Impact of Expanded FDA Indication for Icosapent Ethyl On Enhanced Cardiovascular Residual Risk Reduction

Figures & data

Table 1.  Frederickson-Levy phenotypes characterized by hypertriglyceridemia^†.

Frederickson-Levy phenotype	Main features	Diagnostic criteria
Type I	Chylomicron excess	TG:TC ratio >10 and VLDL-C <90th percentile
Type III	Remnant lipoprotein cholesterol excess	VLDL-C:TG ratio >0.3, TG >130 mg/dl and LDL-C <90th percentile
Type IV	VLDL-C excess	VLDL-C >90th percentile, LDL-C <90th percentile and VLDL-C:TG ratio <0.3
Type V	Chylomicron and VLDL-C excess	TG:TC ratio >10 and VLDL-C >90th percentile

† Not listed within the table are phenotypes primarily characterized by high LDL-C: type IIa (main feature is LDL-C excess; diagnostic criteria are LDL-C >90th percentile, VLDL-C <90th percentile and VLDL-C:TG ratio <0.3) and type IIb (main features are LDL-C and VLDL-C excess; diagnostic criteria are LDL-C, VLDL-C >90th percentile and VLDL-C:TG ratio <0.3).

LDL-C: Low-density lipoprotein cholesterol; TG: Triglyceride; VLDL-C: Very-low-density lipoprotein cholesterol.

Reproduced from [11], CC BY-NC-SA.

Table 2. Genetic polymorphisms underlying hypertriglyceridemia.

Genetic target polymorphism	Pathogenesis	Typical lipid/lipoprotein profile	Ref.
Apo C2 deficiency	Absence of needed cofactor, apo C2, leads to increased chylomicrons	Homozygotes TG:cholesterol ratio 10:1; TG >1000 mg/dl; increased chylomicrons Obligate heterozygotes with normal TG despite apo C2 levels ∼30–50% of normal	[10,12]
Apo C3	Deficiency in apo C3 associated with low TG levels; gain of function mutation associated with enhanced hepatic de novo lipogenesis		[13,14]
Angiopoietin-like protein 3 and 4	Loss of function mutations associated with lower TG levels		[13,15]
Apo A5 deficiency	Mutations in the APOA5 gene, which lead to truncated apo A5 devoid of lipid-binding domains located in the carboxy-terminal end of the protein	Homozygotes: TG:cholesterol ratio 10:1; TG >1000 mg/dl; increased chylomicrons	[10,12,16]
Lipoprotein lipase deficiency	Very low or undetectable levels of lipoprotein lipase lead to increased chylomicrons; circulating inhibitor to lipoprotein lipase has been reported	Homozygotes: TG:cholesterol ratio 10:1; TG >1000 mg/dl; increased chylomicrons	[10,12]
Hepatic lipase deficiency	Relatively rare LIPC mutations lead to loss in circulating hepatic lipase activity (due to impaired secretion or inactive enzyme)	Increase in TG-rich HDL and VLDL remnants	[17]
Glycosylphosphatidylinositol-anchored HDL-binding protein (GPIHBP1) deficiency	Mutations in GPIHBP1 may reduce binding to LPL and hydrolysis of chylomicron TGs	TG:cholesterol ratio 7:1; TG >500 mg/dl; increased chylomicrons partially responsive to low-fat diet	[10,12]

Apo: Apolipoprotein; HDL: High-density lipoprotein; LPL: Lipoprotein lipase; TG: Triglycerides; VLDL: Very-low-density lipoprotein.

Source: American Heart Association, Inc. [10].

Table 3. Randomized controlled cardiovascular outcomes trials of niacin and fibrates.

