Targeting the Cholesterol Paradigm in the Risk Reduction for Atherosclerotic Cardiovascular Disease: Does the Mechanism of Action of Pharmacotherapy Matter for Clinical Outcomes?

Abstract

Hypercholesterolemia is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein cholesterol (LDL-C) has been labeled as “bad” cholesterol and high-density lipoprotein cholesterol (HDL-C) as “good” cholesterol. The prevailing hypothesis is that lowering blood cholesterol levels, especially LDL-C, reduces vascular deposition and retention of cholesterol or apolipoprotein B (apoB)-containing lipoproteins which are atherogenic. We review herein the clinical trial data on different pharmacological approaches to lowering blood cholesterol and propose that the mechanism of action of cholesterol lowering, as well as the amplitude of cholesterol reduction, are critically important in leading to improved clinical outcomes in ASCVD. The effects of bile acid sequestrants, fibrates, niacin, cholesteryl ester transfer protein (CETP) inhibitors, apolipoprotein A-I and HDL mimetics, apoB regulators, acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitors, cholesterol absorption inhibitors, statins, and proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, among other strategies are reviewed. Clinical evidence supports that different classes of cholesterol lowering or lipoprotein regulating approaches yielded variable effects on ASCVD outcomes, especially in cardiovascular and all-cause mortality. Statins are the most widely used cholesterol lowering agents and have the best proven cardiovascular event and survival benefits. Manipulating cholesterol levels by specific targeting of apoproteins or lipoproteins has not yielded clinical benefit. Understanding why lowering LDL-C by different approaches varies in clinical outcomes of ASCVD, especially in survival benefit, may shed further light on our evolving understanding of how cholesterol and its carrier lipoproteins are involved in ASCVD and aid in developing effective pharmacological strategies to improve the clinical outcomes of ASCVD.

Keywords

atherosclerosis cholesterol lipoproteins clinical outcome mechanism of action lipid lowering agents

Introduction

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death on a global basis.¹ Pioneering work in 19th century led to the discovery of cholesterol deposition in the blood vessel wall (labeled as atheroma), and this led to the cholesterol hypothesis of atherosclerosis, which included the assumption that plasma cholesterol and especially low-density lipoprotein cholesterol (LDL-C) is a causal factor for atherosclerosis.² Lipoproteins are carriers of lipid in the circulation and are primarily composed of cholesterol, triglyceride, phospholipids, and apolipoproteins. For a long time, high-density lipoprotein cholesterol (HDL-C) has been labeled as “good” cholesterol and LDL-C as “bad” cholesterol partly due to their respective inverse and positive correlation with ASCVD. No currently accepted hypothesis is perfect in completely delineating the pathogenesis of ASCVD. The cholesterol hypothesis assumes that plasma cholesterol causes atherosclerosis primarily via LDL-C. But how cholesterol or LDL causes atherosclerosis is still a topic of extensive research. Regardless of the findings of mechanistic studies, human randomized controlled trials targeting LDL-C or LDL components should provide the final and strongest level of evidence to guide clinical practice and for proof of concept. In addition, reducing cardiovascular and all-cause mortality should be a main goal of preventive cardiology. Decades long efforts to improve clinical outcomes in patients with ASCVD by modifying patient lipoprotein profiles have resulted in major successes but also some notable failures, especially in terms of cardiovascular and all-cause mortality.

Lowering LDL-C via different mechanisms of action has resulted in variations in clinical outcomes in patients with ASCVD especially in cardiovascular and all-cause mortality, as reviewed in this article. Thus far no clinical trial of nonstatin therapies has directly proved a reduction in cardiovascular mortality in primary prevention populations. The lack of an effect on cardiovascular mortality has been attributed to various factors including lack of sufficient statistical power of the trials, insufficient duration of follow-up, insufficient LDL-C reduction when added to statin therapy, wrong patient population, or low baseline LDL-C level. But as reviewed, failing to demonstrate survival benefit with up to 4-7 years of follow-up in the nonstatin therapy trials raises reasonable question about their efficacy especially in survival benefits. In contrast, clinical trials evaluating statins, which target the MVA pathway, have consistently shown reduction in cardiovascular events including cardiovascular and all-cause mortality even in the patients with traditionally normal baseline levels of cholesterol/LDL-C and in those without preexisting cardiovascular disease, irrespective of age, with a mean follow up period of as short as 2 years. Therefore, besides the absolute reduction of LDL-C, the mechanism whereby cholesterol or LDL-C is lowered could be clinically important.

In this article, we aim to review and discuss the significance of clinical trial data of the currently available cholesterol lowering agents or lipoprotein regulators on the clinical outcomes of ASCVD (Table 1 and Figure 1) and propose that aside from the absolute or relative cholesterol or LDL-C reduction the mechanism of action of cholesterol lowering approaches is important in the prevention and treatment of ASCVD.

Table 1.

Lipid or Lipoprotein Regulators Studied by Major Clinical Trials.

