Key Articles and Guidelines in the Management of Dyslipidemia: 2019 Update

Abstract

Although the mortality from cardiovascular disease has declined, it remains the leading cause of morbidity and mortality in the United States. Dyslipidemia is a modifiable risk factor that plays a significant role in the development of atherosclerotic cardiovascular disease. Treating dyslipidemia by lowering cholesterol, predominately low-density lipoprotein cholesterol, has been shown to reduce cardiovascular events. The first article that provided dyslipidemia bibliographies was published in 2006. Since this time, new therapies have become available and older therapies that were once thought to provide benefit have since been shown to lack positive outcomes and have therefore fallen out of favor for routine use. As the body of evidence continues to expand, clinicians are faced with reevaluating their treatment strategies to ensure optimal outcomes and appropriate use of lipid-lowering therapies. Therefore, this compilation was created to serve as a resource for clinicians. This publication provides an update of key articles in dyslipidemia management including various guidelines and practice-changing randomized controlled trials.

Keywords

dyslipidemia statins PCSK9

Introduction

Obtaining and retaining knowledge in the field of cardiology is often challenging given the number of articles, guidelines, and trials that are published. Therefore, in an attempt to highlight the most important articles, compilations of annotated bibliographies in various aspects of cardiology have been published.^1

-7 These select bibliographies are intended to serve as a resource for clinicians to quickly identify important and relevant publications that are considered the most clinically impactful within the cardiovascular (CV) literature. The concise and informative nature of these bibliographies is becoming more relevant as the breadth and depth of the cardiology literature continues to expand. Since the original bibliography for dyslipidemia was published in 2006, there have been new pharmacologic agents added to our armamentarium to lower low-density lipoprotein cholesterol (LDL-C) and triglycerides (TGs), which further reduces CV risk.^2,8
-10 Data have also become available demonstrating a lack of benefit with certain therapies, such as niacin, which was previously thought to provide clinical value.¹¹ Another major change that transpired was the publication of the American College of Cardiology/American Heart Association (ACC/AHA) guidelines that completely modified the approach to managing high blood cholesterol to reduce atherosclerotic cardiovascular disease (ASCVD) risk.¹² Rather than identify a goal LDL-C, the guidelines recommended a fixed-dose statin regimen based on intensity to lower LDL-C given a specific patient risk group. This guideline created a significant amount of controversy by eliminating specific LDL-C goals and shifting to a percentage of LDL-C reduction as the focus. Controversy also surrounded the recommendations for nonstatin therapies and their role in clinical practice. In addition, risk factors utilized in the new ASCVD risk calculator greatly expanded the number of patients in which statin therapy was recommended.¹² Given the significant deviation from years past, it was no surprise that this guideline was not well received nor endorsed by many organizations. Recently, new ACC/AHA guidelines were released that were broadly endorsed by other professional organizations, including the National Lipid Association (NLA) and American Diabetes Association (ADA). The 2018 guidelines still emphasize high-intensity statin therapy for certain high-risk patient subgroups. However, a more nuanced approach was provided for “very high-risk” patients whose LDL-C was >70 mg/dL. The document further outlined additional treatment options in patients who do not achieve an appropriate response to statins or who have statin-associated adverse effects.¹³ The 2018 guideline should result in more congruency among the various organizational guidelines. Despite the controversies, the consensus among all of the guidelines is that statin therapy should be first-line therapy in the management of dyslipidemia. New pharmacologic therapies have also been approved by the food and drug administration (FDA), including the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and 2 orphan drugs, mipomersen and lomitapide. While the exact role of these agents in clinical practice continues to be defined, recent data have helped shaped perspectives on the use in select patients. This review provides a summation of the key articles that are considered the most clinically impactful including the various guideline documents that have been published since the 2006 bibliography. This should serve as a valuable resource for clinicians who practice in the area of dyslipidemia.

Articles

Guidelines and Position Statements

Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. J Am Coll Cardiol. 2018; doi:https://doi.org/10.1016/j.jacc.2018.11.003.

This guideline was developed by ACC/AHA in partnership with 10 partnering organizations and provided an update to the 2013 ACC/AHA Cholesterol guideline. Continued emphasis was placed on promoting a heart-healthy lifestyle across the life span, as well as the use of fixed-dose statins to reduce ASCVD risk in the 4 statin benefit groups. Patients with clinical ASCVD should receive high-intensity statins to achieve a >50% reduction in LDL-C; however, in very high-risk patients (eg, multiple major ASCVD events, diabetes, current smokers) with an LDL-C >70 mg/dL despite maximally tolerated statin, the guideline recommends adding ezetimibe before a PCSK9 inhibitor unless clinical judgment overrules. This was primarily due to the low cost value of PCSK9 inhibitors using list prices from mid-2018. Patients diagnosed with severe hypercholesterolemia (LDL-C >190 mg/dL) should receive maximally tolerated statin therapy, and ezetimibe is reasonable in those who achieve less than a 50% reduction in LDL-C. A PCSK9 inhibitor may also be considered; however, the cost value of PCSK9 inhibitors in patients with familial hypercholesterolemia (FH) remains unclear. Individuals with diabetes, regardless of estimated ASCVD risk, should receive moderate-intensity statin therapy and aim to reduce LDL-C levels by >50%. Ezetimibe may be added to maximally tolerated statin therapy to achieve >50% reduction in LDL-C. Major changes were made in assessing ASCVD risk in the primary prevention population. Four risk categories were identified using the 10-year ASCVD risk calculated by the Pooled Cohort Equations: low risk (<5%), borderline risk (5 to <7.5%), intermediate risk (>7.5% to <20%), and high risk (>20%). Additionally, ASCVD risk enhancers, for example, history of premature ASCVD, elevated lipoprotein(a), Lp(a), history of inflammatory diseases, not included in the Pooled Cohort Equations should be considered as part of the overall risk assessment. Regardless of risk, a discussion between the patient and clinician is warranted and should involve a discussion of lifestyle changes to reduce ASCVD risk and the potential risks and benefits of statin therapy, if indicated. Another important change was the recommendation to consider measuring coronary artery calcium (CAC) if the risk decision is uncertain. Patients with a CAC score of zero would be deemed at lower risk and not offered statin therapy, while those with a CAC of 1 to 99 should be offered a statin and those with a CAC >100 should be initiated on statin therapy. The importance of monitoring the response to lipid-lowering therapy was also emphasized, and nonfasting lipid panels were deemed acceptable for estimating ASCVD risk unless TG levels exceeded 400 mg/dL at which a fasting lipid panel is recommended. Of note, the management of hypertriglyceridemia was discussed but primarily focused on addressing the underlying causes and initiating statin therapy in patients at high ASCVD risk. The guideline also provided recommendations for select subpopulations, including women, ethnic groups, adults with chronic inflammatory disorders, and HIV. The guideline recommended avoiding the phrase “statin intolerance” and instead using “statin-associated side effects” since many patients are able to tolerate statins after a rechallenge or dose reduction.

Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation. 2014;129:S1-S45.