Trial	Treatment and patient population	Findings	Ref.
AIM-HIGH	• Niacin + statin vs placebo + statin in 3414 adults • Age ≥45 years with established ASCVD and atherogenic dyslipidemia • HDL-C <40 mg/dl for men and <50 mg/dl for women • TG 150–400 mg/dl • LDL-C <180 mg/dl	Niacin + statin did not achieve the primary end point (composite of the first event of death from coronary heart disease, nonfatal MI, ischemic stroke, hospitalization [for >23 h] for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization)	[32]
		TG-related subgroup analysis In patients with baseline TG ≥198 mg/dl and HDL-C <33 mg/dl, CV risk reduction with niacin was suggested but not significant (HR, 0.74; p = 0.073); the trend toward risk reduction with niacin was more pronounced in patients with TG ≥200 mg/dl and HDL-C <32 mg/dl (HR: 0.64; p = 0.032)	[34]
HPS2-THRIVE	• Niacin + laropiprant added to statin vs placebo added to statin in 25,673 adults • Ages 50–80 years with a history of MI, cerebrovascular disease, PAD, or diabetes with evidence of symptomatic coronary disease	Niacin + laropiprant added to statin did not achieve the primary end point (composite of major vascular events: nonfatal MI, death from coronary causes, stroke of any type, or coronary or non-coronary revascularization)	[33]
		TG-related subgroup analysis No significant difference in major vascular events was found between niacin + laropiprant and placebo in the subgroup of patients with TG >151 mg/dl and low HDL-C (<40 mg/dl in men, <51 mg/dl in women)
VA-HIT	• Gemfibrozil vs placebo in 2531 men with a documented history of coronary heart disease • HDL-C ≤40 mg/dl, LDL-C ≤140 mg/dl and TG ≤300 mg/dl	Gemfibrozil reduced the rate of the primary end point (death from coronary heart disease or nonfatal MI) vs placebo by 22% (95% CI: 7–35%; p = 0.006)	[35]
		TG-related subgroup analysis Gemfibrozil was associated with relative risk reduction in death from coronary heart disease, nonfatal MI and confirmed stroke: 28% (95% CI: 8–44) in patients with TG <151 mg/dl and 27% (95% CI: 75–42%) in patients with TG ≥151 mg/dl (p = 0.01 for both)
FIELD	• Fenofibrate vs placebo in 9795 non-statin–treated adults • Ages 50–75 years with type 2 diabetes and total cholesterol 116.0–251.4 mg/dl and TG 88.6–442.9 mg/dl • Not treated with lipid-modifying treatment at study entry	Fenofibrate did not achieve the primary end point (first occurrence of nonfatal MI or death from coronary heart disease); however, fenofibrate did reduce total CVD events (CVD death, MI, stroke and coronary or carotid revascularization) vs placebo by 11% (HR: 0.89; 95% CI: 0.80–0.99; p = 0.035)	[36]
		TG-related subgroup analysis In patients with baseline TG ≥150.6 mg/dl, there was a trend (p = 0.07) toward fenofibrate reducing total CVD events
BIP	• Bezafibrate 400 mg vs placebo in adults aged 45–74 years with history of MI ≥6 months but <5 years before study enrollment and/or stable angina pectoris • Lipid entry criteria included total cholesterol 180–250 mg/dl; LDL-C ≤180 mg/dl (≤160 mg/dl if aged <50 years); HDL-C ≤45 mg/dl, and TG ≤300 mg/dl	Bezafibrate did not achieve the primary end point (fatal MI, nonfatal MI, or sudden death [occurring within 24 h of onset of symptoms])	[37]
		TG-related subgroup analysis In patients with baseline TG ≥200 mg/dl, the adjusted relative risk for primary end points associated with bezafibrate was 0.57 (95% CI: 0.35–0.93)
ACCORD	• Fenofibrate + statin vs placebo + statin in 5518 patients with type 2 diabetes • Ages 40–79 years if clinical CVD, or ages 55–79 years if subclinical CVD or ≥2 additional risk factors • Lipid criteria: LDL-C 60–180 mg/dl; TG <750 mg/dl if no lipid treatment or <400 mg/dl if on lipid treatment; low HDL-C (<55 mg/dl for women and black patients; <50 mg/dl for other groups)	Fenofibrate + statin did not achieve primary end point (first occurrence of major cardiovascular event, including nonfatal MI, nonfatal stroke or death from cardiovascular causes)	[38]
		TG-related subgroup analysis In patients with TG ≥204 mg/dl and HDL-C ≤34 mg/dl, the primary outcome rate was 12.4% for fenofibrate + statin vs 17.3% for placebo + statin (nonsignificant suggestion of heterogeneity; p = 0.057)

ACCORD: Action to Control Cardiovascular Risk in Diabetes; ACS: Acute coronary syndrome; AIM-HIGH: Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes; ASCVD: Atherosclerotic cardiovascular disease; BIP: Bezafibrate Infarction Prevention; CVD: Cardiovascular disease; FIELD: Fenofibrate Intervention and Event Lowering in Diabetes; HPS2-THRIVE: Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events; HR: Hazard ratio; MI: Myocardial infarction; PAD: Peripheral artery disease; VA-HIT: Veterans Affairs Cooperative Studies Program High-Density Lipoprotein Cholesterol Intervention Trial.

Table 4. Cardiovascular outcomes trials of mixed omega-3 fatty acids.

