the alpha omega trial is a multicenter , double - blind , placebo - controlled trial with a 2  2 factorial design , which has been described in detail elsewhere ( 6,7 ) . in collaboration with cardiologists from 32 hospitals in the netherlands
, we recruited 4,837 patients aged 6080 years with a clinically diagnosed mi up to 10 years before randomization .
for the current study , the results of 1,014 patients with diabetes were analyzed ( supplementary fig .
these patients were randomly assigned to daily consumption of four different trial margarines for a period of 40 months .
the patients were randomly allocated to four groups and received either no additional n-3 fatty acids or 400 mg / day epa+dha , 2 g / day ala , or the combination .
the doses corresponded to recommended dietary allowances of those fatty acids . in trial margarines for active treatment groups ,
the margarines were developed by unilever research and development and could not be distinguished from each other in taste , odor , texture , and color .
the trial was conducted in accordance with the helsinki declaration and approved by one central medical ethics committee and by the committees of all participating hospitals . written informed consent was obtained from all patients . for logistical reasons , all patients used placebo margarine during the first 46 weeks after randomization , after which actual treatment started .
after randomization , the patients received eight blinded margarine tubs of 250 g every 12 weeks .
based on this information , the daily intakes of margarine and n-3 fatty acids were calculated .
an objective measure of compliance was obtained by determining fatty acids in plasma cholesteryl esters in random subgroups of patients at baseline and after 20 and 40 months of intervention .
our definition of diabetes was based on a physician s diagnosis , use of antidiabetic drugs , and/or elevated blood glucose , defined as a casual plasma glucose level of 7.0 mmol / l ( 126 mg / dl ) for patients who had fasted > 4 h or a level 11.1 mmol / l ( 200.0 mg / dl ) in patients who did not fast .
demographic factors , lifestyle , drug use , and medical history were assessed by questionnaire ( 6 ) .
medication was coded according to the anatomical therapeutic chemical ( atc ) classification system ( world health organization , 2009 ) , including atc code a10 for antidiabetic medication .
physical activity was assessed by the validated physical activity scale for the elderly ( pase ) questionnaire .
a patient was called physically active when he or she had at least 5 days per week of > 30 min / day of physical activities of at least three metabolic equivalents of task .
anthropometric measures , blood pressure , and heart rate were taken , and nonfasting blood was collected for determining serum lipids , plasma cholesteryl esters , and glucose ( 6 ) .
examinations were repeated in a random sample of 159 ( 15.7% ) patients after 20 months and after 40 months in 476 patients ( 46.9% ) who completed the trial before 1 january 2009 .
due to budget constraints , the remainder of the cohort filled out mailed questionnaires only .
all patients were followed for clinical events , including those who discontinued margarine use during the trial .
we monitored vital status of all patients using a computerized link with municipal registers with 100% coverage .
for fatal cases , death certificates were obtained from statistics netherlands and general practitioners filled out a standard form on primary and contributing causes of death .
additional information on fatal events was obtained from hospitals , nursing homes , and family members .
three members of the endpoint adjudication committee who were blinded for patient identity , treating physician , and allocated treatment coded the fatal events independently according to the 10th revision of the international classification of diseases . in the cases of disagreement , information about the underlying causes of death was discussed until consensus was reached . in the original trial protocol ,
the primary end point was fatal chd , and one of the secondary end points was sudden death , a proxy for fatal arrhythmias ( 6 ) . due to the low mortality rate ,
the steering committee approved the switch from primary to secondary end point for fatal chd , and the extension with placement of cardioverter defibrillators for the definition of sudden death , as described in the statistical analysis plan ( 7 ) .
fatal chd was defined as mortality from mi ( i20i25 ) , cardiac arrest ( i46 ) , and sudden death undefined ( r96 ) and the composite end - point ventricular arrhythmia  related events as nonfatal or fatal cardiac arrest ( i46 ) , sudden death ( r96 ) , and implantable cardioverter defibrillator placement ( 6,7 ) .
