while the present invention is capable of being embodied in various forms , the description below of several embodiments is made with the understanding that the present disclosure is to be considered as an exemplification of the invention , and is not intended to limit the invention to the specific embodiments illustrated . headings are provided for convenience only and are not to be construed to limit the invention in any manner . embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading . the use of numerical values in the various quantitative values specified in this application , unless expressly indicated otherwise , are stated as approximations as though the minimum and maximum values within the stated ranges were both preceded by the word “ about .” in this manner , slight variations from a stated value can be used to achieve substantially the same results as the stated value . as used herein , the terms “ about ” and “ approximately ” when referring to a numerical value shall have their plain and ordinary meanings to one skilled in the pertinent art at issue . also , the disclosure of ranges is intended as a continuous range including every value between the minimum and maximum values recited as well as any ranges that can be formed by such values . also disclosed herein are any and all ratios ( and ranges of any such ratios ) that can be formed by dividing a recited numeric value into any other recited numeric value . accordingly , the skilled person will appreciate that many such ratios , ranges , and ranges of ratios can be unambiguously derived from the numerical values presented herein and in all instances such ratios , ranges , and ranges of ratios represent various embodiments of the present invention . without being held to a particular theory , it is believed that eicosapentaenoic acid is a competitive inhibitor of arachidonate metabolism in the cyclo - oxygenase pathway and that reduction of pgd 2 levels by epa attenuates niacin flushing . in addition to attenuating niacin - induced flushing , it is also believed , without being bound by theory , that epa can provide beneficial cardiovascular effects such as reduced platelet aggregation , vasodilation and plaque stabilization , which are independent of an in crease in hdl - c as seen at low doses of niacin . as such , in one embodiment of the invention , a combination of low dose niacin with epa ( or pre - treatment with epa followed by low dose niacin ) is provided . in another embodiment , such therapy provides effective cardiovascular benefits with reduced side effects compared to conventional niacin dosing . in one embodiment , compositions of the invention comprise eicosapentaenoic acid or a pharmaceutically acceptable ester , derivative , conjugate or salt thereof , or mixtures of any of the foregoing , collectively referred to herein as “ epa .” the term “ pharmaceutically acceptable ” in the present context means that the substance in question does not produce unacceptable toxicity to the subject or interaction with other components of the composition . in one embodiment , the epa comprises an eicosapentaenoic acid ester . in another embodiment , the epa comprises a c 1 - c 5 alkyl ester of eicosapentaenoic acid , in another embodiment , the epa comprises eicosapentaenoic acid ethyl ester , eicosapentaenoic acid methyl ester , eicosapentaenoic acid propyl ester , or eicosapentaenoic acid butyl ester . in another embodiment , the epa is in the form of ethyl - epa , lithium epa , mono -, di - or triglyceride epa or any other ester or salt of epa , or the free acid form of epa . the epa may also be in the form of a 2 - substituted derivative or other derivative which slows down its rate of oxidation but does not otherwise change its biological action to any substantial degree . in another embodiment , the epa comprises an epa - fatty acid conjugate , in one embodiment , the epa - fatty acid conjugates are diesters formed between epa , a second fatty acid or epa , and a linker as shown in structures ( i )-( ii ), wherein r 1 and r 2 are acyl fatty acid groups derived from epa or another fatty acid . r 1 and r 2 may both be derived from epa ( epa - epa ) or may be derived from epa and a different fatty acid ( epa - fatty acid ). r 3 is generally either hydrogen , fully hydrocarbon , or containing heteroatoms , and is preferably a c 1 - c 4 alkyl group . the linker may be any suitable diol including , for example , an alkyl diol such as 1 , 3 - propanediol , an alkenyl diol , an alkynyl diol , an aryl diol such as 1 , 4 - dihydroxybenzene ( hydroquinone ), etc ., or a geminal diol , for example a c 1 - c 4 alkyl geminal diol , an alkyl geminal diol , etc . the second fatty acid may be any suitable fatty acid including for example epa , la , aa , ala , sta , eta , or dpa . synthesis of the diester conjugate is accomplished according to methods well known in the art , including for example , using metals , metal - chlorides , or organic acids as catalysts ; using fatty acid chlorides such as epa - chloride , γ - linolenic acid chloride ( gla - chloride ), dihomo - γ - linolenic acid chloride ( dgla - chloride ), linoleic acid chloride ( la - chloride ), arachidonic acid chloride ( aa - chloride ), conjugated linoleic acid chloride ( cla - chloride ), ala - chloride , sta - chloride , eta - chloride , dpa - chloride , etc . ; and the use of immobilized enzymes as catalysts . in another embodiment , a composition of the present invention includes a mixture of epa - fatty acid diesters . in a related embodiment , compositions of the present invention include less than 20 % epa - dha conjugate , less than 15 % epa - dha conjugate , less than 10 % epa - dha conjugate , less than 9 % epa - dha conjugate , less than 8 % epa - dha conjugate , less than 7 % epa - dha conjugate , less than 6 % epa - dha conjugate , less than 5 % epa - dha conjugate , less than 4 % epa - dha conjugate , less than 3 % epa - dha conjugate , less than 2 % epa - dha conjugate , less than 1 % epa - dha conjugate , less than 0 . 5 % epa - dha conjugate , or less than 0 . 1 % epa - dha conjugate , by weight of all fatty acids present . in another embodiment , a composition of the present invention includes at least 96 % epa - epa conjugate , at least 97 % epa - epa conjugate , at least 98 % epa - epa conjugate , or at least 99 % epa - epa conjugate by weight of all fatty acids present . in another embodiment , a composition of the present invention contains not more than 10 %, not more than 9 %, not more than 8 %, not more than 7 %, not more than 6 %, not more than 5 %, not more than 4 %, not more than 3 %, not more than 2 %, not more than 1 %, not more than 0 . 6 %, not more than 0 . 5 %, not more than 0 . 4 %, not more than 0 . 3 %, not more than 0 . 2 , or not more than 0 . 1 % of any epa - fatty acid conjugate other than epa - epa diester by weight of all fatty acids present . in another embodiment , epa is present in a composition of the invention in an amount of about 50 mg to about 5000 mg , about 75 mg to about 2500 mg , or about 100 mg to about 1000 mg , for example about 75 mg , about 100 mg , about 125 mg , about 150 mg , about 175 mg , about 200 mg , about 225 mg , about 250 mg , about 275 mg , about 300 mg , about 325 mg , about 350 mg , about 375 mg , about 400 mg , about 425 mg , about 450 mg , about 475 mg , about 500 mg , about 525 mg , about 550 mg , about 575 mg , about 600 mg , about 625 mg , about 650 mg , about 675 mg , about 700 mg , about 725 mg , about 750 mg , about 775 mg , about 800 mg , about 825 mg , about 850 mg , about 875 mg , about 900 mg , about 925 mg , about 950 mg , about 975 mg , about 1000 mg , about 1025 mg , about 1050 mg , about 1075 mg , about 1100 mg , about 1025 mg , about 1050 mg , about 1075 mg , about 1200 mg , about 1225 mg , about 1250 mg , about 1275 mg , about 1300 mg , about 1325 mg , about 1350 mg , about 1375 mg , about 1400 mg , about 1425 mg , about 1450 mg , about 1475 mg , about 1500 mg , about 1525 mg , about 1550 mg , about 1575 mg , about 1600 mg , about 1625 mg , about 1650 mg , about 1675 mg , about 1700 mg , about 1725 mg , about 1750 mg , about 1775 mg , about 1800 mg , about 1825 mg , about 1850 mg , about 1875 mg , about 1900 mg , about 1925 mg , about 1950 mg , about 1975 mg , about 2000 mg , about 2025 mg , about 2050 mg , about 2075 mg , about 2100 mg , about 2125 mg , about 2150 mg , about 2175 mg , about 2200 mg , about 2225 mg , about 2250 mg , about 2275 mg , about 2300 mg , about 2325 mg , about 2350 mg , about 2375 mg , about 2400 mg , about 2425 mg , about 2450 mg , about 2475 mg or about 2500 mg . in one embodiment , a composition of the invention contains not more than about 10 %, not more than about 9 %, not more than about 8 %, not more than about 7 %, not more than about 6 %, not more than about 5 %, not more than about 4 %, not more than about 3 %, not more than about 2 %, not more than about 1 %, or not more than about 0 . 