Prescription omega-3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications

Figures & data

Figure 1. Relationship between adiposopathy (pathogenic adipose tissue) and metabolic disease.

Increased circulating FFAs may be lipotoxic to muscle, liver and pancreas. When adipocytes become excessively enlarged, especially in the setting of visceral adiposity, adipocyte and adipose tissue dysfunction (i.e., ‘adiposopathy’) may result in adverse metabolic consequences. One of the manifestations of adiposopathy is a relative increase of intra-adipocyte lipolysis over that of intra-adipocyte lipogenesis, leading to a net release of FFAs, insulin resistance and diminished pancreatic insulin secretion, all leading to hyperglycemia and possible diabetes mellitus, as well as other metabolic diseases. Steatosis, or ‘fatty liver’, is another consequence of increased FFA delivery to the liver.

FFA: Free faty acid.

Adapted with permission from Future Medicine Ltd [7].

Figure 2. Potential TG-lowering mechanisms of eicosapentaenoic acid and docosahexaenoic acid.

Pathogenic adipose tissue, increased postprandial CHYL and increased VLDL particles may increase free FA delivery to the liver, and increase hepatic lipid content, which are substrates for TG synthesis and, thus, VLDL production. Most evidence supports that omega-3 fatty acids inhibit hepatic TG synthesis, decrease VLDL production/secretion and increase VLDL metabolism by: decreasing lipogenesis by decreasing the enzymatic conversion of acetyl CoA to FAs; increasing β-oxidation of FA; inhibiting both PAP (an enzyme that catalyzes that reaction of converting PA to DAG) and DGAT (an enzyme that catalyzes the final step in TG synthesis); potentially increasing the degradation of apolipoprotein B; and increasing LPL activity, which is an enzyme that increases the conversion of VLDL particles to LDL particles.

CHYL: Chylomicrons; DAG: diacylglycerol; DGAT: Diacylglycerol acyltransferase; FA: Fatty acid; LPL: Lipoprotein lipase; PA: Phosphatidic acid; PAP: phosphatidic acid phosphatase/phosphohydrolase; TG: Triglyceride; VLDL: Very low-density lipoprotein.

Adapted from [98].

Figure 3. Effects of statins, fish oils and their combination on lipoprotein secretion rate (not lipid levels) and conversion.

P-OM3 and atorvastatin lower triglyceride levels by different mechanisms. (A) Percentage change in the secretion rate of apoB-containing lipoproteins into the plasma. (B) Percentage change in the interconversion of apoB-containing lipoproteins. P-OM3, alone or in combination with atorvastatin, increased conversion of TG-rich lipoproteins to LDL.

*p < 0.01 compared with placebo group.

IDL: Intermediate-density lipoprotein; P-OM3: Prescription omega-3-acid ethyl esters; VLDL: Very-low-density lipoprotein.

Reproduced from [118].

© 2002 American Diabetes Association.

Figure 4. Effect of P-OM3 on non-HDL-C in patients with triglycerides of 500 mg/dl.

Non-HDL-C is reduced in many P-OM3 trials, concomitantly with an apparent paradoxical increase in LDL-C levels. This can be explained by P-OM3’s increased conversion of VLDL to LDL particles. Thus, in this case, P-OM3 resulted in a decrease in VLDL-C levels and decrease in VLDL particle size, and an increase in LDL-C levels and increase in LDL particle size, with a net decrease in the total cholesterol carried by atherogenic lipoproteins, as represented by non-HDL-C.

HDL-C: HDL cholesterol; LDL-C: LDL cholesterol; P-OM3: Prescription omega-3-acid ethyl esters; VLDL: Very-low-density lipoprotein.

Reproduced from [92].

Figure 5. Revealing the underlying atherogenic potential of hypertriglyceridemia.

Many patients with hypertriglyceridemia have increased cholesterol carried by atherogenic particles, which is best assessed by measuring non-HDL-C levels. VLDL particles are considered to be atherogenic. Omega-3 fatty acid therapy decreases the cholesterol carried by VLDL particles, and is a cholesterol effect not typically measured in clinical practice. Omega-3 fatty acids may also decrease VLDL particle size. Conversely, omega-3 fatty acids may increase LDL-C levels, which is a lipid parameter that is often measured in clinical practice. This is thought to be due to the increased conversion of VLDL particles to LDL particles. Finally, omega-3 fatty acids may increase LDL particle size, which may render them less atherogenic. Overall, despite a potential increase in LDL-C levels, many studies have reported that P-OM3 reduces non-HDL-C, which may be a better predictor of atherosclerotic coronary heart disease risk than LDL-C alone.

HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; P-OM3: Prescription omega-3-acid ethyl esters; VLDL: Very-low-density lipoprotein.

Table 1. Pharmacotherapy effect of lipid-altering drugs on triglycerides, LDL-C and HDL-C levels.

Lipid-altering agent	Change in triglycerides (%)	Change in LDL-C (%)	Change in HDL-C (%)
Omega-3 fatty acids (EPA/DHA)	↓20–50	↑/no change	↑/no change
Nicotinic acid (niacin)	↓20–50	↓5–25	↑ 15–35
Fibric acids (fibrates)	↓20–50	↑/↓0–20*	↑6–20
Statins	↓ 7–40	↓18–60	↑ 3–15
Bile acid sequestrants (resins)	↑/no change	↓10–30	↑ 3–5
Ezetimibe	↓ 4–11	↓17–22	↑ 2–5

*Fibrates may increase LDL-C lev,els in some patients with hypertriglyceridemia.

↑: Increase; ↓: Decrease; DHA: Docosahexaenoic acid; EPA: Eicosapentaenoic acid; HDL-C: HDL cholesterol; LDL-C: LDL cholesterol.

Adapted from [27,28].

Table 2. Physical–chemical characteristics of lipoproteins.

Lipoprotein	Density (g/ml)	Lipid (%)*
		Triglyceride	Cholesterol	Phospholipid
Chylomicrons	0.95	80–95	2–7	3–9
VLDL	0.95–1.006	55–80	5–15	10–20
IDL	1.006–1.019	20–50	20–40	15–25
LDL	1.019–1.063	5–15	40–50	20–25
HDL	1.063–1.21	5–10	15–25	20–30

*Percentage composition of lipids; apolipoproteins make up the rest.

IDL: Intermediate-density lipoprotein; VLDL: Very-low-density lipoprotein.

Adapted with permission from [188].

© Elsevier (1994).

Table 3. Clinical studies of 4 g/day prescription omega-3-acid ethyl esters for the treatment of patients with severe hypertriglyceridemia.

Study	Patients (n)	Duration (weeks)	Baseline TG; mg/dl (mmol/l)	Change from baseline (%)			Ref.
				TG	LDL-C	HDL-C
Harris et al.	42	16	926 (10.4)	-45	+31	+13	[79]
McKeone et al.	40	6	500–2000 (5.6–22.6)	-26	No data	+14	[189]
Abe et al.	27	>28	876 (9.8)	-47	No data	NS	[190]
Pownall et al.	40	6	801 (9.0)	-39	+17	NS	[191]
Westphal et al.	12	6	1210 (13.6)	-40	+46	NS	[192]
Stalenhoef et al.	28	12	872 (9.8)	-37	+30	+11	[193]

HDL-C: HDL cholesterol; LDL-C: LDL cholesterol; NS: Not significant; TG: Triglyceride.

Adapted from [85].

Table 4. Effects of prescription omega-3-acid ethyl esters plus simvastatin on lipid and lipoprotein parameters compared with simvastatin alone.

Parameter	BL	EOT	Median change (%)		BL	EOT	Median change (%)	p-value
	P-OM3 + simvastatin (n = 122)				Placebo + simvastatin (n = 132)
Non-HDL-C	137	123	-9.0		141	134	-2.2	<0.0001
TG	268	182	-29.5		271	260	-6.3	<0.0001
VLDL-C	52	37	-27.5		52	49	-7.2	<0.05
ApoB	86	80	-4.2		87	85	-1.9	<0.05
HDL-C	46	48	+3.4		43	44	-1.2	<0.05
LDL-C	91	88	+0.7		88	85	-2.8	0.05

ApoB: Apolipoprotein B-100; BL: Baseline (mg/dl); EOT: End of treatment (mg/dl); HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; Median change (%): Median percent change from baseline; P-OM3: Prescription omega-3-acid ethyl esters; TG: Triglycerides; VLDL: Very-low-density lipoprotein cholesterol.

Adapted from [92].