Upon release, ACC/AHA guideline surprised the medical community by straying from the traditional lipoprotein goal approach of its predecessor, the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guideline, by eliminating specific goals for LDL-C. Through an extensive literature review of RCT, systematic reviews, and meta-analyses, the ACC/AHA Expert Panel was unable to find RCT evidence to make a recommendation either for or against goals of therapy. Overall, recommendations emphasize statin therapy for patients using a fixed-dose statin treatment based on the degree of CV risk and potential risks of lipid-lowering therapies. This treatment approach was based on the landmark clinical trials’ utilization of demonstrated reductions in CV events in primary and secondary prevention patients when comparing mostly a fixed dose of a statin to either placebo or a fixed dose of a different statin. Four statin-benefit groups were identified that focus efforts to reduce ASCVD events in primary and secondary prevention populations where the benefits outweigh the risks. High-intensity and moderate-intensity statin therapies were identified for use in primary and secondary prevention. The guideline also concludes that nonstatin therapies, as compared with statin therapy, do not provide acceptable ASCVD risk reduction benefits relative to their potential for adverse effects. Lastly, a new Pooled Cohort Equation was introduced to estimate 10-year ASCVD risk in both white and black men and women without clinical ASCVD. This scoring tool is more comprehensive than the popular Framingham Risk Score, which only predicts the risk of coronary artery disease (CAD). The evidence-based review involved in the development of this guideline was compliant with Institute of Medicine (IOM) standards.

Eckel R, Jakicic J, Ard J, et al. 2013 ACC/AHA guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. J Am Coll Cardiol. 2014;63:2960-2984.

The intent of this ACC/AHA Work Group was to evaluate the evidence and the role that particular dietary patterns, nutrient intake, and levels and types of physical activity can play with regard to CV disease prevention and treatment through effects on modifiable CV disease risk factors. Evidence statements and recommendations are presented by critical questions and grouped by topic. Recommendations were derived from randomized trials, meta-analyses, and observational studies evaluated for quality and were not created when sufficient evidence was not available. Pertinent recommendations include advising adults, who would benefit from LDL-C or blood pressure lowering, to consume a dietary pattern that emphasizes intake of vegetables, fruits, and whole grains; include low-fat dairy products, poultry, fish, legumes, nontropical vegetable oils, and nuts; and limit intake of sweets and red meat. This dietary pattern may be achieved by following plans such as the Dietary Approaches to Stop Hypertension dietary pattern, the US Department of Agriculture Food Pattern, or the AHA diet. The recommendation for salt intake was no more than 2400 mg of sodium/d. In addition, physical activity to reduce LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) and blood pressure should include 3 to 4 sessions per week, lasting an average 40 minutes per session, and involving moderate to vigorous intensity physical activity.

Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011;123(20):2292-2333.

The purpose of this comprehensive scientific statement was to provide an update for clinicians regarding the role of TG and TG-rich lipoproteins (eg, chylomicrons, very low-density lipoprotein cholesterol [VLDL]) in the evaluation and management of CV risk. While this is not a guideline per se, the authors intended for this document to shape future cholesterol guidelines. The authors point out that TG levels in the United States have risen since the 1970’s and they attribute this to the obesity and diabetes epidemics. Despite strong evidence demonstrating an association between elevated TG levels and CV disease, there remains a lack of high-quality evidence to support an independent relationship between TG levels and risk of CV events. Clinicians should also consider the potential risk of pancreatitis in patients with hypertriglyceridemia, which accounts for 10% of all cases of acute pancreatitis, particularly if TG levels exceed 1000 mg/dL or the patient has a history of acute pancreatitis. The pathophysiology and causes of hypertriglyceridemia (eg, genetic, drug-induced) are reviewed extensively, including the effects of select medications (eg, atypical antipsychotics, estrogens, protease inhibitors), lifestyle factors (eg, alcohol, high saturated-fat diet), and comorbidities (eg, diabetes) that should be evaluated and managed before considering a TG-lowering therapy in most cases. A practical algorithm for screening and managing elevated TG levels is provided, and the authors contend that a TG level <100mg/dL should be considered optimal, while recommending nonpharmacological interventions when TG levels exceed 150 mg/dL and pharmacological therapy only for TG levels >500 mg/dL. Nonpharmacological interventions include 5% to 10% reduction in body weight, reducing calories from added sugars and fructose, substituting saturated fats for unsaturated fats, and increasing physical activity. Specific recommendations regarding which agents to implement for TG lowering are not provided; however, fibrates are the most potent TG-lowering therapies (30%-50%) followed by omega-3 fatty acids (20%-50%), niacin (20%-50%), statins (10%-30%), and then ezetimibe (5%-10%).

Goldberg A, Hopkins P, Toth P, et al. Familial hypercholesterolemia: screening, diagnosis, and management of pediatric and adult patients. Clinical guidance from the National Lipid Association Expert Panel of Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:133-140.

The NLA held a consensus conference in 2011 to bring together experts on FH for the generation of an NLA statement on the clinical guidance for the diagnosis and treatment of FH. This document goes beyond previously published FH guidelines by providing specific clinical guidance for the primary care clinician and lipid specialist with the goal of improving care of patients with FH and reducing their risk for CAD. Screening first-degree relatives of those with FH is emphasized by the NLA Expert Panel, as it facilitates early detection and treatment. Key elements for control of FH that are recommended include reducing the LDL-C levels below 100 mg/dL and non-HDL-C below 130 mg/dL in higher risk patients and management of additional CV risk factors, such as elevated blood pressure and smoking, and improving adherence to and persistence with lifestyle modifications and pharmacotherapy. Ezetimibe, niacin, and bile acid sequestrants are reasonable treatment options for intensification of therapy or for those intolerant to statins. Long-term drug therapy of patients with FH is noted to significantly reduce the excess lifetime risk of CAD, lowering the level of risk to that of the general population. Of note, the PCSK9 inhibitors are not listed in this document as they were not yet approved by the FDA until 2015.

Jacobson T. NLA Task Force on Statin Safety—2014 update. J Clin Lipidol. 2014;8:S1-S4.

In 2012, the FDA made labeling changes that included the removal of routine periodic monitoring of liver function tests (LFTs) in patients taking statins. Additional information was added regarding the potential for generally nonserious and reversible cognitive side effects and reports of increased risk of new-onset type 2 diabetes associated with statin use. This followed an FDA-mandated labeling change in 2011 limiting the use of simvastatin 80 mg due to increased risk of muscle damage. These labeling changes raised numerous questions among clinicians regarding the benefits versus risks of statin use and prompted the formation of a new NLA Statin Safety Task Force to update the 2006 NLA Task Force on Statin Safety review. A hybrid of the National Heart Lung and Blood Institute (NHLBI) rating system was used to evaluate the evidence base. Six specific statin-related safety issues were addressed including the effects of statins on cognition, diabetes risk, liver function, muscle symptoms, interactions with other drugs, and statin intolerance. The task force determined that there was a lack of consistent, quality evidence of an effect of statins on cognition. In response to clinical trial data suggesting modest, but statistically significant increase in the incidence of new-onset type 2 diabetes with statin use, the task force concludes that given the well-established benefits of statin therapy in the primary and secondary prevention of CV events among those with indications for treatment, no changes to current clinical practices are recommended. Exceptions include the measurement of hemoglobin A_1c (HbA₁c) or fasting glucose in those deemed to also be at elevated diabetes risk following statin initiation.

Jacobson T, Ito M, Maki K, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1—full report. J Clin Lipidol. 2015;9:129-169.

