madman
Super Moderator
New Approaches for the Prevention and Treatment of Cardiovascular Disease: Focus on Lipoproteins and Inflammation
Abstract
Although numerous trials have convincingly shown the benefits of statin therapy in both primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD), most showed relative risk reductions of 25–40%, and thus many individuals continue to have ASCVD events despite statin therapy. Substantial progress has been made in developing therapies that address the residual risk for ASCVD despite statin therapy. In this review, we summarize the progress of currently available therapies along with therapies under development that further reduces low-density lipoprotein cholesterol and apolipoprotein B–containing lipoproteins, reduce lipoprotein(a), reduce ASCVD events in patients with high triglycerides, and directly target inflammation to reduce ASCVD risk.
INTRODUCTION
Elevated low-density lipoprotein cholesterol (LDL-C) is a well-known risk factor for atherosclerotic cardiovascular disease (ASCVD) (1). A large meta-analysis of landmark statin clinic trials showed that more intensive LDL-C–lowering therapy provided greater reduction in ASCVD events (2). Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVEIT) was the first trial to show that additional LDL-C lowering with ezetimibe reduced cardiovascular events compared with a statin alone (3). Two other trials, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) (4) and Evaluation of Cardiovascular Outcomes after an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY OUTCOMES) (5), demonstrated that substantial LDL-C lowering beyond that obtained with statin monotherapy provided an additional reduction in ASCVD risk and further validated the hypothesis that lowering LDL-C leads to a reduction in ASCVD events. These studies, in aggregate was the basis for the recommendations of the American Heart Association/American College of Cardiology (AHA/ACC) Guideline for the Management of Blood Cholesterol (2018) (6) and the European Society of Cardiology/European Atherosclerosis Society Guidelines for the Management of Dyslipidaemias (2019) (7) to use high-intensity statin therapy in all individuals with established ASCVD, with consideration of additional, nonstatin therapy if LDL-C remains above 100 mg/dl (70 mg/dl in higher-risk patients).
However, even in individuals treated with an optimal statin and other evidence-based lipid-lowering therapy, considerable residual ASCVD risk persists (2). In the recent past, we have seen dramatic progress toward identifying determinants of this residual cardiovascular risk. It may reflect atherogenic apolipoprotein (apo) B–containing particles besides LDL, including triglyceride (TG)–rich lipoproteins and lipoprotein(a), which are not reflected in the LDL-C level. The Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT), which evaluated the addition of icosapent ethyl to optimal statin therapy, demonstrated a dramatic reduction in cardiovascular events, not only in patients with known ASCVD but also in patients with diabetes who had multiple risk factors and residual hypertriglyceridemia (8). Atherosclerosis is an inflammatory process. The past decade has ushered in a renewed interest in the role of inflammation in ASCVD prevention, including the landmark Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS), which provided clinical proof of concept that an anti-inflammatory agent could result in significant ASCVD risk reduction beyond that obtained by reducing LDL-C (9).
*In this review, we focus on key advances in preventive cardiology for the treatment and prevention of ASCVD. In particular, we discuss recent LDL-C–lowering therapies that are currently available or in clinical trials, emerging approaches to target non-LDL-C lipid parameters such as TG and lipoprotein(a), and immune-modulatory therapies targeting atherosclerosis that have recently been tested in clinical trials or are currently in development (Figure 1). Other approaches to address residual risk, such as more-aggressive reductions in blood pressure, new treatments for diabetes, and lifestyle changes with diet, have also shown benefit and are critical for optimal reduction of not only ASCVD but also heart failure but is beyond the scope of this review.
NEW THERAPIES TARGETING LDL-C
*PCSK9 Inhibitors
*Bempedoic Acid
*Inclisiran
NEW THERAPIES TARGETING TRIGLYCERIDE PATHWAYS
*Omega-3 Fatty Acids
*Pemafibrate
*Apo C-III
*Angiopoietin-like Protein 3 Inhibition
NEW THERAPIES TARGETING LIPOPROTEIN(A)
*PCSK9 Inhibitors
*APO(a)-LRx
*AMG 890
NEW APPROACHES TO INFLAMMATION
Anti-inflammatory Therapies with Cardiovascular Outcomes Trials
*Canakinumab
*Methotrexate
*Colchicine
Anti-inflammatory Drugs in Development
CONCLUSION
Although statins remain the first-line lipid therapy for ASCVD prevention, residual ASCVD risk despite guideline-recommended statin use emphasizes the need for additional therapies. Recently approved and emerging agents offer options for further LDL-C reductions, in combination with a statin or as monotherapy, as well as alternative targets including TG and TG-rich lipoproteins, lipoprotein(a), and inflammation (see Figure 1). The clinical utility of these agents is the subject of recently completed and ongoing clinical trials, including essential outcomes studies, to evaluate their potential for risk reduction in clinical practice.
