The ORIGIN Trial (Outcome Reduction With Initial Glargine Intervention) (ORIGIN)

A Multicenter, International Randomized, 2x2 Factorial Design Study to Evaluate the Effects of Lantus (Insulin Glargine) Versus Standard Care, and of Omega-3 Fatty Acids Versus Placebo, in Reducing Cardiovascular Morbidity and Mortality in High Risk People With Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT) or Early Type 2 Diabetes Mellitus: The ORIGIN Trial (Outcome Reduction With Initial Glargine Intervention)

The primary objectives of the ORIGIN study were:

• To determine whether insulin glargine-mediated normoglycemia can reduce cardiovascular morbidity and/or mortality in people at high risk for vascular disease with either Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (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 secondary objectives of the insulin glargine study were to determine if insulin glargine-mediated normoglycemia can reduce:

• total mortality (all causes);
• the risk of diabetic microvascular outcomes;
• the rate of progression of IGT or IFG to type 2 diabetes.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Non-Insulin-Dependent
• Intervention / Treatment: Drug: insulin glargine (HOE901); Drug: omega-3 polyunsaturated fatty acids (PUFA); Device: reusable pen device for insulin injection; Drug: placebo

Detailed Description

The ORIGIN study was conducted by the Population Health Research Institute in Hamilton, Ontario (Canada), working in conjunction with the sponsor, and an independent Steering Committee.

Routine visits were to occur at 2, 4, 8, and 16 weeks following randomization, then every four months for the rest of the study, for all participants

The duration of the study was based on the number of events observed (event-driven study) and was originally planned to be 5 years. In 2008-2009 ORIGIN's follow-up was extended by approximately 2 years, because of published literature of completed studies suggesting that a longer period of effective glycemic contrast between treatments might be needed to see an effect on cardiovascular events.

• Study Type: Interventional
• Enrollment (Actual): 12537
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Sanofi-Aventis Administrative Office
• Australia
  • New South Wales
    • Cove, New South Wales, Australia
      • Sanofi-Aventis Administrative Office
• Austria
  • Vienna, Austria
    • Sanofi-Aventis Administrative Office
• Belarus
  • Minsk, Belarus
    • Sanofi-Aventis Administrative Office
• Bermuda
  • Hamilton, Bermuda
    • Sanofi-Aventis Administrative Office
• Brazil
  • Sao Paulo, Brazil
    • Sanofi-Aventis Administrative Office
• Canada
  • Quebec
    • Laval, Quebec, Canada
      • Sanofi-Aventis Administrative Office
• Chile
  • Santiago, Chile
    • Sanofi-Aventis Administrative Office
• China
  • Beijing, China
    • Sanofi-Aventis Administrative Office
• Colombia
  • Cali, Colombia
    • Sanofi-Aventis Administrative Office
• Croatia
  • Zagreb, Croatia
    • Sanofi-Aventis Administrative Office
• Denmark
  • Horsholm, Denmark
    • Sanofi-Aventis Administrative Office
• Estonia
  • Tatari, Estonia
    • Sanofi-Aventis Administrative Office
• Finland
  • Helsinki, Finland
    • Sanofi-Aventis Administrative Office
• France
  • Paris, France
    • Sanofi-Aventis Administrative Office
• Germany
  • Berlin, Germany
    • Sanofi-Aventis Administrative Office
• Hungary
  • Budapest, Hungary
    • Sanofi-Aventis Administrative Office
• India
  • Mumbai, India
    • Sanofi-Aventis Administrative Office
• Ireland
  • Dublin, Ireland
    • Makati City
• Israel
  • Netanya, Israel
    • Sanofi-Aventis Administrative Office
• Italy
  • Milano, Italy
    • Sanofi-Aventis Administrative Office
• Korea, Republic of
  • Seoul, Korea, Republic of
    • Sanofi-Aventis Administrative Office
• Latvia
  • Riga, Latvia
    • Sanofi-Aventis Administrative Office
• Lithuania
  • Vilnius, Lithuania
    • Sanofi-Aventis Administrative Office
• Mexico
  • Mexico, Mexico
    • Sanofi-Aventis Administrative Office
• Netherlands
  • Gouda, Netherlands
    • Sanofi-Aventis Administrative Office
• Norway
  • Lysaker, Norway
    • Sanofi-Aventis Administrative Office
• Philippines
  • Makati City, Philippines
    • Sanofi-Aventis Administrative Office
• Poland
  • Warszawa, Poland
    • Sanofi-Aventis Administrative Office
• Romania
  • Bucuresti, Romania
    • Sanofi-Aventis Administrative Office
• Russian Federation
  • Moscow, Russian Federation
    • Sanofi-Aventis Aministrative Office
• Slovakia
  • Bratislava, Slovakia
    • Sanofi-Aventis Administrative Office
• South Africa
  • Midrand, South Africa
    • Sanofi-Aventis Administrative Office
• Spain
  • Barcelona, Spain
    • Sanofi-Aventis Administrative Office
• Sweden
  • Bromma, Sweden
    • Sanofi-Aventis Administrative Office
• Switzerland
  • Geneva, Switzerland
    • Sanofi-Aventis Administrative Office
• Turkey
  • Istanbul, Turkey
    • Sanofi-Aventis Administrative Office
• United Kingdom
  • Surrey
    • Guildford, Surrey, United Kingdom
      • Sanofi-Aventis Administrative Office
• United States
  • New Jersey
    • Bridgewater, New Jersey, United States, 08807
      • Sanofi-Aventis Administrative Office
• Venezuela
  • Caracas, Venezuela
    • Makati City