In response to the 2013 ACC/AHA guidelines, which the NLA did not endorse, the organization published Recommendations for Patient-Centered Management of Dyslipidemia reaffirmed the importance of the traditional lipoprotein goal approach for dyslipidemia management to prevent CAD and stroke. The evidence base considered for these recommendations was not formulated according to the IOM standards published in 2011; but rather, the NLA used the traditional approach, considering results from RCT, including subgroup assessments and pooled analyses from multiple trials and epidemiological evidence. The 5 major conclusions from the NLA Expert Panel include (1) an elevated level of cholesterol carried by circulating atherogenic cholesterol (non-HDL-C and LDL-C) is a root cause of atherosclerosis, the key underlying process contributing to most clinical ASCVD events; (2) reducing elevated levels of atherogenic cholesterol will lower ASCVD risk in proportion to the extent that atherogenic cholesterol is reduced. This benefit is presumed to result from atherogenic cholesterol lowering by multiple means, including lifestyle and lipid-lowering therapies; (3) the intensity of risk-reduction therapy should generally be adjusted to the patient’s absolute risk for an ASCVD event; (4) atherosclerosis is a process that often begins early in life and progresses for decades before resulting in a clinical ASCVD event. Therefore, both intermediate-term and lifetime risk should be considered when assessing the potential benefits and hazards of risk-reduction therapies; (5) for patients in whom lipid-lowering therapy is indicated, statin treatment is the primary modality for reducing ASCVD. Lastly, the Panel also emphasizes the importance of taking a patient-centered approach in counseling patients with dyslipidemia about the benefits and risks of lifestyle and pharmacologic management.

Jacobson T, Maki K, Orringer C, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 2. J Clin Lipidol. 2015;9:S1-S122.

The intent of the second part (part 2) of the NLA Expert Panel recommendations was to expand upon the part 1 recommendations in areas where clinicians may desire additional guidance for dyslipidemia management, specifically where the evidence base is less robust. The recommendations focus on ASCVD risk assessment and management of atherogenic cholesterol levels (non-HDL-C and LDL-C) that cross the life span from children to older adults in addition to underrepresented, special populations, including women from pregnancy to menopause, certain ethnic and racial groups, patients with conditions associated with increased ASCVD risk (such as HIV and rheumatoid arthritis), and patients with residual risk despite statin and lifestyle therapies. Additional highlights include guidance specifically for patients with FH or hypertriglyceridemia. Lifestyle therapies are also re-emphasized as the cornerstone of therapy in dyslipidemia management. New detailed advice is provided for specific changes in diet as well as the amount of physical activity and exercise important to CV health. Lastly, the document focuses on strategies to improve patient outcomes by addressing adherence and utilization of team-based collaborative care.

Kidney Disease: Improving Global Outcomes (KDIGO) Lipid Work Group. KDIGO clinical practice guideline for lipid management in chronic kidney disease. Kidney Inter Suppl. 2013;3:259-305.

This guideline is an update from 2007 and provides guidance on lipid management and treatment for both adults and children with chronic kidney disease (CKD). Appraisal of the quality of the evidence and the strength of recommendations followed the GRADE approach. Given the lack of data in individuals with and without CKD regarding treatment escalation to achieve specific LDL-C goals, the Kidney Disease: Improving Global Outcomes (KDIGO) work group no longer recommends this approach for the management of dyslipidemia in patients with CKD. Clinicians should measure the lipid profile ideally in the fasting state at initial presentation with CKD. A follow-up lipid profile is not required unless the results would change management. The risk of CAD is sufficiently high in this population to justify the prescribing of statins in adults ≥50 years of age with CKD and an estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73 m² but not treated with long-term dialysis or kidney transplantation. Also of note, the Work Group also recommends the use of statins in CKD patients with eGFR < 60 mL/min/1.73 m² or receiving renal replacement therapy. The statin should be based on regimens and doses that have been shown to be beneficial in randomized trials done specifically in the populations with CKD. Many of these doses are reduced as compared to the doses of statins recommended by the 2013 ACC/AHA cholesterol guideline.

Orringer CE, Jacobson TA, Saseen J et al. Update on the use of PCSK9 inhibitors in adults: recommendations from an expert panel of the National Lipid Association. J Clin Lipidol. 2017;11:880-890.

This is a focused update on the recommendations for the PCSK9 inhibitors. These are recommendations that add to the 2015 NLA recommendations for the patient-centered management of dyslipidemia: part 2. An Expert Panel convened by the NLA was charged with updating the recommendations on the use of PCSK9 inhibitor therapy. This update was driven by multiple factors. First, there have been a number of studies demonstrating PCSK9 inhibitors ability to significantly lower LDL-C and non-HDL-C across various patient populations with and without baseline statin therapy. Furthermore, results from the CV outcome trial Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) demonstrated evolocumab reduced ASCVD risk in high-risk patients with established ASCVD on moderate-high intensity statin therapy. As a result, the PCSK9 inhibitors are recommended for use in 4 key patient populations. These include patients with stable ASCVD, progressive ASCVD, LDL-C >190 mg/dL, and very high-risk patients with statin intolerance. The recommendation with the highest strength of evidence is for the use of PCSK9 inhibitors in patients with established ASCVD with additional risk factors already taking maximum tolerated statin therapy with or without ezetimibe and an LDL-C >70 mg/dL. This is a moderate strength recommendation for those with progressive ASCVD. Moderate strength recommendations are included for patients with an LDL-C >190 mg/dL at baseline who are 40 to 79 years and on statin treatment, an LDL >100 mg/dL without the presence of risk factors, and an LDL > 70 mg/dL the presence of risk factors. They align well with recommendations for PCSK9 inhibitor use from the 2017 ACC Expert Consensus Decision Pathway on the role of nonstatin therapies for LDL-C lowering in the management of ASCVD risk.

Triglycerides, Lipoproteins, and Apolipoprotein Levels: Role in CV Risk

Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369:1090-1098.

Data from epidemiological studies suggest a high intake of omega-3 polyunsaturated fatty acids (PUFA), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are associated with reduced risk of CV disease and mortality. Given that EPA does not appear to increase LDL-C levels, unlike DHA, there has been considerable interest in developing PUFA products containing only EPA. The Japan EPA Lipid Intervention Study (JELIS) was the first RCT to evaluate the effects of low-dose omega-3 PUFA on ASCVD risk when added to statin therapy compared to statin therapy alone. Nearly 20 000 subjects from Japan were enrolled in this prospective, randomized open-label, blinded study. Most subjects had no prior history of ASCVD, and the baseline LDL-C was 180 mg/dL in each group. Patients were initiated on either pravastatin 10 mg daily or simvastatin 5 mg daily plus EPA ethyl ester 600 mg 3 times daily after meals (1800 mg total daily dose), or statin alone. The pravastatin and simvastatin doses could be increased to 20 mg daily and 10 mg daily, respectively, in subjects with uncontrolled hypercholesterolemia. After a mean follow-up of 4.6 years, the primary composite endpoint of any major coronary event, including sudden cardiac death, fatal and nonfatal myocardial infarction (MI), unstable angina (UA), angioplasty, stenting, or coronary artery bypass graft surgery occurred in 2.8% of subjects in the intervention group compared to 3.5% in the control group (19% relative risk reduction (RRR); P = .011). This outcome was primarily driven by a reduction in nonfatal coronary events (such as UA). Importantly, this benefit was only observed in those with a history of CV disease as the 18% RRR observed in the primary prevention subjects did not meet statistical significance (P = .132). There were important limitations to this study, it was open-label and there was no true placebo group. Additionally, since this trial only enrolled subjects from Japan, these results cannot be generalized to other populations. These data do suggest, however, that omega-3 PUFA supplementation may confer additional CV risk reduction when used in combination with statin therapy.

Boekholdt SM, Arsenault BJ, Mora S, et al. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events. JAMA. 2012;307(12):1302-1309.