5 %, by weight , docosahexaenoic acid or derivative thereof , by weight of the total composition or of all fatty acids present . in another embodiment , a composition of the invention contains substantially no docosahexaenoic acid or derivative thereof . in still another embodiment , a composition of the invention contains no docosahexaenoic acid or derivative thereof . in another embodiment , epa comprises at least 60 %, at least 70 %, at least 80 %, at least 90 %, at least 95 %, at least 97 %, at least 98 %, at least 99 %, or 100 %, by weight of all fatty acids present in a composition . in another embodiment , a composition of the invention contains less than 10 %, less than 9 %, less than 8 %, less than 7 %, less than 6 %, less than 5 %, less than 4 %, less than 3 %, less than 2 %, less than 1 %, less than 0 . 5 %, less than 0 . 25 %, by weight of the total composition or by weight of the total fatty acid content , of any fatty acid other than epa . illustrative examples of a “ fatty acid other than epa ” include linolenic acid ( la ), arachidonic acid ( aa ), docosahexaenoic acid ( dha ), alpha - linolenic acid ( ala ), stearadonic acid ( sta ), eicosatrienoic acid ( eta ) and / or docosapentaenoic acid ( dpa ). in another embodiment , a composition of the invention has one or more of the following features : ( a ) eicosapentaenoic acid ethyl ester represents at least 96 %, at least 97 %, or at least 98 %, by weight , of all fatty acids present in the composition ; the composition contains not more than 4 %, not more than 3 %, or not more than 2 %, by weight , of total fatty acids other than eicosapentaenoic acid ethyl ester ; ( c ) the composition contains not more than 0 . 6 %, 0 . 5 %, or 0 . 4 % of any individual fatty acid other than eicosapentaenoic acid ethyl ester ; the composition has a refractive index ( 20 ° c .) of about 1 to about 2 , about 1 . 2 to about 1 . 8 or about 1 . 4 to about 1 . 5 ; the composition has a specific gravity ( 20 ° c .) of about 0 . 8 to about 1 . 0 , about 0 . 85 to about 0 . 95 or about 0 . 9 to about 0 . 92 ; contains not more than 20 ppm , 15 ppm or 10 ppm heavy metals , contains not more than 5 ppm , 4 ppm , 3 ppm , or 2 ppm arsenic , and / or has a peroxide value not more than 5 , 4 , 3 , or 2 meq / kg . in one embodiment , a composition of the invention comprises nicotinic acid ( also referred to herein as “ niacin ”, “ 3 - pyridine carboxamide ” and / or “ vitamin b3 ”). in another embodiment , the nicotinic acid is in crystalline form . in one embodiment , the epa and nicotinic acid are not covalently linked . in one embodiment , the nicotinic acid is present in a composition of the invention in an amount of about 5 mg to about 1200 mg , about 10 mg to about 800 mg , about 15 mg to about 750 mg , about 20 mg to about 500 mg , about 25 mg to about 400 mg , or about 50 mg to about 200 mg , for example in an amount of about 25 mg , about 50 mg , 75 mg , about 100 mg , about 125 mg , about 150 mg , about 175 mg , about 200 mg , about 225 mg , about 250 mg , about 275 mg , about 300 mg , about 325 mg , about 350 mg , about 375 mg , about 400 mg , about 425 mg , about 450 mg , about 475 mg , about 500 mg , about 525 mg , about 550 mg , about 575 mg , about 600 mg , about 625 mg , about 650 mg , about 675 mg , about 700 mg , about 725 mg , about 750 mg , about 775 mg , about 800 mg , about 825 mg , about 850 mg , about 875 mg , about 900 mg , about 925 mg , about 950 mg , about 975 mg , about 1000 mg , about 1025 mg , about 1050 mg , about 1075 mg , about 1100 mg , about 1125 mg , about 1150 mg , about 1175 mg , or about 1200 mg . in various embodiments , the nicotinic acid can be in immediate - release , extended - release or sustained - release form . the term “ immediate - release ” in the present context refers to nicotinic acid formulations from which nicotinic acid , upon ingestion by a human subject , is absorbed at a rate of about 400 to about 600 mg / hr , for example about 500 mg / hr . typically , immediate - release nicotinic acid is not coated with any release - modifying barrier or layer . the immediate - release nicotinic acid can be in crystalline form . niacor ® ( upsher - smith laboratories ) is an illustrative immediate - release nicotinic acid formulation . the term “ extended - release nicotinic acid ” herein refers to nicotinic acid formulations from which nicotinic acid , upon ingestion by a human subject , is absorbed at a rate of about 80 to about 200 mg / hr , for example about 100 mg / hr . niaspan ® ( kos pharmaceuticals ) is an illustrative extended - release nicotinic acid formulation . the term “ sustained - release ” in the present context refers to nicotinic acid formulations from which the nicotinic acid , when ingested by a human subject , is absorbed at a rate of about 25 mg / hr to about 75 mg / hr , for example about 50 mg / hr . in one embodiment , nicotinic acid and epa are present in a composition of the invention , or are co - administered in a weight ratio of about 1 : 1000 to about 1000 : 1 , about 1 : 500 to about 500 : 1 , about 1 : 100 to about 100 : 1 , about 1 : 50 to about 50 : 1 , about 1 : 25 to about 25 : 1 , about 1 : 10 to about 10 : 1 , about 1 : 5 to about 5 : 1 , about 1 : 4 to about 4 : 1 about 1 : 3 to about 3 : 1 , about 1 : 2 to about 2 : 1 or about 1 : 1 . in another embodiment , an additional cardiovascular agent is co - formulated with epa and / or nicotinic acid , or is co - administered with epa and / or nicotinic acid . the additional cardiovascular agent can illustratively include a 3 - hydroxy - 3 - methyl glutaryl coenzyme a ( hmg - coa ) reductase inhibitor ( also referred to as a “ statin ”), a fibrate , or a bile salt sequesterant or binding resin . in one embodiment , a composition of the invention comprises epa and a statin . non - limiting examples of suitable statins that can be used in accordance with various embodiments of the invention include prevastatin , lovastatin , simvastatin , atorvastatin , fluvastatin , pitavastatin and rosuvastatin and salts thereof . in a related embodiment , the composition contains not more than 10 % dha or derivative thereof , if any . in another related embodiment , the composition contains no dha or derivative thereof such as ethyl - dha . a statin , if present in a composition or compositions of the invention , can be present in an amount of about 1 to about 300 mg , about 5 mg to about 200 mg , about 10 mg to about 180 mg , about 20 mg to about 150 mg , about 30 mg about 100 mg , or about 40 mg to about 60 mg . pravastatin ( pravachol ®; manufactured by bristol - myers squibb , princeton , n . j .) is hydrophilic and is best absorbed without food . prevastatin can be present in a composition of the invention ( or co - administered therewith ) in an amount of about 1 to about 80 mg , about 5 mg to 60 mg , or about 10 mg to about 40 mg . lovastatin ( mevacor ®; by merck , whitehouse station , n . j .) can be present in a composition of the invention ( or co - administered therewith ) in an amount of about 1 mg to about 100 mg , about 5 mg to about 80 mg , or about 10 mg to about 40 mg . simvastatin ( zocor ® by merck , whitehouse station , n . j .) can be present in a composition of the invention ( or co - administered therewith ) in an amount of about 1 mg to about 80 mg per day , about 2 mg to 60 about