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

I1. Individuals with IFG and/or IGT, or early diabetes, as defined below.

Glucose tolerance status was determined by a 75 g oral glucose tolerance test (OGTT) that was performed fasting (ie, no consumption of food or beverage other than water for at least 8 hours) at the time of screening for all candidates who were not known to have diabetes. The qualifying OGTT could be obtained up to 4 weeks prior to screening provided that anti-diabetic therapy (if any) remained unchanged between the qualifying OGTT and the screening visit. Two plasma glucose values were drawn during the OGTT - a fasting value (FPG) and a value drawn two hours after the 75 g oral glucose load was administered (postprandial plasma glucose [PPG]).

- Impaired glucose tolerance (IGT), defined as a PPG value ≥140 and <200 mg/dL (ie, ≥7.8 and <11.1 mmol/L), with a FPG <126 mg/dL (7.0 mmol/L).

OR

- Impaired fasting glucose (IFG), defined as an FPG ≥110 and <126 mg/dL (≥6.1 and <7 mmol/L), without diabetes mellitus (PPG must be <200 mg/dL [11.1 mmol/L]).

OR

- Early type 2 diabetes, defined as a FPG ≥126 mg/dL (7.0 mmol/L) or a PPG of ≥200 mg/dL (11.1 mmol/L), or a previous diagnosis of diabetes, and either:

• on no pharmacological treatment (while ambulatory) for at least 10 weeks prior to screening, with screening glycated hemoglobin <150% of the upper limit of normal (ULN) for the laboratory (eg, <9% if the ULN is 6%)
• or taking one oral antidiabetic drug (OAD) from among sulfonylureas (SU), biguanides, thiazolidinediones (TZDs), alpha-glucosidase inhibitors (AGIs), and meglitinides (MGTs) at a stable dose while ambulatory 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 ULN for the laboratory (eg, <8% if the ULN is 6%) if taking this medication at half-maximum dose or greater, and glycated hemoglobin <142% of the ULN for the laboratory (eg, <8.5% if the ULN is 6%) if taking this medication at less than half-maximum dose. Individuals taking combination products containing two or more OADs were not eligible.