Debate over the most predictive lipid parameter for CV risk has persisted for decades. While LDL-C has demonstrated strong predictive value and has been the primary lipid parameter used in clinical practice, others have advocated for the use of non-HDL-C and apolipoprotein B (apoB). This meta-analysis sought to determine the strength of the associations between LDL-C, non-HDL-C, and apoB to future risk of CV events in subjects receiving statin therapy. The primary outcome was time to first major adverse cardiovascular event (MACE), fatal other CAD, hospitalization for UA, and fatal or nonfatal stroke). The authors identified 8 RCTs between 1994 and 2008 that enrolled 38 153 subjects allocated to statin therapy. The RCTs were of high quality (median Delphi score of 9), and heterogeneity between trials was low for the association between the risk of CV events and LDL-C, non-HDL-C, and apoB. Overall, the risk of MACE was highly associated with LDL-C, non-HDL-C, and apoB; however, the associations were strongest for non-HDL-C (hazard ratio [HR]: 1.42, 95% confidence interval [CI]: 1.29-1.56, P < .001) and apoB (HR: 1.33, 95% CI: 1.22-1.45, P < .001). The adjusted HRs for MACE per 1-standard deviation increase were significantly higher for non-HDL-C than LDL-C and apoB, suggesting that non-HDL-C may be a more appropriate target than LDL-C. The use of individual patient-level data was a major strength of this meta-analysis, while the major limitations were the variability between baseline characteristics and outcome definitions of the individual trials. These data suggest non-HDL-C and apoB are better predictors of CV risk than LDL-C. Clinically, non-HDL-C is useful in patients who are not fasting since it is calculated based on the difference of 2 direct measurements, total cholesterol, and HDL-C. Patients with metabolic syndrome and diabetes frequently have lower LDL-C levels but remain at increased CV risk due to an abundance of TG-rich lipoproteins, notably VLDL. As such, non-HDL-C may be more useful than LDL-C in these patients.

Tsimikas S, Fazio S, Ferdinand KC, et al. NHLBI working group recommendations to reduce lipoprotein(a)-mediated risk of cardiovascular disease and aortic stenosis. J Am Coll Cardiol. 2018;71(2):177-192.

The apoB-containing LDL-like particle, Lp(a) is a significant genetic risk factor for CAD and calcific aortic valvular disease affecting nearly 30% of the world’s population. Data from several studies have shown that elevated Lp(a) is associated with a higher CV risk regardless of LDL-C levels. Although select lipid-lowering therapies (eg, PCSK9 inhibitors, niacin) modestly reduce Lp(a) levels, the effect of this on clinical outcomes remains unknown. In response to increasing awareness of Lp(a) as a CAD risk factor and knowledge gaps that exist, a workgroup organized by the NHLBI published this review focusing on the challenges and opportunities to improve the understanding of Lp(a). The workgroup recommended the NHLBI explores ways to facilitate more research on Lp(a); foster collaborative research; support an ICD-10 code for diagnosing elevated Lp(a); standardizing Lp(a) measurements; educating the public, clinicians, and regulatory agencies; and developing evidence-based guidelines for managing patients with elevated Lp(a). The workgroup also identified 6 key research priorities, including: (1) fully defining the mechanisms of Lp(a) synthesis, assembly, and clearance; (2) understanding the mechanism by which Lp(a) increases CV risk; (3) need to develop a globally standardized measurement of Lp(a); (4) understanding the mechanism of action for drugs shown to reduce Lp(a) levels; (5) focusing research efforts on populations at high risk with elevated Lpa(a); and (6) testing of Lp(a) lowering in a RCT.

Secondary Prevention Trials

The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;335:549-559.

The stroke prevention by aggressive reduction in cholesterol levels (SPARCL) trial was the first to evaluate the use of a high-intensity statin, atorvastatin 80 mg daily for secondary prevention of stroke in subjects with no history of CAD, and moderately elevated LDL-C levels (100-190 mg/dL). This trial was a randomized, double-blind controlled trial that included 4731 subjects with a history of transient ischemic attack (TIA) or stroke that occurred within 1 to 6 months of study enrollment. Following a median follow-up of 4.9 years, the mean LDL-C achieved in the atorvastatin group was 72.9 mg/dL and 128.5 mg/dL in the placebo group (P < .001). Atorvastatin reduced the risk of the primary end point of nonfatal or fatal stroke (11.2% vs 13.1%, P = .05). The RRR of nonfatal or fatal stroke associated with atorvastatin was 16% (95% CI: 0.71-0.99, P = .03, unadjusted P = .05). Atorvastatin also reduced the risk of secondary end points of stroke or TIA (15.9% vs 20.1%, P < .001) and CV events including major coronary events and revascularization procedures (22.4% vs 29.0%, P < .001). Mortality rates were similar between groups. Adverse events were also similar between groups with the exception of elevated LFTs, which was more frequent in the atorvastatin group (2.2% vs 0.5%, P < .001); however, no cases of liver failure occurred. The benefit of atorvastatin was driven by a reduction in the risk of cerebral infarction, likely due to the reductions in LDL-C. Notably, a posthoc analyses reflected more hemorrhagic strokes in the atorvastatin group compared to placebo (55 vs 33). However, due to the small number of subjects with a history of hemorrhagic stroke at study enrollment, authors concluded limitations in evaluating this risk and that the results support the initiation of atorvastatin following a stroke or TIA. Overall, SPARCL demonstrated that a high intensity statin was effective for secondary prevention of stroke in subjects with no previous history of CAD and moderately elevated baseline LDL-C levels. The lingering question that was answered in this trial was whether statins reduced the risk of stroke in subjects without established CAD. Based on available evidence at the time of this trial, authors also concluded that stains should be considered for stroke subjects but the appropriate dose likely needs further evaluation, and the risk of recurrent hemorrhagic stroke should be considered prior to statin initiation.

AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255-2267.

This study set out to answer the question of whether or not increasing HDL-C with niacin would reduce CV events. This trial evaluated the impact of raising HDL-C with extended-release niacin on CV events in 3414 patients with CV disease plus high TGs and low HDL-C. The primary end point was the composite of death from CAD, nonfatal MI, ischemic stroke, hospitalization for acute coronary syndrome (ACS), or revascularization. Patients in this trial were aggressively treated with statins prior to enrollment as most subjects (93.6%) were taking a statin as baseline and had a mean LDL-C goal of ≤70 mg/dL. Subjects received simvastatin 40 mg daily and niacin extended release (ER) titrated to a dose of 2000 mg daily in the 4- to 8-week open label phase. Subjects who tolerated niacin ER 1500 mg daily were then randomized to receive niacin or placebo (which also contained a small dose of 50 mg of immediate release niacin). The simvastatin dose was increased and ezetimibe added to achieve LDL-C levels of 40 to 80 mg/dL according to the study protocol. Subjects in the placebo group were more likely to be on ezetimibe compared to those treated with niacin (21.5% vs 9.5%, P < .001). The results demonstrated a 25% increase in HDL-C, 28.6% reduction in TG levels, and 12% reduction in LDL-C levels in the niacin group compared to a 9.8% increase, 8.1% decrease, and 5.5% decrease in the placebo group, respectively, at 2 years. The mean LDL-C was 68.3 ± 19.3 mg/dL in the placebo group compared to 65.2 ± 21.8 mg/dL in the niacin–simvastatin group at 3-year follow-up. Despite these favorable changes in lipoproteins, there was no significant difference between groups in the primary end point (16.4% vs 16.2%, P = .79). In this patient population with a history of stable ASCVD and other CV risk factors, no additional benefit was observed when niacin was added to a moderate intensity statin with or without ezetimibe to achieve an aggressive LDL-C goal of 40 to 80 mg/dL. Due to the lack of benefit demonstrated, the study was ultimately halted 18 months early as it met the criterion of futility according to the data safety monitoring board. There is a lot of speculation as to why this study failed to show a benefit. One hypothesis is that the patients studied were well-treated with an average baseline LDL-C of 71 mg/dL. This was a specific subgroup of subjects and it is difficult to extrapolate the ineffectiveness of raising HDL-C in all populations. Unfortunately, this contributes to a growing body of evidence showing futility with niacin to produce positive outcomes. Therefore, the use of niacin and emphasis of raising HDL-C have fallen out of favor and are no longer recommended by current guidelines.

