Emerging Drugs for Residual CV Risk in Statin-Treated Adults

Abstract and Introduction

Abstract

Epidemiological studies and meta-analyses have consistently suggested the importance of lowering low-density lipoprotein cholesterol (LDL-C) to reduce cardiovascular (CV) events. However, these studies and mechanistic studies using intracoronary imaging modalities have reported patients who continue to experience CV events or disease progression despite optimal LDL-C levels on statins. These findings, including statin intolerance, have highlighted the importance of exploring additional potential therapeutic targets to reduce CV risk. Genomic insights have presented a number of additional novel targets in lipid metabolism. In particular, proprotein convertase subtilisin/kexin type 9 inhibitors have rapidly developed and recently demonstrated their beneficial impact on CV outcomes. Triglyceride (TG)-rich lipoproteins have been recently reported as a causal factor of atherosclerotic cardiovascular disease (ASCVD). Indeed, several promising TG-targeting therapies are being tested at various clinical stages. In this review, we present the evidence to support targeting atherogenic lipoproteins to target residual ASCVD risk in statin-treated patients.

Introduction

Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality despite continuous efforts for the improvement of cardiovascular (CV) care.^[1] In addition to the established benefits of statins for reducing ASCVD risk, recently the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) demonstrated an incremental benefit of low-density lipoprotein cholesterol (LDL-C) lowering with ezetimibe on ASCVD events.^[2] However, many patients who achieved target LDL-C levels with lipid-lowering therapies (LLTs) still experience CV events or progression of coronary atherosclerosis,^[3] underscoring the importance of novel strategies for lipid management in high ASCVD risk patients. Recent findings in genetic studies have established causal roles in ASCVD and developed therapeutic approaches. In this review, we focus on novel lipid-modifying drugs that have the potential to control the residual ASCVD risk.

Table 1. Summary of promising lipid-lowering therapies and current status
Target	Agent	Mechanism	Changes in lipids	Current stage	Cardiovascular outcome trial
LDL-C	Ezetimibe	NPC1L1 inhibitor	LDL-C: ≈ − 20%	Approved (Zetia^®)	SEAS [7] SHARP [8] IMPROVE-IT [2] PRECISE-IVUS [12]
Alirocumab	PCSK9 mAb	LDL-C: ≈ − 60%	Approved (Praluent^®)	ODYSSEY LONG TERM [26] ODYSSEY Outcomes [30]
Evolocumab	PCSK9 mAb	LDL-C: ≈ − 60%	Approved (Repatha^®)	FOURIER [50] GLAGOV [41]
Inclisiran	PCSK9 siRNA	LDL-C: ≈ − 50%	Phase 3	–
Bempedoic acid	ACL inhibitor	LDL-C: ≈ − 30 to 40%	Phase 3	CLEAR Outcomes [82]
Mipomersen	ApoB ASO	LDL-C: ≈ − 30%	Approved (Kynamro^®)	–
Lomitapide	MTP inhibitor	LDL-C: ≈ − 50%	Approved (Juxtapid^®)	–
TG	Icosapent ethyl	New omega-3 fish oils	TG: ≈ − 20 to 30%	Approved (Vascepa^®)	REDUCE-IT [110]
Omega-3 carboxylic acids	New omega-3 fish oils	TG: ≈ − 30%	Approved (Epanova^®)	STRENGTH [108]
Volanesorsen	ApoC-III ASO	TG: ≈ − 60 to 70%	Phase 3	–
APOCIII-L_Rx	ApoC-III ASO	TG: ≈ − 70%	Phase 2	–
Pemafibrate	PPARα agonist	TG: ≈ − 50%, HDL-C: ≈ + 20%	Phase 3 (Approved in only Japan: Parmodia™)	PROMINENT [158]
CAT-2003	SREBP inhibitor	TG: ≈ − 30%	Phase 2	–
TG and LDL-C	Evinacumab	ANGPTL3 mAb		Phase 2	–
Gemcabene	ApoC-III and CRP modulator	TG: ~ − 40%, LDL-C: −20 to 30%	Phase 2	–
Lp(a)	IONIS APO(a)-L_RX	Apo(a) ASO	Lp(a): ~ − 80%	Phase 2	–

Table 1. Summary of promising lipid-lowering therapies and current status

Target

Agent

Mechanism

Changes in lipids

Current stage

Cardiovascular outcome trial

LDL-C

Ezetimibe

NPC1L1 inhibitor

LDL-C: ≈ − 20%

Approved (Zetia^®)

SEAS [7]
SHARP [8]
IMPROVE-IT [2]
PRECISE-IVUS [12]

Alirocumab

PCSK9 mAb

LDL-C: ≈ − 60%

Approved (Praluent^®)

