Diabetes Mellitus, Non-Insulin-Dependent
Conditions
Keywords
Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT)
Brief summary
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.
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.
Interventions
Cartridges for use in a pen device, each containing 3 mL of insulin glargine 100 U/mL solution for injection
DRUGomega-3 polyunsaturated fatty acids (PUFA)
Gelatin capsules (containing icosapent ethyl esters 465 mg and doconexent ethyl esters 375 mg) for oral administration
DRUGplacebo
Matching placebo gelatin capsules (containing olive oil) for oral administration
DEVICEreusable pen device for insulin injection
Sponsors
Population Health Research Institute
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI) or Nonfatal Stroke | from randomization until study cut-off date (median duration of follow-up: 6.2 years) | 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. |
| Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Revascularization Procedure or Hospitalization for Heart Failure (HF) | from randomization until study cut-off date (median duration of follow-up: 6.2 years) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Development of Type 2 Diabetes Mellitus in Participants With IGT and/or IFG | from randomization until the last follow-up visit or last OGTT (median duration of follow-up: 6.2 years) | 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). |
| Composite Diabetic Microvascular Outcome (Kidney or Eye Disease) | from randomization until study cut-off date (median duration of follow-up: 6.2 years) | 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 \[at least 300 mg/g creatinine\]). |
| Total Mortality (All Causes) | from randomization until study cut-off date (median duration of follow-up: 6.2 years) | Number of deaths due to any cause |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Various Types of Symptomatic Hypoglycemia Events | on-treatment period (median duration of follow-up: 6.2 years) | 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. |
| Number of Patients With First Occurrence of Any Type of Cancer | from randomization until study cut-off date (median duration of follow-up: 6.2 years) | 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. |
Countries
Argentina, Australia, Austria, Belarus, Bermuda, Brazil, Canada, Chile, China, Colombia, Croatia, Denmark, Estonia, Finland, France, Germany, Hungary, India, Ireland, Israel, Italy, Latvia, Lithuania, Mexico, Netherlands, Norway, Philippines, Poland, Romania, Russia, Slovakia, South Africa, South Korea, Spain, Sweden, Switzerland, Turkey (Türkiye), United Kingdom, United States, Venezuela
Participant flow
Recruitment details
This study was conducted at 575 sites in 40 countries between August 22, 2003 and December 19, 2011. Three sites were closed and data from these sites were not analyzed following site audits and in compliance with rulings from national health authorities.
Pre-assignment details
The purpose of the factorial design was to efficiently answer two independent scientifically worthwhile questions regarding insulin glargine and omega-3 fatty acids within the context of a single clinical trial. Sample size was determined based on the insulin glargine study objective. Results reported below are those of the insulin glargine study.
Participants by arm
| Arm | Count |
|---|---|
| Insulin Glargine Treatment with Insulin Glargine with or without omega-3 polyunsaturated fatty acids | 6,264 |
| Standard Care Standard care with or without omega-3 polyunsaturated fatty acids | 6,273 |
| Total | 12,537 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 105 | 0 |
| Overall Study | Other | 17 | 0 |
| Overall Study | Withdrawal by Subject | 1,090 | 0 |
Baseline characteristics
| Characteristic | Insulin Glargine | Standard Care | Total |
|---|---|---|---|
| Age Continuous | 63.5 years STANDARD_DEVIATION 7.8 | 63.5 years STANDARD_DEVIATION 7.9 | 63.5 years STANDARD_DEVIATION 7.8 |
| Any previous cardiovascular event No | 2552 participants | 2607 participants | 5159 participants |
| Any previous cardiovascular event Yes | 3712 participants | 3666 participants | 7378 participants |
| Baseline Body Mass Index | 29.77 kg/m² STANDARD_DEVIATION 5.17 | 29.88 kg/m² STANDARD_DEVIATION 5.33 | 29.82 kg/m² STANDARD_DEVIATION 5.25 |
| Baseline Weight | 83.33 kg STANDARD_DEVIATION 16.77 | 83.13 kg STANDARD_DEVIATION 17.28 | 83.23 kg STANDARD_DEVIATION 17.03 |
| Diabetes diagnosis at time of screening Established diabetes with no OAD treatment | 1414 participants | 1467 participants | 2881 participants |
| Diabetes diagnosis at time of screening Established diabetes with one OAD treatment | 3748 participants | 3692 participants | 7440 participants |
| Diabetes diagnosis at time of screening IFG and/or IGT | 735 participants | 717 participants | 1452 participants |
| Diabetes diagnosis at time of screening Newly diagnosed diabetic | 365 participants | 395 participants | 760 participants |
| Diabetes diagnosis at time of screening Unclear diabetes status | 2 participants | 2 participants | 4 participants |
| Duration of diabetes for established diabetes patients | 3.50 years | 3.50 years | 3.50 years |
| Fasting Plasma Glucose | 6.94 mmol/L | 6.90 mmol/L | 6.94 mmol/L |
| Glycated Hemoglobin A1c (HbA1c) | 6.41 percent | 6.40 percent | 6.40 percent |
| Sex/Gender, Customized Female | 2082 participants | 2304 participants | 4386 participants |
| Sex/Gender, Customized Male | 4181 participants | 3969 participants | 8150 participants |
| Sex/Gender, Customized Missing value | 1 participants | 0 participants | 1 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 6,231 | 0 / 6,273 |
| serious Total, serious adverse events | 303 / 6,231 | 232 / 6,273 |
Outcome results
Primary
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.