HPS2-THRIVE) Collaborative Group, Landray MJ, Haynes R, Hopewell JC, et al. Effects of extended-release niacin with laropiprant in high risk patients. N Engl J Med. 2014;371:203-212.

The Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) study was a large international trial (n = 25 673) that evaluated the use of high-dose niacin ER in patients with a history of ASCVD on background statin therapy. Unlike other trials with niacin, this study evaluated the combination of niacin and laropiprant, a prostaglandin antagonist designed to reduce flushing. Most of the subjects had CAD (78.4%), followed by cerebrovascular disease (31.8%), and peripheral arterial disease (12.5%). Nearly 70% of the subjects had diabetes or metabolic syndrome. The primary end point was a composite of first vascular event including nonfatal MI, death from CV causes, stroke, or arterial revascularization. Ezetimibe was added to simvastatin 40 mg daily if TC was ≥135 mg/dL after 4 weeks. The mean baseline LDL-C and HDL-C following the initial run in phase was 63 mg/dL and 44 mg/dL, respectively. Subjects were then randomized to receive 2 g of niacin ER with laropiprant 40 mg or placebo after confirmation that subjects tolerated initial doses of these agents for 4 weeks and study doses for 3 to 6 weeks. Of note, a considerable portion of subjects (33.1%) withdrew during this phase secondary to adverse effects. After a median follow-up of 3.9 years, niacin–laropiprant reduced LDL-C 10 mg/dL, increased HDL-C 6 mg/dL, and reduced TG levels 33 mg/dL. The primary end point occurred in 13.2% of subjects in the niacin–laropiprant group compared to 13.7% of patients in the placebo group (rate ratio: 0.96, 95% CI: 0.90-1.03, P = .29). There was also no significant difference in incidence of major vascular events. Discontinuation rates were higher in the niacin–laropiprant group compared to placebo (25.4% vs 16.6%, P < .001). More subjects in this group also discontinued statin therapy. Additionally, subjects assigned to niacin–laropiprant experienced more fatal and nonfatal adverse effects compared to placebo (P < .001). Among the serious adverse effects, a 55% proportional increase in disturbances in glucose control among diabetes subjects was observed. Interesting, even in those without diabetes treated with niacin–laropiprant, there was a 32% proportional increase in the number of new-onset cases of diabetes (P < .001) compared to placebo. Other adverse effects that were significantly more common in the niacin–laropiprant group included gastrointestinal effects, myopathy, skin-related effects, infection, and bleeding. Even more striking was the 9% increase in the risk of death in the niacin–laropiprant treated patients (P = .08). Overall, the niacin–laropiprant combination added to a moderate intensity statin did not reduce major vascular events in patients with a history of ASCVD. These findings reaffirmed the lack of benefit of niacin, lending further evidence that routine use should be discouraged.

IMPROVE-IT) Investigators, Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-2397.

This trial was the first to evaluate the efficacy of ezetimibe when added to a moderate intensity statin in 18 144 subjects with an ACS within 10 days of study randomization. The primary end point was a composite of CV death, nonfatal MI, UA requiring hospitalization, coronary revascularization ≥30 days after randomization, and nonfatal stroke. Subjects had a mean baseline LDL-C of 93.8 mg/dL with or without lipid-lowering therapy prior to study enrollment. Subjects were randomized to receive simvastatin 40 mg with ezetimibe 10 mg daily or simvastatin 40 to 80 mg as monotherapy. If subjects did not meet prespecified LDL-C goals, simvastatin was increased to 80 mg daily or an alternative, more potent statin was prescribed. Mean LDL-C was 53.7 mg/dL in the simvastatin–ezetimibe group compared to 69.5 mg/dL in the simvastatin-monotherapy group over the duration of the trial. The primary end point was lower in the simvastatin–ezetimibe group (32.7%) compared to the simvastatin-monotherapy group (34.7%) at 7 years (HR: 0.936, 95% CI: 0.89-0.99, P = .016). Rates of MI and ischemic stroke were also lower in the simvastatin–ezetimibe group: MI (12.8% vs 14.4%; HR: 0.87; P = .002) and ischemic stroke (3.4% vs 4.1%; HR: 0.79; P = .008). Furthermore, there were no significant safety concerns with simvastatin–ezetimibe. Overall, the addition of ezetimibe to a moderate intensity statin in subjects with recent ACS and CV risk factors with baseline LDL-C levels <125 mg/dL resulted in reduced CV events. The results of this trial suggest that lower LDL-C is better despite the use of a moderate intensity statin dose rather than a high intensity statin (as recommended by the ACC/AHA 2013 Cholesterol guidelines). This also translates to an additional treatment option especially for those subjects unable to tolerate high-intensity statins or statins in general. Results from this trial support recommendations provided in the 2017 ACC Recommendations for Non-Statin Therapy in the Management of ASCVD. Additionally, a mean LDL-C of 54 mg/dL achieved in the combination group compared to the control group of 70 mg/dL adds additional data to support lower LDL-C levels. Notably, the American Association of Clinical Endocrinologist 2017 guidelines for management of dyslipidemia adopted a target LDL-C of <55 mg/dL in patients at extreme risk.

FOURIER) Steering Committee and Investigators, Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713-1722.

The FOURIER trial was a randomized, double-blind, placebo-controlled, international trial assessing the clinical benefit of evolocumab added to background moderate–high-intensity statin therapy in 27 564 subjects with a history of CV disease. At baseline, the majority of subjects were taking high-intensity statin doses (69.3%), and 30.4% were taking moderate-intensity statin doses with or without ezetimibe. The mean baseline LDL-C was 92 mg/dL. The primary end point was a composite of CV death, MI, stroke, hospitalization for UA, or coronary revascularization. The results demonstrated a significant reduction in LDL-C in subjects randomized to receive evolocumab (140 mg subcutaneously every 2 weeks or 420 mg monthly) compared to placebo (mean absolute reduction of 56 mg/dL) with a median achieved LDL-C of 30 mg/dL at 48 weeks. Most subjects achieved an LDL-C level of ≤70 mg/dL. The primary end point occurred less frequently in the evolocumab group compared to placebo (9.8% vs 11.3%; HR: 0.85, 95% CI: 0.79-0.92, P < .001). No difference was observed between groups for rates of CV death. The addition of evolocumab to moderate–high-intensity statin therapy with or without ezetimibe was associated with a 15% risk reduction of CV events in high-risk subjects regardless of baseline LDL-C level and background lipid-lowering therapy. The clinical benefit of aggressive reduction of LDL-C in this trial supports a “treat to goal approach” and an aggressive LDL-C goal in high-risk subjects with a history of CV disease. These results now add to our armamentarium for treating individuals who remain at high risk. Limitations of this study are the relative short follow-up (median 2.2 years) and it only evaluated subjects with known CV disease. Additionally, the impact of long-term sustainment of LDL-C levels and any potential negative consequences of such will also need to be evaluated.