Classification of drugs with clinical trials	Drugs tested	Studies/trials (references)	Type of trial	No. of patients (treatment vs control)	Study population	Follow up, average time	Changes in lipids	Primary outcomes	Cardiovascular or coronary death	All-cause mortality
Bile acid sequestrants	cholestyramine	The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT)^3,4	multicenter, randomized, double-blind, placebo controlled	cholestyramine vs placebo (1906 vs 1900)	asymptomatic middle-aged men with primary hypercholesterolemia	7.4 years	reduction in TC, LDL-C; increase in HDL-C, TG	reduction in risk of primary end point (CHD death and/or definite nonfatal MI)	not detailed in Z score or p value	no reduction
Fibrates	clofibrate	The World Health Organization (WHO) Cooperative Trial⁵	randomized, double-blind, controlled	clofibrate vs high cholesterol control vs low cholesterol control, (5331, 5296, 5118)	healthy men	5.3 years	reduction in TC	reduction in major IHD incidence, confined to non-fatal MI	no change in fatal heart attacks and the incidence of angina	increased
	clofibrate and niacin	The Coronary Drug Project (CDP) study⁶	randomized, double blind, placebo controlled	clofibrate, niacin, placebo (1103, 1119, 2789)	men with previous MI	at least 5, up to 8.5 years	reduction in TC and TG	no benefit in the combination of coronary death or definite, nonfatal MI.	no benefit in coronary death	no efficacy
	gemfibrozil	The Helsinki Heart Study (HHS)⁷	randomized double-blind, placebo-controlled primary prevention	gemfibrozil vs placebo (2051 vs 2030)	asymptomatic middle-aged men with dyslipidemia	5 year	reduction in TC, LDL-C, non-HDL-C, TG; increase in HDL-C	reduction in cardiac end points, primarily due to significant reduction in nonfatal MI	no benefit in IHD death	no efficacy
	gemfibrozil	Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group (VA-HIT)⁸	multicenter, randomized double-blind placebo-controlled	gemfibrozil vs placebo (1267 vs 1264)	men with CHD and low levels of HDL-C	5.1 years	reduction in TG, TC; no change in LDL-C; increase in HDL-C	reduction in the combined outcome of CHD death, nonfatal MI, and stroke	no change in CHD death	no change
	bezafibrate	BIP⁹	multicenter, placebo controlled, randomized	bezafibrate vs placebo (1548 vs 1542)	patients with a previous MI or stable angina, TC 180 to 250 mg/dL, HDL-C ≤45 mg/dL, TG ≤300 mg/dL, and LDL-C ≤180 mg/dL	6.2 years	reduction in TG; increase in HDL-C	no benefit in the primary end point (fatal or nonfatal MI or sudden death)	no benefit	no benefit
	fenofibrate	FIELD¹⁰	multinational, double-blind, randomized, placebo controlled	fenofibrate vs placebo (4895 vs 4900)	patients with type 2 diabetes diagnosed according to WHO criteria and aged 50-75 years	median 5 years	reduction in TC, LDL-C, and TG; increase in HDL-C	no change in primary outcome, first MI or CHD death, a finding corresponding to a relative reduction in non-fatal MI, with a non-significant increase in CHD death.Reduction in secondary outcome of total CVD events (the composite of CV death, MI, stroke, and coronary and carotid revascularization, due mainly to the reduction in non-fatal MI and a significant reduction in coronary revascularization)	no benefit	no benefit
	fenofibrate	ACCORD-Lipid study¹¹	multicenter, randomized, placebo controlled	fenofibrate + simvastatin vs placebo + simvastatin(2765 vs 2753)	patients with type 2 diabetes being treated with open-label simvastatin to receive either masked fenofibrate or placebo	4.7 years	reduction in TC and TG; increase in HDL-C; no change in LDL-C	no benefit in the first occurrence of nonfatal MI, nonfatal stroke, or CV death	no benefit	no benefit
HDL increasing agents	niacin	AIM-HIGH¹²	multicenter, randomized, double-blind, parallel-group, controlled	Niacin vs placebo (1718 vs 1696)	patients with ASCVD and LDL-C < 70 mg/dl (1.81 mmol/L). All patients received simvastatin, plus ezetimibe as needed.	3 years	reduction in TG; increase in HDL-C	no incremental benefit in primary end points, the composite of CHD death, nonfatal MI, ischemic stroke, hospitalization for an ACS, or symptom-driven coronary or cerebral revascularization.	no change in CV death or in CHD death	no change in death from any cause
	Niacin-laropiprant	HPS2-THRIVE¹³	multicenter, randomized, double-blind	Niacin-laropiprant vs placebo (12838 vs 12835)	patients with symptomatic CAD and history of MI, cerebrovascular disease, PAD, or DM	median 3.9 years (mean 3.6 years)	reduction in LDL-C; increase in HDL-C	no reduction in major vascular events (nonfatal MI, coronary death, stroke, or arterial revascularization; increase in adverse events	no change in vascular and nonvascular mortality	no change in death from any cause
CETP inhibitors	torcetrapib	ILLUSTRATE trial¹⁴	phase 3, multi-Center, double-blind, randomized, parallel group	atorvastatin only vs torcetrapib-atorvastatin: Initially (597 vs 591); after 24 mos, 910 patients remained (446 vs 464)	patients with CAD underwent IVUS	24 months	reduction in LDL-C; increase in HDL-C	no benefit in reducing progression of coronary atherosclerosis	NA	NA
	torcetrapib	ILLUMINATE¹⁵	prospective, randomized, multicenter, double-blind	torcetrapib + atorvastatin vs atorvastatin alone (7533 vs 7534)	patients at high cardiovascular risk	mean 550 days	reduction in LDL-C, TG; increase in HDL-C	increase in primary cardiovascular composite outcome: CHD death, nonfatal MI, stroke, and hospitalization for unstable angina	no change in CHD death	increased death from any cause
	evacetrapib	ACCELERATE¹⁶	multicenter, randomized, double-blind, placebo-controlled phase 3 trial	evacetrapib vs placebo, in addition to standard medical therapy (6038 vs 6054)	patients with at least one of the following conditions: an ACS within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, PAD, or DM with CAD	median 26 months	reduction in LDL-C, ApoB, TG, Lp(a); increase in HDL-C and ApoA1	no benefit in primary end-point composite of CV death, MI, stroke, coronary revascularization, or hospitalization for unstable angina	no efficacy	reduction in death from any cause (unadjusted for multiple comparisons), P = 0.04
	anacetrapib	REVEAL¹⁷	randomized, double-blind, placebo-controlled	anacetrapib or placebo (15225 vs 15224)	patients with preexisting ASCVD, treated with atorvastatin	median 4.1 years (mean 3.8)	reduction in LDL-C, TG, ApoB, Lp(a); increase in HDL-C	reduction in major coronary events, defined as the occurrence of coronary death, MI, or coronary revascularization	no efficacy in coronary death or CV death	no change in all-cause mortality
ApoAI/HDL mimetics	CER-001 (a Pre-β HDL mimetic)	No trial name¹⁸	multicenter, double-blind, randomized	301 patients randomized but finally CER-001 vs placebo (135 vs 137)	statin-treated patients with ACS and high plaque burden	weekly use x 10 weeks and IVUS 7 to 21 days after the final infusion	no change in LDL-C, HDL-C	no efficacy in promoting regression of coronary atherosclerosis by coronary IVUS	not studied	not studied
	MDCO-216 (HDL mimetic)	The MILANO-PILOT¹⁹	multicenter, double-blind, randomized	MDCO-216 vs placebo (59 vs 67)MDCO-216 (n = 59) vs placebo (n = 67)	statin-treated patients with ACS and atheroma	weekly use x 5 weeks (day1-36)	reduction in HDL-C; no effect on TG or LDL-C	no effect on atherosclerosis regression by coronary IVUS	not studied	not studied