Trial	Treatment and patient population^†	Primary finding	Ref.
GISSI Prevenzione	DHA + EPA (<1 g/day) vs vitamin E vs DHA + EPA with vitamin E vs placebo in 11,324 patients within 3 months post-MI	DHA + EPA significantly reduced the co-primary composite end points vs placebo over 3.5 years: all-cause death, nonfatal MI and nonfatal stroke was reduced by 15% (95% CI: 2–26%; p = 0.023) and CV death, nonfatal MI and nonfatal stroke was reduced by 20% (95% CI: 5–32%; p = 0.008)	[55]
GISSI Heart Failure	DHA + EPA (1 g/day) vs placebo in 7046 patients with clinical evidence of heart failure (those with LVEF >40% had to have had at least one hospital admission for heart failure in the prior year); unless contraindicated, patients were also randomly assigned rosuvastatin 10 mg or placebo	DHA + EPA produced a moderate reduction vs placebo in the coprimary end points over 3.9 years: reduction in all-cause mortality risk was 1.8% (95% CI: 0.3–3.9%) and reduction in mortality or hospitalization for cardiovascular causes risk was 2.3% (95% CI: 0–4.6%)	[62]
OMEGA	DHA + EPA (∼1 g/day) vs placebo in 3851 patients aged ≥18 years and admitted to the hospital for acute MI	DHA + EPA did not achieve the primary end point of sudden cardiac death (unexpected death from heart disease within 1 h for first symptoms or unwitnessed overnight and/or sudden cardiac arrest within 1 h of first symptoms with initially successful cardiopulmonary resuscitation and subsequent death during the hospital stay within 3 weeks)	[56]
Alpha Omega	DHA + EPA (376 mg/day in a margarine) vs placebo in 4837 adults aged 60–80 years who had MI up to 10 years before randomization	DHA + EPA did not achieve the primary end point (major cardiovascular events: fatal and nonfatal cardiovascular events and the cardiac interventions percutaneous coronary intervention and coronary artery bypass grafting)	[58]
ORIGIN	DHA + EPA (<1 g/day) vs placebo in 12,536 adults aged ≥50 years with diabetes/dysglycemia and additional CVD risk factors	DHA + EPA did not achieve the primary end point of death from cardiovascular causes	[57]
Risk and Prevention Study	DHA + EPA (1 g/day) vs placebo in 12,513 adults at high risk for CVD (multiple risk factors), clinical evidence for ASCVD, but no prior MI	DHA + EPA did not achieve the primary composite end point (time to death from cardiovascular causes or hospital admission for cardiovascular causes)	[59]
ASCEND	DHA + EPA (<1 g/day) in 15,480 adults aged ≥40 years with diabetes but no evidence of CVD	DHA + EPA did not achieve the primary composite end point (nonfatal MI or stroke [excluding confirmed intracranial hemorrhage], transient ischemic attack, or vascular death excluding intracranial hemorrhage)	[60]
VITAL	DHA + EPA (<1 g/day) and vitamin D vs placebo in 25,871 men aged ≥50 years and women aged ≥55 years	DHA + EPA did not achieve the primary end point (major cardiovascular events [composite of MI, stroke and death from cardiovascular causes] and invasive cancer of any type)	[61]

† Baseline statin use varied widely among these studies: <5% in GISSI-Prevenzione, 35% in VITAL, 41% in risk and prevention, 54% in ORIGIN, 75% in ASCEND, 86% in Alpha Omega and 94% (at discharge) in OMEGA.

ASCEND: A Study of Cardiovascular Events in Diabetes; DHA: Docosahexaenoic acid; EPA: Eicosapentaenoic acid; GISSI: Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico; HR: Hazard ratio; LVEF: Left ventricular ejection fraction; MI: Myocardial infarction; ORIGIN: Outcome Reduction with an Initial Glargine Intervention; VITAL, Vitamin D and Omega-3 Trial.

Figure 1. REDUCE-IT primary end point.

(A) Time to first primary composite end point event [9]. (B) Total (first and subsequent) primary composite end point events [71].

*The number of patients at risk for recurrent events.

Reproduced with permission from Bhatt et al. [9,71]. CC BY-NC-ND 4.0.

Figure 2. Pleiotropic effects of EPA.

AA: Arachidonic acid; EPA: Eicosapentaenoic acid; hsCRP: High-sensitivity C-reactive protein; ICAM-1: Intercellular adhesion molecule 1; IL: Interleukin; Lp-PLA2: Lipoprotein-associated phospholipase 2; MMPs: Matrix metalloproteinases; NO: Nitric oxide; oxLDL: Oxidized low-density lipoprotein; RLP-C: Remnant lipoprotein cholesterol.

Data taken from [47,50].

Table 5. Weighted prevalence of TG ≥150 mg/dl among different subgroups of adults aged 20 and over in NHANES 2007–2014.

Population	Prevalence of TG ≥150 mg/dl, % (Number/Total Population)
Overall	25.9 (56.9 M/219.9 M)
Statin-treated subgroup	31.6 (12.3 M/38.9 M)
Statin-treated + LDL-C <100 mg/dl subgroup	27.6 (6.0 M/21.7 M)
Statin-treated + DM subgroup	39.5 (4.9 M/12.4 M)
Statin-treated + ASCVD subgroup	30.5 (3.1 M/10.1 M)
Statin-treated + DM or ASCVD subgroup	34.4 (6.4 M/18.6 M)

ASCVD: Atherosclerotic cardiovascular disease; DM: Diabetes mellitus; LDL-C: Low-density lipoprotein cholesterol; M: Million; TG: Triglycerides.

Reproduced from CC BY-NC 4.0 [96.

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