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

Kohei Takata; Stephen J. Nicholls

Am J Cardiovasc Drugs. 2019;19(2):113-131.

Methods

We conducted a literature review of randomized clinical trials (RCTs), meta-analyses, retrospective studies, and reviews in PubMed and Google Scholar using the keywords according to each theme of the section. Those details were also searched for in ClinicalTrial.gov (www.clinicaltrial.com) and Drugs@FDA (https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm).

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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	–
TG and LDL-C	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	–

ACL adenosine triphosphate citrate lyase, ANGPTL3 angiopoietin-related protein 3, Apo(a) apolipoprotein (a), ApoB apolipoprotein B, ApoC-III apolipoprotein C-III, ASO antisense oligonucleotide, CRP C-reactive protein, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a), mAb monoclonal antibody, MTP microsomal triglyceride transfer protein, NPC1L1 Niemann-Pick C1-Like 1, PCSK9 proprotein convertase subtilisin/kexin type 9, PPARα peroxisome proliferator-activated receptor α, siRNA small interfering RNA, SREBP sterol regulatory element-binding protein, TG triglyceride

Table 2. Summary of recent phase 3 cardiovascular outcome trials
Agent CVOT name	Subjects		Duration (years)	Endpoint	Results
Agent CVOT name	Number	Setting	Duration (years)	Endpoint	Results
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

ACS acute coronary syndrome, ASCVD atherosclerotic cardiovascular disease, CAD coronary artery disease, CHD coronary heart disease, CI confidence interval, CV cardiovascular, CVOT cardiovascular outcome trial, HDL-C high-density lipoprotein cholesterol, HR hazard ratio, IVUS intravascular ultrasound, LDL-C low-density lipoprotein cholesterol, MI myocardial infarction, PAV percent atheroma volume, TG triglyceride, UAP unstable angina pectoris