sudden death was extended with placement of cardioverter defibrillators because ventricular arrhythmias are the main cause of sudden death and cardioverter defibrillators are implanted in patients who are at high risk for developing ventricular arrhythmias ( 16,17 ) .
self - reported data on implantable cardioverter defibrillator placement were verified against hospital records by trained research nurses or the research physician .
all indications for implantable cardioverter defibrillator placement could be retrieved and verified from hospital discharge letters or by telephone with the departments of cardiology where the placements had taken place .
the definitions of fatal chd and of the composite end - point ventricular arrhythmia  related events include both fatal cardiac arrest ( i46 ) and sudden death undefined ( r96 ) ( 7 ) . to prevent overlap in these definitions
, we limited in the present analysis fatal chd to death from mi ( i20i25 ) .
baseline characteristics were compared among the four treatment groups of patients using anova or  tests , when appropriate .
time - to - event data were analyzed with the kaplan - meier method and the log - rank test .
the three treatment groups ( i.e. , epa - dha , ala , and epa - dha plus ala groups ) were compared with the placebo group for each outcome .
hazard ratios ( hrs ) and 95% cis were computed for ventricular arrhythmia  related events , fatal mi , and the combination of these two end points , using cox proportional hazard models .
no adjustments were made for multiple comparisons because only a priori  formulated hypotheses were tested based on animal experiments of the effects of n-3 fatty acids on atherosclerosis and cardiac arrhythmias ( 5 ) .
the alpha omega trial is a multicenter , double - blind , placebo - controlled trial with a 2  2 factorial design , which has been described in detail elsewhere ( 6,7 ) . in collaboration with cardiologists from 32 hospitals in the netherlands
, we recruited 4,837 patients aged 6080 years with a clinically diagnosed mi up to 10 years before randomization .
for the current study , the results of 1,014 patients with diabetes were analyzed ( supplementary fig .
these patients were randomly assigned to daily consumption of four different trial margarines for a period of 40 months .
the patients were randomly allocated to four groups and received either no additional n-3 fatty acids or 400 mg / day epa+dha , 2 g / day ala , or the combination .
the doses corresponded to recommended dietary allowances of those fatty acids . in trial margarines for active treatment groups ,
the margarines were developed by unilever research and development and could not be distinguished from each other in taste , odor , texture , and color .
the trial was conducted in accordance with the helsinki declaration and approved by one central medical ethics committee and by the committees of all participating hospitals . written informed consent was obtained from all patients .
for logistical reasons , all patients used placebo margarine during the first 46 weeks after randomization , after which actual treatment started .
after randomization , the patients received eight blinded margarine tubs of 250 g every 12 weeks .
based on this information , the daily intakes of margarine and n-3 fatty acids were calculated .
an objective measure of compliance was obtained by determining fatty acids in plasma cholesteryl esters in random subgroups of patients at baseline and after 20 and 40 months of intervention .
our definition of diabetes was based on a physician s diagnosis , use of antidiabetic drugs , and/or elevated blood glucose , defined as a casual plasma glucose level of 7.0 mmol / l ( 126 mg / dl ) for patients who had fasted > 4 h or a level 11.1 mmol / l ( 200.0 mg / dl ) in patients who did not fast .
demographic factors , lifestyle , drug use , and medical history were assessed by questionnaire ( 6 ) .
medication was coded according to the anatomical therapeutic chemical ( atc ) classification system ( world health organization , 2009 ) , including atc code a10 for antidiabetic medication .
physical activity was assessed by the validated physical activity scale for the elderly ( pase ) questionnaire .
a patient was called physically active when he or she had at least 5 days per week of > 30 min / day of physical activities of at least three metabolic equivalents of task .
anthropometric measures , blood pressure , and heart rate were taken , and nonfasting blood was collected for determining serum lipids , plasma cholesteryl esters , and glucose ( 6 ) .
examinations were repeated in a random sample of 159 ( 15.7% ) patients after 20 months and after 40 months in 476 patients ( 46.9% ) who completed the trial before 1 january 2009 . due to budget constraints ,
all patients were followed for clinical events , including those who discontinued margarine use during the trial .
we monitored vital status of all patients using a computerized link with municipal registers with 100% coverage .