mg , or about 5 mg to about 40 mg . atorvastatin ( lipitor ® by pfizer , new york , n . y .) can be present in a composition of the invention ( or co - administered therewith ) in an amount of about 1 mg to about 100 mg , about 5 mg to about 80 mg , or about 10 mg to about 40 mg . fluvastatin , ( lescol ® by novartis , new york , n . y .) can be present in a composition of the invention ( or co - administered therewith ) in an amount of about 5 mg to about 160 mg , about 10 mg to about 120 mg , or about 20 mg to about 80 mg . rosuvastatin ( crestor ® by astra zeneca , wilmington , del .) the dosage of rosuvastatin , in the combined administration of concentrated omega - 3 fatty acids is from 1 to 80 mg , preferably 2 to 60 mg , and more preferably from 5 to 40 mg per dosage of concentrated omega - 3 fatty acids . in another embodiment , a pharmaceutical composition consisting of , or consisting essentially of , epa , nicotinic acid ( and optionally a statin and / or a fibrate ) and one or more pharmaceutically acceptable excipients is provided . in another embodiment , a pharmaceutical composition containing active ingredients consisting of , or consisting essentially of , epa and nicotinic acid niacin is provided . in another embodiment , a pharmaceutical composition containing active ingredients consisting of , or consisting essentially of , epa , nicotinic acid and a statin is provided . in one embodiment , compositions of the invention are orally deliverable . the terms “ orally deliverable ” or “ oral administration ” herein include any form of delivery of a therapeutic agent or a composition thereof to a subject wherein the agent or composition is placed in the mouth of the subject , whether or not the agent or composition is swallowed . thus “ oral administration ” includes buccal and sublingual as well as esophageal administration . in some embodiments , compositions of the invention are in the form of solid dosage forms . non - limiting examples of suitable solid dosage forms include tablets ( e . g . suspension tablets , bite suspension tablets , rapid dispersion tablets , chewable tablets , melt tablets , effervescent tablets , bilayer tablets , etc ), caplets , capsules ( e . g . a soft or a hard gelatin capsule filled with solid and / or liquids ), powder ( e . g . a packaged powder , a dispensable powder or an effervescent powder ), lozenges , sachets , cachets , troches , pellets , granules , microgranules , encapsulated microgranules , powder aerosol formulations , or any other solid dosage form reasonably adapted for oral administration . epa , nicotinic acid , a statin and / or any other desired active ingredient can be co - formulated in the same dosage unit , or can be individually formulated in separate dosage units . the terms “ dose unit ” and “ dosage unit ” herein refer to a portion of a pharmaceutical composition that contains an amount of a therapeutic agent suitable for a single administration to provide a therapeutic effect . such dosage units may be administered one to a plurality ( i . e . 1 to about 10 , 1 to 8 , 1 to 6 , 1 to 4 or 1 to 2 ) of times per day , or as many times as needed to elicit a therapeutic response . in one embodiment , a composition of the invention comprises nicotinic acid and / or a statin dispersed or suspended in epa , wherein the dispersion or suspension is present in a capsule ( for example gelatin or hpmc capsule ), sachet , or other dosage form or carrier as described herein . in another embodiment , the dispersion or suspension is substantially uniform . in still another embodiment , where co - administration of two or more dosage units is desired , the epa is present in a first dosage unit , for example a suspension in a capsule , and the nicotinic acid is present in second dosage unit , for example a tablet . optionally , any desired statin can be present in a third composition . in another embodiment , composition ( s ) of the invention can be in the form of liquid dosage forms or dose units to be imbibed directly or they can be mixed with food or beverage prior to ingestion . non - limiting examples of suitable liquid dosage forms include solutions , suspension , elixirs , syrups , liquid aerosol formulations , etc . in one embodiment , compositions of the invention , upon storage in a closed container maintained at room temperature , refrigerated ( e . g . about 5 to about 5 - 10 ° c .) temperature , or frozen for a period of about 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , or 12 months , exhibit at least about 90 %, at least about 95 %, at least about 97 . 5 %, or at least about 99 % of the active ingredient ( s ) originally present therein . compositions of the invention optionally comprise one or more pharmaceutically acceptable excipients . the term “ pharmaceutically acceptable excipient ” herein means any substance , not itself a therapeutic agent , used as a carrier or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a unit dose of the composition , and that does not produce unacceptable toxicity or interaction with other components in the composition . compositions of the invention optionally comprise one or more pharmaceutically acceptable diluents as excipients . suitable diluents illustratively include , either individually or in combination , lactose , including anhydrous lactose and lactose monohydrate ; starches , including directly compressible starch and hydrolyzed starches ( e . g ., celutab ™ and emdex ™); mannitol ; sorbitol ; xylitol ; dextrose ( e . g ., cerelose ™ 2000 ) and dextrose monohydrate ; dibasic calcium phosphate dihydrate ; sucrose - based diluents ; confectioner &# 39 ; s sugar ; monobasic calcium sulfate monohydrate ; calcium sulfate dihydrate ; granular calcium lactate trihydrate ; dextrates ; inositol ; hydrolyzed cereal solids ; amylose ; celluloses including microcrystalline cellulose , food grade sources of α - and amorphous cellulose ( e . g ., rexcel ™) and powdered cellulose ; calcium carbonate ; glycine ; bentonite ; polyvinylpyrrolidone ; and the like . such diluents , if present , constitute in total about 5 % to about 99 %, about 10 % to about 85 %, or about 20 % to about 80 %, of the total weight of the composition . compositions of the invention optionally comprise one or more pharmaceutically acceptable disintegrants as excipients . suitable disintegrants include , either individually or in combination , starches , including sodium starch glycolate ( e . g ., explotab ™ of penwest ) and pregelatinized corn starches ( e . g ., national ™ 1551 , national ™ 1550 , and colocorn ™ 1500 ), clays ( e . g ., veegum ™ hv ), celluloses such as purified cellulose , microcrystalline cellulose , methylcellulose , carboxymethylcellulose and sodium carboxymethylcellulose , croscarmellose sodium ( e . g ., ac - di - sol ™ of fmc ), alginates , crospovidone , and gums such as agar , guar , xanthan , locust bean , karaya , pectin and tragacanth gums . such disintegrants , if present , typically comprise in total about 0 . 2 % to about 30 %, about 0 . 2 % to about 10 %, or about 0 . 2 % to about 5 %, of the total weight of the composition . compositions of the invention optionally comprise one or more antioxidants . illustrative antioxidants include sodium ascorbate and vitamin e ( tocopherol ). one or more antioxidants , if present , are typically present in a composition of the invention in an amount of about 0 . 001 % to about 5 %, about 0 . 005 % to about 2 . 5 %, or about 0 . 01 % to about 1 %, by weight . compositions of the invention optionally comprise one or more pharmaceutically acceptable binding agents or adhesives as excipients . such binding agents and adhesives can impart sufficient cohesion to a powder being tableted to allow for normal processing operations such as sizing , lubrication , compression and packaging , but still allow the tablet to disintegrate and the composition to be absorbed upon ingestion . suitable binding agents and adhesives include , either individually or in combination , acacia ; tragacanth ; sucrose ; gelatin ; glucose ; starches such as , but not limited to , pregelatinized starches ( e . g ., national ™ 1511 and national ™ 1500 ); celluloses such as , but not limited to , methylcellulose and carmellose sodium ( e . g ., tylose ™); alginic acid and salts of alginic acid ; magnesium aluminum silicate ; peg ; guar gum ; polysaccharide acids ; bentonites ; povidone , for example povidone k - 15 , k - 30 and k - 29 / 32 ; polymethacrylates ; hpmc ; hydroxypropylcellulose ( e . g ., klucel ™); and ethylcellulose ( e . g ., ethocel ™). such binding agents and / or adhesives , if present , constitute in total about 0 . 