Beyond Statins: Emerging Lipid-lowering Therapies for Reducing Cardiovascular Risk

2024 Statins: Then and Now

The discovery of statins (3-hydroxy-3-methylglutaryl CoA reductase inhibitors) is a consequence of the highly targeted, arduous search for naturally occurring compounds that inhibit cholesterol biosynthesis. An enormous amount of basic scientific, genetic, and clinical research substantiated the role of lipoprotein-derived cholesterol in atherogenesis. Quantifying the impact of lipid lowering on cardiovascular event rates became an issue of utmost urgency. Although a variety of nonstatin drugs had been tested in clinical trials, they found limited utility in the clinical setting due to lack of mortality reduction or tolerability issues. As multiple prospective randomized statin trials began publishing their results, it became clear that reducing atherogenic lipoprotein burden with these drugs was highly efficacious, safe, and generally well tolerated. Statins have been shown to reduce risk for nonfatal MI, ischemic stroke, need for revascularization, and cardiovascular and all-cause mortality. They have also been shown to stabilize and even regress established atherosclerotic plaque. For the first 2 decades of their use, statin dosing was largely determined by risk-stratified low-density lipoprotein cholesterol (LDL-C) goals. More recently, there has been a transition away from LDL-C goal attainment with a focus more on cardiovascular risk and percent LDL-C reduction. Unfortunately, long-term adherence rates with statin therapy remain low and, even when used, they tend to be underdosed. 1

2024 New and emerging lipid-lowering therapies for reducing cardiovascular risk: beyond statins

Atherosclerotic cardiovascular disease (ASCVD) continues to pose a significant global health challenge, contributing to high rates of morbidity and mortality. Extensive research has underscored the pivotal role of dyslipidemia, particularly the abnormal elevation of plasma low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG), in the development and progression of ASCVD. While statins have long been established as the primary pharmacological intervention for ASCVD prevention and treatment, there remains a pressing need for more effective strategies, particularly in addressing the persistent challenge of reducing TG levels. Despite the success of statins in lowering LDL-C, a substantial residual cardiovascular risk persists among patients who adhere to statin therapy. Even with the advent of PCSK9 inhibitors, which enhance the clearance of LDL-C by up-regulating hepatic LDL receptor (LDLR), there exists a treatment gap for individuals with familial hypercholesterolemia, especially those with complete LDLR deficiency. This unmet need presents a formidable therapeutic hurdle for lipidologists, cardiologists, and the pharmaceutical industry. In response to this critical gap, researchers have delved into diverse therapeutic targets for lipid modulation, exploring avenues beyond LDLR-focused interventions. Pre-clinical and clinical investigations have shed light on potential targets such as angiopoietin-like protein 3 (ANGPTL3), apolipoprotein C3 (ApoC3), apolipoprotein B (ApoB), lipoprotein (a), and microsomal triglyceride transfer protein (MTTP). Among these, ANGPTL3 has emerged as a particularly promising target, demonstrating the ability to effectively reduce plasma LDL-C and TG levels, independent of LDLR, in patients with refractory hypercholesterolemia, including those with heterozygous familial hypercholesterolemia (HeFH). The breakthrough in lipids-lowering strategies not only holds promise for addressing the limitations of current therapies but also underscores the importance of furthering our understanding of the molecular mechanisms governing lipid metabolism. It is imperative to foster a collaborative platform for robust discussion, knowledge exchange, and the dissemination of new insights into lipid metabolism regulation and emerging lipid-lowering therapies. 2

2023 Combination Moderate-Intensity Statin and Ezetimibe Therapy for Elderly Patients With Atherosclerosis

The routine use of high-intensity statins should be considered carefully in elderly patients because of their higher risk of intolerance or adverse events. We evaluated the impact of moderate-intensity statin with ezetimibe combination therapy compared with high-intensity statin monotherapy in elderly patients with atherosclerotic cardiovascular disease (ASCVD). Among the 3,780 enrolled patients, 574 (15.2%) were aged ≥75 years. The rates of the primary endpoint were not different between the moderate-intensity statin with ezetimibe combination therapy group and the high-intensity statin monotherapy group among patients aged ≥75 years and those <75 years. Moderate-intensity statin with ezetimibe combination therapy was associated with lower rates of intolerance-related drug discontinuation or dose reduction among patients aged ≥75 years and those <75 years. Moderate-intensity statin with ezetimibe combination therapy showed similar cardiovascular benefits to those of high-intensity statin monotherapy with lower intolerance-related drug discontinuation or dose reduction in elderly patients with ASCVD having a higher risk of intolerance, nonadherence, and discontinuation with high-intensity statin therapy. 3