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

*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.

*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).

*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).

HDL-C: HDL cholesterol; LDL-C: LDL cholesterol; NS: Not significant; TG: Triglyceride.
Adapted from reference 85.

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.

HDL-C: HDL cholesterol; LDL-C: LDL cholesterol; NS: Not significant; TG: Triglyceride.
Adapted from reference 85.

P-OM3: Prescription omega-3-acid ethyl esters.
Data from reference 198.

Authors and Disclosures

Harold E Bays,¹ Ann P Tighe,² Richard Sadovsky,³ Michael H Davidson <sup>4

1</sup>Louisville Metabolic and Atherosclerosis Research Center (L-MARC), Louisville, KY
²Scientiae, LLC, New York, NY
³SUNY-Downstate Medical Center at Brooklyn, Brooklyn, NY
⁴University of Chicago, Pritzker School of Medicine, Chicago, IL

Disclosure: Dr Harold Bays has served as a Clinical Investigator for, and has received research grants from, pharmaceutical companies including: Abbott, Amylin, Alteon, Arena, AstraZeneca, Aventis, Bayer, Boehringer Ingelheim, Boehringer Mannheim, Bristol Myers Squibb, Ciba Geigy, Daiichi Sankyo, Eli Lilly, Esperion, Fujisawa, GelTex, Genetech, GlaxoSmithKline, Hoechst Roussel, Hoffman LaRoche, InterMune, KOS, Kowa, Lederle, Marion Merrell Dow, Merck, Merck Schering Plough, Miles, Microbia, Novartis, Obecure, Orexigen, Parke Davis, Pfizer, Pliva, Purdue, Reliant, Roche, Rorer, Regeneron, Sandoz, Sanofi, Sciele, Searle, Shionogi, Schering Plough, SmithKline Beacham, Takeda, TAP, UpJohn, Upsher Smith, Warner Lambert and Wyeth-Ayerst. He has also served as a consultant, speaker, and/or advisor to, and for, pharmaceutical companies such as Abbott, Arena, AstraZeneca, Aventis, Bayer, Bristol Myers Squibb, Daiichi Sankyo, KOS, Merck, Merck Schering Plough, Metabasis Therapeutics, Microbia, Novartis, Nicox, Ortho-McNeil, Parke Davis, Pfizer, Reliant, Roche, Sandoz, Sanofi Aventis, Schering Plough, SmithKline Beacham, Takeda, UpJohn, and Warner Lambert. Funding from Reliant Pharmaceuticals, Inc., a subsidiary of SmithKline Beecham Corporation, helped support the preparation of this paper for publication. Dr Tighe is an employee of Scientiae, which provides editorial assistance to Reliant Pharmaceuticals. Dr Sadovsky has served as a consultant for Reliant. Dr Davidson has received grant/research support or honoraria, or served as a consultant or on the speakers' bureau, for Abbott, AstraZeneca, Bristol-Myers Squibb, Kos and Reliant.

Sidebar: Examples of Factors Contributing to Hypertriglyceridemia

Primary

• Familial hypertriglyceridemia (hyperprebetalipoproteinemia)
  
  

• Familial combined hyperlipidemia
  
  

• Lipoprotein lipase deficiency
  
  

• Apolipoprotein CII deficiency
  
  

• Familial dysbetalipoproteinemia

Secondary

• Adipocyte hypertrophy and/or visceral adipose tissue accumulation (adiposopathy)
  
  

• A positive energy-balance diet with a high fat or high glycemic index content
  
  

• Acute alcohol consumption with fatty liver
  
  

• Diabetes mellitus
  
  

• Hypothyroidism
  
  

• Nephrotic syndrome

Medications

• Antiretroviral regimens, especially for HIV disease
  
  

• Psychotropic medications, such as some phenothiazines and second-generation antipsychotics
  
  

• Bile acid sequestrants
  
  

• Non-selective ß-blockers, thiazide diuretics
  
  

• Cyclophosphamide
  
  

• Oral estrogens
  
  

• Glucocorticosteroids
  
  

• Tamoxifen
  
  

• Isotretinoin

Sidebar: Key Issues

• Severe hypertriglyceridemia (≥500 mg/dl [5.65 mmol/l]) should be treated to reduce the risk of pancreatitis.
  
  

• The omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) effectively lower triglyceride (TG) levels.
  
  

• In patients with persistent elevation of TG levels (>200 mg/dl [2.26 mmol/l]) while on statin therapy, the treatment goal is to reduce non-HDL-C levels in patients with persistent hypertriglyceridemia.
  
  

• In statin-treated patients, omega-3 fatty acids may effectively reduce non-HDL-C levels.
  
  

• The mechanisms of action of EPA and DHA are not completely known, but appear to include a combination of decreased hepatic secretion of TG-containing lipoproteins (very low-density lipoprotein) and enhanced clearance of TG from circulating TG-containing lipoproteins (VLDL and chylomicrons) from the bloodstream.