Cholesterol absorption inhibitors	ezetimibe + simvastatin vs simvastatin	ENHANCE study²⁰	prospective, randomized, double-blind, active-comparator, multicenter study	simvastatin-plus-ezetimibe vs simvastatin-only (357 vs 363); The intention-to-treat population (322 vs 320)	patients with FH	2 years	reduction in LDL-C, TG, and CRP in simvastatin-plus-ezetimibe vs simvastatin only	no changes in carotid intima-media thickness	not studied	not studied
	ezetimibe + atorvastatin vs atorvastatin	PRECISE-IVUS²¹	prospective, randomized, controlled, multicenter study	ezetimibe + atorvastatin vs atorvastatin (100 vs 102)	Japanese patients who underwent percutaneous coronary intervention	9 to 12 months	reduction in TC, LDL-C and ApoB; increase in Apo A1I	atorvastatin/ezetimibe noninferior to atorvastatin-alone in the primary endpoint: absolute change in percentage atheroma volume (PAV); atorvastatin/ezetimibe superior to atorvastatin alone for the absolute change in PAV; No change in CV events (events number was too small)	no death in both groups	N/A
	ezetimibe + simvastatin vs simvastatin	IMPROVE-IT²²	double-blind, randomized placebo controlled	Ezetimibe + simvastatin vs placebo + simvastatin (9067 vs 9077)	patients with recent ACS within the preceding 10 days	median 6 years	incremental reduction of LDL-C by ezetimibe	reduction in the component of nonfatal MI, and nonfatal stroke. No reduction in coronary revascularizations and no change in unstable angina event	no reduction in CV or CHD death	no reduction in all-cause mortality
	pitavastatin + ezetimibe vs pitavastatin only	HIJ-PROPER study²³	prospective, open label, randomized	pitavastatin + ezetimibe vs pitavastatin (864 vs 857 analyzed, due to patients lost to follow up)	patients with ACS and dyslipidemia	mean 3.86 years	further reduction in LDL-C by ezetimibe	no additional clinical benefit in the primary endpoint, a composite of all-cause death, non-fatal MI, non-fatal stroke, unstable angina, and ischemia-driven revascularization	not studied specifically	no change
Inhibitor of foam cell formation	pactimibe	ACTIVATE²⁴	double-blind, randomized placebo controlled	pactimibe vs placebo (206 vs 202)	patients with coronary disease by angiography	1.5 years	no change in LDL-C, HDL-C, TG	no benefit on coronary atherosclerosis but instead potentially proatherogenic by coronary atheroma by IVUS; no change in combined outcomes of CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina, and coronary or carotid revascularization	no change	not studied
	pactimibe	CAPTIVATE²⁵	prospective, randomized, stratified, double-blind, placebo-controlled	pactimibe vs matching placebo, in addition to standard lipid-lowering therapy (443 vs 438)	patients with heterozygous FH	terminated prematurely, follow-up of 15 months	increase in LDL-C and ApoB; no change in HDL-C, TG; reduction in Apo A-I	increase in ultrasound carotidintima-media thickness with pactimibe; worsened composite end point of all CV events as well as the composite of CV death, MI, and stroke with pactimibe vs placebo	no change in CV death but increase in CV events	not studied
Statins	simvastatin	4 S trial²⁶	randomized, double blind, placebo controlled	4444 patients, simvastatin vs placebo (2221 vs 2223)	patients with angina pectoris or previous MI with serum cholesterol level of 5.5-8.0 mmol/L (212-308mg/dl) on a lipid-lowering diet	median 5.4 years	reduction in LDL-C, TC; increase in HDL-C	reduction in both primary and secondary endpoint eventsThe primary endpoint is total mortality; the secondary study endpoint is major coronary events (coronary death and nonfatal definite MI or probable MI, silent MI or resuscitated cardiac arrest)	reduction in coronary death and in CV death	reduced
	statins	Metanalysis, Cholesterol Treatment Trialists’ (CTT) Collaborators²⁷	meta-analysis of 27 randomized trials	22 trials of statin vs control (134,537 participants); 5 trials of more vs less statin (39,612 participants)	statin vs control trials: patients with or without previous vascular diseasemore vs less statin trials: patients with previous CAD	22 trials of statin vs control, mean 4.8 years5 trials of more vs less statin, mean 5.1 years	LDL-C reduction by statin vs control or by more intensive vs less intensive statin	reduction in major vascular events by statin vs control or by more intensive statin vs less statin, including non-fatal MI or coronary death, strokes, or coronary revascularizations	reduced coronary mortality and reduced vascular mortality	reduced all-cause mortality
	rosuvastatin	JUPITOR²⁸	randomized, double-blind, multicenter, placebo-controlled	rosuvastatin vs placebo (8901 vs 8901)	apparently healthy persons without hyperlipidemia but with elevated high-sensitivity CRP levels	median 1.9 years, maximal 5.0 years	reduction in LDL-C, TG; increase in HDL-C; reduction in CRP	reduction in primary end point of MI, stroke, arterial revascularization, hospitalization for unstable angina, or CV death	reduced CV death	reduced death from any cause
PCSK9 inhibition antibody	evolocumab	FOURIER²⁹	randomized, double-blind, placebo-controlled	evolocumab vs placebo (13784 vs 13780), all on statin treatment at baseline and throughout the trial	patients with ASCVD and LDL-C ≥70mg/dl (1.8mmol/l)	median 2.2 years	reduction in LDL-C, non-HDL-C, ApoB, Lp(a), TG; increase in HDL-C, ApoA1	reduced risk of primary endpoint as the composite of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization; reduction in key secondary end point as the composite of CV death, MI, or stroke	no change in CV death	no change in death from any cause
	alirocumab	ODYSSEY Outcomes trial³⁰	multicenter, randomized, double-blind, placebo-controlled	alirocumab vs placebo (9462 vs 9462). Most patients were on high dose of potent statin treatment	patients with ACS within the prior 1-12 months with an LDL-C level of at least 70 mg per deciliter (1.8 mmol/L), a non−HDL-C of at least 100 mg/dl, or an ApoB level of at least 80 mg/dl	median 2.8 years	further reduction of LDL-C	reduced primary end point, a composite of CHD death, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization	no change in CHD death or CV death	all-cause mortality in alirocumab vs placebo group with a hazard ratio of 0.85; (95% CI, 0.73-0.98) by hierarchical analysis
	alirocumab	ODYSSEY Outcomes trial further analysis³¹						reduction in a composite of CHD death, MI, ischemic stroke, or unstable angina requiring hospitalization, irrespective of age	no change in CHD death or CV death	reduction in all-cause mortality in the older (≥65 years) vs younger population
	bococizumabhumanized monoclonal antibody against PCSK9	SPIRE-1 and SPIRE-2 trials³² Two trials were stopped prematurely	parallel multinational randomized trials, with combined analysis as well	bococizumab vs placeboSPIRE-1 (8408 vs 8409); SPIRE-2 (5312 vs 5309); combined analysis (13720 vs 13178)	high-risk primary prevention cohort: a history of DM,CKD, or PVDwith additional cardiovascular risk conditionsor a history of FH; secondaryprevention cohort: a previous cardiovascular event	Median 7 months in SPIRE-1 trial, 12 months in SPIRE-2 trial	reduction in TC, ApoB,non-HDL-C, Lp(a), TG	no effect on primary endpoint in lower-risk patients; a significant benefit in higher-risk patients; but in the combined analysis of both SPIRE trials, no benefit in the primary end point (nonfatal MI, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or CV death)	no effect in CV death	no effect in death from any cause