ODYSSEY OUTCOMES Committees and Investigators, Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379:2097-2107.

The ODYSSEY outcomes trial evaluated alirocumab compared to placebo in 18 924 subjects with an ACS (UA or MI) with the previous 12 months. These subjects had residual LDL-C levels of >70 mg/dL, non-HDL-C >100 mg/dL, or apolipoprotein >80 mg/dL after 2 to 16 weeks of intensive or maximally tolerated statin therapy with either atorvastatin or rosuvastatin. Subjects were randomized to alirocumab 75 mg every 2 weeks or placebo. The target LDL-C was 25 to 50 mg/dL. Unlike in the FOURIER trial, subjects in this study had their alirocumab dose increased to 150 mg every 2 weeks if their LDL-C was >50 mg/dL. Additionally, the dose of alirocumab was decreased if their LDL-C was consistently below 15 mg/dL. The primary end point was time to major adverse CV events, time to nonfatal MI, death from heart disease, or UA requiring hospitalization. The median LDL-C levels obtained were 53.3 mg/dL for the alirocumab group compared to 101.4 mg/dL for the placebo group after a median follow-up of 2.8 years. Nonfatal MI, ischemic stroke, and UA were all significantly reduced with alirocumab compared to placebo (6.6% vs 7.6% [P = .006]; 1.2% vs 1.6% [P = .01]; and 0.4% vs 0.6%; [P = .02], respectively). The results failed to show a difference in the reduction in CAD death (2.2% vs 2.3%; P = .38). However, there was a significant reduction in all-cause mortality in those treated with alirocumab (4.1% vs 3.5%, P = .026). Of note, the mortality reduction did not meet the predetermined statistical analysis plan and therefore can only be considered an observational finding. When compared to FOURIER, ODYSSEY enrolled a higher risk population with a longer duration of follow-up. This is the second trial with PCSK9 inhibitors demonstrating significant reductions in LDL-C as well as reductions in CV outcomes.

Triglycerides

ACCORD) Study Group, Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563-1574.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study sought to determine the optimal approach to preventing CV disease in subjects with type 2 diabetes using a double 2 × 2 factorial design to compare intensive glycemic control, intensive blood pressure control, and combination lipid-lowering therapy to a standard strategy. The ACCORD-LIPID trial compared the combination of fenofibrate plus simvastatin to simvastatin alone in 5518 subjects with type 2 diabetes and dyslipidemia. The mean age was 62 years, with 36.5% of subjects having had a prior CV event. The remaining two-thirds of subjects had at least 2 major risk factors for CV disease. Mean baseline HbA_1c was 8.3%, mean LDL-C was 100.6 mg/dL, mean HDL-C was 38.1 mg/dL, and median TG level was 162 mg/dL. The primary end point was first occurrence of nonfatal MI, nonfatal stroke, or death from CV causes over a mean duration of 4.7 years. The average dose of simvastatin was similar in both the fenofibrate and placebo groups (22.3 mg daily vs 22.4 mg daily, respectively) at follow-up but was subject to change during the study based on guideline recommendations. The dose of fenofibrate was also reduced or discontinued based on dose adjustment recommendations for renal dysfunction per the study protocol. The mean LDL-C and HDL-C levels were comparable between the 2 groups at the end of the study (81.1 mg/dL vs 80.0 mg/dL and 41.2 mg/dL vs 40.5 mg/dL, respectively). Median TG levels decreased to 122 mg/dL in the fenofibrate group and to 144 mg/dL in the placebo group. The rate of the primary end point was similar between those who received fenofibrate compared to placebo (2.2% vs 2.4%, respectively, P = .32). There was also no significant difference in the rate of secondary outcomes between groups. Assessment of subgroup effects for sex reflected a lower occurrence of the primary end point in men on fenofibrate compared to placebo (11.2% vs 13.3%) and a higher occurrence in women on fenofibrate compared to placebo (9.1% vs 6.6%, P = .01 for interaction). Although not statistically significant, the primary outcome occurred less in subjects with lower mean baseline HDL-C (≤34 mg/dL) and higher TG levels (>204 mg/dL) treated with fenofibrate compared to placebo (12.4% vs 17.3%, respectively, P = .057 for interaction). Overall, the addition of fenofibrate to simvastatin in subjects with type 2 diabetes at high CV risk with baseline low HDL-C and elevated TG levels did not demonstrate a reduction in major CV events. This trial was included to support the ACC/AHA 2013 Blood Cholesterol Guidelines for the lack of benefit of the addition of nonstatin therapy to a statin to target low HDL-C or high TG for ASCVD risk reduction.

Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) Investigators, Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2018. doi:10.1056/NEJMoa1812791.

The REDUCE-IT trial was a randomized, double-blind, placebo-controlled trial involving 8179 patients from 11 countries with hypertriglyceridemia (fasting TG > 150 mg/dL and < 500 mg/dL and LDL-C > 40 mg/dL) and either established CAD or at high CAD risk. Patients (n = 8179) were randomized to EPA (4 g/d) or placebo and were on background statin therapy for at least 4 weeks prior to randomization. The primary outcome measure was a composite of CV death, nonfatal MI, nonfatal stroke, coronary revascularization, and UA determined to be caused by myocardial ischemia by noninvasive testing and requiring emergent hospitalization. After a median follow-up of 4.9 years, the primary end point occurred in 17.2% of patients receiving icosapent ethyl compared to 22% for the placebo group (HR: 0.75, 95% CI: 0.68-0.83, P < .001). Additionally, those treated with icosapent ethyl had a significant reduction in TG levels at 1 year compared to placebo (−39.0 mg/dL vs 4.5 mg/dL). However, subjects in the icosapent ethyl group had a higher incidence of being hospitalized for atrial fibrillation or flutter compared to placebo (3.1% vs 2.1%; P = .004). These results indicate that the use of icosapent ethyl 4 g daily is superior to placebo in not only reducing TGs but also reducing CV events and CV death among patients with high TGs and either known CV disease or those at high risk already on statin therapy with well controlled LDL-C levels. The results of this trial will likely have major implications given that there have been several negative trials with lower doses (less than 2 g/d) of n–3 fatty acid supplementation. It is not yet clear why the EPA product was effective when other trials with the EPA/DHA combination have failed to show benefit. However, it may have to do with the dosing of EPA compared to lower doses used in other studies (eg, JELIS) or EPA’s ability to reduce systemic inflammation, which has a well-recognized role in CAD development. To date, this is the only multinational, randomized clinical trial that has demonstrated improved clinical outcomes using EPA to lower TGs on top of statin therapy. The results of this trial now provide us with a treatment option for patients with high TG’s with or at high risk for CV disease that will improve outcomes.

Lipid-Lowering Medication Safety

Gadarla M, Kearns AK, Thompson PD. Efficacy of rosuvastatin (5 and 10 mg) twice a week in patients intolerant to daily statins. Am J Cardiol. 2008;101:1747-1748.

