Outcome Reduction With Initial Glargine Intervention - ORIGIN Fatty Acids


The goal of the trial was to evaluate treatment with n-3 fatty acids compared with placebo among patients at elevated cardiac risk with impaired fasting glucose, impaired glucose tolerance, or diabetes.


n-3 fatty acids will reduce cardiovascular mortality.

Study Design

  • Placebo Controlled
  • Blinded
  • Randomized
  • Parallel

Patient Populations:

  • Patients at least 50 years of age with one of the following criteria: Impaired fasting glucose, impaired glucose tolerance, or diabetes (no more than one oral diabetes medication)
  • And at least one of the following criteria for elevated cardiovascular risk: Prior myocardial infarction, stroke, or revascularization; angina with documented ischemia; ratio of urinary albumin to creatinine >30 mg/g; left ventricular hypertrophy; or ‚Č•50% coronary, carotid, or lower extremity artery stenosis
  • Ankle-brachial index <0.9

    Number of screened applicants: 15,392
    Number of enrollees: 12,611
    Duration of follow-up: Median 6.2 years
    Mean patient age: 64 years
    Percentage female: 35%


  • Unwilling to stop nonstudy n-3 fatty acids
  • Glycated hemoglobin >9%
  • Coronary artery bypass grafting within 4 years
  • Severe heart failure
  • Cancer

Primary Endpoints:

  • Cardiovascular mortality

Secondary Endpoints:

  • Cardiovascular mortality, nonfatal myocardial infarction, or nonfatal stroke
  • All-cause mortality
  • Mortality due to arrhythmias
  • Major vascular events

Drug/Procedures Used:

Patients with impaired fasting glucose, impaired glucose tolerance, or diabetes, at elevated risk for a cardiovascular event, were randomized to 1 g capsule of n-3 fatty acids (n = 6,319) versus placebo (n = 6,292).

The n-3 fatty acid capsule contained 465 mg of eicosapentaenoic acid and 375 mg of docosahexaenoic acid. The placebo capsule contained 1 g of olive oil.

Concomitant Medications:

At baseline, the use of:

Angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker: 69%
Thiazide diuretics: 19%
Aspirin 70%
Beta-blocker 53%
Statin 53%

Principal Findings:

Overall, 12,611 patients were randomized. The mean age was 64 years; 35% were women; 59% had a history of myocardial infarction, stroke, or revascularization; mean body mass index was 30 kg/m2, mean blood pressure was 146/84 mm Hg, mean low-density lipoprotein (LDL) cholesterol was 112 mg/dl, and mean glycated hemoglobin was 6.4%.

Study drug was continued in 96% of participants in both groups at 1 year. Triglyceride levels were reduced by 14.5 mg/dl with n-3 fatty acids versus placebo (p < 0.001).

At a median follow-up of 6.2 years, cardiovascular death had occurred in 9.1% of the n-3 fatty acid group versus 9.3% of the placebo group (p = 0.72). There was no between-group difference in the primary outcome among various tested subgroups.

Cardiovascular death, myocardial infarction, or stroke: 16.5% versus 16.3%
All-cause mortality: 15.1% versus 15.4%
Deaths from arrhythmia: 4.6% versus 4.1%
Hospitalization for heart failure: 5.3% versus 5.2%
Revascularization: 13.8% versus 14.3%
Angina: 11.5% versus 11.6%
Limb amputation for ischemia: 0.8% versus 0.8%
Hospitalization for any cardiovascular cause: 32.7% versus 33.4%


Among patients with diabetes (or at risk for diabetes) and high-risk for a cardiovascular event, the use of 1 g of n-3 fatty acids did not reduce cardiovascular outcomes. At least three other trials studying fatty acids are currently underway. The current trial is a large, well-designed study with long-term follow-up, and did not find any benefit with this dose and formulation of n-3 fatty acids.


The ORIGIN Trial Investigators. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med 2012;367:309-18.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Acute Heart Failure, Diet

Keywords: Hypertrophy, Left Ventricular, Follow-Up Studies, Blood Pressure, Risk Factors, Lower Extremity, Creatinine, Hemoglobin A, Glycosylated, Cholesterol, Glucose Tolerance Test, Myocardial Infarction, Stroke, Ankle Brachial Index, Constriction, Pathologic, Eicosapentaenoic Acid, Lipoproteins, LDL, Body Mass Index, Docosahexaenoic Acids, Blood Glucose, Heart Failure, Triglycerides, Fasting, Diabetes Mellitus

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