I2. Men or women aged 50 years and older

I3. At least one of the following CV risk factors:

• previous myocardial infarction (MI) (≥ 5 days prior to randomization)
• previous stroke (≥ 5 days prior to randomization)
• previous coronary, carotid or peripheral arterial revascularization
• angina with documented ischemic changes (at least 2 mm ST segment depression on electrocardiogram 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 μg/mg in at least one or timed collection of urine with albumin excretion ≥20 μg/min or ≥30 mg/24 hours or total protein excretion ≥500 mg/24 hours)
• left ventricular hypertrophy by electrocardiogram or echocardiogram
• significant stenosis on angiography of coronary, carotid, or lower extremity arteries (ie, 50% or more stenosis)
• ankle-brachial index < 0.9.

I4. Provision of signed and dated informed consent prior to any study procedures.

I5. Ability and willingness to complete study diaries and questionnaires.

I6. Demonstrated ability to use the self-glucose-monitoring device, and to self-inject insulin prior to randomization.

I7. A negative pregnancy test for all women of childbearing potential (ie, ovulating, pre- menopausal, and not surgically sterile) and the agreement of these women to use a reliable method of birth control to prevent pregnancy during the duration of the study .

I8. Willingness to discontinue prior omega-3 PUFA supplements for the duration of the study.

Exclusion criteria

E1. Type 1 diabetes.

E2. Requiring ambulatory insulin treatment or uncontrolled or symptomatic hyperglycemia that is likely to require the addition of ambulatory insulin therapy or a new antidiabetic agent either before or within 2 weeks after randomization.

E3. Known anti-glutamic acid decarboxylase antibody (anti-GAD Ab) positivity in the past.

E4. Screening glycated hemoglobin ≥150% of the ULN for the laboratory (eg, ≥9% if the ULN is 6%).

E5. Unwillingness to inject insulin or perform self-monitoring of blood glucose.

E6. Nonadherence to the run-in requirement to inject placebo insulin and do capillary glucose monitoring for at least 4 days prior to randomization.

E7. Coronary artery bypass grafting (CABG) either planned at the time of screening, or CABG within the 4 years prior to screening - however, participants with angina, MI, or stroke since a previous CABG will be eligible for randomization, even if the last CABG was within 4 years.

E8. Serum creatinine >2.0 mg/dL (176 μmol/L) at screening.

E9. Active liver disease, or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 times ULN at screening.

E10. Chronic or recurrent treatment with systemic corticosteroids, or niacin treatment for hyperlipidemia.

E11. Heart failure of New York Heart Association (NYHA) Functional Class III or IV.

E12. Expected survival of <3 years for non-CV causes such as cancer.

E13. Any other factor likely to limit protocol compliance or reporting of adverse events (AEs).

E14. Unwilling or unable to discontinue TZDs.

E15. Simultaneous participation in any other clinical trial of an active pharmacologic agent.

E16. Unwillingness to permit sites to contact their primary physicians to communicate information about the study and the participant's data and treatment assignment.

E17. History of hypersensitivity to the investigational products.

E18. Previous randomization in this study.

E19. A prior heart transplant, or awaiting a heart transplant.