5 % to about 25 %, about 0 . 75 % to about 15 %, or about 1 % to about 10 %, of the total weight of the composition . compositions of the invention optionally comprise one or more pharmaceutically acceptable wetting agents as excipients . non - limiting examples of surfactants that can be used as wetting agents in compositions of the invention include quaternary ammonium compounds , for example benzalkonium chloride , benzethonium chloride and cetylpyridinium chloride , dioctyl sodium sulfosuccinate , polyoxyethylene alkylphenyl ethers , for example nonoxynol 9 , nonoxynol 10 , and octoxynol 9 , poloxamers ( polyoxyethylene and polyoxypropylene block copolymers ), polyoxyethylene fatty acid glycerides and oils , for example polyoxyethylene ( 8 ) caprylic / capric mono - and diglycerides ( e . g ., labrasol ™ of gattefossé ), polyoxyethylene ( 35 ) castor oil and polyoxyethylene ( 40 ) hydrogenated castor oil ; polyoxyethylene alkyl ethers , for example polyoxyethylene ( 20 ) cetostearyl ether , polyoxyethylene fatty acid esters , for example polyoxyethylene ( 40 ) stearate , polyoxyethylene sorbitan esters , for example polysorbate 20 and polysorbate 80 ( e . g ., tween ™ 80 of ici ), propylene glycol fatty acid esters , for example propylene glycol laurate ( e . g ., lauroglycol ™ of gattefossé ), sodium lauryl sulfate , fatty acids and salts thereof , for example oleic acid , sodium oleate and triethanolamine oleate , glyceryl fatty acid esters , for example glyceryl monostearate , sorbitan esters , for example sorbitan monolaurate , sorbitan monooleate , sorbitan monopalmitate and sorbitan monostearate , tyloxapol , and mixtures thereof . such wetting agents , if present , constitute in total about 0 . 25 % to about 15 %, about 0 . 4 % to about 10 %, or about 0 . 5 % to about 5 %, of the total weight of the composition . compositions of the invention optionally comprise one or more pharmaceutically acceptable lubricants ( including anti - adherents and / or glidants ) as excipients . suitable lubricants include , either individually or in combination , glyceryl behapate ( e . g ., compritol ™ 888 ); stearic acid and salts thereof , including magnesium ( magnesium stearate ), calcium and sodium stearates ; hydrogenated vegetable oils ( e . g ., sterotex ™); colloidal silica ; talc ; waxes ; boric acid ; sodium benzoate ; sodium acetate ; sodium fumarate ; sodium chloride ; dl - leucine ; peg ( e . g ., carbowax ™ 4000 and carbowax ™ 6000 ); sodium oleate ; sodium lauryl sulfate ; and magnesium lauryl sulfate . such lubricants , if present , constitute in total about 0 . 1 % to about 10 %, about 0 . 2 % to about 8 %, or about 0 . 25 % to about 5 %, of the total weight of the composition . suitable anti - adherents include talc , cornstarch , dl - leucine , sodium lauryl sulfate and metallic stearates . talc is a anti - adherent or glidant used , for example , to reduce formulation sticking to equipment surfaces and also to reduce static in the blend . talc , if present , constitutes about 0 . 1 % to about 10 %, about 0 . 25 % to about 5 %, or about 0 . 5 % to about 2 %, of the total weight of the composition . glidants can be used to promote powder flow of a solid formulation . suitable glidants include colloidal silicon dioxide , starch , talc , tribasic calcium phosphate , powdered cellulose and magnesium trisilicate . compositions of the present invention optionally comprise one or more flavoring agents , sweetening agents , and / or colorants . flavoring agents useful in the present invention include , without limitation , acacia syrup , alitame , anise , apple , aspartame , banana , bavarian cream , berry , black currant , butter , butter pecan , butterscotch , calcium citrate , camphor , caramel , cherry , cherry cream , chocolate , cinnamon , citrus , citrus punch , citrus cream , cocoa , coffee , cola , cool cherry , cool citrus , cyclamate , cylamate , dextrose , eucalyptus , eugenol , fructose , fruit punch , ginger , glycyrrhetinate , glycyrrhiza ( licorice ) syrup , grape , grapefruit , honey , isomalt , lemon , lime , lemon cream , magnasweet ®, maltol , mannitol , maple , menthol , mint , mint cream , mixed berry , nut , orange , peanut butter , pear , peppermint , peppermint cream , prosweet ® powder , raspberry , root beer , rum , saccharin , safrole , sorbitol , spearmint , spearmint cream , strawberry , strawberry cream , stevia , sucralose , sucrose , swiss cream , tagatose , tangerine , thaumatin , tutti fruitti , vanilla , walnut , watermelon , wild cherry , wintergreen , xylitol , and combinations thereof , for example , anise - menthol , cherry - anise , cinnamon - orange , cherry - cinnamon , chocolate - mint , honey - lemon , lemon - lime , lemon - mint , menthol - eucalyptus , orange - cream , vanilla - mint , etc . sweetening agents that can be used in the present invention include , for example , acesulfame potassium ( acesulfame k ), alitame , aspartame , cyclamate , cylamate , dextrose , isomalt , magnasweet ®, maltitol , mannitol , neohesperidine dc , neotame , prosweet ® powder , saccharin , sorbitol , stevia , sucralose , sucrose , tagatose , thaumatin , xylitol , and the like . flavoring agents , sweetening agents , and / or colorants can be present in compositions of the invention in any suitable amount , for example about 0 . 01 % to about 10 %, about 0 . 1 % to about 8 %, or about 1 % to about 5 %, by weight . compositions of the invention optionally comprise a suspending agent . non - limiting illustrative examples of suitable suspending agents include silicon dioxide , bentonite , hydrated aluminum silicate ( e . g . kaolin ) and mixtures thereof . one or more suspending agents are optionally present in compositions of the invention in a total amount of about 0 . 01 % to about 3 . 0 %, about 0 . 1 % to about 2 . 0 %, or about 0 . 25 % to about 1 . 0 %, by weight the foregoing excipients can have multiple roles as is known in the art . for example , starch can serve as a filler as well as a disintegrant . the classification of excipients above is not to be construed as limiting in any manner . excipients categorized in any manner may also operate under various different categories of excipients as will be readily appreciated by one of ordinary skill in the art . in one embodiment , compositions of the invention are useful for treatment and / or prevention of a cardiovascular - related disease or disorder . the term “ cardiovascular - related disease or disorder ” herein refers to any disease or disorder of the heart or blood vessels ( i . e . arteries and veins ) or any symptom thereof . non - limiting examples of a cardiovascular - related disease or disorder include hypertriglyceridemia , hypercholesterolemia , mixed dyslipidemia , coronary heart disease , vascular disease , stroke , atherosclerosis , arrhythmia , hypertension , myocardial infarction , and other cardiovascular events . the term “ treatment ” in relation a given disease or disorder , includes , but is not limited to , inhibiting the disease or disorder , for example , arresting the development of the disease or disorder ; relieving the disease or disorder , for example , causing regression of the disease or disorder ; or relieving a condition caused by or resulting from the disease or disorder , for example , relieving , preventing or treating symptoms of the disease or disorder . the term “ prevention ” in relation to a given disease or disorder means : preventing the onset of disease development if none had occurred , preventing the disease or disorder from occurring in a subject that may be predisposed to the disorder or disease