ORIGIN: Insulin Glargine and CVD and Other Outcomes in Dysglycemia

ORIGIN: Insulin Glargine and CVD and Other Outcomes in Dysglycemia
ORIGIN Trial Investigators, Gerstein HC, Bosch J, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367(4):319-328. 

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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. (Click here for more information on the omega-3 fatty acid arm of ORIGIN.)   

In the glargine arm, subjects received insulin glargine (N=6,264) or standard care (n=6,273).  

  • Those in the insulin glargine group added an evening glargine injection to their current glycemic-control regimen; the dose was titrated at least once weekly to target FPG ≤95 mg/dL. Subjects in the glargine group who did not receive a diabetes diagnosis by the next-to-the-last study visit reduced their insulin dose by 10 units/day and stopped metformin by the last visit.  
  • Those in the standard care group were treated as per the investigator’s best judgment and local guidelines. Subjects receiving standard care who had not received a diagnosis of diabetes and were not using glucose-lowering drugs by the last study visit were scheduled to receive a 75-g OGTT 3-4 weeks later; the test was repeated after 10-12 weeks (subjects continued to not use diabetes medications during this period) if the first test did not establish a diabetes diagnosis.  

Eligible subjects were aged ≥50 years; had history of type 2 diabetes and using ≤1 OAD; had IGT (PG 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) or newly detected diabetes; prior CV event (myocardial infarction [MI], stroke, or revascularization); angina with documented ischemia; 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 coprimary composite CV outcomes were CV death, nonfatal MI, or nonfatal stroke; and CV death, nonfatal MI, nonfatal stroke, revascularization (cardiac, carotid, or peripheral), or hospitalized heart failure. Secondary outcomes included a microvascular composite, new cases of type 2 diabetes among those without diabetes at baseline, new or recurrent cancer, and all-cause mortality. Hypoglycemic episodes since the previous visit were recorded at each visit; annual weight measurements were also taken.  

Results:
Subjects included in the analysis had a mean age of 63 years and 65% were male. Follow-up was 6.2 years (median). Similar rates of incident CV outcomes were seen for glargine and standard care.  

 

   Insulin glargine (N=6,264)
no (%) 
 Standard care (N=6,273)
no (%) 
 HR (95% CI)   P for log rank 
 CV death, nonfatal MI, or nonfatal stroke (first coprimary outcome)   1,041 (16.6)   1,013 (16.1)   1.02 (0.94-1.11)   0.63 
 CV death, nonfatal MI, nonfatal stroke, revascularization, hosp’d heart failure (second coprimary outcome)   1,792 (28.6)   1,727 (27.5)   1.04 (0.97-1.11)   0.27 
 Microvascular composite   1,323 (21.1)   1,363 (21.7)   0.97 (0.90-1.05)   0.43 
 All-cause mortality   951 (15.2)   965 (15.4)   0.98 (0.90-1.08)   0.70 
 

Analysis of additional outcomes found:  

  • No significant difference in cancer incidence between the two groups: glargine group, 7.6% vs standard care group, 7.6%; HR, 1.00 (95% CI, 0.88-1.13; P=0.97)  
  • New diabetes was seen among 24.7% in the insulin glargine group vs 31.2% in the standard care group (HR, 0.72 [95% CI, 0.58-0.91]; P=0.006; from time of randomization to first OGTT; based on OGTT performed in 64% of those receiving insulin glargine and 65% of those receiving standard care).  
  • The incidence of severe hypoglycemia per 100 person-years was 1.00 in the insulin glargine group vs 0.31 in the standard care group (P<0.001). Over median follow-up of 6.2 years, no episodes of hypoglycemia occurred among 42.9% of those in the glargine group vs 74.8% in the standard care group (P<0.001).  
  • Median weight increased by 1.6 kg for glargine, while a 0.5-kg decrease was seen for standard care. 

Note: insulin glargine is indicated to improve glycemic control in adults and children with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. The subjects treated in the glargine arm of this study had IFG, IGT, or newly diagnosed diabetes. 

 

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 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  

 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  

Last Modified: 11/18/2013