E20. Known infection with human immunodeficiency virus (HIV).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Insulin glargine + omega-3 polyunsaturated fatty acids; Insulin glargine once daily by subcutaneous injection in a titrated regimen targeting a fasting plasma glucose (FPG) level of ≤95 mg/dL (5.3 mmol/L); One capsule of omega-3 polyunsaturated fatty acids once daily	Drug: insulin glargine (HOE901); Cartridges for use in a pen device, each containing 3 mL of insulin glargine 100 U/mL solution for injection; Other Names: Lantus®; Drug: omega-3 polyunsaturated fatty acids (PUFA); Gelatin capsules (containing icosapent ethyl esters 465 mg and doconexent ethyl esters 375 mg) for oral administration; Other Names: Omacor®; Device: reusable pen device for insulin injection; Other Names: OptiPen® Pro 1
Experimental: Insulin glargine + placebo; Insulin glargine once daily by subcutaneous injection in a titrated regimen targeting a fasting plasma glucose (FPG) level of ≤95 mg/dL (5.3 mmol/L); One capsule of placebo once daily	Drug: insulin glargine (HOE901); Cartridges for use in a pen device, each containing 3 mL of insulin glargine 100 U/mL solution for injection; Other Names: Lantus®; Device: reusable pen device for insulin injection; Other Names: OptiPen® Pro 1; Drug: placebo; Matching placebo gelatin capsules (containing olive oil) for oral administration
Experimental: Standard care + omega-3 polyunsaturated fatty acids; • One capsule of omega-3 polyunsaturated fatty acids once daily	Drug: omega-3 polyunsaturated fatty acids (PUFA); Gelatin capsules (containing icosapent ethyl esters 465 mg and doconexent ethyl esters 375 mg) for oral administration; Other Names: Omacor®
Placebo Comparator: Standard care + placebo; • One capsule of placebo once daily	Drug: placebo; Matching placebo gelatin capsules (containing olive oil) for oral administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI) or Nonfatal Stroke	Number of participants with a first occurrence of one of the above events. The outcome's evaluation is based on the number of such positively-adjudicated first events occurring for patients assigned to the study groups. Assessments of the above events were reviewed by the Event Adjudication Committee who was kept blinded to the group assignment of participants. Statistical analysis is performed on the time from randomization to the first occurrence of the events. Number of participants with a composite endpoint (i.e. with first occurrence of CV death, nonfatal MI or nonfatal stroke) is provided in the first row of the statistical table.	from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Revascularization Procedure or Hospitalization for Heart Failure (HF)	Number of participants with a first occurrence of one of the above events (revascularization procedures included coronary artery bypass graft, percutaneous transluminal coronary angioplasty (PTCA) i.e. balloon, PTCA with stent, other percutaneous intervention, carotid angioplasty with/without stent, carotid endarterectomy, peripheral angioplasty with or without stent, peripheral vascular surgery, and limb amputation due to vascular disease). The outcome's evaluation is based on the number of such positively-adjudicated first events occurring for patients assigned to the study groups. Assessments of the above events were reviewed by the Event Adjudication Committee who was kept blinded to the group assignment of participants. Statistical analysis is performed on the time from randomization to the first occurrence of the events. Number of participants with a composite endpoint (i.e. with first occurrence of the events) is provided in the first row of the statistical table.	from randomization until study cut-off date (median duration of follow-up: 6.2 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Mortality (All Causes)	Number of deaths due to any cause	from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Composite Diabetic Microvascular Outcome (Kidney or Eye Disease)	The composite outcome used to analyze microvascular disease progression contained components of clinical events: the occurrence of laser surgery or vitrectomy for diabetic retinopathy (DR);; the development of blindness due to DR;; the occurrence of renal death or renal replacement therapy; as well as the following laboratory-based events:; doubling of serum creatinine; or; progression of albuminuria (from none to microalbuminuria [at least 30 mg/g creatinine], to macroalbuminuria [at least 300 mg/g creatinine]).	from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Incidence of Development of Type 2 Diabetes Mellitus in Participants With IGT and/or IFG	The incidence was determined by calculating the proportion of randomized participants without diabetes at randomization who either developed diabetes during the study or who were classified as having possible diabetes based on results of two oral glucose tolerance tests (OGTT) performed after the last follow-up visit (within 21-28 days for OGTT#1 and within 10-14 weeks for OGTT#2).	from randomization until the last follow-up visit or last OGTT (median duration of follow-up: 6.2 years)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Various Types of Symptomatic Hypoglycemia Events	Symptomatic hypoglycemia was defined as an event with clinical symptoms consistent with hypoglycemia, based on data recorded in the participant's diary. These were further categorized as confirmed (ie, with a concomitant home glucose reading ≤54 mg/dL [≤3.0 mmol/L]) or unconfirmed. Severe hypoglycemia was defined as an event with clinical symptoms consistent with hypoglycemia in which the participant required the assistance of another person, and one of the following: the event was associated with a documented self-measured or laboratory plasma glucose level ≤36 mg/dL (≤2.0 mmol/L), or; the event was associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration.	on-treatment period (median duration of follow-up: 6.2 years)
Number of Patients With First Occurrence of Any Type of Cancer	Data on cancers that occurred in association with hospitalizations were collected systematically in both groups from the start of the study. All reported cancers occurring during the trial (new or recurrent) were adjudicated by the Event Adjudication Committee.	from randomization until study cut-off date (median duration of follow-up: 6.2 years)

