Outcome Reduction With Initial Glargine Intervention - ORIGIN Basal Insulin


This trial sought to study if early normalization of fasting glucose levels by early provision of basal insulin in patients with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or early type 2 diabetes mellitus (DM) would be associated with improved cardiovascular (CV) outcomes.


Early initiation of basal insulin in the form of titrated insulin glargine would be superior to placebo for improving CV outcomes in patients with IFG, IGT, and early type 2 DM in addition to other CV risk factors.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Patients at least 50 years of age with impaired fasting glucose, impaired glucose tolerance, or diabetes (no more than one oral diabetes medication); and
  • Prior MI, stroke, or revascularization; or
  • Angina with documented ischemia; or
  • Ratio of urinary albumin to creatinine >30 mg/g; or
  • Left ventricular hypertrophy; or
  • ≥50% coronary, carotid, or lower extremity artery stenosis; or
  • Ankle-brachial index <0.9

    Number of screened applicants: 15,392
    Number of enrollees: 12,537
    Duration of follow-up: Median 6.2 years
    Mean patient age: 63.5 years
    Percentage female: 35%


  • HbA1c >9%
  • Coronary artery bypass grafting within 4 years
  • Severe heart failure
  • Cancer

Primary Endpoints:

  • CV death/MI/stroke
  • CV death/MI/stroke/revascularization/CHF hospitalization

Secondary Endpoints:

  • All-cause mortality
  • Composite microvascular outcome
  • Incident DM in those without DM at baseline
  • Incident cancers

Drug/Procedures Used:

Patients with IFG, IGT, or early type 2 DM, with elevated risk for a CV disease event, were randomized to insulin glargine given as a once daily injection in addition to their glycemic-control regimen or placebo. Dose could be increased weekly in the glargine insulin arm to achieve a self-measured finger stick blood glucose (FSBG) level ≤95 mg/dl.

Concomitant Medications:

Angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker (69%), thiazide diuretics (19%), aspirin (70%), beta-blockers (53%), and statin (53%)

Principal Findings:

A total of 12,537 patients were randomized at 573 sites in 40 countries, 6,264 to glargine insulin and 6,273 to placebo. Baseline characteristics were fairly similar between the two arms. About 59% of patients were on oral agents. IFG/IGT was noted in 11%; the overall mean duration of DM was 5.4 years. The median glycated hemoglobin (HbA1c) was 6.4. Approximately 59% had experienced a prior CV event. At the end of 1 year, 50% of patients in the glargine insulin arm had achieved goal FSBG readings. Adherence at 5 years was high (85%). Approximately 11% of patients in the placebo arm were using insulin at the end of the study period. Median glucose levels were lower in the glargine insulin arm at 2 years (90 mg/dl vs. 119 mg/dl). Median HbA1c levels were also lower (6.0% vs. 6.3%). This was sustained up to 7 years of follow-up.

Over a median duration of follow-up of 6.2 years, the incidence of the two coprimary endpoints: CV death/myocardial infarction (MI)/stroke (16.6% vs. 16.1%; hazard ratio [HR] 1.02, 95% confidence interval [CI] 0.94-1.11, p = 0.63) and CV death/MI/stroke/revascularization/congestive heart failure (CHF) hospitalization (28.6% vs. 27.5%; HR 1.04, 95% CI 0.97-1.11, p = 0.27) was similar between the glargine insulin and placebo arms. Other outcomes including mortality (15.2% vs. 15.4%, p = 0.70), microvascular complications (21.1% vs. 21.7%, p = 0.43), and any cancer (7.6% vs. 7.6%, p = 0.97) were similar between the two arms.

Among the 1,456 patients without DM at baseline, the risk of incident diabetes was lower in the glargine insulin arm (25% vs. 31%, p = 0.006). In all patients, the incidence of a first episode of severe hypoglycemia was higher in the glargine arm (1/100 patient-year [P-Y] vs. 0.31/100 P-Y, p < 0.001). Other nonsevere hypoglycemic episodes were also more common in the glargine arm. Patients in the glargine arm gained a median of 1.5 kg versus a loss of 0.5 kg in the placebo arm.


Among patients with diabetes or at risk for diabetes, with high risk for a CV event, the addition of basal insulin in the form of glargine insulin to normalize FSBGs does not reduce CV outcomes as compared with placebo. No difference was noted in the incidence of microvascular complications either. Among patients without DM at baseline, there was a reduction in the incidence of new DM. However, nonsevere and severe hypoglycemic episodes were more common with glargine insulin. Thus, there seems to be no role for long-acting insulin analogues in the initial management of IFG/IGT/early DM. Oral agents, particularly metformin, have the most evidence for use in this patient population.


The ORIGIN Trial Investigators. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012;367:319-28.

Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure, Diet

Keywords: Hypertrophy, Left Ventricular, Myocardial Infarction, Stroke, Neoplasms, Follow-Up Studies, Ankle Brachial Index, Diabetes Mellitus, Type 2, Risk Factors, Creatinine, Lower Extremity, Constriction, Pathologic, Hypoglycemia, Hemoglobin A, Glycosylated, Insulin, Long-Acting, Metformin, Blood Glucose, Heart Failure, Hypoglycemic Agents, Confidence Intervals, Fasting

< Back to Listings