ODYSSEY LONG TERM [26]
ODYSSEY Outcomes [30]

Evolocumab

PCSK9 mAb

LDL-C: ≈ − 60%

Approved (Repatha^®)

FOURIER [50]
GLAGOV [41]

Inclisiran

PCSK9 siRNA

LDL-C: ≈ − 50%

Phase 3

–

Bempedoic acid

ACL inhibitor

LDL-C: ≈ − 30 to 40%

Phase 3

CLEAR Outcomes [82]

Mipomersen

ApoB ASO

LDL-C: ≈ − 30%

Approved (Kynamro^®)

–

Lomitapide

MTP inhibitor

LDL-C: ≈ − 50%

Approved (Juxtapid^®)

–

Icosapent ethyl

New omega-3 fish oils

TG: ≈ − 20 to 30%

Approved (Vascepa^®)

REDUCE-IT [110]

Omega-3 carboxylic acids

New omega-3 fish oils

TG: ≈ − 30%

Approved (Epanova^®)

STRENGTH [108]

Volanesorsen

ApoC-III ASO

TG: ≈ − 60 to 70%

Phase 3

–

APOCIII-L_Rx

ApoC-III ASO

TG: ≈ − 70%

Phase 2

–

Pemafibrate

PPARα agonist

TG: ≈ − 50%, HDL-C: ≈ + 20%

Phase 3 (Approved in only Japan: Parmodia™)

PROMINENT [158]

CAT-2003

SREBP inhibitor

TG: ≈ − 30%

Phase 2

–

TG and LDL-C

Evinacumab

ANGPTL3 mAb

Phase 2

–

Gemcabene

ApoC-III and CRP modulator

TG: ~ − 40%, LDL-C: −20 to 30%

Phase 2

–

Lp(a)

IONIS APO(a)-L_RX

Apo(a) ASO

Lp(a): ~ − 80%

Phase 2

–

Table 2. Summary of recent phase 3 cardiovascular outcome trials
Agent CVOT name	Subjects	Duration (years)	Endpoint	Results
Number	Setting
Completed trials
Ezetimibe IMPROVE-IT [2]	18,144	Statin-naïve or statin-treated patients hospitalized with ACS (< 10 days); LDL-C 50–125 mg/dl (statin-naïve) or 50–100 mg/dl (statin-treated)	6	Combined CHD death, nonfatal MI, nonfatal stroke, UAP, revascularization	32.7% event rate in the ezetimibe group; 34.7% event rate in the placebo group (HR 0.936, 95% CI 0.89–0.99)
Ezetimibe PRECISE-VUS [12]	202	CAD patients; LDL-C > 100 mg/dl	0.75–1.0	Change in PAV assessed by IVUS	− 1.4% in the ezetimibe group; − 0.3% in the placebo group; (difference − 1.5%, 95% CI − 3.1 to 0.003)
Alirocumab ODYSSEY LONG TERM [26]	2341	Statin-treated patients at high CV risk; LDL-C ≥ 70 mg/dl	1.5	Combined CHD death, nonfatal MI, fatal or nonfatal stroke, UAP	3.3% event rate in the alirocumab group; 1.7% event rate in the placebo group; (HR 0.52, 95% CI 0.31–0.90)
Alirocumab ODYSSEY Outcomes [30]	18,924	Statin-treated patients hospitalized with ACS (< 52 weeks); LDL-C ≥ 70 mg/dl	2.8	Combined CHD death, AMI, hospitalization for UAP or stroke	9.5% event rate in the alirocumab group; 11.1% event rate in the placebo group; (HR 0.85, 95% CI 0.78–0.93)
Evolocumab] FOURIER [50]	27,564	Statin-treated patients with stable ASCVD; LDL-C ≥ 70 mg/dl	2.2	Combined CV death, MI, stroke, UAP, revascularization	9.8% event rate in the evolocumab group; 11.3% event rate in the placebo group; (HR 0.85, 95% CI 0.79–0.92)
Evolocumab GLAGOV [41]	968	Statin-treated patients with CAD; LDL-C ≥ 70 mg/dl	1.5	Change in PAV assessed by IVUS	− 0.95% in the evolocumab group; 0.05% in the placebo group; (difference − 1.0%, 95% CI − 1.8% to − 0.64%)
Ongoing trials
Bempedoic acid CLEAR Outcomes [82]	12,600	Statin-intolerant patients at high CV risk; LDL-C 100–190 mg/dl	3.5	Combined CV death, nonfatal MI, nonfatal stroke, UAP, revascularization	March 2022
Icosapent ethyl REDUCE-IT [110]	8179	Statin-treated patients at high CV risk; LDL-C 41–100 mg/dl; TG 135– 499 mg/dl	4.9	Combined CV death, nonfatal MI, nonfatal stroke, UAP, revascularization	17.2% event rate in the icosapent ethyl group; 22.0% event rate in the placebo group; (HR 0.75, 95% CI 0.68–0.83)
Omega-3 carboxylic acids STRENGTH [108]	13,086	Statin-treated patients at high CV risk; LDL-C < 100 mg/dl; TG 180–500 mg/dl; HDL-C < 42 (male) or 47 (female) mg/dl	Up to 5	Combined CV death, nonfatal MI, nonfatal stroke, UAP, revascularization	October 2019
Pemafibrate PROMINENT [158]	10,000	Statin-treated diabetic patients with or without stable ASCVD; 200 ≤ TG < 500 mg/dl; HDL-C ≤ 40 mg/dl	4	Combined CV death, nonfatal MI, nonfatal stroke, UAP, revascularization	May 2022