for fatal cases , death certificates were obtained from statistics netherlands and general practitioners filled out a standard form on primary and contributing causes of death .
additional information on fatal events was obtained from hospitals , nursing homes , and family members .
three members of the endpoint adjudication committee who were blinded for patient identity , treating physician , and allocated treatment coded the fatal events independently according to the 10th revision of the international classification of diseases . in the cases of disagreement , information about the underlying causes of death was discussed until consensus was reached . in the original trial protocol ,
the primary end point was fatal chd , and one of the secondary end points was sudden death , a proxy for fatal arrhythmias ( 6 ) . due to the low mortality rate ,
the steering committee approved the switch from primary to secondary end point for fatal chd , and the extension with placement of cardioverter defibrillators for the definition of sudden death , as described in the statistical analysis plan ( 7 ) .
fatal chd was defined as mortality from mi ( i20i25 ) , cardiac arrest ( i46 ) , and sudden death undefined ( r96 ) and the composite end - point ventricular arrhythmia  related events as nonfatal or fatal cardiac arrest ( i46 ) , sudden death ( r96 ) , and implantable cardioverter defibrillator placement ( 6,7 ) .
sudden death was extended with placement of cardioverter defibrillators because ventricular arrhythmias are the main cause of sudden death and cardioverter defibrillators are implanted in patients who are at high risk for developing ventricular arrhythmias ( 16,17 ) .
self - reported data on implantable cardioverter defibrillator placement were verified against hospital records by trained research nurses or the research physician .
all indications for implantable cardioverter defibrillator placement could be retrieved and verified from hospital discharge letters or by telephone with the departments of cardiology where the placements had taken place .
the definitions of fatal chd and of the composite end - point ventricular arrhythmia  related events include both fatal cardiac arrest ( i46 ) and sudden death undefined ( r96 ) ( 7 ) . to prevent overlap in these definitions
, we limited in the present analysis fatal chd to death from mi ( i20i25 ) .
baseline characteristics were compared among the four treatment groups of patients using anova or  tests , when appropriate .
time - to - event data were analyzed with the kaplan - meier method and the log - rank test .
the three treatment groups ( i.e. , epa - dha , ala , and epa - dha plus ala groups ) were compared with the placebo group for each outcome .
hazard ratios ( hrs ) and 95% cis were computed for ventricular arrhythmia  related events , fatal mi , and the combination of these two end points , using cox proportional hazard models .
no adjustments were made for multiple comparisons because only a priori  formulated hypotheses were tested based on animal experiments of the effects of n-3 fatty acids on atherosclerosis and cardiac arrhythmias ( 5 ) .
data were analyzed with spss 17.0 statistical software ( spss inc . , chicago , il ) .
the definition of diabetes was made in 72.4% on the combination of elevated blood glucose levels , physician - diagnosed self - report , and drug treatment , in 14.4% on elevated glucose levels only , in 9.9% on self - report only , and in 3.4% on drug treatment only .
insulin was used by 273 ( 26.9% ) patients and 577 ( 56.9% ) used other antidiabetic medication , of whom 110 used both insulin and other antidiabetic medication .
the proportion of women was lowest in the placebo group and highest in the ala group , and 5 ( 1.9% ) of the 267 women used hormone replacement therapy .
the percentage of smokers was highest in the placebo group and lowest in the epa - dha plus ala group .
baseline characteristics of the 1,014 patients with an mi and diabetes , * according to n-3 fatty acid supplementation group data are means  sd unless otherwise indicated . as data for
a number of patients were missing from several variables ( bmi , 4 patients ; alcohol use , 1 patient ; and physical activity , 9 patients ) , some percentages are based on a smaller number than the column total . * diabetes was considered to be present if a patient reported having received the diagnosis from a physician , was taking antidiabetic drugs , or had an elevated plasma glucose level ( 7.0
mmol / l [ 126 mg / dl ] in the case of patients who had fasted more than 4 h or 11.1 mmol / l [ 200.0 mg / dl ] in the case of nonfasting patients ) . to
convert the values for cholesterol to milligrams per deciliter , divide by 0.02586 . to convert the values for triglycerides to milligrams per deciliter , divide by 0.01129 .