Collaborators and Investigators

• Sponsor: Sanofi
• Collaborators: Population Health Research Institute
• Investigators: Principal Investigator: Hertzel Gerstein, M.D., McMaster University and Hamilton Health Sciences; Principal Investigator: Salim Yusuf, M.D., McMaster University and Hamilton Health Sciences

Publications and helpful links

General Publications

• Morieri ML, Gao H, Pigeyre M, Shah HS, Sjaarda J, Mendonca C, Hastings T, Buranasupkajorn P, Motsinger-Reif AA, Rotroff DM, Sigal RJ, Marcovina SM, Kraft P, Buse JB, Wagner MJ, Gerstein HC, Mychaleckyj JC, Pare G, Doria A. Genetic Tools for Coronary Risk Assessment in Type 2 Diabetes: A Cohort Study From the ACCORD Clinical Trial. Diabetes Care. 2018 Nov;41(11):2404-2413. doi: 10.2337/dc18-0709. Epub 2018 Sep 27.
• Shao H, Kianmehr H, Guo J, Li P, Fonseca V, Shi L. Efficacy of iGlarLixi on 5-year risk of diabetes-related complications: A simulation study. J Diabetes Complications. 2022 Mar;36(3):108132. doi: 10.1016/j.jdiacomp.2022.108132. Epub 2022 Jan 25.
• Origin Trial Investigators; Gerstein H, Yusuf S, Riddle MC, Ryden L, Bosch J. Rationale, design, and baseline characteristics for a large international trial of cardiovascular disease prevention in people with dysglycemia: the ORIGIN Trial (Outcome Reduction with an Initial Glargine Intervention). Am Heart J. 2008 Jan;155(1):26-32, 32.e1-6. doi: 10.1016/j.ahj.2007.09.009. Epub 2007 Nov 26.
• Hanefeld M, Koehler C, Hoffmann C, Wilhelm K, Kamke W, Gerstein H. Effect of targeting normal fasting glucose levels with basal insulin glargine on glycaemic variability and risk of hypoglycaemia: a randomized, controlled study in patients with early Type 2 diabetes. Diabet Med. 2010 Feb;27(2):175-80. doi: 10.1111/j.1464-5491.2009.02915.x.
• Badings EA, Dyal L, Schoterman L, Lok DJ, Stoel I, Gerding MN, Gerstein HC, Tijssen JG. Strategies to detect abnormal glucose metabolism in people at high risk of cardiovascular disease from the ORIGIN (Outcome Reduction with Initial Glargine Intervention) trial population. J Diabetes. 2011 Sep;3(3):232-7. doi: 10.1111/j.1753-0407.2011.00124.x.
• Ramachandran A, Riddle MC, Kabali C, Gerstein HC; ORIGIN Investigators. Relationship between A1C and fasting plasma glucose in dysglycemia or type 2 diabetes: an analysis of baseline data from the ORIGIN trial. Diabetes Care. 2012 Apr;35(4):749-53. doi: 10.2337/dc11-1918. Epub 2012 Feb 8.
• ORIGIN Trial Investigators; Gerstein HC, Bosch J, Dagenais GR, Diaz R, Jung H, Maggioni AP, Pogue J, Probstfield J, Ramachandran A, Riddle MC, Ryden LE, Yusuf S. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012 Jul 26;367(4):319-28. doi: 10.1056/NEJMoa1203858. Epub 2012 Jun 11.
• ORIGIN Trial Investigators; Bosch J, Gerstein HC, Dagenais GR, Diaz R, Dyal L, Jung H, Maggiono AP, Probstfield J, Ramachandran A, Riddle MC, Ryden LE, Yusuf S. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012 Jul 26;367(4):309-18. doi: 10.1056/NEJMoa1203859. Epub 2012 Jun 11.