Table 5. Ongoing prescription omega-3-acid ethyl esters trials registered at The US NIH.

Trial	Dose of P-OM3	Duration of treatment	ClinicalTrials.gov ID
A Randomized Controlled Trial of Mycophenolate Mofetil in Patients With IgA Nephropathy	Not listed	2 years	NCT00318474
An Evaluation of Simvastatin 20 mg Plus Omacor^® 4 g Compared to Simvastatin 20 mg Plus Placebo in Subjects With Mixed Dyslipidemia	4 g/day	6 weeks – crossover (12 weeks total)	NCT00487591
The Effect of Fish Oil Supplementation on Endothelial Function, Heart Rate Variability and Intimal Media Thickness of Patients With Coronary Artery Disease	2 g/day	12 months	NCT00454493
Omega-3 Fatty Acids for High Triglycerides in HIV-Infected Patients	Not listed	Not listed	NCT00346697
Omacor for Perimenopausal Depression & Somatic Symptoms for Perimenopause	Not listed	8 weeks	NCT00517972
Niacin, N-3 Fatty Acids and Insulin Resistance	Not listed	Not listed	NCT00286234
Lovaza’s Effect on the Activation of Platelets (LEAP)	1, 2, 4, 8 g/day	24 weeks	NCT00515541
Vascular and Lipid Effects of Omega-3 Fatty Acids in People With Moderately Elevated Triglycerides (OMEGA)	Not listed	8 weeks	NCT00504309
Fish Oil for Atrial Fibrillation – Effects and Mechanisms	Not listed	6 months	NCT00552084
Omega-3 Fatty Acids for the Prevention of Atrial Fibrillation After Cardiac Surgery	Not listed	Not listed	NCT00446966
The Outcome Reduction With Initial Glargine Intervention Trial (ORIGIN)	Not listed	Not listed	NCT00069784
A Study of Cardiovascular Events in Diabetes (ASCEND)	1g/day	Not listed	NCT00135226
Effects of n-3 PUFA and Rosuvastatin on Mortality-Morbidity of Patients With Symptomatic CHF (GISSI-HF)	1 g/day	Not listed	NCT00336336
Effect of Omega 3-Fatty Acids on the Reduction of Sudden Cardiac Death After Myocardial Infarction	1 g/day	12 months	NCT00251134
Evaluation of Efficacy and Safety of Omacor (Omega-3-Acid Ethyl Esters) as Add-on Therapy in Hypertriglyceridemic Subjects Treated With Antara (Fenofibrate)	Not listed	Not listed	NCT00246636
Evaluation of Efficacy and Safety of Omacor, Co-Administered With Atorvastatin, in Subjects with Hypertriglyceridemia	4 g/day	16 weeks	NCT00435045
Evaluation of Efficacy and Safety of Lovaza (Omega-3-Acid-Ethyl Esters) in Recurrent, Symptomatic Atrial Fibrillation	4 g/day	6 months	NCT00402363
Omacor for the Treatment of Vascular Dysfunction in Patients with Type 2 Diabetes Mellitus	4 g/day	6 weeks	NCT00328536
Omacor and Cardiovascular Risk Factors in HIV Patients on HAART Treatment	4 g/day	12 weeks	NCT00296153
Lovaza Therapy of Peripheral Arterial Disease	4 g/day	12 months	NCT00569686
Effect of Omacor on Triglycerides in HIV Infected Subjects	Not listed	12 weeks	NCT00598910
Study to Evaluate the Efficacy and Safety of Omega-3 Fatty Acids for the Treatment of IgA Nephropathy	4 g/day	24 months	NCT00549692
Use of Omega-3 Fatty Acids (Fish Oil) in Patients with Chronic Hepatitis C Infection	4 g/day	To be determined by hepatitis C genotype	NCT00547716
Effects of Fatty Acid Delivery on Heart Metabolism and Function in Type 2 Diabetes	4 g/day	4 months	NCT00577590
Efficacy of Omega-3 Fatty Acids on Borderline Personality Disorder	1680, 3360 mg/day	12 weeks	NCT00437099
Effects of Fish Oils on Inflammation and Insulin Resistance	4 g/day	12 weeks	NCT00579436
Omega 3 Fatty Acids and Atrial Fibrillation	1g/day	6 months	NCT00508248

P-OM3: Prescription omega-3-acid ethyl esters.

Data from [205].

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