Abstract
Although numerous trials have convincingly shown the benefits of statin therapy in both primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD), most showed relative risk reductions of 25–40%, and thus many individuals continue to have ASCVD events despite statin therapy. Substantial progress has been made in developing therapies that address the residual risk for ASCVD despite statin therapy. In this review, we summarize the progress of currently available therapies along with therapies under development that further reduces low-density lipoprotein cholesterol and apolipoprotein B–containing lipoproteins, reduce lipoprotein(a), reduce ASCVD events in patients with high triglycerides, and directly target inflammation to reduce ASCVD risk.
INTRODUCTION
Elevated low-density lipoprotein cholesterol (LDL-C) is a well-known risk factor for atherosclerotic cardiovascular disease (ASCVD) (1). A large meta-analysis of landmark statin clinic trials showed that more intensive LDL-C–lowering therapy provided greater reduction in ASCVD events (2). Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVEIT) was the first trial to show that additional LDL-C lowering with ezetimibe reduced cardiovascular events compared with a statin alone (3). Two other trials, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) (4) and Evaluation of Cardiovascular Outcomes after an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY OUTCOMES) (5), demonstrated that substantial LDL-C lowering beyond that obtained with statin monotherapy provided an additional reduction in ASCVD risk and further validated the hypothesis that lowering LDL-C leads to a reduction in ASCVD events. These studies, in aggregate was the basis for the recommendations of the American Heart Association/American College of Cardiology (AHA/ACC) Guideline for the Management of Blood Cholesterol (2018) (6) and the European Society of Cardiology/European Atherosclerosis Society Guidelines for the Management of Dyslipidaemias (2019) (7) to use high-intensity statin therapy in all individuals with established ASCVD, with consideration of additional, nonstatin therapy if LDL-C remains above 100 mg/dl (70 mg/dl in higher-risk patients).
However, even in individuals treated with an optimal statin and other evidence-based lipid-lowering therapy, considerable residual ASCVD risk persists (2). In the recent past, we have seen dramatic progress toward identifying determinants of this residual cardiovascular risk. It may reflect atherogenic apolipoprotein (apo) B–containing particles besides LDL, including triglyceride (TG)–rich lipoproteins and lipoprotein(a), which are not reflected in the LDL-C level. The Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT), which evaluated the addition of icosapent ethyl to optimal statin therapy, demonstrated a dramatic reduction in cardiovascular events, not only in patients with known ASCVD but also in patients with diabetes who had multiple risk factors and residual hypertriglyceridemia (8). Atherosclerosis is an inflammatory process. The past decade has ushered in a renewed interest in the role of inflammation in ASCVD prevention, including the landmark Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS), which provided clinical proof of concept that an anti-inflammatory agent could result in significant ASCVD risk reduction beyond that obtained by reducing LDL-C (9).
*In this review, we focus on key advances in preventive cardiology for the treatment and prevention of ASCVD. In particular, we discuss recent LDL-C–lowering therapies that are currently available or in clinical trials, emerging approaches to target non-LDL-C lipid parameters such as TG and lipoprotein(a), and immune-modulatory therapies targeting atherosclerosis that have recently been tested in clinical trials or are currently in development (Figure 1). Other approaches to address residual risk, such as more-aggressive reductions in blood pressure, new treatments for diabetes, and lifestyle changes with diet, have also shown benefit and are critical for optimal reduction of not only ASCVD but also heart failure but is beyond the scope of this review.
NEW THERAPIES TARGETING LDL-C
*PCSK9 Inhibitors
*Bempedoic Acid
*Inclisiran
NEW THERAPIES TARGETING TRIGLYCERIDE PATHWAYS
*Omega-3 Fatty Acids
*Pemafibrate
*Apo C-III
*Angiopoietin-like Protein 3 Inhibition
NEW THERAPIES TARGETING LIPOPROTEIN(A)
*PCSK9 Inhibitors
*APO(a)-LRx
*AMG 890
NEW APPROACHES TO INFLAMMATION
Anti-inflammatory Therapies with Cardiovascular Outcomes Trials
*Canakinumab
*Methotrexate
*Colchicine
Anti-inflammatory Drugs in Development
CONCLUSION
Although statins remain the first-line lipid therapy for ASCVD prevention, residual ASCVD risk despite guideline-recommended statin use emphasizes the need for additional therapies. Recently approved and emerging agents offer options for further LDL-C reductions, in combination with a statin or as monotherapy, as well as alternative targets including TG and TG-rich lipoproteins, lipoprotein(a), and inflammation (see Figure 1). The clinical utility of these agents is the subject of recently completed and ongoing clinical trials, including essential outcomes studies, to evaluate their potential for risk reduction in clinical practice.
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