but has not yet been diagnosed as having the disorder or disease , and / or preventing further disease / disorder development if already present . in one embodiment , the present invention provides a method of blood lipid therapy comprising administering to a subject in need thereof 1 to a plurality of dosage units comprising a composition or compositions as disclosed herein . in another embodiment , the subject being treated has a baseline triglyceride level , prior to treatment with a composition of the present invention , greater than about 150 mg / dl or greater than about 175 mg / dl , for example about 200 mg / dl to about 600 mg / dl or about 200 mg / dl to about 500 mg / dl . in a related embodiment , upon treatment with a composition of the present invention , for example over a period of about 1 to about 200 weeks , about 1 to about 100 weeks , about 1 to about 80 weeks , about 1 to about 50 weeks , about 1 to about 40 weeks , about 1 to about 20 weeks , about 1 to about 15 weeks , about 1 to about 10 weeks , about 1 to about 5 weeks , about 1 to about 2 weeks or about 1 week , the subject or subjects exhibit one or more of : ( a ) reduced triglyceride levels compared to baseline , ( b ) reduced apo b levels compared to baseline , ( c ) increased hdl - c levels compared to baseline , ( d ) no increase in ldl - c levels compared to baseline , ( e ) a reduction in ldl - c levels compared to baseline , ( f ) a reduction in non - hdl - c levels compared to baseline , and / or ( g ) no flushing or reduced flushing compared to : ( i ) treatment with more than 1 g per day of nicotinic acid , ( ii ) treatment with more than 3 g per day of nicotinic acid , or ( iii ) treatment with a combination of about 1 to about 3 g per day of nicotinic acid plus about 4 g of omacor ®. each omacor ® capsule contains 900 mg of the ethyl ester of omega - 3 fatty acids — approximately 465 mg epa and 375 mg dha — and 4 mg α - tocopherol . relevant serum total cholesterol , hdl - c , non - hdl - c , and ldl - c levels can be measured in accordance with any of the well known analytical methods available in the art , for example using a synchron 4cx ® 4ce to perform a blood panel analysis . in one embodiment , subjects fast for up to 12 hours prior to blood sample collection . in another embodiment , upon treatment with a composition of the present invention , the subject or subjects exhibit one or more of ( a ) a reduction in triglyceride level of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, or at least about 50 % as compared to baseline ; ( b ) a reduction in non - hdl - c levels of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, or at least about 50 % as compared to baseline ; ( c ) an increase in hdl - c levels of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, or at least about 50 % as compared to baseline ; ( d ) a reduction in ldl - c levels of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, or at least about 50 % as compared to baseline ; ( e ) a reduction in apo b levels of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, or at least about 50 % as compared to baseline ; and / or ( f ) no flushing or reduced flushing compared to : treatment with 1 g or more per day of nicotinic acid or 3 g or more per day of nicotinic acid , or a combination of about 1 to about 3 g per day of nicotinic acid plus omacor ®, for example about 4 g per day of omacor ®. in another embodiment , the present invention provides a method of treating or preventing primary hypercholesteremia and / or mixed dyslipidemia ( fredrickson types iia and iib ) in a subject in need thereof , comprising administering to the subject one or more compositions as disclosed herein . in a related embodiment , the present invention provides a method of reducing triglyceride levels in a subject or subjects when treatment with a statin or nicotinic acid extended - release monotherapy is considered inadequate ( frederickson type iv hyperlipidemia ). in another embodiment , the present invention provides a method of treating or preventing risk of recurrent nonfatal myocardial infarction in a subject with a history of myocardial infarction , comprising administering to the subject one or more compositions as disclosed herein . in another embodiment , the present invention provides a method of slowing progression of or promoting regression of atherosclerotic disease in a subject in need thereof , comprising administering to a subject in need thereof one or more compositions as disclosed herein . in another embodiment , the present invention provides a method of treating or preventing very high serum triglyceride levels ( e . g . types iv and v hyperlipidemia ) in a subject in need thereof , comprising administering to the subject one or more compositions as disclosed herein . in another embodiment , the present invention provides a method of treating subjects having very high serum triglyceride levels ( e . g . greater than 1000 mg / dl or greater than 2000 mg / dl ) and that are at risk of developing pancreatitis , comprising administering to the subject one or more compositions as disclosed herein . in another embodiment optionally associated with any of the methods disclosed herein , administration of any composition or compositions disclosed herein to a subject results in an absence of flushing or reduced flushing by comparison with administration of conventional high dose ( e . g . & gt ; 1 . 5 g , for example about 2 g to about 3 g maintenance dose ) immediate - release , extended - release or sustained - release nicotinic acid therapy or combination therapy . the term “ flushing ” herein includes facial flushing or flushing associated with any other area of the skin , for example redness , itching , burning and / or tingling sensations that typically occur on the face , neck , chest , and back . in another embodiment , administration of a composition of the invention to a subject or plurality of subjects results in no flushing , tolerable flushing or decreased flushing by comparison with : ( a ) 3 g or more per day of nicotinic acid therapy , ( b ) 2 g or more per day of nicotinic acid therapy , ( c ) 1 g or more per day of nicotinic acid therapy , ( d ) at least 2 g , 3 g or 4 g of omacor ® per day plus greater than 1 g per day of nicotinic acid therapy , or ( e ) at least 2 g , 3 g or 4 g omacor ® per day plus 2 g or more per day of nicotinic acid therapy or 3 g or more per day of nicotinic acid therapy . in another embodiment optionally associated with any of the methods disclosed herein , administration of any of the compositions of the invention to a subject or plurality of subjects results in substantially no or no liver toxicity or reduced liver toxicity compared to administration of extended - release or sustained - release nicotinic acid dosage units to a subject or plurality of subjects in an amount of more than 1 . 5 g per day or greater , for example 2 g per day or greater , or 3 g per day or greater . in still another embodiment , administration of any of the compositions disclosed herein to a subject results in no flushing or decreased flushing , and no increase in ldl or reduced increase in ldl by comparison with daily co - administration of four 1 g omacor ® capsules plus 3 g of immediate - release nicotinic acid . in still another embodiment , administration of any of the compositions disclosed herein to a subject results in increased subject compliance and or decreased subject withdrawal from treatment by comparison with daily administration of four 1 g omacor ® capsules plus 3 g of immediate - release nicotinic acid . in another embodiment , subject compliance (% of subjects substantially complying with the prescribed dosage regimen ) is greater than 70 %, greater than 80 %, greater than 90 %, greater than 93 %, greater than 95 %, or greater than 98 %, for example over a period of 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 or 20 days , and / or subject withdrawal or non - compliance due to flushing (% of subjects substantially not complying with the prescribed dosage regimen due to flushing effects ) is less than 8 %, less than 7 %, less than 5 % or