Table 2. Summary of recent phase 3 cardiovascular outcome trials

Agent CVOT name

Subjects

Duration (years)

Endpoint

Results

Number

Setting

Completed trials

Ezetimibe IMPROVE-IT [2]

18,144

Statin-naïve or statin-treated patients hospitalized with ACS (< 10 days); LDL-C 50–125 mg/dl (statin-naïve) or 50–100 mg/dl (statin-treated)

Combined CHD death, nonfatal MI, nonfatal stroke, UAP, revascularization

32.7% event rate in the ezetimibe group; 34.7% event rate in the placebo group (HR 0.936, 95% CI 0.89–0.99)

Ezetimibe PRECISE-VUS [12]

202

CAD patients; LDL-C > 100 mg/dl

0.75–1.0

Change in PAV assessed by IVUS

− 1.4% in the ezetimibe group; − 0.3% in the placebo group; (difference − 1.5%, 95% CI − 3.1 to 0.003)

Alirocumab ODYSSEY LONG TERM [26]

2341

Statin-treated patients at high CV risk; LDL-C ≥ 70 mg/dl

1.5

Combined CHD death, nonfatal MI, fatal or nonfatal stroke, UAP

3.3% event rate in the alirocumab group; 1.7% event rate in the placebo group; (HR 0.52, 95% CI 0.31–0.90)

Alirocumab ODYSSEY Outcomes [30]

18,924

Statin-treated patients hospitalized with ACS (< 52 weeks); LDL-C ≥ 70 mg/dl

2.8

Combined CHD death, AMI, hospitalization for UAP or stroke

9.5% event rate in the alirocumab group; 11.1% event rate in the placebo group; (HR 0.85, 95% CI 0.78–0.93)

Evolocumab] FOURIER [50]

27,564

Statin-treated patients with stable ASCVD; LDL-C ≥ 70 mg/dl

2.2

Combined CV death, MI, stroke, UAP, revascularization

9.8% event rate in the evolocumab group; 11.3% event rate in the placebo group; (HR 0.85, 95% CI 0.79–0.92)

Evolocumab GLAGOV [41]

968

Statin-treated patients with CAD; LDL-C ≥ 70 mg/dl

1.5

Change in PAV assessed by IVUS

− 0.95% in the evolocumab group; 0.05% in the placebo group; (difference − 1.0%, 95% CI − 1.8% to − 0.64%)

Ongoing trials

Bempedoic acid CLEAR Outcomes [82]

12,600

Statin-intolerant patients at high CV risk; LDL-C 100–190 mg/dl

3.5

Combined CV death, nonfatal MI, nonfatal stroke, UAP, revascularization

March 2022

Icosapent ethyl REDUCE-IT [110]

8179

Statin-treated patients at high CV risk; LDL-C 41–100 mg/dl; TG 135– 499 mg/dl

4.9

Combined CV death, nonfatal MI, nonfatal stroke, UAP, revascularization

17.2% event rate in the icosapent ethyl group; 22.0% event rate in the placebo group; (HR 0.75, 95% CI 0.68–0.83)

Omega-3 carboxylic acids STRENGTH [108]

13,086

Statin-treated patients at high CV risk; LDL-C < 100 mg/dl; TG 180–500 mg/dl; HDL-C < 42 (male) or 47 (female) mg/dl

Up to 5

Combined CV death, nonfatal MI, nonfatal stroke, UAP, revascularization

October 2019

Pemafibrate PROMINENT [158]

10,000

Statin-treated diabetic patients with or without stable ASCVD; 200 ≤ TG < 500 mg/dl; HDL-C ≤ 40 mg/dl

Combined CV death, nonfatal MI, nonfatal stroke, UAP, revascularization

May 2022

Tackling Residual Atherosclerotic Risk in Statin-Treated Adults: Focus on Emerging Drugs

Abstract and Introduction

Abstract

Introduction

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