the bmi is the weight in kilograms divided by the square of the height in meters . *
* greater than or equal to three metabolic equivalent of task ( indicating at least moderate intensity for at least 30 min / day ) during 6 or 7 days / week .
the mean intake ( sd ) of the trial margarine was 18.6 ( 5.2 ) g / day ; 86.7% of the patients adhered fully to the protocol and consumed a mean of 20.7 ( 4.2 ) g / day .
patients in the two epa - dha groups received , on average , an additional amount of 223 ( 62 ) mg epa and 149 ( 42 ) mg of dha per day and those in the two groups of ala 1.9 ( 0.5 ) g / day .
plasma cholesteryl esters were determined as a measure of compliance . at the final examination ,
the effect of n-3 fatty acid supplementation on fatty acids in serum cholesteryl esters was compared with placebo ( supplementary fig .
2 ) . ala supplementation increased ala by 64.2% and epa by 40.8% ; epa - dha supplementation increased plasma epa by 49.8% and dha by 30.9% ; and epa - dha plus ala supplementation increased plasma ala by 67.4% , epa by 118.4% , and dha by 44.0% .
the median follow - up period was 40.7 months ( iqr 36.641.6 months ) , during which 3,195 person - years of follow - up were accumulated . during follow - up , 29 patients developed a ventricular arrhythmia 
related event , 2 died suddenly , 1 had a nonfatal cardiac arrest , 11 had a fatal cardiac arrest , and 15 had a cardioverter defibrillator implanted .
indications for these implantable cardioverter defibrillator placements were a left ventricular ejection fraction 35% ( n = 13 ; 87% ) , resuscitated ventricular fibrillation ( n = 1 ) , and ventricular tachycardia with a left ventricular ejection fraction of 45% ( n = 1 ) .
in addition , 27 patients died of mi , 23 from other vascular diseases , 34 from cancer , and 26 from other causes .
the kaplan - meier curves showed that both epa - dha and ala reduced ventricular arrhythmia  related events compared with placebo ( fig .
the lowest incidence was observed in patients who were randomized to the combined supplementation of epa - dha plus ala .
after adjustment for imbalances in age , sex , and current smoking , the combined supplementation of n-3 fatty acids reduced the ventricular arrhythmia  related events by 84% compared with placebo ( cumulative incidence at median follow - up 0.9 vs. 5.6% , fig .
similar effects were observed for the combined end - point cardiac arrest and sudden death ( 0.13 ; ci 0.021.09 ) and for placement of cardioverter defibrillators ( 0.19 : 0.021.55 ) .
kaplan - meier curves of ventricular arrhythmia  related events ( a ) , death from mi ( b ) , or both end points combined ( c ) .
the cumulative incidence of end points is shown in 1,014 patients with an mi and diabetes . patients
were randomly assigned to receive a margarine containing supplemental epa combined with dha , a margarine containing supplemental ala , a margarine containing both epa - dha and ala , or a placebo margarine .
unadjusted and adjusted hrs of n-3 fatty acid supplementation on end points in 1,014 patients with diabetes , according to n-3 fatty acid supplementation group * data are hrs with 95% cis and p values , with the use of cox proportional hazards models .
adjusted for age , sex , and smoking status . for fatal mi , the kaplan - meier curves did not differ significantly among the four groups ( fig .
after adjustment for confounders , the strongest , although not significant , effect was observed for epa - dha plus ala ( hr 0.53 ; 95% ci 0.151.81 ; table 2 ) .
the kaplan - meier curves for the composite end - point ventricular arrhythmia  related events and fatal mi showed the strongest effect for epa - dha plus ala ( fig .
after adjustment , these three n-3 fatty acids together reduced this combined end point by 72% ( cumulative incidence at median follow - up 2.6 vs. 8.5% , fig .
the definition of diabetes was made in 72.4% on the combination of elevated blood glucose levels , physician - diagnosed self - report , and drug treatment , in 14.4% on elevated glucose levels only , in 9.9% on self - report only , and in 3.4% on drug treatment only .