Abbreviations: ASCVD, atherosclerotic cardiovascular disease; CV, cardiovascular; CHD, coronary heart disease; IHD, ischemic heart disease; MI, myocardial infarction; ACS, acute coronary syndrome; CAD, coronary artery disease; PAD; peripheral arterial disease; PAD, peripheral arterial disease; DM, diabetes mellitus; IVUS; intravascular ultrasound; CKD, chronic kidney disease; FH, familial hypercholesterolemia; CRP, C-reactive protein; TC, total cholesterol; TG, triglyceride, HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol.

Figure 1.

A schematic overview of cholesterol or lipoprotein regulators. The cholesterol or lipoprotein regulators are in blue. Traditionally cholesterol hypothesis for ASCVD implies that liver synthesizes and releases lipids/cholesterol as lipoproteins to the blood circulation. LDL-C enters vascular wall via monocytes to become foam cells. LDL-C can also be taken up by smooth muscle cells to form foam cells leading to lipid core/atheroma formation. LDL binds to LDL-R and is internalized for intracellular LDL degradation. The LDL-R is then recycled to the cell membrane or degraded. The degradation of LDL-R is facilitated by PCSK9. PCSK9 inhibitor binds to and inhibits PCSK9, which facilitates the recycling of LDL-R to the cell membrane. ACAT, acyl coenzyme A: cholesterol acyltransferase; LDL, low density lipoprotein; IDL, intermediate-density lipoprotein; VLDL, very-low-density lipoprotein; LDL-R, LDL receptor; Apo, apolipoprotein; CETP, cholesteryl ester transfer protein; MTP, microsomal triglyceride transfer protein; FC, free cholesterol; CE, cholesterol ester; PPAR, peroxisome proliferator-activated alpha-receptor; ACLY, ATP-citrate lyase.

Pharmacological Lipid Regulation and ASCVD Outcomes

Bile Acid Sequestrants

Bile acid sequestrants including cholestyramine, colestipol, and colesevelam are polymeric compounds that bind to bile salts in the small intestine and inhibit their reabsorption. This inhibits the enterohepatic circulation of bile acids which results in bile acid depletion leading to increased hepatic bile acid biosynthesis. Since cholesterol is used to make bile acids, plasma LDL-C levels are lowered. Some bile acid sequestrants can also improve glycemic control in type 2 diabetic patients. The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), was a multicenter, randomized, double-blind study, which tested the efficacy of cholestyramine in reducing the risk of coronary heart disease in 3,806 asymptomatic middle-aged men with primary hypercholesterolemia during an average of 7.4 years of treatment. The cholestyramine group had a statistically significant 19% reduction in the primary end point including coronary heart disease (CHD) death and/or definite nonfatal myocardial infarction (MI). However, the risk of all-cause mortality was not significantly reduced in the cholestyramine group, due to a greater number of violent and accidental deaths.^3,4 In the statin era, studies of the addition of cholestyramine to statins have not shown added benefit of cholestyramine in reducing cardiovascular events.³³ Adequately powered randomized controlled trials for the effects of colesevelam or colestipol on the risk of major cardiovascular events are lacking.³⁴ Nowadays bile acid sequestrants are rarely used for hypercholesterolemia partly because of its poor tolerance, drug-drug interactions, and elevation of triglycerides.

Fibrates

Fibric acid derivatives referred to as fibrates act as agonists for peroxisome proliferator-activated alpha-receptors (PPAR-alpha) and have been used in clinical practice for more than 2 decades to increase HDL-C and decrease triglyceride (TG) and total cholesterol (TC) levels. But while fibrates decrease TC, LDL-C, and TG levels and increase HDL-C levels they have demonstrated mixed cardiovascular outcomes and no benefit on cardiovascular or total mortality in the primary and secondary prevention of ASCVD.

The World Health Organization Cooperative Trial studied the effects of clofibrate in the primary prevention of ischemic heart disease in 1960-1970’s, and found a reduction by 20% in first major coronary events among healthy men given clofibrate compared with randomly selected controls.³⁵ However, clofibrate treatment was associated with higher all-cause mortality compared with the high cholesterol controls and a significant excess in all-cause mortality from causes other than ischemic heart disease compared with a second, low cholesterol, control group.^5,35 Other large scale long term trials including CDP,⁶ HHS,⁷ VA-HIT,⁸ BIP,⁹ and FIELD,¹⁰ showed variable CV benefit but no cardiovascular and total mortality benefit (Table 1). The ACCORD-lipid trial was a major fibrate-statin combination study with 5518 participants included and 4.7 years of follow-up. There were no significant additional benefits in patients on simvastatin blindly assigned to fenofibrate versus placebo with respect to the primary outcome (combination of first occurrence of nonfatal MI, nonfatal stroke, or CV death) or individual endpoints of fatal cardiovascular events, nonfatal MI, or nonfatal stroke, as compared with simvastatin alone.¹¹

Agents That Increase HDL-C Level

Epidemiological studies show that HDL cholesterol level is inversely related to the incidence of cardiovascular disease, therefore medications capable of raising HDL-C have been extensively studied in an attempt to reduce ASCVD events.

Niacin

Niacin is one of the most effective agents to increase serum level of HDL-C and can also lower the levels of LDL-C and TG. In the niacin treatment group of the CDP trial conducted in 1970’s, niacin did not show benefit in reducing the total or cause specific mortality although nonfatal MI was reduced.⁶ More recent large-scale clinical trials have cast doubt about the effects of niacin on ASCVD clinical outcomes in the statin era. The 2 largest clinical trials AIM-HIGH and HPS2-THRIVE demonstrated no clinical benefits for niacin on ASCVD.^12,13 The AIM-HIGH trial was stopped after a mean follow-up period of 3 years due to a lack of clinical efficacy. Among patients with ASCVD and LDL-C < 70 mg/dl (1.81 mmol/L), addition of niacin to statin significantly improved HDL-C and TG level but there was no incremental clinical benefit in primary end points including the composite of death from CHD, nonfatal MI, ischemic stroke, hospitalization for an acute coronary syndrome (ACS), or symptom-driven coronary or cerebral revascularization.¹² The HPS2-THRIVE trial showed that the addition of extended-release niacin-laropiprant to statin therapy increased HDL-C and reduced LDL-C levels but failed to reduce major vascular events including nonfatal MI, death from coronary causes, stroke, or arterial revascularization, and in contrast increased adverse events in patients with vascular disease.¹³ Overall, current data fail to demonstrate incremental cardiovascular or all-cause mortality benefit of niacin in the statin era and moreover, niacin has been associated with an increase in glucose levels. A meta-analysis demonstrated a 34% increase in the risk of developing diabetes with niacin compared with placebo.³⁶

Cholesteryl ester transfer protein inhibitors

Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein produced in the liver that facilitates the transfer of cholesteryl esters from HDL to apoB-containing lipoproteins such as LDL and VLDL. Inhibition of CETP is associated with significant increases in HDL-C levels and reductions in LDL-C levels but they have not been shown to yield clinical benefits and may even cause harm to patients with ASCVD.

Several clinical trials testing CETP inhibitors in the prevention and treatment of ASCVD have been conducted (Table 1). The ILLUSTRATE trial investigated the effect of torcetrapib on coronary atherosclerosis and failed to show any benefits in reducing the progression of coronary atherosclerosis.¹⁴ The ILLUMINATE trial conducted in patients at high cardiovascular risk showed that despite the favorable lipid profile changes with torcetrapib there was an increased risk of death and cardiac events in patients treated with torcetrapib.¹⁵ The ACCELERATE trial investigated the effect of another CETP inhibitor evacetrapib on cardiovascular events among patients with high-risk vascular disease. This study showed that even with favorable lipid profile changes evacetrapid did not demonstrate significant benefit in death from cardiovascular causes, MI, stroke, coronary revascularization, or hospitalization for unstable angina.¹⁶ The more recent REVEAL trial studied the clinical effects of anacetrapib among patients with established vascular disease treated with atorvastatin.¹⁷ MI was reduced after 3 or more years of treatment in the patient group treated with ancetrapib compared with the placebo group. The benefit of anacetrapib was believed to be largely from the reduction of non-HDL cholesterol level instead of the increase of HDL-C level and there was no benefit in coronary death.