• Cukierman-Yaffe T, Lee SF, Pare G, McQueen M, Hess S, Gerstein HC. Biomarkers of Prevalent and Incident Cognitive Dysfunction in People with Dysglycemia: Data from the ORIGIN Trial. J Alzheimers Dis. 2022;87(3):1143-1150. doi: 10.3233/JAD-215195.
• Pigeyre M, Hess S, Gomez MF, Asplund O, Groop L, Pare G, Gerstein H. Validation of the classification for type 2 diabetes into five subgroups: a report from the ORIGIN trial. Diabetologia. 2022 Jan;65(1):206-215. doi: 10.1007/s00125-021-05567-4. Epub 2021 Oct 21.
• Wang A, Gerstein HC, Lee SF, Hess S, Pare G, Ryden L, Mellbin LG. Testosterone and sex hormone-binding globulin in dysglycemic women at high cardiovascular risk: A report from the Outcome Reduction with an Initial Glargine Intervention trial. Diab Vasc Dis Res. 2021 Mar-Apr;18(2):14791641211002475. doi: 10.1177/14791641211002475.
• Pigeyre M, Sjaarda J, Chong M, Hess S, Bosch J, Yusuf S, Gerstein H, Pare G. ACE and Type 2 Diabetes Risk: A Mendelian Randomization Study. Diabetes Care. 2020 Apr;43(4):835-842. doi: 10.2337/dc19-1973. Epub 2020 Feb 4.
• Theriault S, Sjaarda J, Chong M, Hess S, Gerstein H, Pare G. Identification of Circulating Proteins Associated With Blood Pressure Using Mendelian Randomization. Circ Genom Precis Med. 2020 Feb;13(1):e002605. doi: 10.1161/CIRCGEN.119.002605. Epub 2020 Jan 12.
• Gerstein HC, Pare G, McQueen MJ, Lee SF, Bangdiwala SI, Kannt A, Hess S; ORIGIN Trial Investigators. Novel Biomarkers for Change in Renal Function in People With Dysglycemia. Diabetes Care. 2020 Feb;43(2):433-439. doi: 10.2337/dc19-1604. Epub 2019 Nov 14.
• Pigeyre M, Sjaarda J, Mao S, Chong M, Hess S, Yusuf S, Gerstein H, Pare G. Identification of Novel Causal Blood Biomarkers Linking Metabolically Favorable Adiposity With Type 2 Diabetes Risk. Diabetes Care. 2019 Sep;42(9):1800-1808. doi: 10.2337/dc18-2444. Epub 2019 Jun 24.
• Cukierman-Yaffe T, Bosch J, Jung H, Punthakee Z, Gerstein HC. Hypoglycemia and Incident Cognitive Dysfunction: A Post Hoc Analysis From the ORIGIN Trial. Diabetes Care. 2019 Jan;42(1):142-147. doi: 10.2337/dc18-0690. Epub 2018 Nov 13.
• Mohammadi-Shemirani P, Sjaarda J, Gerstein HC, Treleaven DJ, Walsh M, Mann JF, McQueen MJ, Hess S, Pare G. A Mendelian Randomization-Based Approach to Identify Early and Sensitive Diagnostic Biomarkers of Disease. Clin Chem. 2019 Mar;65(3):427-436. doi: 10.1373/clinchem.2018.291104. Epub 2018 Oct 18.
• Birkeland KI, Grill V, Wium C, McQueen MJ, Lopez-Jaramillo P, Lee SF, Gerstein HC. The association of basal insulin treatment versus standard care with outcomes in anti-GAD positive and negative subjects: A post-hoc analysis of the ORIGIN trial. Diabetes Obes Metab. 2019 Feb;21(2):429-433. doi: 10.1111/dom.13528. Epub 2018 Oct 3.
• Sjaarda J, Gerstein H, Chong M, Yusuf S, Meyre D, Anand SS, Hess S, Pare G. Blood CSF1 and CXCL12 as Causal Mediators of Coronary Artery Disease. J Am Coll Cardiol. 2018 Jul 17;72(3):300-310. doi: 10.1016/j.jacc.2018.04.067. Epub 2018 Jul 9.