insulin was used by 273 ( 26.9% ) patients and 577 ( 56.9% ) used other antidiabetic medication , of whom 110 used both insulin and other antidiabetic medication .
the proportion of women was lowest in the placebo group and highest in the ala group , and 5 ( 1.9% ) of the 267 women used hormone replacement therapy .
the percentage of smokers was highest in the placebo group and lowest in the epa - dha plus ala group .
baseline characteristics of the 1,014 patients with an mi and diabetes , * according to n-3 fatty acid supplementation group data are means  sd unless otherwise indicated . as data for
a number of patients were missing from several variables ( bmi , 4 patients ; alcohol use , 1 patient ; and physical activity , 9 patients ) , some percentages are based on a smaller number than the column total . * diabetes was considered to be present if a patient reported having received the diagnosis from a physician , was taking antidiabetic drugs , or had an elevated plasma glucose level ( 7.0
mmol / l [ 126 mg / dl ] in the case of patients who had fasted more than 4 h or 11.1 mmol / l [ 200.0 mg / dl ] in the case of nonfasting patients ) . to
convert the values for cholesterol to milligrams per deciliter , divide by 0.02586 . to convert the values for triglycerides to milligrams per deciliter , divide by 0.01129 .
the bmi is the weight in kilograms divided by the square of the height in meters . *
* greater than or equal to three metabolic equivalent of task ( indicating at least moderate intensity for at least 30 min / day ) during 6 or 7 days / week .
the mean intake ( sd ) of the trial margarine was 18.6 ( 5.2 ) g / day ; 86.7% of the patients adhered fully to the protocol and consumed a mean of 20.7 ( 4.2 ) g / day .
patients in the two epa - dha groups received , on average , an additional amount of 223 ( 62 ) mg epa and 149 ( 42 ) mg of dha per day and those in the two groups of ala 1.9 ( 0.5 ) g / day .
plasma cholesteryl esters were determined as a measure of compliance . at the final examination ,
the effect of n-3 fatty acid supplementation on fatty acids in serum cholesteryl esters was compared with placebo ( supplementary fig .
2 ) . ala supplementation increased ala by 64.2% and epa by 40.8% ; epa - dha supplementation increased plasma epa by 49.8% and dha by 30.9% ; and epa - dha plus ala supplementation increased plasma ala by 67.4% , epa by 118.4% , and dha by 44.0% .
the median follow - up period was 40.7 months ( iqr 36.641.6 months ) , during which 3,195 person - years of follow - up were accumulated . during follow - up , 29 patients developed a ventricular arrhythmia 
related event , 2 died suddenly , 1 had a nonfatal cardiac arrest , 11 had a fatal cardiac arrest , and 15 had a cardioverter defibrillator implanted .
indications for these implantable cardioverter defibrillator placements were a left ventricular ejection fraction 35% ( n = 13 ; 87% ) , resuscitated ventricular fibrillation ( n = 1 ) , and ventricular tachycardia with a left ventricular ejection fraction of 45% ( n = 1 ) .
in addition , 27 patients died of mi , 23 from other vascular diseases , 34 from cancer , and 26 from other causes .
the kaplan - meier curves showed that both epa - dha and ala reduced ventricular arrhythmia  related events compared with placebo ( fig .
the lowest incidence was observed in patients who were randomized to the combined supplementation of epa - dha plus ala . after adjustment for imbalances in age , sex , and current smoking ,
the combined supplementation of n-3 fatty acids reduced the ventricular arrhythmia  related events by 84% compared with placebo ( cumulative incidence at median follow - up 0.9 vs. 5.6% , fig .
similar effects were observed for the combined end - point cardiac arrest and sudden death ( 0.13 ; ci 0.021.09 ) and for placement of cardioverter defibrillators ( 0.19 : 0.021.55 ) .
kaplan - meier curves of ventricular arrhythmia  related events ( a ) , death from mi ( b ) , or both end points combined ( c ) .
the cumulative incidence of end points is shown in 1,014 patients with an mi and diabetes .