This is a small, retrospective study evaluating the efficacy of rosuvastatin twice weekly in a cohort of subjects who were intolerant to at least 1 statin dosed daily. Thirty subjects received 5 mg twice weekly and 10 patients received 10 mg twice weekly. Following ≥3 weeks of treatment, mean LDL-C levels were reduced by 26% (43 ± 26 mg/dL) and 54% of the subjects achieved their LDL-C goal as recommended by NCEP ATP III, the guidelines in place at the time the study was conducted. Of the 40 subjects, 8 (20%) discontinued rosuvastatin twice weekly due to muscle aches following the 3-week lipid measurement but the remaining patients tolerated therapy for a mean of 3 months. Although the study was limited by the small sample size, retrospective design, and short follow-up period, it was able to demonstrate that intermittent dosing with rosuvastatin twice a week provided a treatment option for subjects who were intolerant to daily dosing of at least 1 statin. However, the impact of this type of dosing strategy on outcomes is unknown.

Ruisinger JF, Backes JM, Gibson CA, et al. Once-a-week rosuvastatin (2.5 to 20 mg) in patients with a previous statin intolerance. Am J Cardiol. 2009;103:393-394.

This was a retrospective study to determine the efficacy of rosuvastatin dosed once weekly in subjects with a previous statin adverse event, including myalgias, elevated creatinine kinase levels, elevated hepatic transaminases, and gastrointestinal complaints. Of the 50 subjects, 37 (74%) were able to tolerate rosuvastatin once weekly. The doses ranged from 2.5 to 20 mg with an average weekly dose of 10 mg. This results demonstrated a mean LDL-C reduction of 23% (42 mg/dL), a 12% decrease in TGs, and a 5% increase in HDL-C (all P < .001) following 4 months of treatment. Of these 37 subjects, 10 (27%) were able to achieve their LDL-C goal as recommended by NCEP ATP III. This study was also able to show that measuring lipid levels 1 to 3 days after the subject’s last weekly dose were similar to measuring lipid levels 4 to 7 days after the last dose. Although this was limited by the lack of a control group, small size, observational nature, and short follow-up period, the study showed that once-a-week rosuvastatin therapy was a reasonable option for subjects who experienced adverse events to previous statin therapy. Long-term studies are still needed to assess whether alternate dosing schedules of statins can result in reductions in CV events. Additionally, long-term tolerability also needs to be evaluated.

Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects (EBBINGHAUS) Investigators, Giugliano RP, Mach F, Zavitz K, et al. Cognitive function in a randomized trial of evolocumab. N Engl J Med. 2017;377:633-643.

Earlier trials of PCSK9 inhibitors found numerically higher rates of cognitive function-related adverse effects but the numbers were too small to determine the significance of this effect. Furthermore, this effect would seem unlikely given the PCSK9 inhibitors are monoclonal antibodies and are too large of molecules to cross the blood–brain barrier. The EBBINGHAUS study prospectively evaluated the neurocognitive effects of evolocumab in a subgroup of patients from the FOURIER trial. Cognition was prospectively evaluated using the Cambridge Neuropsychological Test Automated Battery in 1204 patients who were randomized to evolocumab or placebo, in addition to statin therapy. The primary end point was defined as the score on the spatial working memory strategy index (SWMSI) of executive function. Secondary end points evaluated spatial working memory, episodic memory, and psychomotor speed. The results demonstrated a change in SWMSI was −0.21 in the evolocumab group compared to −0.29 in the placebo group (P < .001 for noninferiority; P = .85 for superiority). There were no significant differences in secondary end points between the 2 groups after a median follow-up of 19 months. Interestingly, even when patients were stratified by lowest attained LDL-C levels (<25 mg/dL, 25-39 mg/dL, and ≥40 mg/dL), there were no differences between the evolocumab and placebo groups. This study was the first to show that using a PCSK9 inhibitor to achieve very low levels of LDL-C does not negatively impact cognition. This alleviates some concerns that were raised with reports of statin-associated cognitive impairment. EBBINGHAUS is the first study to prospectively evaluate cognition with PCSK9 inhibitors. An ongoing 5-year extension of EBBINGHAUS will help determine the long-term effects of evolocumab on cognition.

Sabatine MS, Leiter LA, Wiviott SD, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol. 2017;5(12):941-950.

This prespecified analysis of the FOURIER study evaluated the efficacy and safety of evolocumab in subjects according to the baseline diabetes status. At baseline, 40% had diabetes (n = 11 031), while 10 344 had prediabetes and only 6189 participants had normal glycemic levels. Following 48 weeks of treatment, similar reductions in LDL-C were observed in the diabetes subgroup (57%) and nondiabetes subgroup (60%). The CV event rate was nearly 50% higher in the diabetes subgroup further reinforcing the fact that patients with diabetes are at higher CV risk than those without diabetes. The CV benefit observed in the overall FOURIER study was found to be consistent irrespective of baseline diabetes status; however, those with diabetes had greater absolute risk reductions in the primary end point with evolocumab (2.7%) compared to those without diabetes (1.6%) at 3 years. This was primarily driven by a reduction in coronary revascularization. There were no differences between groups in the overall rates of adverse events, and evolocumab did not increase the risk of new-onset diabetes in subjects without diabetes at baseline. These findings support the use of evolocumab in subjects with diabetes and established CV disease who are on maximally tolerated statin therapy to further reduce CV risk. Unlike what has been observed with high-intensity statins, which have been shown to increase the risk of new-onset diabetes, especially in those with preexisting risk factors for its development, this study suggests that PCSK9 inhibitors do not increase this risk.

Giugliano RP, Pedersen TR, Park JG, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: A prespecified secondary analysis of the FOURIER trial. Lancet. 2017;390:1962-1971.

This prespecified analysis of the FOURIER study evaluated the relationship between very low levels of achieved LDL-C with evolocumab at 4 weeks and CV and safety outcomes. Subjects were divided into 5 subgroups according to their LDL-C levels at 4 weeks: <20 mg/dL (10%), 21 to 50 mg/dL (31%), 51 to 70 mg/dL (13%), 71 to 100 mg/dL (29%), and >100 mg/dL (17%). A regression analysis demonstrated a reduction in CV events that persisted across all subgroups down to the first percentile of achieved LDL-C (<8 mg/dL). Importantly, no association was found between these unprecedented low levels of achieved LDL-C and adverse events, including liver enzyme and creatine kinase elevations, neurocognitive events, new-onset diabetes, cancer, and hemorrhagic stroke. It should be noted that the frequency of some safety events was low and others (eg, cancer) may not become evident during such a short follow-up period (2.2 years). While this study was the first to achieve such low LDL-C levels and confirm such low levels are safe in the short-term, the long-term safety of maintaining such low levels of LDL-C remains unknown. These data from this study continue to support the use of intensive lipid-lowering therapies to prevent recurrent CV events in high-risk patients. The results of this study also suggest that very low LDL-C concentrations are likely safe, at least in the short term.

Special Populations

AURORA Study Group, Fellstrom BC, Jardine AG, Schmieder R, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med. 2009;360:1395-1407.

