Prescription Omega-3 Fatty Acids and Their Lipid Effects: Physiologic Mechanisms of Action and Clinical Implications

Harold E Bays; Ann P Tighe; Richard Sadovsky; Michael H Davidson

Expert Rev Cardiovasc Ther. 2008;6(3):391-409.

Five-year View

Due to its unique benefits, interest continues to increase regarding new formulations of omega-3 fatty acids, such as potential combination agents with other lipid-altering drugs, such as niacin, fibrates and statins.

In addition to its therapeutic use for hypertriglyceridemia, omega-3 fatty acids, in general, have also been studied for potential efficacy in the treatment of numerous noncardiac conditions, such as inflammatory and arthritic disorders,^{[122,123,124,125,126,127,128,129,130,131,132,133,134,135]} neurologic/neuropsychiatric disorders,^{[122,136,137,138,139,140,141,142,143,144,145,146,147,148]} ophthalmic disorders,^[149,150] women's health issues,^{[135,151,152]} cancer^{[153,154,155]} and other disorders.^{[156,157,158]} However, the benefits in treating many, if not most of these noncardiac disorders have yet to be definitively proven. Results of future clinical trials should better define the efficacy and safety of omega-3 fatty acid therapy in these conditions.

In contrast to noncardiovascular effects, the evidence supporting the cardiovascular benefits of omega-3 fatty acid therapy is more compelling,^[27,77,159] and includes possible antidysrhythmic,^{[160,161,162,163,164,165,166,167,168,169,170]} antiatherogenic,^{[82,171,172,173,174,175,176,177,178,179]} antithrombotic^{[172,180,181,182,183,184]} and anti-inflammatory endothelial effects.^{[183,185,186,187]} However, yet again, more definitive evidence is needed in order to substantiate these potential benefits. As such, ongoing clinical trials are seeking to better define these potential beneficial effects of omega-3 fatty acids. Specific ongoing cardiac and noncardiac P-OM3 trials are registered at ClinicalTrials.gov^[198] and summarized in Table 5 .

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Acknowledgments

Writing assistance was utilized in the production of this manuscript. The authors thank Scientiae, LLC, and DesignWrite, LLC, for editorial assistance with the manuscript.

Reprint Address

Harold E Bays Medical Director/President, Louisville Metabolic and Atherosclerosis Research Center (L-MARC), 3288 Illinois Avenue, Louisville, KY 40213. E-mail: hbaysmd@aol.com .

Expert Rev Cardiovasc Ther. 2008;6(3):391-409. © 2008 Expert Reviews Ltd.
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Cite this: Prescription Omega-3 Fatty Acids and Their Lipid Effects: Physiologic Mechanisms of Action and Clinical Implications - Medscape - Mar 01, 2008.

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 references 27, 28.

Physical-chemical Characteristics of Lipoproteins
Lipoprotein	Density (g/ml)	Lipid (%)*
Lipoprotein	Density (g/ml)	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 reference 188.
© Elsevier (1994).

Physical-chemical Characteristics of Lipoproteins
Lipoprotein	Density (g/ml)	Lipid (%)*
Lipoprotein	Density (g/ml)	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

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.
Study	Patients (n)	Duration (weeks)	Baseline TG; mg/dl (mmol/l)	TG	LDL-C	HDL-C	Ref.
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 reference 85.

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
Parameter	P-OM3 + simvastatin (n = 122)			Placebo + simvastatin (n = 132)			p-value
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 reference 92.

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.
Study	Patients (n)	Duration (weeks)	Baseline TG; mg/dl (mmol/l)	TG	LDL-C	HDL-C	Ref.
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 reference 85.

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 reference 198.

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