ApoAI Milano and apoAI/HDL mimetics

Animal studies have shown that the HDL particle and its principal protein component apolipoprotein A-I (apoA-I) have atheroprotective properties. In the past decades, efforts have been made to develop HDL mimetics with therapeutic potential. ApoA-I Milano is an apoA-I mutant, initially found in a family from a small Italian village, that has atheroprotective capabilities. Carriers of ApoA-I Milano have exceptionally low prevalence of CVD despite decreased HDL-C and apoA-I levels. Compounds containing ApoA-I Milano have been tested in preclinical and in early clinical trial phases and currently, several infusible HDL mimetics have reached clinical trials. These products include MDCO-216 (ApoA-I Milano),³⁷ CER-001 consisting of recombinant human apoA-I and the phospholipid sphingomyelin formulated to mimic the atheroprotective properties of prebeta HDL,³⁸ and the HDL mimetic CSL-112, a reconstituted HDL particle containing apoA-I purified from human plasma reconstituted with phosphatidylcholine.³⁹ However, a double-blind, randomized, multicenter trial studying the effect of 10 weekly intravenous infusions of CER-001vs placebo in patients from 34 academic and community hospitals in Australia, Hungary, the Netherlands, and the United States failed to show efficacy of CER-001 in promoting regression of coronary atherosclerosis as assessed by coronary IVUS imaging in statin-treated patients with acute coronary syndromes (ACS) and high plaque burden.¹⁸ The MILANO-PILOT trial conducted in 22 hospitals in Canada and Europe studied the effects of 5 weekly intravenous infusions of MDCO-216 compared with placebo in statin-treated patients with ACS and found that MDCO-216 did not result in incremental atherosclerosis regression from baseline to day 36 as measured by coronary IVUS imaging.¹⁹

ApoB Regulators

ApoB-containing lipoproteins are believed to be the culprits for ASCVD. In the assembly and secretion of apoB-containing lipoprotein from the liver and intestines, microsomal triglyceride transfer protein (MTP) plays an important role in the transfer of TG and phospholipids onto apoB. Lomitapide, an MTP inhibitor, induces post-translational degradation of apoB, hence reducing the secretion of apoB-containing lipoproteins into the blood, resulting in lower serum cholesterol and TG levels. Lomitapide is now licensed in the United Kingdom and the United States but is restricted to use in homozygous familial hypercholesterolemia (FH).⁴⁰ Another lipid regulator mipomersen, an apolipoprotein B antisense oligonucleotide, has been used for treatment of homozygous FH. Mipomersen induces degradation of the apoB100 mRNA, and subsequently inhibits the synthesis of apoB protein and therefore lowers apoB-containing lipoprotein levels. Both drugs lower LDL-C, but data on their impact on cardiovascular events are lacking.

Cholesterol Absorption Inhibitors

Ezetimibe is a cholesterol-absorption blocker that inhibits cholesterol absorption via Niemann-Pick C1 Like 1 protein (NPC1-L1) in the membrane of enterocytes in the proximal small intestine. Ezetimibe can reduce levels of TC and LDL-C but there has been no randomized controlled trial to test the effects of solitary use of ezetimibe on ASCVD clinical outcomes. When combined with statin therapy, ezetimibe further decreases TC or LDL-C level, but large-scale data on clinical outcomes are mixed or show no cardiovascular or all-cause mortality benefit in ASCVD.

The ENHANCE study compared the effects of daily therapy with 80 mg of simvastatin + 10 mg of ezetimibe versus 80 mg of simvastatin + placebo in patients with FH. Ezetimibe further reduced the levels of LDL-C, TG, and C-reactive protein (CRP) when used along with simvastatin. This study showed that the additional drop in LDL-C and CRP levels did not translate into significant difference in changes in carotid intima-media thickness (CIMT) at 2 years, as compared with simvastatin alone,²⁰ but the study was criticized for trial design, an attempt to change the endpoints and a nearly 2 year delay in releasing the results. The SHARP trial studied the effect of ezetimibe (10 mg daily) + simvastatin (20 mg daily) vs placebo in 4650 patients with chronic kidney disease and no history of MI or coronary revascularization. During a median follow-up of 4·9 years, there was a 17% reduction in manor atherosclerotic events but no significant benefit on nonfatal MI or CHD mortality.⁴¹ The IMPROVE-IT study showed that in the patients with recent ACS, ezetimibe provided incremental LDL-C reduction, which translated into an improved primary cardiovascular outcome with a Kaplan-Meier event rate at 7 years of 32.7% in the simvastatin+ezetimibe group, as compared with 34.7% in the simvastatin control group. The difference was driven by decreases in nonfatal MI and nonfatal stroke with no reduction in coronary revascularization, total unstable angina events, death from cardiovascular causes, from CHD, or from all causes, at 7 years of follow-up.²²

PRECISE-IVUS was a multicenter randomized trial in Japan that included 202 patients who underwent IVUS imaging at the time of PCI and then again 9-12 months later and who were randomized to atorvastatin + ezetimibe versus atorvastatin + placebo. The results did not reach the pre-defined noninferiority criteria although ezetimibe + atorvastatin was superior to atorvastatin alone in terms of absolute change in percentage atheroma volume.²¹ The HIJ-PROPER trial conducted in 19 hospitals in Japan included 1,734 patients and assessed whether intensive LDL-C lowering with pitavastatin plus ezetimibe further reduced cardiovascular events compared with pitavastatin monotherapy in patients with ACS and dyslipidemia.²³ Ezetimibe added to pitavastatin led to a significant further LDL-C reduction, which however did not translate into additional clinical benefit in the primary endpoint, a composite of all-cause death, non-fatal MI, non-fatal stroke, unstable angina, and ischemia-driven revascularization.

Inhibition of Foam Cell Formation and ASCVD

Monocyte/macrophage internalization of apoB-containing lipoproteins can lead to foam cell formation, macrophage apoptosis and subsequent cholesterol deposition in arterial wall, characteristic of the necrotic core of atheromas. Acyl-coenzyme A: cholesterol acyltransferase (ACAT) is the enzyme that esterifies the excess cellular free cholesterol to cholesteryl esters for cholesterol storage and thus regulates cellular cholesterol homeostasis. ACAT1 is present in macrophages and many other tissues; ACAT2 is present in intestinal epithelial cells and hepatocytes. While drugs targeting ACAT1 to block the esterification of cholesterol were thought to be able to prevent macrophage transformation into foam cells and thus prevent atherogenesis, studies of pactimibe, a nonselective ACAT inhibitor, have shown that it did not prevent and might have even promoted atherosclerosis and was associated with more adverse ASCVD clinical outcomes.

