Resumen

Los objetivos primarios del estudio ORIGIN fueron: * Determinar si la normoglucemia mediada por insulina glargina puede reducir la morbilidad y/o mortalidad cardiovascular en personas con alto riesgo de enfermedad vascular con glucemia en ayunas alterada (GAA), tolerancia alterada a la glucosa (TAG) o diabetes tipo 2 temprana. * Determinar si los ácidos grasos omega-3 pueden reducir la mortalidad cardiovascular en personas con GAA, TAG o diabetes tipo 2 temprana. Los objetivos secundarios del estudio de insulina glargina fueron determinar si la normoglucemia mediada por insulina glargina puede reducir: * La mortalidad total (todas las causas). * El riesgo de desenlaces microvasculares diabéticos. * La tasa de progresión de TAG o GAA a diabetes tipo 2.

Descripción detallada

El estudio ORIGIN fue conducido por el Population Health Research Institute en Hamilton, Ontario (Canadá), trabajando en conjunto con el patrocinador y un Comité Directivo independiente. Las visitas de rutina debían ocurrir a las 2, 4, 8 y 16 semanas después de la aleatorización, luego cada cuatro meses durante el resto del estudio, para todos los participantes. La duración del estudio se basó en el número de eventos observados (estudio impulsado por eventos) y originalmente se planificó en 5 años. En 2008-2009, el seguimiento de ORIGIN se extendió aproximadamente 2 años, porque la literatura publicada de estudios completados sugería que podría ser necesario un período más prolongado de contraste glucémico efectivo entre tratamientos para observar un efecto sobre los eventos cardiovasculares.

Elegibilidad

Edad mínima: 50 YearsSexo: ALL

Criterios de inclusión

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.

Criterios de exclusión

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).

Intervenciones

drug

insulin glargine (HOE901)

Cartridges for use in a pen device, each containing 3 mL of insulin glargine 100 U/mL solution for injection

drug

omega-3 polyunsaturated fatty acids (PUFA)

Gelatin capsules (containing icosapent ethyl esters 465 mg and doconexent ethyl esters 375 mg) for oral administration

drug

placebo

Matching placebo gelatin capsules (containing olive oil) for oral administration

device

Resumen

Descripción detallada

Elegibilidad

Criterios de inclusión

Criterios de exclusión

Intervenciones

insulin glargine (HOE901)

omega-3 polyunsaturated fatty acids (PUFA)

placebo

reusable pen device for insulin injection

Ubicaciones

Sanofi-Aventis Administrative Office

Patrocinadores