less than 3 %, for example over a period of 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 or 20 days . one embodiment of the invention comprises treating or preventing a cardiovascular - related disease or disorder as defined herein by administering to a subject in need thereof about 50 mg to about 1500 mg per day of immediate - release nicotinic acid , about 50 mg to about 5 g per day of epa , for example ethyl ester epa containing no dha , and / or about 10 mg to about 300 mg per day of a statin . in another embodiment , a composition of the invention is administered to a subject in an amount sufficient to provide a daily maintenance dose of nicotinic acid of about 5 mg to about 1500 mg , about 10 mg to about 1000 mg , about 20 mg to about 800 mg , about 50 mg to about 500 mg , or about 75 mg to about 450 mg , for example in a daily amount of about 25 mg , about 50 mg , 75 mg , about 100 mg , about 125 mg , about 150 mg , about 175 mg , about 200 mg , about 225 mg , about 250 mg , about 275 mg , about 300 mg , about 325 mg , about 350 mg , about 375 mg , about 400 mg , about 425 mg , about 450 mg , about 475 mg , about 500 mg , about 525 mg , about 550 mg , about 575 mg , about 600 mg , about 625 mg , about 650 mg , about 675 mg , about 700 mg , about 725 mg , about 750 mg , about 775 mg , about 800 mg , about 825 mg , about 850 mg , about 875 mg , about 900 mg , about 925 mg , about 950 mg , about 975 mg , about 1000 mg , about 1025 mg , about 1050 mg , about 1075 mg , about 1100 mg , about 1125 mg , about 1150 mg , about 1175 mg , about 1200 mg , about 1225 mg , about 1250 mg , about 1275 mg , about 1300 mg , about 1325 mg , about 1350 mg , about 1375 mg , about 1400 mg , about 1425 mg , about 1450 mg , or about 1475 mg . in one embodiment , a composition of the invention is administered to a subject in an amount sufficient to provide a daily epa dose of about 1 mg to about 10 , 000 mg , 25 about 5000 mg , about 50 to about 3000 mg , about 75 mg to about 2500 mg , or about 100 mg to about 1000 mg , for example about 75 mg , about 100 mg , about 125 mg , about 150 mg , about 175 mg , about 200 mg , about 225 mg , about 250 mg , about 275 mg , about 300 mg , about 325 mg , about 350 mg , about 375 mg , about 400 mg , about 425 mg , about 450 mg , about 475 mg , about 500 mg , about 525 mg , about 550 mg , about 575 mg , about 600 mg , about 625 mg , about 650 mg , about 675 mg , about 700 mg , about 725 mg , about 750 mg , about 775 mg , about 800 mg , about 825 mg , about 850 mg , about 875 mg , about 900 mg , about 925 mg , about 950 mg , about 975 mg , about 1000 mg , about 1025 mg , about 1050 mg , about 1075 mg , about 1100 mg , about 1025 mg , about 1050 mg , about 1075 mg , about 1200 mg , about 1225 mg , about 1250 mg , about 1275 mg , about 1300 mg , about 1325 mg , about 1350 mg , about 1375 mg , about 1400 mg , about 1425 mg , about 1450 mg , about 1475 mg , about 1500 mg , about 1525 mg , about 1550 mg , about 1575 mg , about 1600 mg , about 1625 mg , about 1650 mg , about 1675 mg , about 1700 mg , about 1725 mg , about 1750 mg , about 1775 mg , about 1800 mg , about 1825 mg , about 1850 mg , about 1875 mg , about 1900 mg , about 1925 mg , about 1950 mg , about 1975 mg , about 2000 mg , about 2025 mg , about 2050 mg , about 2075 mg , about 2100 mg , about 2125 mg , about 2150 mg , about 2175 mg , about 2200 mg , about 2225 mg , about 2250 mg , about 2275 mg , about 2300 mg , about 2325 mg , about 2350 mg , about 2375 mg , about 2400 mg , about 2425 mg , about 2450 mg , about 2475 mg or about 2500 mg . in another embodiment , the statin is administered to the subject in a daily amount of about 1 to about 300 mg , about 5 mg to about 200 mg , about 10 mg to about 180 mg , about 20 mg to about 150 mg , about 30 mg about 100 mg , or about 40 mg to about 60 mg . nicotinic acid , epa and / or a statin can be administered as a co - formulation or as individual dosage units . where the nicotinic acid , epa and / or a statin are co - administered as separate dosage units , each dosage unit can be administered to a subject over a time period of 24 hours , 18 hours , 12 hours , 10 hours , 8 hours , 6 hours , 4 hours , 2 hours , 1 hour , 0 . 5 hours , or substantially simultaneously . in another embodiment , nicotinic acid , epa and / or a statin can be administered sequentially . for example , epa can be administered to a subject as a sole agent during an epa loading period . the loading period can be , for example , 1 day , 2 days , 4 days , 6 days , 2 weeks , 3 weeks , 4 weeks , 5 weeks , 6 weeks , 7 weeks , 8 weeks , 9 weeks or 10 weeks . after any such loading period , nicotinic acid and / or statin treatment can be initiated together with epa or in place of epa treatment . in another embodiment , epa is administered to a subject in the morning , for example from about 4 am to about 10 am , and low dosee nicotinic acid ( i . e . less than 1500 mg is administered to the same subject in the afternoon or evening , for example from about 12 pm to about 11 pm . in a related embodiment , upon treatment in accordance with the present invention , for example over a period of about 1 to about 200 weeks , about 1 to about 100 weeks , about 1 to about 80 weeks , about 1 to about 50 weeks , about 1 to about 40 weeks , about 1 to about 20 weeks , about 1 to about 15 weeks , about 1 to about 12 weeks , about 1 to about 10 weeks , about 1 to about 5 weeks , about 1 to about 2 weeks or about 1 week , the subject or subject group exhibits one or more of the following outcomes : ( i ) an increase in apo a - i / apo b ratio compared to baseline ; ( o ) a reduction in fasting plasma glucose ( fpg ) compared to baseline ; ( p ) a reduction in hemoglobin a 1c ( hba 1c ) compared to baseline ; ( q ) a reduction in homeostasis model insulin resistance compared to baseline ; ( r ) a reduction in lipoprotein associated phospholipase a2 compared to baseline ; ( v ) a reduction in high sensitivity c - reactive protein ( hscrp ) compared to baseline ; ( x ) an increase in red blood cell membrane epa compared to baseline ; and / or ( y ) a reduction or increase in one or more of serum phospholipid and / or red blood cell content of docosahexaenoic acid ( dha ), docosapentaenoic acid ( dpa ), arachidonic acid ( aa ), palmitic acid ( pa ), staeridonic acid ( sa ) or oleic acid ( oa ) compared to baseline . in one embodiment , methods of the present invention comprise measuring baseline levels of one or more markers set forth in ( a )-( y ) above prior to dosing the subject or subject group . in another embodiment , the methods comprise administering a composition as disclosed herein to the subject after baseline levels of one or more markers set forth in ( a )-( y ) are determined , and subsequently taking an additional measurement of said one or more markers . in another embodiment , upon treatment with a composition of the present invention , for example over a period of about 1 to about 200 weeks , about 1 to about 100 weeks , about 1 to about 80 weeks , about 1 to about 50 weeks , about 1 to about 40 weeks , about 1 to about 20 weeks , about 1 to about 15 weeks , about 1 to about 12 weeks , about 1 to about 10 weeks , about 1 to about 5 weeks , about 1 to about 2 weeks or about 1 week , the subject or subject group exhibits any 2 or more of , any 3 or more of , any 4 or more of , any 5 or more of , any 6 or more of , any 7 or more of , any 8 or more of , any 9 or more of , any 10 or more of , any 11 or more of , any 12 or more of , any 13 or more of , any 14 or more of , any 15 or more of , any 16 or more of , any 17 or more of , any 18 or more of , any 19 or more of , any 20 or more of , any 21 or more of , any 22 or more of , any 23 or more , any 24 or more , or all 25 of outcomes ( a )-( y ) described immediately above . in another embodiment , upon treatment with a composition of the present invention , the subject or subject group exhibits one or more of the following outcomes : ( a ) a reduction in triglyceride level of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, at least about 50 %, at least about 55 % or at least about 75 % ( actual % change or