• Gerstein HC, Ferrannini E, Riddle MC, Yusuf S; ORIGIN Trial Investigators. Insulin resistance and cardiovascular outcomes in the ORIGIN trial. Diabetes Obes Metab. 2018 Mar;20(3):564-570. doi: 10.1111/dom.13112. Epub 2017 Oct 8.
• Papademetriou V, Nylen ES, Doumas M, Probstfield J, Mann JFE, Gilbert RE, Gerstein HC. Chronic Kidney Disease, Basal Insulin Glargine, and Health Outcomes in People with Dysglycemia: The ORIGIN Study. Am J Med. 2017 Dec;130(12):1465.e27-1465.e39. doi: 10.1016/j.amjmed.2017.05.047. Epub 2017 Aug 31.
• Yates T, Davies MJ, Jung H, Bosch J, Spinas GA, Sreenan S, Commerford P, Gerstein HC; ORGIN investigators. Effect of insulin glargine on recreational physical activity and TV viewing: Analysis of the randomised ORIGIN trial. Diabetes Res Clin Pract. 2017 Oct;132:137-143. doi: 10.1016/j.diabres.2017.07.035. Epub 2017 Jul 31.
• Rautio A, Boman K, Gerstein HC, Hernestal-Boman J, Lee SF, Olofsson M, Mellbin LG. The effect of basal insulin glargine on the fibrinolytic system and von Willebrand factor in people with dysglycaemia and high risk for cardiovascular events: Swedish substudy of the Outcome Reduction with an Initial Glargine Intervention trial. Diab Vasc Dis Res. 2017 Jul;14(4):345-352. doi: 10.1177/1479164117703034. Epub 2017 Apr 12.
• Gerstein HC, Pare G, McQueen MJ, Lee SF, Hess S; ORIGIN Trial Investigators. Validation of the ORIGIN Cardiovascular Biomarker Panel and the Value of Adding Troponin I in Dysglycemic People. J Clin Endocrinol Metab. 2017 Jul 1;102(7):2251-2257. doi: 10.1210/jc.2017-00273.
• Gerstein HC, Pare G, Hess S, Ford RJ, Sjaarda J, Raman K, McQueen M, Lee S, Haenel H, Steinberg GR; ORIGIN Investigators. Growth Differentiation Factor 15 as a Novel Biomarker for Metformin. Diabetes Care. 2017 Feb;40(2):280-283. doi: 10.2337/dc16-1682. Epub 2016 Dec 14.
• ORIGIN Trial Investigators. Cardiovascular and Other Outcomes Postintervention With Insulin Glargine and Omega-3 Fatty Acids (ORIGINALE). Diabetes Care. 2016 May;39(5):709-16. doi: 10.2337/dc15-1676. Epub 2015 Dec 17.
• Gerstein HC, Pare G, McQueen MJ, Haenel H, Lee SF, Pogue J, Maggioni AP, Yusuf S, Hess S; Outcome Reduction With Initial Glargine Intervention Trial Investigators. Identifying Novel Biomarkers for Cardiovascular Events or Death in People With Dysglycemia. Circulation. 2015 Dec 15;132(24):2297-304. doi: 10.1161/CIRCULATIONAHA.115.015744. Epub 2015 Oct 30.
• Cukierman-Yaffe T, Bosch J, Diaz R, Dyal L, Hancu N, Hildebrandt P, Lanas F, Lewis BS, Marre M, Yale JF, Yusuf S, Gerstein HC; ORIGIN Investigators. Effects of basal insulin glargine and omega-3 fatty acid on cognitive decline and probable cognitive impairment in people with dysglycaemia: a substudy of the ORIGIN trial. Lancet Diabetes Endocrinol. 2014 Jul;2(7):562-72. doi: 10.1016/S2213-8587(14)70062-2. Epub 2014 Jun 2.