The ACTIVATE trial assessed the effects of pactimibe on progression of coronary atherosclerosis by IVUS imaging and found that pactimibe failed to show benefit on coronary atherosclerosis and instead was potentially proatherogenic.²⁴ The CAPTIVATE study assessed the efficacy and safety of pactimibe in reducing atherosclerosis as measured by CIMT in patients with heterozygous FH and found that pactimibe was associated with an increase in mean CIMT and nonfatal MI occurred more frequently in patients receiving pactimibe than in patients receiving placebo. The composite end point of all cardiovascular events occurred more frequently in patients receiving pactimibe vs placebo.²⁵

Statins

Statins proven to reduce cardiovascular events with survival benefits in ASCVD

Statins inhibit the cholesterol biosynthesis pathway, also known as the mevalonate (MVA) pathway, by inhibition of the 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase (HMGCR), the rate-limiting enzyme in cholesterol biosynthesis. Statins have revolutionized the clinical practice in the management of cardiovascular disease. The first statin was discovered in 1976 by Akira Endo at the Sankyo Company in Tokyo when he isolated a statin, named compactin, from a penicillium mold. The first clinically used statin was mevinolin, discovered in 1980 by Alfred W. Alberts and colleagues at Merck.⁴² Mevonolin, also known as lovastatin or Mevacor, is closely related to compactin. In 1987 the FDA approved Mevacor based on studies showing that it lowered plasma LDL-C with good tolerance.⁴³ Evidence that a statin could reduce cardiovascular events came in 1994 when the landmark Scandinavian Simvastatin Survival Study (4 S) was published.²⁶ The 4 S was the first large-scale statin trial in 4444 patients with angina pectoris or previous MI with serum TC level of 5.5-8.0 mmol/L (212-308mg/dl) on a lipid-lowering diet. The 4 S trial demonstrated that simvastatin, a second-generation statin, reduced cardiac events and overall mortality during a 5.4-year median follow-up period.

Statins are thus far the only class of lipid/cholesterol regulating agents well proven to be effective in the treatment of ASCVD, reducing cardiac events, as well as cardiovascular and total mortality by solitary use. The meta-analysis of individual data from 27 randomized trials by Cholesterol Treatment Trialists’ (CTT) Collaborators, demonstrated that statins prevent vascular events even in people considered at low risk of vascular events.²⁷ Most recently, a retrospective cohort study including 326,981 US veteran participants, 75 years and older and free of ASCVD at baseline, showed that new statin use, compared with no statin use, was associated with a lower risk of all-cause and cardiovascular mortality.⁴⁴ In patients with diabetes, statins led to a reduction in MI, coronary revascularization and vascular mortality as well as all-cause mortality. The effects of statin therapy were similar irrespective of the presence of prior history of vascular disease and other baseline characteristics.⁴⁵ High intensity statin therapy is associated with even further survival benefit in patients with ASCVD.⁴⁶ In a real world nationwide Swedish observational study of MI patients, a total of 40,607 patients were followed for a median of 3.78 years. Larger early LDL-C reduction and higher intensity statin therapy after MI were associated with a reduced adverse CV events, CV mortality, and all-cause mortality.⁴⁷ Statin use can also reduce the MACE in patients undergoing PCI,⁴⁸ although preloading or periprocedural use of statin may not be superior to the routine postprocedural use of statin.⁴⁹

Statins and pleiotropic effects

Atherosclerosis carries pathological features of inflammation.⁵⁰ Abundant data from experimental studies in vascular biology and clinical research have shown a strong association between inflammation and adverse cardiovascular outcomes. Proinflammatory state with elevated levels of interleukins and other inflammatory markers in patients with ASCVD including ACS has been well-recognized.^51

-54 The JUPITER trial randomly assigned 17,802 traditionally normocholesterolemic apparently healthy subjects with LDL-C levels below 130 mg/dl (3.4 mmol/L) but high-sensitivity C-reactive protein (hs-CRP) levels of 2.0 mg/dl or higher to rosuvastatin or placebo. Rosuvastatin decreased LDL-C levels by 50% and hs-CRP levels by 37%. Rosuvastatin treatment led to a significant reduction in primary end point including significant decreases, respectively in MI, stroke, revascularization or unstable angina, and the combined end point of MI, stroke, or death from cardiovascular causes, as well as in death from any cause.²⁸ The JUPITER trial suggested that a proinflammatory state as reflected by high levels of hs-CRP is a risk factor for ASCVD and that there is a link between reduction in cholesterol biosynthesis and inflammation modulation by statins in the prevention of ASCVD events including cardiovascular death and all-cause mortality, even in normocholesterolemic apparently healthy population.

HMG-CoA is an intermediate committed solely to the biosynthesis of cholesterol and other isoprenoids including farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Isoprenoids play an essential role in cell proliferation and migration and in inflammation processes for antherogensis and vasculopathy. A body of evidence points to the pleiotropic effects of statins through inhibition of isopenoids intermediates production during cholesterol biosynthesis, which are believed to be at least partly responsible for the clinical beneficial effect of statins.⁵⁵

Based on strong consistent clinical trial data, AHA/ACC recommends statin be initiated regardless of baseline LDL-C in patients with clinical ASCVD unless contraindicated.⁵⁶

PCSK9 Inhibitors

Proprotein convertase subtilisin kexin 9 (PCSK9) is a key regulator of LDL receptor (LDL-R) levels. A mutation of PCSK9 was reported by Abifadel et al in 2003 in 2 French families with autosomal dominant FH.⁵⁷ Similar mutation in PCSK9 were later reported by others in FH patients and a relationship between PCSK9 gene polymorphism and cholesterol levels in a general population were proven.⁵⁸ The loss-of-function mutations in PCSK9 are associated with lower concentrations of LDL-C and reduced CHD,^59,60 while gain-of-function mutations in PCSK9 are associated with autosomal dominant hypercholesterolemia.⁵⁷ PCSK9 is a protease which cleaves itself once and the inactive protease is secreted and binds to the LDL-R at the surface of hepatocyte. PCSK9 then targets the LDL-R for endosomal/lysosomal degradation, resulting in less LDL-R on cell surface thus reduced internalization of LDL particles (Figure 1). PCSK9 can also function as an intracellular chaperone and impairs the translocation of LDL-R to the cell surface membrane. Inhibition of PCSK9 can therefore reduce the PCSK9 mediated degradation of internalized LDL-R, thereby promoting the recycling of LDL-R back to the cell surface to lower LDL-C. Although the exact roles of PCSK9 in extrahepatic tissues is not completely understood, clinical data have shown that PCSK9 inhibitors such as alirocumab and evolocumab are highly effective in reducing TC and LDL-C and can decrease the incidence of cardiovascular events.

