Atherosclerotic vascular disease (ASCVD) is the leading cause of death in the United States.1 Approximately 92.1 million people in the US have at least one type of cardiovascular disease (CVD), with more than 45 million additional being at an increased risk for developing CVD within 10 years.1 The economic burden of CVD on the US economy is staggering and currently estimated at $316.1 billion; with this cost expected to rise to $818 billion by 2030.1 Dyslipidemia, which is a key modifiable risk factor for heart disease, encompasses both elevated levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), or triglycerides (TG), and abnormally low levels of lipoproteins such as high-density lipoprotein cholesterol (HDL-C).2 High levels of LDL-C have been shown to be associated with greater ASCVD risk and have traditionally been the primary target of therapy in lipid guidelines.2 Since their introduction more than 30 years ago, statins have been the treatment of choice in lowering cholesterol.
High-intensity statins reduce LDL-C by an average of ≥50% and have been shown to reduce ASCVD events in randomized controlled trials.3 The concepts of “treat to target” and “lower is better” have been proposed and debated in the medical literature; although specific LDL-C targets are still controversial. Clinical trials investigating the safety and efficacy of statins provide strong evidence that aiming for and achieving the lowest feasible LDL-C levels is a reasonable treatment goal.2 Results of the IMPROVE-IT trial showed that adding ezetimibe to simvastatin led to incremental lowering of LDL-C levels—even to levels as low as 50 mg/dL—and improved cardiovascular outcomes compared with simvastatin plus placebo.2 However, statins may not fully eliminate ASCVD risk and residual risk persists among patients receiving maximum tolerated intensity of statins or in patients with statin intolerance or statin resistance.
Aggressive LDL-C lowering: non-statin therapies
In addition to statin-resistant and statinintolerant patients, statin therapy may not be sufficient to achieve target LDL-C reduction for patients with ASCVD and comorbidities.2 Comorbidities such as diabetes, an ASCVD event while on statin therapy, prior stroke or myocardial infarction (MI), put these patients at increased risk of adverse cardiovascular events; possibly requiring the addition of non-statin agents for secondary prevention if significant LDL-C reduction is not achieved even after optimization of statin therapy.2
The clinical guidelines from the American Diabetes Association support additional lowering of LDL-C in patients with diabetes who have elevated LDL-C levels (≥70 mg/dL) despite maximally tolerated statin therapy.4 In the 2017 update from the American College of Cardiology (ACC) on the role of non-statin therapies for LDL-C lowering, it was suggested that for high-risk individuals (including those with clinical ASCVD, LDL-C ≥190 mg/dL, or with diabetes 40-75 years of age) who may not have an adequate response to statin therapy, the addition of non-statin therapies may be considered.2 The intensity or the specific targets of cholesterol therapy are not fully defined, so much so that the 2013 ACC and American Heart Association (AHA) guidelines for cholesterol treatment did not support the use of LDL-C target levels for ASCVD prevention.3 However, the approval of new non-statin therapies that aggressively lower LDL-C, such as proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors, has invigorated the debate about specific LDL-C targets, with many experts advocating for achieving very low levels of LDL-C (below 50 mg/dL and in some cases, ≤20 mg/dL) early in the treatment regimen in order to maximize cardiovascular benefits.5
PCSK9 inhibitors are monoclonal antibodies that block PCSK9 and thus inhibit the ability of PCSK9 to degrade the LDL receptor.2 FDA-approved PCSK9 inhibitors alirocumab and evolocumab have demonstrated their effectiveness in reducing LDL-C levels and ASCVD risk, either alone or in combination with statins.2 Evolocumab and alirocumab are indicated as adjuncts to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical ASCVD who require additional LDL-C-lowering.2 Evolocumab is also approved for use as an adjunct to other LDL-C-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with homozygous familial hypercholesterolemia (HoFH) who require additional LDL-C lowering.2 In the FOURIER