• ORIGIN trial investigators; Gilbert RE, Mann JF, Hanefeld M, Spinas G, Bosch J, Yusuf S, Gerstein HC. Basal insulin glargine and microvascular outcomes in dysglycaemic individuals: results of the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial. Diabetologia. 2014 Jul;57(7):1325-31. doi: 10.1007/s00125-014-3238-4. Epub 2014 Apr 26.
• Lopez-Jaramillo P, Cohen DD, Gomez-Arbelaez D, Bosch J, Dyal L, Yusuf S, Gerstein HC; ORIGIN Trial Investigators. Association of handgrip strength to cardiovascular mortality in pre-diabetic and diabetic patients: a subanalysis of the ORIGIN trial. Int J Cardiol. 2014 Jun 15;174(2):458-61. doi: 10.1016/j.ijcard.2014.04.013. Epub 2014 Apr 13. No abstract available.
• Lamy A, Tong W, Jung H, Gafni A, Singh K, Tyrwhitt J, Yusuf S, Gerstein HC; ORIGIN Investigators. Cost implications of the use of basal insulin glargine in people with early dysglycemia: the ORIGIN trial. J Diabetes Complications. 2014 Jul-Aug;28(4):553-8. doi: 10.1016/j.jdiacomp.2014.02.012. Epub 2014 Mar 2.
• Bordeleau L, Yakubovich N, Dagenais GR, Rosenstock J, Probstfield J, Chang Yu P, Ryden LE, Pirags V, Spinas GA, Birkeland KI, Ratner RE, Marin-Neto JA, Keltai M, Riddle MC, Bosch J, Yusuf S, Gerstein HC; ORIGIN Trial Investigators. The association of basal insulin glargine and/or n-3 fatty acids with incident cancers in patients with dysglycemia. Diabetes Care. 2014;37(5):1360-6. doi: 10.2337/dc13-1468. Epub 2014 Feb 26.
• ORIGIN Trial Investigators; Mellbin LG, Ryden L, Riddle MC, Probstfield J, Rosenstock J, Diaz R, Yusuf S, Gerstein HC. Does hypoglycaemia increase the risk of cardiovascular events? A report from the ORIGIN trial. Eur Heart J. 2013 Oct;34(40):3137-44. doi: 10.1093/eurheartj/eht332. Epub 2013 Sep 2.
• ORIGIN Trial Investigators. Characteristics associated with maintenance of mean A1C<6.5% in people with dysglycemia in the ORIGIN trial. Diabetes Care. 2013 Oct;36(10):2915-22. doi: 10.2337/dc12-2238. Epub 2013 May 8.
• Lonn EM, Bosch J, Diaz R, Lopez-Jaramillo P, Ramachandran A, Hancu N, Hanefeld M, Krum H, Ryden L, Smith S, McQueen MJ, Dyal L, Yusuf S, Gerstein HC; GRACE and ORIGIN Investigators. Effect of insulin glargine and n-3FA on carotid intima-media thickness in people with dysglycemia at high risk for cardiovascular events: the glucose reduction and atherosclerosis continuing evaluation study (ORIGIN-GRACE). Diabetes Care. 2013 Sep;36(9):2466-74. doi: 10.2337/dc12-2129. Epub 2013 Apr 5.

Study record dates

Study Major Dates

• Study Start: August 1, 2003
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: October 1, 2003
• First Submitted That Met QC Criteria: October 3, 2003
• First Posted (Estimate): October 6, 2003

Study Record Updates

• Last Update Posted (Estimate): January 31, 2013
• Last Update Submitted That Met QC Criteria: January 24, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Keywords: Impaired Fasting Glucose (IFG); Impaired Glucose Tolerance (IGT)
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin; Insulin, Globin Zinc; Insulin Glargine
• Other Study ID Numbers: LTS6035; HOE901/4032 (Other Identifier: previous Aventis study number)