ORIGIN: Omega-3 Fatty Acid and CVD Outcomes in Patients with Dysglycemia

ORIGIN: Omega-3 Fatty Acid and CVD Outcomes in Patients with Dysglycemia 

ORIGIN Trial Investigators, Bosch J, Gerstein HC, et al. N-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012;367(4):309-318. 

Exclusive!
Vivian A. Fonseca, MD, provides expert commentary on ORIGIN.
Click here

More data from ADA 2012 are available in our OnsiteInsight® eNewsletter. Click here.  

The Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial is a randomized, double-blind trial with a 2X2 factorial design that enrolled 12,537 patients who were at high risk for CV events and who had IFG, IGT, or newly diagnosed diabetes. The factorial design of ORIGIN allowed for investigators to examine two interventions in a single study. Via two arms, the study investigated whether insulin replacement therapy with insulin glargine targeting fasting normoglycemia (FPG ≤95 mg/dL) reduces CV outcomes more than standard approaches, and whether the addition of omega-3 fatty acids reduces CV death. 

Subjects in ORIGIN received the following interventions, in accordance with the 2x2 factorial design: (a) either insulin glargine or standard approaches to glycemic control; and (b) either prescription omega-3 fatty acid or placebo. For the design of ORIGIN, it was assumed that any effect of the factorial treatment arms was independent. One subject who underwent randomization in the glucose-lowering portion of the study died before randomization to omega-3 fatty acid or placebo; as such, N=12,536 total subjects were included in the omega-3 fatty acid analysis. (Click here for more information on the glargine arm of ORIGIN.) 

In the omega-3 fatty acid trial, patients were randomized to 1-g capsule containing ≥900 mg (90% or more) of ethyl esters of omega-3 fatty acids/day (N=6,281) or placebo (N=6,255) in a double-blind fashion after a 10-day run-in period.  

Eligible subjects were aged ≥50 years; were diagnosed with diabetes and using ≤1 OAD; had IGT (defined as plasma glucose level at 2 hours, ≥140 mg/dL and <200 mg/dL after a 75-g oral glucose load) or IFG (range, ≥110 mg/dL to <126 mg/dL); history of myocardial infarction (MI), stroke, or revascularization; angina with documented ischemia; urinary albumin to creatinine ratio >30 mg/g; left ventricular hypertrophy; ≥50% stenosis of a coronary, carotid, or lower-limb artery on angiography; or an ankle–brachial index of <0.9. Those with A1C ≥9%, history of CABG within previous 4 years with no intervening CV event, severe heart failure, or cancer that might affect survival were excluded from the study population.  

The study’s primary endpoint was CV death; secondary endpoints included a composite of CV death, or nonfatal MI, or nonfatal stroke; all-cause mortality; arrhythmic death. Additional outcomes assessed included all MI, all strokes, revascularizations, heart failure, angina, limb amputation for ischemia, and hospitalization for CV causes. Outcomes were assessed during follow-up visits at months 0.5, 1, 2, and 4 months after randomization, and every 4 months thereafter.  

Results:
Subjects included in the analysis had a mean age of 64 years and 65% were male. Follow-up was 6.2 years (median). History of MI, stroke, or revascularization was present among 59% of subjects.  

No difference was seen for omega-3 fatty acids vs placebo for the primary endpoint of CV death: -9.1% in the omega-3 fatty acid group vs -9.3% in the placebo group (HR, 0.98 [95% confidence interval, 0.87-1.10]; P=0.72).  