trial, the addition of evolocumab to statin therapy led to a 59% mean LDL-C reduction (from a baseline value of 92 mg/dL to 30 mg/dL) in patients with clinical ASCVD and baseline LDL-C ≥70 mg/dL.6 Furthermore, evolocumab treatment significantly reduced the risk of the primary (composite of cardiovascular mortality, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization) and secondary (composite of cardiovascular mortality, myocardial infarction, or stroke) endpoints.6 A secondary analysis of the FOURIER trial showed that evolocumab reduced LDL-C by 66% in patients with a baseline LDL-C ≤70 mg/dL, coupled with significant reductions in both primary and secondary endpoints, demonstrating that aggressive LDL-C lowering conveys cardiovascular benefits in high-risk patients.7
Results from another marque clinical trial, ODYSSEY Outcomes, presented at the ACC 2018 conference, demonstrated the efficacy of alirocumab in lowering LDL-C in patients with a recent acute coronary syndrome event and baseline LDL-C ≥70 mg/dL despite maximal statin therapy. Alirocumab treatment reduced LDL-C levels by 54.7%, as well as significantly reduced the risk of primary endpoint, a composite of coronary heart disease mortality, myocardial infarction, fatal and non-fatal ischemic stroke, or unstable angina requiring hospitalization.8 Results from the FOURIER and ODYSSEY Outcomes studies showed that aggressive LDL-C lowering has tremendous cardiovascular benefits, with excellent safety profiles.8 Due to the strong evidence from the FOURIER trial, recently FDA also approved evolocumab for the prevention of stroke, myocardial infarction, and coronary revascularization in patients with established cardiovascular disease.
The efficacy and safety of PCSK9 inhibitors has also been demonstrated in patients with diabetes or dyslipidemia. About 40% of patients in the FOURIER trial were diabetics, and evolocumab also significantly reduced the risk of adverse cardiovascular events, without increasing blood glucose and other glycemic safety parameters in this subset of patients.9 Recently, alirocumab was evaluated in insulintreated type 1 or type 2 diabetic patients with dyslipidemia and high cardiovascular risk (ODYSSEY DM-INSULIN trial), showing significant reduction in LDL-C (a mean 59% reduction) and non-HDL-C in this patient population.10 Another trial, ODYSSEY DMDyslipidemia, demonstrated that alirocumab effectively and safely lowered LDL-C and non-HDL-C in individuals with type 2 diabetes and dyslipidemia on maximally tolerated statin therapy.11 Emerging therapies evaluating new molecular targets that can lead to LDL-C reduction in hypercholesterolemic patients are currently being developed in clinical trials. Inclisiran, an siRNA agent that downregulates PCSK9 gene expression, was shown to significantly lower LDL-C (about 50% reduction) in patients at high risk for CVD with elevated LDL-C in a phase II trial.12 Bempedoic acid is an ATP-citrate lyase inhibitor that lowers LDL-C levels by upregulating the LDL receptor.13 Its efficacy in decreasing adverse cardiovascular events in patients with CVD and who are statin- resistance is currently evaluated in a phase III study, and preliminary results demonstrated that it lowers LDL-C by 20- 28%.13 Evinacumab, an angiopoietin-like 3 (ANGPTL3) inhibitor, recently received FDA-breakthrough therapy designation for HoFH and is also currently being evaluated in a phase II clinical study as a potential LDL-C lowering agent in patients with high-risk of ASCVD an elevated LDL-C despite maximally tolerated statin therapy.14 Gemcabene, an agent that lowers LDL-C and TG by inhibiting liver acetyl CoA carboxylase (ACC) and HMG-CoA Synthase, was shown to lower LDL-C in patients with ASCVD and elevated LDL-C despite optimized statin therapy in a phase II trial.15
In some high-risk patients, particularly those with comorbidities, target LDL-C reduction is not achieved with optimized statin therapy alone, and additional LDL-C lowering may be required. The recent results with non-statin therapies have provided significant evidence towards the early and aggressive lowering of LDL-C therapy, showing that this approach can maximize cardiovascular benefits and is generally well tolerated. The approval of PCSK9 inhibitors has given clinicians more options in decreasing CVD risk in these patients, and additional emerging therapeutics might also be available in the near future.