median % change ) as compared to baseline ; ( b ) a less than 30 % increase , less than 20 % increase , less than 10 % increase , less than 5 % increase or no increase in non - hdl - c levels or a reduction in non - hdl - c levels of at least about 1 %, at least about 3 %, at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, at least about 50 %, at least about 55 % or at least about 75 % ( actual % change or median % change ) as compared to baseline ; ( c ) an increase in hdl - c levels of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, at least about 50 %, at least about 55 % or at least about 75 % ( actual % change or median % change ) as compared to baseline ; ( d ) a less than 30 % increase , less than 20 % increase , less than 10 % increase , less than 5 % increase or no increase in ldl - c levels or a reduction in ldl - c levels of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, at least about 50 %, at least about 55 %, at least about 55 % or at least about 75 % ( actual % change or median % change ) as compared to baseline ; ( e ) a decrease in apo b levels of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, at least about 50 %, at least about 55 % or at least about 75 % ( actual % change or median % change ) as compared to baseline ; ( f ) a reduction in vldl levels of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, at least about 50 %, or at least about 100 % ( actual % change or median % change ) compared to baseline ; ( g ) an increase in apo a - i levels of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, at least about 50 %, or at least about 100 % ( actual % change or median % change ) compared to baseline ; ( h ) an increase in apo a - i / apo b ratio of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, at least about 50 %, or at least about 100 % ( actual % change or median % change ) compared to baseline ; ( i ) a reduction in lipoprotein ( a ) levels of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, at least about 50 %, or at least about 100 % ( actual % change or median % change ) compared to baseline ; ( j ) a reduction in mean ldl particle number of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, at least about 50 %, or at least about 100 % ( actual % change or median % change ) compared to baseline ; ( k ) an increase in mean ldl particle size of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, at least about 50 %, or at least about 100 % ( actual % change or median % change ) compared to baseline ; ( l ) a reduction in remnant - like particle cholesterol of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, at least about 50 %, or at least about 100 % ( actual % change or median % change ) compared to baseline ; ( m ) a reduction in oxidized ldl of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, at least about 50 %, or at least about 100 % ( actual % change or median % change ) compared to baseline ; ( n ) a reduction in fasting plasma glucose ( fpg ) of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, at least about 50 %, or at least about 100 % ( actual % change or median % change ) compared to baseline ; ( o ) a reduction in hemoglobin a 1c ( hba 1c ) of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, or at least about 50 % ( actual % change or median % change ) compared to baseline ; ( p ) a reduction in homeostasis model index insulin resistance of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, at least about 50 %, or at least about 100 % ( actual % change or median % change ) compared to baseline ; ( q ) a reduction in lipoprotein associated phospholipase a2 of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, at least about 50 %, or at least about 100 % ( actual % change or median % change ) compared to baseline ; ( r ) a reduction in intracellular adhesion molecule - 1 of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, at least about 50 %, or at least about 100 % ( actual % change or median % change ) compared to baseline ; ( s ) a reduction in interleukin - 2 of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, at least about 50 %, or at least about 100 % ( actual % change or median % change ) compared to baseline ; ( t ) a reduction in plasminogen activator inhibitor - 1 of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, at least about 50 %, or at least about 100 % ( actual % change or median % change ) compared to baseline ; ( u ) a reduction in high sensitivity c - reactive protein ( hscrp ) of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, at least about 50 %, or at least about 100 % ( actual % change or median % change ) compared to baseline ; ( v ) an increase in serum phospholipid epa of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, at least about 50 %, at least about 100 %, at least about 200 % or at least about 400 % ( actual % change or median % change ) compared to baseline ; ( w ) an increase in serum phospholipid and / or red blood cell membrane epa of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, r at least about 50 %, at least about 100 %, at least about 200 %, or at least about 400 % ( actual % change or median % change ) compared to baseline ; ( x ) a reduction or increase in one or more of serum phospholipid and / or red blood cell dha , dpa , aa , pa and / or oa of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, at least about 50 %, at least about 55 % or at least about 75 % ( actual % change or median % change ) compared to baseline ; and / or ( y ) a reduction in total cholesterol of at least about 5 %, at least about 10 %, at least about 15 %, at least about 20 %, at least about 25 %, at least about 30 %, at least about 35 %, at least about 40 %, at least about 45 %, at least about 50 %, at least about 55 % or at least about 75 % ( actual % change or median % change ) compared to baseline . in one embodiment , methods of the present invention comprise measuring baseline levels of one or more markers set forth in ( a )-( y ) prior to dosing the subject or subject group . in another embodiment , the methods comprise administering a composition as disclosed herein to the subject after baseline levels of one or more markers set forth in ( a )-( y ) are determined , and subsequently taking a second measurement of the one or more markers as measured at baseline for comparison thereto . in another embodiment , upon treatment with a composition of the present invention , for example over a period of about 1 to about 200 weeks , about 1 to about 100 weeks , about 1 to about 80 weeks , about 1 to about 50 weeks , about 1 to about 40 weeks , about 1 to about 20 weeks , about 1 to about 15 weeks , about 1 to about 12 weeks , about 1 to about 10 weeks , about 1 to about 5 weeks , about 1 to about 2 weeks or about 1 week , the subject or subject group exhibits any 2 or more of , any 3 or more of , any 4 or more of , any 5 or more of , any 6 or more of , any 7 or more of , any 8 or more of , any 9 or more of , any 10 or more of , any 11 or more of , any 12 or more of , any 13 or more of , any 14 or more of , any 15 or more of , any 16 or more of , any 17 or more of , any 18 or more of , any 19 or more of , any 20 or more of , any 21 or more of , any 22 or more of , any 23 or more of , any 24 or more of , or all 26 or more of outcomes ( a )-( y ) described immediately above . parameters ( a )-( y ) can be measured in accordance with any clinically acceptable methodology . for example , triglycerides , total cholesterol , hdl - c and fasting blood sugar can be sample from serum and analyzed using standard photometry techniques . vldl - tg , ldl - c and vldl - c can be calculated or determined using serum lipoprotein fractionation by preparative ultracentrifugation and subsequent quantitative analysis by refractometry or by analytic ultracentrifugal methodology . apo a1 , apo b and hscrp can be determined from serum using standard nephelometry techniques . lipoprotein ( a ) can be determined from serum using standard turbidimetric immunoassay techniques . ldl particle number and particle size can be determined using nuclear magnetic resonance ( nmr ) spectrometry . remnants lipoproteins and