCVD regardless of medical history.

Age thresholds for definitions of "older" vary significantly. The American Association of Retired Persons includes as members those age of 50 years or older. However, 65 years and older is most often used to define "older" in subgroup analyses of randomized prospective controlled trials, which represents the greatest evidence for lipid-lowering drug therapy. Using 65 years of age as the defining point of older is sometimes limiting, as higher cut points (e.g., 75 or 80 years) more clearly define patients most likely to be frail and those who are more challenging to treat. Categorizations of the young old (65-74), middle old (75-84), and very old (≥85) are sometimes used. Those in the two older groups are typically represented poorly in clinical trials, yet they are at higher risk for changes in organ function, drug-related adverse effects, and drug-drug interactions.

General consensus is that older patients with ASCVD (also called secondary prevention) should be treated with statin therapy.^11,14 Other lipid-lowering drug therapies have not been as well studied. The ACC/AHA guideline has age-specific recommendations to limit adverse effects and recommends moderate-intensity statin therapy (instead of high-intensity) for patients older than 75 years with ASCVD.¹¹ The NLA provides more specific recommendations for lipid-lowering therapy in special populations in their Part 2 recommendations.¹⁵

The exact benefits of statin therapy in primary prevention in older patients is unclear. Most clinicians agree that older patients who have additional major CV risk factors might benefit from primary prevention strategies with statins, and that avoiding lipid-lowering therapy based solely on advanced age alone is incorrect. However, little evidence addresses primary prevention with statin therapy in older patients.

Collectively, evidence evaluating the benefits of lipid-lowering therapy in the elderly have demonstrated overall reductions in CV events.⁴⁶ However, unlike in other populations, no single study provides robust, clear support of statin therapy for primary prevention in older patients, especially in the very old. Importantly, among patients with CV risk factors, meta-analyses have demonstrated significant reductions in major coronary events, major cerebrovascular events, and total mortality when statins have been used for primary prevention.⁴⁷

Clinicians should feel comfortable in using statin-based therapy in older patients, but should always use clinical judgment to assess risk and benefits. Suggesting age- appropriate diet and exercise regimens as a part of comprehensive lifestyle recommendations is appropriate. For patients who require lipid-lowering drug therapy, clinicians should consider factors such as risk of drug-drug interactions, adverse effects, decreased drug elimination, and cost. The strongest evidence in older patients with dyslipidemia supports use of statins. However, this class's adverse effects and drug-drug interactions can be more common in older patients. Pharmacokinetic changes in statins have been demonstrated in older patients, but statins generally do not require an empiric dose adjustment based on age (Table 7).⁴⁵

Table 7. Summary of FDA Product Label Dosing Recommendations for Statins in Older Patients46

CONCLUSION

The ACC/AHA guideline represents an evidence-based approach to treating most patients with dyslipidemia in clinical practice. Its publication radically altered the way we manage patients with dyslipidemia. This guideline recommends a simplified treatment approach—use primarily fixed-dose statin based on intensity. In contrast, the NLA recommends using the historic strategy of prescribing therapy to achieve specific lipid goals. Despite these differences, statin therapy in at-risk patients is the foundation of lipid-lowering pharmacotherapy. Several FDA approvals of newer drug therapies and extended recommendations for managing special populations represent advances in treatment.

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