Statins are known to reduce the incidence CV events in a broad range of patient populations. While patients on maintenance hemodialysis are at very high risk of CV disease, the benefit of statins in this population is unknown. This international multicenter, randomized, double-blind prospective trial evaluated 2776 subjects (age 50-80 years) who were undergoing maintenance hemodialysis. Subjects were randomized to receive 10 mg of rosuvastatin daily or placebo with a median follow-up of 3.8 years. The primary end point was death from CV causes, nonfatal MI, or nonfatal stroke. Secondary end points were all-cause death and individual cardiac and vascular events. After 3 months of follow-up, LDL-C was reduced 43% in the rosuvastatin group compared to 1.9% in the placebo group (P < .001). In terms of primary outcomes, there was no difference between the 2 treatment groups (9.2 events per 100 patient years) for rosuvastatin and 9.5 events per 100 patient years from placebo (P = .59). There was also no significant difference between the 2 groups on any of the individual components of the primary end point and no significant effect on all-cause mortality. Despite significant reductions in LDL-C observed in this trial, there was no benefit observed with the use of rosuvastatin in this patient population. However, it is important to point out that this study included a select age range of subjects (50-80 years) and may not be applicable to those less than 50. Additionally, subjects already taking statin therapy were excluded. Therefore, other studies are likely needed to further tease out dialysis patients who may benefit from statin therapy. This trial did inform the KDIGO lipid management guidelines, which do not recommend initiating statins in subjects who start dialysis; however, those previously on statins at the time of starting dialysis should remain on therapy.

Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: The Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects 3 (GAUSS3) randomized clinical trial. JAMA. 2016;315(15):1580-1590.

Muscle-related adverse effects are frequently cited as a primary reason for statin discontinuation. While some subjects may tolerate lower doses of statins, most will not achieve desired levels of LDL-C. The GAUSS-3 compared the effectiveness and tolerability of evolocumab and ezetimibe in subjects with statin-associated muscle symptoms. The study was conducted in 2 phases. Phase A of the study involved a 4-week washout period of any lipid-lowering agent and subsequent rechallenge with either atorvastatin 20 mg daily or a placebo for 10 weeks, followed by a 2-week washout period, then a crossover to the alternate therapy for a second 10-week follow-up period. Subjects with confirmed muscle-related adverse effects on atorvastatin in phase A were then randomized to ezetimibe plus subcutaneous placebo or evolocumab plus oral placebo for 24 weeks in phase B of the study. The primary end point was the mean percentage change in LDL-C from baseline to study end, and adverse events were collected for both groups. Of the 492 subjects randomized for phase A, 218 were randomized for phase B. Notably, approximately 80% of all randomized subjects reported a history of intolerance to 3 or more statins and had a mean baseline LDL-C of 212 mg/dL. During phase A, 42.6% reported intolerable muscle symptoms with atorvastatin but not placebo, while 26.5% reported intolerable muscle symptoms with placebo but not atorvastatin. As expected, evolocumab provided a greater reduction in LDL-C compared to ezetimibe (52.8% vs 16.7%; P < .001) and more subjects achieved an LDL-C of <70 mg/dL (30% vs 1.4%, P < .001). The incidence of muscle symptoms was not significantly different between the ezetimibe- and evolocumab-treated groups (28.8% vs 20.7%, P = .17). The major strength of this study is that it is the largest trial to date using a blinded rechallenge in subjects with a history of statin intolerance due to muscle-related adverse effects. Both evolocumab and ezetimibe were well tolerated in patients with a history of statin intolerance due to muscle-related adverse effects. The population size was, however, quite modest, and the study duration was relatively short at just 24 weeks. However, this taken with other study results places the PCSK9 inhibitors and/or ezetimibe as alternatives to statins in those with statin intolerance.

Homozygous Familial Hypercholesterolemia

Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolemia; A randomized, double blind, placebo controlled trial. Lancet. 2010;375:998-1006.

This trial was an international phase 3 study assessing the effects of mipomersen in 51 subjects (mean age of 31 years with homozygous FH (HoFH) on background maximally tolerated lipid-lowering therapy. Subjects were randomized to receive mipomersen 200 mg (or weight-based dosing) subcutaneously every week (n = 34) or placebo (n = 17) in a 2:1 ratio for a duration of 26 weeks. Most subjects (86%) had genetic confirmation of HoFH, and more than half had a history of ASCVD. Notably, subjects could have been on a combination of statins, ezetimibe, bile acid sequestrants, or niacin and continued this therapy throughout the trial. A majority of subjects (76%) were taking a combination of lipid-lowering regimen, which included a statin (74% were taking a statin with ezetimibe), while 24% were taking a statin as monotherapy. While specific statins and doses were not reported, authors stated that 88% of statin-treated subjects were on a maximum dose. As expected, mean baseline LDL-C levels were extremely elevated despite background lipid-lowering therapy (402.2 mg/dL in the placebo group vs 440.8 mg/dL in the mipomersen group). The primary outcome measure was percentage change in LDL-C from baseline. The mean percentage change in LDL-C from baseline was approximately 25% in the mipomersen group compared to 3% in the placebo group (difference: −21.3, 95% CI: −32.9 to −9.8, P = .0003). Mipomersen provided significant reductions in lipid parameters in this extremely high risk and difficult-to-treat patient population on background lipid-lowering therapy; however, significant safety concerns exist. Subjects in the mipomersen group were also more likely to experience alanine aminotransferase (ALT) elevations >3 the upper limit of normal (12% in the mipomersen group compared to no cases in the placebo group), with 1 patient noted to have an increase in hepatic fat from baseline associated with persistent ALT elevation. Notably, 6 subjects in the mipomersen group did not complete the 26 weeks of therapy, mostly due to adverse effects. Due to the risk of hepatotoxicity and concern for hepatic steatosis, mipomersen is available only through a restricted Risk Evaluation and Mitigation Strategies (REMS) program. Due to lack of benefit on CV morbidity and mortality, the use of lomitapide should be reserved for patients with HoFH who fail to have an adequate response to statin therapy with or without with ezetimibe and/or a PCSK9 inhibitor.

Blom DJ, Averna MR, Meagher EA. Long-term efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in patients with homozygous familial hypercholesterolemia. Circulation. 2017;136:332-335.

This trial was a 48-week extension trial of the original phase 3, open-label 78-week trial assessing the safety and efficacy of lomitapide in subjects with HoFH. The original trial included 23 subjects (mean age 30.4 years) with a baseline mean LDL-C of 356 ± 127 mg/dL. Background lipid-lowering therapy established during a 6-week run in phase included mostly statins with or without ezetimibe; however, a small number of subjects were on niacin, a fibrate, or a bile acid sequestrant and 18 of the 29 subjects in the original trial received LDL-C apheresis. The addition of maximally tolerated dose of lomitapide (median dose of 40 mg once daily) demonstrated a significant mean reduction in LDL-C of 50% from baseline at week 26 and was sustainable with an LDL-C reduction of 38% at 78 weeks. Almost all subjects experienced at least one adverse effect, most commonly gastrointestinal adverse effects followed by LFT elevation and increases in hepatic fat. Of the 23 subjects in the original trial, 17 patients completed the 48-week extension trial. The median dose of lomitapide remained similar to the original trial, but the mean duration was 5.1 years. Reductions in LDL-C remained significant with a mean percentage decrease of −45.5% (95% CI: −61.6 to −29.4, P < .001) at week 78 of the extension trial. Less adverse effects were reported in the extension trial compared to the original trial. The LFT elevations ≥5 the upper limit of normal occurred in 21.1% of patients. Due to the risk of hepatotoxicity, lomitapide is available only through a restricted REMS program. While this agent has high risk of serious adverse effects, it adds to the current armamentarium in patients with HoFH. Due to lack of benefit on CV morbidity and mortality, the use of lomitapide should be reserved for patients with HoFH who fail to have an adequate response to statin therapy with or without ezetimibe and/or a PCSK9 inhibitor.

Footnotes

Author's Note

The author Jessica Bellone, was working as Associate Professor of Pharmacy Practice, Concordia University. Wisconsin School of Pharmacy before joining Sanofi in August, 2018.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Barbara S. Wiggins, PharmD

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