ldl - phospholipase a2 can be determined from edta plasma or serum and serum , respectively , using enzymatic immunoseparation techniques . oxidized ldl , intercellular adhesion molecule - 1 and interleukin - 2 levels can be determined from serum using standard enzyme immunoassay techniques . these techniques are described in detail in standard textbooks , for example tietz fundamentals of clinical chemistry , 6 th ed . ( burtis , ashwood and borter eds . ), wb saunders company . in one embodiment , subjects fast for up to 12 hours prior to blood sample collection , for example about 10 hours . in another embodiment , the invention provides the use of nicotinic acid , epa and optionally a statin or fibrate in the manufacture of a medicament for treatment or prevention of a cardiovascular - related disease or disorder such as hypertriglyceridemia , hypercholesterolemia , mixed dyslipidemia , coronary heart disease , vascular disease , stroke , atherosclerosis , arrhythmia , hypertension , myocardial infarction , and other cardiovascular events . in one embodiment , the composition contains not more than 10 % dha , if any . in another embodiment , the composition contains no dha . in another embodiment , the invention provides a pharmaceutical composition comprising nicotinic acid and epa for the treatment and / or prevention of a cardiovascular - related disease or disorder , wherein the composition contains not more than 10 % dha , if any . in a related embodiment , the composition contains no dha . in one embodiment , the invention provides a method of treating a cardiovascular - related disease or disorder in a subject in need thereof comprising providing the subject with epa pre - treatment followed by one or more doses of nicotinic acid . in one embodiment , the dose of nicotinic acid is sufficient to provide the subject with not more than 3000 mg , not more than 2000 mg , not more than 1000 mg , not more than 750 mg , not more than 500 mg , or not more than 250 mg of nicotinic acid . the term “ pre - treatment ” in the present context means providing the subject with one or more doses of epa about 0 . 1 to about 96 hours , about 1 to about 48 hours , about 2 to about 24 hours , about 3 to about 15 hours , or about 4 to about 12 hours prior to providing the subject with an initial dose of nicotinic acid as set forth herein , for example a dose of not more than 3000 mg , not more than 2000 mg , not more than 1000 mg , not more than 750 mg , not more than 500 mg , or not more than 250 mg of nicotinic acid . in a related embodiment , the subject is pre - treated with epa in an amount of about 1 mg to about 5000 mg per day , 1 mg to about 4000 mg per day , 1 mg to about 3000 mg per day , 1 mg to about 2000 mg per day , or 1 mg to about 1000 mg per day for a period of about 1 to about 30 days , 1 to about 20 days , 1 to about 15 days , 1 to about 10 days , 1 to about 8 days , 1 to about 6 days , 1 to about 4 days or 1 to about 2 days . in another embodiment , the invention provides a method of preventing or reducing niacin - induced flushing in a subject comprising ( a ) providing a subject that is to begin niacin therapy , ( b ) pre - treating the subject with epa and ( c ) administering niacin to the subject after said pre - treatment . in one embodiment , the niacin is administered at a dose of not more than 3000 mg , not more than 2000 mg , not more than 1000 mg , not more than 750 mg , not more than 500 mg , or not more than 250 mg per day . in another embodiment , the subject is pre - treated with epa in an amount of about 1 mg to about 5000 mg per day , 1 mg to about 4000 mg per day , 1 mg to about 3000 mg per day , 1 mg to about 2000 mg per day , or 1 mg to about 1000 mg per day for a period of about 1 to about 30 days , 1 to about 20 days , 1 to about 15 days , 1 to about 10 days , 1 to about 8 days , 1 to about 6 days , 1 to about 4 days or 1 to about 2 days . in another embodiment , the invention provides a method of reducing or attenuating niacin - induced flushing in a subject on niacin therapy , comprising ( a ) identifying a subject on niacin therapy and that is experiencing flushing and ( b ) administering epa to the subject . in one embodiment , the niacin is administered at a dose of not more than 3000 mg , not more than 2000 mg , not more than 1000 mg , not more than 750 mg , not more than 500 mg , or not more than 250 mg per day . in another embodiment , the epa is administered to the subject in an amount of about 1 mg to about 5000 mg per day , 1 mg to about 4000 mg per day , 1 mg to about 3000 mg per day , 1 mg to about 2000 mg per day , or 1 mg to about 1000 mg per day . in other embodiments , any of the methods disclosed herein are used in treatment or prevention of a subject or subjects that consume a traditional western diet . in one embodiment , the methods of the invention include a step of identifying a subject as a western diet consumer or prudent diet consumer and then treating the subject if the subject is deemed to consume a western diet . the term “ western diet ” herein refers generally to a typical diet consisting of , by percentage of total calories , about 45 % to about 50 % carbohydrate , about 35 to about 40 % fat , and about 10 % to about 15 % protein . a western diet may further be characterized by relatively high intakes of red and processed meats , sweets , refined grains , and desserts , for example where half or more or 70 % or more calories come from these sources . the following example is for illustrative purposes and is not to be construed as limiting the invention in any manner . an analysis was performed to assess the impact of red blood cell ( rbc ) epa incorporation on arachidonic acid formation . in various studies , patients were randomized , on a double - blind basis , to receive either placebo ( liquid paraffin ) or 0 . 5 1 , 2 or 4 g of 97 % pure ethyl - epa / day for 12 weeks . all the doses were administered in eight identical appearing capsules . rbcs were analyzed for epa and aa following in general the methodology of manku et al . m . s . manku , d . f . horrobin , y . s . huang and n . morse , fatty acids in plasma and red cell membranes in normal humans . lipids 18 ( 1983 ), pp . 906 - 908 ). venous blood was collected into a tube pretreated with edta and centrifuged at 1500 gav for 15 min . the plasma layer and the buffy coat were separated off and the red cells washed with an equal volume of 0 . 9 % saline . samples were stored at − 80 ° c . prior to analysis . on thawing , the rbcs were suspended in nacl / h2so4aq . ( 17 mmol / l nacl , 1 mmol / l sulfuric acid , 1 . 8 ml ), then shaken with methanol ( 3 ml ). chloroform ( 6 ml ) and c17 : o internal standard were added and the sample was stirred vigorously using a vortex mixer . after centrifugation at 2000 gav for 10 min , the lower layer containing the total lipid extract was carefully removed and filtered through anhydrous sodium sulphate before evaporation to dryness . the lipids were transesterified using sulfuric acid / methanol . the methyl esters were purified by loading onto an isohexane - washed silica column prior to elution with isohexane : diethyl ether ( 95 : 5 ). the resulting methyl esters of the fatty acids were separated and measured using a hewlett - packard hp5890 series ii plus gas chromatograph ( cp - wax 52cb 25m capillary column , chrompack uk ). the carrier gas was hydrogen ( 1 ml / min ). the oven temperature was programmed to rise from 1701 to 2201 ° c . at 41 ° c ./ min . the detector temperature was 300 ° c . and injector temperature 230 ° c . retention times and peak areas were automatically computed by hewlett - packard hp 3365 chem . station . as shown in fig1 , increasing rbc epa incorporation results in decreasing arachidonic acid formation . the figure below is a average for all data collected from several clinical studies .
the present invention relates to , inter alia , pharmaceutical compositions comprising eicosapentaenoic acid and / or derivatives thereof and nicotinic acid , to methods of manufacturing such compositions , and to therapeutic methods for treating carious diseases and disorders .