patients were randomly assigned to receive a margarine containing supplemental epa combined with dha , a margarine containing supplemental ala , a margarine containing both epa - dha and ala , or a placebo margarine .
unadjusted and adjusted hrs of n-3 fatty acid supplementation on end points in 1,014 patients with diabetes , according to n-3 fatty acid supplementation group * data are hrs with 95% cis and p values , with the use of cox proportional hazards models .
adjusted for age , sex , and smoking status . for fatal mi , the kaplan - meier curves did not differ significantly among the four groups ( fig .
after adjustment for confounders , the strongest , although not significant , effect was observed for epa - dha plus ala ( hr 0.53 ; 95% ci 0.151.81 ; table 2 ) .
the kaplan - meier curves for the composite end - point ventricular arrhythmia  related events and fatal mi showed the strongest effect for epa - dha plus ala ( fig .
after adjustment , these three n-3 fatty acids together reduced this combined end point by 72% ( cumulative incidence at median follow - up 2.6 vs. 8.5% , fig .
low - dose supplementation of n-3 fatty acids epa - dha plus ala significantly reduced ventricular arrhythmia  related events in post - mi patients with diabetes .
the combined supplementation of these three fatty acids also reduced the composite end - point ventricular arrhythmia  related events plus fatal mi but not fatal mi alone .
a limitation of the current study is the small number of patients who developed ventricular arrhythmias ( n = 29 ) or died of mi ( n = 27 ) .
the study had enough power to detect significant effects of combined supplementation of epa - dha and ala on the end - point ventricular arrhythmia  related events whether or not in combination with fatal mi .
significant effects on these end points were not observed for either epa - dha or ala supplementation .
the combined effects of epa - dha and ala on the two composite end points are compatible with additive effects of either epa - dha or ala . assuming an additive model , an hr of 0.47  0.58 = 0.27 is expected for ventricular arrhythmia  related events and of 0.81  0.60 = 0.49 for the combination of ventricular arrhythmias and fatal mi .
these results fit well with the 95% ci of these end points and are compatible with the hypothesis that all three n-3 fatty acids reduce the risk of ventricular arrhythmias .
this is also in accord with the results of animal experiments suggesting that ala , epa , and dha have similar antiarrhythmic effects by influencing the na and l - type ca channels of cardiomyocytes ( 5 ) . in the gissi - prevenzione trial , patients with a recent mi ( <3 months ago ) were supplemented with 0.9 g of epa - dha per day , which reduced their risk of sudden death by 45% ( 8) . in later trials ,
recent meta - analyses quantified the effect of epa - dha supplementation on sudden death at a 19% ( hr 0.81 ; 95% ci 0.521.25 ) ( 2 ) and 13% ( 0.87 ; 0.760.99 ) reduction ( 3 ) .
an explanation for the smaller effect of epa - dha in the more recent trials could be improved drug treatment of cardiovascular risk factors ( 18 ) .
this is supported by the recently published results of the omega trial in which patients were randomized 314 days after acute mi . in these high - risk patients
, a supplement of 0.8 g epa - dha per day did not reduce sudden cardiac death ( 19 ) . in this trial and
in the alpha omega trial , almost all patients received antithrombotic drugs , antihypertensive drugs , and statins ( 7 ) .
the patients in the gissi - prevenzione trial were also well treated with antithrombotic and antihypertensive drugs but only 29% received statins ( 8) .
the alpha omega trial started in 2002 , the omega trial in 2003 , and the gissi - prevenzione in 1993 .
one of the secondary end points in the alpha omega trial was ventricular arrhythmia  related events .
ventricular arrhythmias are the major cause of sudden death and cardiac arrest and cardioverter defibrillators were generally implanted in post - mi patients with a low ejection fraction who are at high risk for these arrhythmias ( 16,17 ) .
the protective effect of the combined supplementation of the three n-3 fatty acids on this end point ( hr 0.16 ; 95% ci 0.040.69 ) contrasts with the absence of an effect of epa - dha in cardiac patients with implanted cardioverter defibrillators ( who all had had a severe arrhythmic event before placement ) ( 2 ) .
