To determine whether insulin glargine-mediated normoglycemia can reduce cardiovascular
morbidity and/or mortality in people at high risk for vascular disease with either IFG, IGT
or early type 2 diabetes;
To determine whether omega-3 fatty acids can reduce cardiovascular mortality in people with
IFG, IGT or early type 2 diabetes.
The ORIGIN study is being conducted by the Population Health Research Institute in Hamilton,
Ontario (Canada) and an independent Steering Committee. The Principal Investigators are Dr.
Hertzel Gerstein and Dr. Salim Yusuf, both at Hamilton Health Sciences and the McMaster
University Faculty of Health Sciences.
Glucose tolerance status for all candidates who are not known to have diabetes will be
determined on the basis of a 75 gram oral glucose tolerance test (OGTT) that will be
performed fasting (i.e. no consumption of food or beverage other than water for at least 8
hours). Two plasma glucose values will be drawn during this OGTT - a fasting value and a
value drawn two hours after the 75g oral glucose load is administered (PPG).
1. Participants must have one of the following:
- Impaired Glucose Tolerance (IGT), defined as a postprandial plasma glucose value
(PPG) ≥ 140 and < 200 mg/dL (≥ 7.8 and < 11.1 mM), with FPG < 126 mg/dL (7.0
- OR Impaired Fasting Glucose (IFG), defined as a fasting plasma glucose (FPG)
≥.110 and <.126 mg/dL (≥.6.1 and < 7 mM), without diabetes mellitus (PPG must be
< 200 mg/dL [11.1 mM]).
- OR Early type 2 diabetes, defined as a FPG ≥ 126 mg/dL (7.0 mM) or a PPG of 200
mg/dL (11.1 mM) or greater, or a previous diagnosis of diabetes, and either: on
no pharmacological treatment for at least 10 weeks prior to screening, with
screening glycated hemoglobin < 150% of the upper limit of normal for the
laboratory ( eg. < 9% if the upper limit is 6%)
- OR taking one oral antidiabetic drug (OAD: from among sulfonylureas, biguanides,
thiazolidinediones, alpha-glucosidase inhibitors, and meglitinides) at a stable
dose for at least 10 weeks at the time of screening (or for the 10 weeks prior
to hospitalization if identified while hospitalized for a CV event), with
screening glycated hemoglobin < 133% of the upper limit of normal for the
laboratory (eg. <.8% if the upper limit is 6%) if taking this medication at
half-maximum dose or greater, and glycated hemoglobin < 142% of the upper limit
of normal for the laboratory ( eg. < 8.5% if the upper limit is 6%) if taking
this medication at less than half-maximum dose.
2. Men or women aged 50 years and older
3. Participants must be at risk for cardiovascular disease, based on satisfying one or
more of the following criteria:
- prior myocardial infarction (MI) (≥ 5 days prior to randomization)
- prior stroke (≥ 5 days prior to randomization)
- prior coronary, carotid or peripheral arterial revascularization
- angina with documented ischemic changes (at least 2 mm ST segment depression on
ECG during a Graded Exercise Test [GXT]; or with a cardiac imaging study
positive for ischemia); or unstable angina with documented ischemic changes
(either ST segment depression of at least 1 mm or an increase in troponin above
the normal range but below the range diagnostic for acute myocardial infarction)
- microalbuminuria or clinical albuminuria (an albumin: creatinine ratio > 30
mg/mg in a first morning urine sample, per ADA criteria of Jan. 2001)
- left ventricular hypertrophy by electrocardiogram or echocardiogram
- at least 50% stenosis on angiography of a coronary, carotid, or lower extremity
- ankle/brachial index < 0.9.
4. Provision of signed and dated informed consent prior to any study procedures.
5. Ability and willingness to complete study diaries and questionnaires.
6. Demonstrated ability to use the self-glucose-monitoring device, and to self-inject
insulin prior to randomization.
7. A negative pregnancy test for all females of childbearing potential.
8. Willingness to discontinue prior omega-3 PUFA supplements for the duration of the
1. Type 1 diabetes.
2. Requiring insulin treatment.
3. Known anti-GAD Ab positivity in the past.
4. Screening glycated hemoglobin ≥ 150% of the upper limit of normal for the
5.laboratory (eg. ≥.9% if the upper limit is 6%).
5. Unwilling to inject insulin or perform self-monitoring of blood glucose
6. Nonadherence with the run-in requirement to inject placebo insulin and do capillary
glucose monitoring for at least 4 days prior to randomization.
7. Coronary artery bypass grafting (CABG) within the 4 years prior to screening -
however, patients with a MI or angina since a previous CABG will be eligible for
randomization, even if the last CABG was within 4 years
8. Serum creatinine > 2.0 mg/dL (176 μM) at screening.
9. Active liver disease, or ALT or AST > 2.5 times upper limit of normal at screening.
10. Chronic or recurrent treatment with systemic corticosteroids, or niacin treatment for
11. Heart failure of NYHA Functional Class III or IV.
12. Expected survival of < 3 years for non- cardiovascular causes, or cancer other than
non-melanoma skin cancer within last 3 years.
13. Any other factor likely to limit protocol compliance or reporting of adverse events.
14. Unwilling or unable to discontinue thiazolidinediones.
15. Simultaneous participation in any other clinical trial of an active pharmacologic
16. Unwillingness to permit sites to contact their primary physicians to communicate
information about the study and the participant's data and treatment assignment.
17. History of hypersensitivity to the investigational products.
18. Previous randomization in this study.
19. A prior heart transplant, or awaiting a heart transplant.