The first 2 monoclonal antibodies targeting PCSK9 were approved in the USA and Europe in 2015. The FOURIER trial studied evolocumab, a humanized PCSK9 antibody inhibitor in 27564 patients with ASCVD and LDL-C ≥ 70mg/dl (1.8mmol/l), all on statin treatment at baseline and throughout the trial.²⁹ Evolocumab treatment led to a significant 15% reduction in the risk of the primary end point (composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization) and a significant 20% reduction in the key secondary end point (composite of cardiovascular death, myocardial infarction, or stroke). The results were consistently seen across important subgroups including those patients in the lowest quartile for baseline LDL-C levels (median, 74 mg/dl, 1.9 mmol/L). The improved ischemic outcomes were seen in a linear relationship to LDL-C levels even to values less than 10 mg/dl.²⁹ However, there was no difference in cardiovascular death, nor death from any cause with evolocumab during a mean follow-up of 2.2 years. Further secondary analyses of the FOURIER trial showed reduced risk of MI (Type 1 and 4) and composite endpoints of cardiovascular events but no specific benefit in cardiovascular or all-cause mortality.^61,62 In a substudy of 14298 patients from the FOURIER trial who underwent genetic testing, there was no benefit from evolocumab for major vascular events in patients diagnosed with ASCVD without multiple clinical risk factors (DM, HTN, LDL-C ≥100mg/dl, and smoking) or without high genetic risk.⁶³

The ODYSSEY Outcomes trial studied alirocumab in patients with a history of an ACS within the prior 1-12 months with a median follow up of 2.8 years. Most patients were on high dose of potent statin treatment. Alirocumab resulted in an absolute LDL-C reduction of 54.7%. The major adverse cardiac events (MACE) including CHD death, non-fatal MI, ischemic stroke, or unstable angina requiring hospitalization, were reduced in the alirocumab group compared with placebo (5% vs. 11.1%).³⁰ The prespecified post hoc analysis by baseline LDL-C level showed reduced CHD or cardiovascular death and all-cause mortality but only in patients with baseline LDL-C level of 100 mg/dl or above. Further analysis of the ODYSSEY Outcomes trial showed that alirocumab, irrespective of patient age, reduced MACE, a composite of CHD death, MI, ischemic stroke, or unstable angina requiring hospitalization, with no change in coronary or cardiovascular death. All-cause mortality was reduced, only in the older (≥65 years) population.³¹

Bococizumab is a humanized monoclonal antibody against PCSK9, as opposed to alirocumab and evolocumab which are fully human antibodies. The SPIRE-1 and SPIRE-2 were 2 parallel, multinational trials for bococizumab with different entry criteria for LDL-C levels. All patients were required to have been treated with a statin for at least the previous 4 weeks except that in the SPIRE-2 trial some patients did not use statin due to a documented statin intolerance. The primary end point was nonfatal MI, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death. The trials were terminated early after the sponsor elected to discontinue the development of bococizumab partly due to high rates of antidrug antibody production. In the combined analysis of SPIRE-1 and SPIRE-2, the primary end point was not significantly different. No significant between-group differences were observed in both trials in the rates of cardiovascular or total mortality.³²

Inclisiran is a small interfering double-stranded RNA (siRNA), the first cholesterol lowering siRNA. The ORION-11 international phase 3 trial conducted in 7 countries at 70 sites for subjects with ACSVD or ACSVD-risk equivalent and elevated LDL-C showed that inclisiran achieved durable and potent LDL-C reduction with only twice-yearly injection with excellent safety profile. Inclisiran resulted in potent consistent PCSK9 inhibition and reduced the LDL-C level by 54% at 17 months and 50% when averaged over time.⁶⁴ Clinical event-powered randomized controlled trials are awaited.

To summarize, PCSK9 inhibitors provide a new class of agents for LDL-C lowering that improve cardiovascular outcomes for patients with established ASCVD when added to statin therapy. But further LDL-C reduction yielded only variable survival benefit in terms of cardiovascular or total mortality, which has been attributed to either not long enough on-treatment time, low baseline LDL-C level, lack of multiple clinical risk factors, or genetic idiosyncrasy.

ATP-Citrate Lyase Inhibitor and Cholesterol Lowering

Bempedoic acid is an oral inhibitor of ATP-citrate lyase (ACLY), an enzyme upstream of HMGCR, the target of statins in cholesterol biosynthesis pathway. It is a prodrug converted to active drug in the liver. The CLEAR Harmony Trial was a randomized, controlled clinical safety and efficacy trial of bempedoic acid in patients with ASCVD, heterozygous FH, or both, and all the patients were receiving maximally tolerated statin therapy with or without additional lipid-lowering therapy. The trial found that bempedoic acid significantly reduced LDL-C level with an overall safety profile similar to that of placebo but bempedoic acid was associated with increased incidence of gout and discontinuation of the regimen due to reported adverse events.⁶⁵ Bempedoic acid has been approved by FDA as an adjunct to diet and maximally tolerated statin therapy for the treatment of hyperlipidemia and also by European Commission for use in adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia, as an adjunct to diet. But clinical trial data on hard cardiovascular endpoints are awaited.

Inhibitor of Angiopoietin-Like 3

Evinacumab is a fully human monoclonal antibody as an inhibitor of angiopoietin-like 3 (ANGPTL3). ANGPTL3 is an inhibitor of lipoprotein and endothelial lipase and can effectively lower the LDL-C in patients with homozygous FH.⁶⁶ In patients with refractory hypercholesterolemia, the use of evinacumab reduced the LDL-C by more than 50% at the maximum dose.⁶⁷ Evinacumab has been approved by the FDA for use in homozygous FH. No clinical trial data for cardiovascular outcomes are available yet.

Lipoprotein (a) Intervention and ASCVD

Lipoprotein(a) [Lp(a)] is an LDL particle with an added apolipoprotein(a) [apo(a)] attached to the apoB component via a disulfide bridge. The role of Lp(a) in ASCVD is still a topic of research despite the observed associations between elevated Lp(a) and ASCVD. Lp(a) level in an individual is 80%-90% genetically determined in an autosomal codominant inheritance pattern and the Lp(a) level remains stable through an individual’s lifetime other than during inflammatory states and is not affected by lifestyle. Among the currently available lipid lowering therapies only a few can lower the Lp(a) levels, such as PCSK9 inhibitors, niacin, and lipoprotein apheresis. However as reviewed here, niacin did not improve ASCVD clinical outcome and long-term data on PCSK-9 inhibitors and mortality are not available. Novel therapies such as apo(a) antisense oligonucleotide selectively targeting Lp(a) are under investigation.⁶⁸ Thus far, there are no large scale randomized controlled clinical trial data showing whether specific targeting of Lp(a) can improve clinical outcome in patients with ASCVD.⁶⁹

Dietary Cholesterol and ASCVD

Recommendations for low cholesterol and low-fat diets to prevent ASCVD began in 1950-1960’s. However, the recent 2015 US Dietary Guidelines Advisory Committee (DGAC) dropped the decades-long recommendation of limitation of dietary cholesterol intake to no more than 300 mg/day due to lack of randomized controlled trials showing appreciable relationship between consumption of dietary cholesterol and serum cholesterol level and stated that unlike dietary saturated fat, “cholesterol is not a nutrient of concern for overconsumption.”⁷⁰ Although beyond the scope of this review, diet remains an important factor in the management of ASCVD.

Dietary cholesterol intake can affect the endogenous cholesterol biosynthesis. In 1933, a landmark study using mice sealed in ventilated bottles by Rudolph Schoenheimer and colleagues first demonstrated that dietary cholesterol could inhibit endogenous cholesterol biosynthesis.⁷¹ When fed a cholesterol free diet mice would make more endogenous cholesterol but when fed cholesterol containing diet endogenous cholesterol synthesis was no longer observed. This was the first demonstration that end-product could inhibit a biosynthetic pathway through a feedback mechanism. The feedback regulation of cholesterol biosynthesis is present in various animal species including humans and in cultured cells as well.^72
-74

Given the lack of evidence supporting the direct contribution of dietary cholesterol consumption to blood cholesterol level and the knowledge that hypercholesterolemia is a well-known risk factor for ASCVD, endogenous cholesterol biosynthesis is believed to be clinically more important than exogenous cholesterol in ASCVD pathogenesis.