these discrepant results suggest that n-3 fatty acids may reduce primary arrhythmias in post - mi patients with diabetes with a low ejection fraction but not secondary arrhythmias in cardiac patients with cardioverter defibrillators .
epa - dha supplementation reduced fatal mi by 47% but this reduction was not significant , possibly due to the small number of events .
a possible protective effect of epa - dha on fatal mi would be in accord with the results of a prospective study carried out in postmenopausal women ( 20 ) . in that study ,
smaller increases in stenosis were observed in diabetic women who consumed greater than two servings of fish or greater than one serving of fatty fish compared with diabetic women who consumed less fish .
an intervention study carried out in japan showed that diabetic patients who were supplemented with 1.8 g epa per day in contrast with the control group did not show an increase in intima - media thickness during 2.1 years of follow - up ( 21 ) .
these results suggest that in diabetic patients , fish and epa supplementation may reduce progression of atherosclerosis and the eventual risk of fatal mi .
diabetes alters smooth muscle function through atherosclerotic lesion formation , plaque instability , and cardiovascular events .
basic research shows that peroxisome proliferator  activated receptor  ( ppar- ) plays a critical role in the regulation of insulin sensitivity . to become functional , ppar- should bind to an appropriate ligand .
cell culture studies provide evidence that epa and dha are potential ligands for ppar- activation ( 22 ) .
recently published results of an in vivo experiment suggested that fish oil increases the expression of glucose uptake genes , leading to reduced glucose levels ( 23 ) .
experiments in obese mice showed that activation of the g protein  coupled receptor 120 ( gpr120 ) by epa and dha inhibited multiple inflammation cascades and reversed insulin resistance caused by a high - fat diet ( 24 ) .
these mechanistic findings support an important role for n-3 fatty acids in the etiology of diabetes , a major risk factor of fatal mi . in conclusion ,
low doses of n-3 fatty acids reduced the risk of ventricular arrhythmia  related events in post - mi patients who also have diabetes .
ongoing trials in diabetic patients , e.g. , origin ( outcome reduction with an initial glargine intervention ; clinical trial reg .
nct00069784 ) ( 25 ) and ascend ( a study of cardiovascular events in diabetes ; nct00135226 ; http://www.ctsu.ox.ac.uk/ascend/ ) , evaluate the effect of epa - dha on sudden death and fatal chd .
the results of more trials on the effect of different n-3 fatty acids are needed before definitive conclusions can be drawn on their role in the etiology of ventricular arrhythmias and fatal chd .
 objectivewe carried out a secondary analysis in high - risk patients with a previous myocardial infarction ( mi ) and diabetes in the alpha omega trial . 
 we tested the hypothesis that in these patients an increased intake of the n-3 fatty acids eicosapentaenoic acid ( epa ) , docosahexaenoic acid ( dha ) , and -linolenic acid ( ala ) will reduce the incidence of ventricular arrhythmias and fatal mi.research design and methodsa subgroup of 1,014 post - mi patients with diabetes aged 6080 years was randomly allocated to receive one of four trial margarines , three with an additional amount of n-3 fatty acids and one placebo for 40 months . 
 the end points were ventricular arrhythmia  related events and fatal mi . 
 the data were analyzed according to the intention - to - treat principle , using multivariable cox proportional hazards models.resultsthe patients consumed on average 18.6 g of margarine per day , which resulted in an additional intake of 223 mg epa plus 149 mg dha and/or 1.9 g ala in the active treatment groups . during follow - up , 29 patients developed a ventricular arrhythmia  related events and 27 had a fatal mi . compared with placebo patients , the epa - dha plus ala group experienced less ventricular arrhythmia  related events ( hazard ratio 0.16 ; 95% ci 0.040.69 ) . 
 these n-3 fatty acids also reduced the combined end - point ventricular arrhythmia  related events and fatal mi ( 0.28 ; 0.110.71).conclusionsour results suggest that low - dose supplementation of n-3 fatty acids exerts a protective effect against ventricular arrhythmia  related events in post - mi patients with diabetes . 