No significant differences were seen for omega-3 fatty acids versus placebo, respectively, for secondary endpoints:  

  • Composite of CV death, or nonfatal MI, or nonfatal stroke: 16.5% vs 16.3%; HR, 1.01 (95% CI, 0.93-1.10); P=0.81  
  • All-cause mortality: 15.1% vs 15.4%; HR, 0.98 (95% CI, 0.89-1.07); P=0.63  
  • Arrythmic death: 4.6% vs 4.1%, HR, 1.10 (95% CI, 0.93-1.30); P=0.26 
   Omega-3 fatty acid (N=6,281)
Number | Rate 
 Placebo (N=6,255)
Number | Rate 
 HR (95% CI)   P  
 CV death (primary outcome)  574 | 1.55  581 | 1.58   0.98 (0.87-1.10)  0.72 
 MI, stroke, CV death  1,034 | 2.92  1,017 | 2.88   1.01 (0.93-1.10)  0.81 
 All-cause mortality  951 | 2.57  964 | 2.62   0.98 (0.89-1.07)  0.63 
 Death from arrhythmia  288 | 0.78  259 | 0.70   1.10 (0.93-1.30)  0.26 

Rate is per 100 patient-years  

The rate of cancer diagnoses was not significantly different between groups. Triglyceride levels were reduced by 14.5 mg/dL more among patients receiving omega-3 versus placebo (P<0.001), without a significant effect on other lipid parameters. Mean changes in lipid values were seen as follows for the omega-3 fatty acid and placebo groups, respectively:  

  • TC: -15.7±1.0 vs -14.6±1.0; P=0.17  
  • LDL-C: -11.8±0.8 vs -12.4±0.8; P=0.44  
  • HDL-C: -0.1±0.3 vs -0.2±0.3; P=0.78  
  • TG: -25.3±3.0 vs -9.0±3.0; P<0.001  

Omega-3 supplementation was well tolerated, with high adherence (88%) at study end.  

Note: the omega-3 fatty acid used in this study is indicated as an adjunct to diet to reduce triglyceride levels in adults with severe (≥500 mg/dL) hypertriglyceridemia. The primary outcome of the study was CV events. 

 

July 2012 

 This overview was created by KnowledgePoint360 Group, LLC, and was not associated with funding via an educational grant or a promotional/commercial interest. 

Related content on the ORIGIN trial: 

 OnsiteInsight® eNewsletter: ADA 2012 

 ORIGIN: Design  

ORIGIN Omega-3 Fatty Acid Trial: Design  

ORIGIN Omega-3 Fatty Acid Trial: Primary and Secondary Outcomes  

ORIGIN Omega-3 Fatty Acid Trial: Additional Outcomes  

ORIGIN Omega-3 Fatty Acid Trial: Eligibility Criteria and Trial Profile  

ORIGIN Omega-3 Fatty Acid Trial: Baseline Characteristics (1 of 2)  

ORIGIN Omega-3 Fatty Acid Trial: Baseline Characteristics (2 of 2)  

ORIGIN Omega-3 Fatty Acid Trial: Primary Outcome—CV Death  

ORIGIN Omega-3 Fatty Acid Trial: Secondary Outcomes  

ORIGIN Omega-3 Fatty Acid Trial: Mean Change in Lipids  

ORIGIN Omega-3 Fatty Acid Trial: Conclusions  

ORIGIN Glargine Trial: Design  

ORIGIN Glargine Trial: Primary and Secondary Outcomes  

ORIGIN Glargine Trial: Eligibility Criteria and Trial Profile  

ORIGIN Glargine Trial: Baseline Characteristics (1 of 2)  

ORIGIN Glargine Trial: Baseline Characteristics (2 of 2)  

ORIGIN Glargine Trial: Insulin Use During Trial  

ORIGIN Glargine Trial: A1C, FPG During Trial  

ORIGIN Glargine Trial: First Coprimary Outcome—CV Death, Nonfatal MI, or Nonfatal Stroke 

ORIGIN Glargine Trial: Second Coprimary Outcome—CV Death, Nonfatal MI, Nonfatal Stroke, Revascularization, or Hospitalized Heart Failure  

ORIGIN Glargine Trial: Secondary Outcomes  

ORIGIN Glargine Trial: Secondary Outcome—Cancer Incidence  

ORIGIN Glargine Trial: Hypoglycemia  

ORIGIN Glargine Trial: Weight Change  

ORIGIN Glargine Trial: Conclusions  

Last Modified: 3/23/2015