Pharmacotherapy of Hypertriglyceridemia and ASCVD

Hypertriglyceridemia is generally believed to be a risk factor for ASCVD and some cholesterol lowering or lipoprotein regulating drugs also have TG lowering effects as reviewed in the article (Table 1). Although hypertriglyceridemia involvement in ASCVD is beyond the scope of this review, it is worth noting that the 2 recent clinical trials on the effects of omega-3 fatty acids on ASCVD clinical outcomes yielded inconsistent results. The REDUCE-IT trial showed that TG-lowering iscosapentyl ethyl, a highly purified eicosapentaenoic acid (EPA) ethyl ester, in addition to statin therapy reduced the risk of major ischemic events, including cardiovascular death, among patients with hypertriglyceridemia and established cardiovascular disease or with diabetes although a small but significantly higher percentage of patients receiving EPA were hospitalized for atrial fibrillation or flutter than in the placebo group (5.3% vs 3.9%).⁷⁵ However, the STRENGTH trial showed that use of EPA and docosahexaenoic acid (DHA) in statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of HDL-C resulted in no difference in a composite outcome of major adverse cardiovascular events including cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization.⁷⁶ The major differences between the 2 large trials include: a) the REDUCE-IT trial used EPA and the STRENGTH trial used both EPA and DHA; and b) the placebo used in the REDUCE-IT trial was mineral oil while the STRENGTH trial used a corn oil as the placebo. The mineral oil placebo was potentially proinflammatory causing elevated high sensitivity CRP. Overall, clinical trials on pharmacological TG lowering have yielded inconsistent results in the clinical outcomes of ASCVD.

Uncertainties Surrounding Cholesterol and Lipoproteins Pharmacological Intervention for ASCVD

In lowering LDL-C, the target level in the primary and secondary prevention of ASCVD is still a matter of debate.⁷⁷ The 2018 2018 ACC/AHA Cholesterol Clinical Practice Guidelines emphasize a 50 percent LDL-C reduction in ASCVD management and recommend an on-statin LDL-C of above 70mg/dl in very high risk secondary prevention as a threshold to initiate a nonstatin drug to lower LDL-C.⁷⁸ The 2019 European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) guidelines recommend treatment to very low LDL-C levels in high risk individuals and note that studies have shown extensive LDL-C reduction can be obtained with addition of PCSK-9 inhibitor or ezetimibe to statin with no significant associated safety concerns.⁷⁹ Notably, the currently proposed LDL-C “treatment ranges” in the guidelines are based largely upon data extrapolated from results of RCTs mostly of statin use, with additional new data from trials examining the addition of nonstatin therapies, such as ezetimibe and PCSK9 inhibitors, in patients with statins. It is important to note that data supporting a specific threshold or target LDL-C level in treating ASCVD are lacking.⁷⁸

Intriguingly, many patients in the acute phase of MI do not have elevated and may have even lower than baseline levels of TC and LDL-C.^80

-83 The changes in lipid profile usually reach their peaks in 4-7 days after AMI and then subside after several months. Lower LDL-C levels during hospitalization phase of acute MI have been associated with worse clinical outcome in some observational registries.^83,84 However, based on strong consistent clinical trial data, AHA/ACC guidelines recommend statin therapy be initiated regardless of baseline LDL-C in patients with clinical ASCVD including acute coronary syndrome unless contraindicated.

The paradoxical negative relationship of serum LDL-C level and in-hospital mortality following AMI was observed in the national registry NRMI 4be5 study where the lowest levels of LDL-C were associated with highest risk of in-patient mortality, but the study did not show evidence to counter the in-hospital use of statins following AMI. Instead, the previous NRMI analyses demonstrated benefits of in-hospital statin use on short-term CV outcomes.⁸³ The mechanism underlying this lipid paradox after AMI is not clear but acute-phase reaction, inflammatory response, and liver function change with alterations of lipid synthesis, concentration, and composition, following AMI have been proposed. One interesting hypothesis is that during the acute phase of MI, the low or “normal” serum cholesterol or LDL-C levels may reflect a change within the mevalonate pathway. The intermediates of the mevalonate/isoprenoids pathway may be funneled, due to biosynthetic enzyme activity modulation in the setting of AMI, from the isoprenoid branch point at farnesyl pyrophosphate (FPP) favorably toward the production of nonsteroid isoprenoids via geranylgeranyl pyrophosphate (GGPP), over the production of the steroid isoprenoids to sequelene and cholesterol. The nonsteroid isoprenoids are known to play a critical role in post-translational modification of a multitude of proteins involved in intracellular signaling and are essential in inflammation and cell migration, differentiation, and proliferation, and in the pathogenesis of ASCVD, acting on which at least in part accounts for the pleiotropic beneficial effect of statin for ASCVD.

All efforts to manipulate apolipoproteins and to raise the level or mimic the function of HDL-C to date have been disappointing. LDL is composed of cholesterol, apoB, and other components in the particle. Data on the effect of specifically reducing the apoB level for ASCVD are lacking and no target therapeutic level of apoB is known. Although HDL-C measurement has a value in risk stratification of ASCVD, there are no large-scale data to show that targeting a specific level of HDL-C is beneficial in the prevention and treatment of ASCVD. The exact role of Lp(a) in ASCVD is unclear. Some lipid lowering drugs can lower the Lp(a) level as reviewed in the article, but drugs or interventions specifically targeting Lp(a) are under investigation and large scale randomized controlled prospective clinical data on cardiovascular events are lacking. Given the lack of demonstrated benefit in targeting HDL-C, VLDL-C, IDL-C, or apolipoproteins for ASCVD, the exact role and cost-effectiveness of measuring the levels of these lipoproteins or apolipoproteins in clinical practice warrant further study.

Conclusions

In the era of evidence-based medicine, understanding the implication of cholesterol in ASCVD is still evolving. Endogenous cholesterol biosynthesis in contrast to exogenous cholesterol ingestion is believed to be more important in atherogenesis. Thus far statins remain the most consistent and effective class of lipid regulators for the primary and secondary prevention of ASCVD likely due to their unique mechanism targeting the MVA cholesterol biosynthesis pathway and related pleiotropic effects. Although the cholesterol hypothesis can only partially explain the pathogenesis of ASCVD, when lowering cholesterol or LDL-C becomes the goal, the future pharmacotherapy or combined therapy may be aimed more at targeting the nonsteroid isoprenoids intermediates production and inhibiting their pleiotropic effects in relation to the MVA endogenous cholesterol biosynthesis pathway, in the prevention and treatment of ASCVD. Based on the available clinical trials, in our opinion, the mechanism by which cholesterol or LDL-C is lowered is clinically important along with its absolute reduction, in preventing and treating ASCVD,

Footnotes

Author Contributions

R.Z., G.A.S., and S.C.S. researched data for the article and contributed substantially to discussions of its content. All authors contributed to writing the article and reviewing or editing of the manuscript before submission.

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

Ruihai Zhou

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