Time frame: from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Population: The analysis was based on the intent-to-treat (ITT) population i.e. all randomized participants.~For the endpoint's composition, the numbers only summarize the event when it was the first occurrence of the endpoint. A participant is counted only once within a category. The same participant may appear in different categories.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Insulin Glargine | Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Revascularization Procedure or Hospitalization for Heart Failure (HF) | Endpoint's composition: CV death | 350 participants |
| Insulin Glargine | Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Revascularization Procedure or Hospitalization for Heart Failure (HF) | Endpoint's composition: nonfatal stroke | 231 participants |
| Insulin Glargine | Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Revascularization Procedure or Hospitalization for Heart Failure (HF) | Participants with a composite endpoint | 1792 participants |
| Insulin Glargine | Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Revascularization Procedure or Hospitalization for Heart Failure (HF) | Endpoint's composition: revascularization | 763 participants |
| Insulin Glargine | Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Revascularization Procedure or Hospitalization for Heart Failure (HF) | Endpoint's composition: nonfatal MI | 257 participants |
| Insulin Glargine | Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Revascularization Procedure or Hospitalization for Heart Failure (HF) | Endpoint's composition: hospitalization for HF | 249 participants |
| Standard Care | Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Revascularization Procedure or Hospitalization for Heart Failure (HF) | Endpoint's composition: hospitalization for HF | 259 participants |
| Standard Care | Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Revascularization Procedure or Hospitalization for Heart Failure (HF) | Participants with a composite endpoint | 1727 participants |
| Standard Care | Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Revascularization Procedure or Hospitalization for Heart Failure (HF) | Endpoint's composition: CV death | 339 participants |
| Standard Care | Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Revascularization Procedure or Hospitalization for Heart Failure (HF) | Endpoint's composition: nonfatal MI | 238 participants |
| Standard Care | Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Revascularization Procedure or Hospitalization for Heart Failure (HF) | Endpoint's composition: nonfatal stroke | 227 participants |
| Standard Care | Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Revascularization Procedure or Hospitalization for Heart Failure (HF) | Endpoint's composition: revascularization | 717 participants |
Comparison: See above additional details provided for the analysis of the first coprimary outcome.p-value: 0.269295% CI: [0.972, 1.109]Log Rank
Primary
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.
Time frame: from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Population: The analysis was based on the intent-to-treat (ITT) population i.e. all randomized participants.~For the endpoint's composition, the numbers only summarize the event when it was the first occurrence of the endpoint. A participant is counted only once within a category. The same participant may appear in different categories.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Insulin Glargine | Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI) or Nonfatal Stroke | Participants with a composite endpoint | 1041 participants |
| Insulin Glargine | Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI) or Nonfatal Stroke | Endpoint's composition: nonfatal MI | 297 participants |
| Insulin Glargine | Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI) or Nonfatal Stroke | Endpoint's composition: CV death | 484 participants |
| Insulin Glargine | Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI) or Nonfatal Stroke | Endpoint's composition: nonfatal stroke | 261 participants |
| Standard Care | Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI) or Nonfatal Stroke | Endpoint's composition: CV death | 476 participants |
| Standard Care | Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI) or Nonfatal Stroke | Participants with a composite endpoint | 1013 participants |
| Standard Care | Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI) or Nonfatal Stroke | Endpoint's composition: nonfatal stroke | 256 participants |
| Standard Care | Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI) or Nonfatal Stroke | Endpoint's composition: nonfatal MI | 282 participants |
Comparison: The total required number of first coprimary outcomes (2200) assumed that a hazard reduction of 14-16% was clinically significant and controlled the overall experiment-wise Type 1 error at 5% with a power of 80% for each outcome. The total number of participants needed to achieve this number of events within the planned enrollment and treatment periods was ultimately estimated to be 12 500 based on the CURE and HOPE study databases.p-value: 0.627395% CI: [0.937, 1.114]Log Rank
Secondary
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 \[at least 300 mg/g creatinine\]).
Time frame: from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Population: The analysis was based on the intent-to-treat (ITT) population i.e. all randomized participants.~For the endpoint's composition, the numbers only summarize the event when it was the first occurrence of the endpoint. A participant is counted only once within a category. The same participant may appear in different categories.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Insulin Glargine | Composite Diabetic Microvascular Outcome (Kidney or Eye Disease) | Endpoint's composition: dialysis | 18 participants |
| Insulin Glargine | Composite Diabetic Microvascular Outcome (Kidney or Eye Disease) | Endpoint's composition: renal transplant | 0 participants |
| Insulin Glargine | Composite Diabetic Microvascular Outcome (Kidney or Eye Disease) | Endpoint's composition: vitrectomy | 24 participants |
| Insulin Glargine | Composite Diabetic Microvascular Outcome (Kidney or Eye Disease) | Endpoint's composition: serum creatinine doubled | 82 participants |
| Insulin Glargine | Composite Diabetic Microvascular Outcome (Kidney or Eye Disease) | Endpoint's composition: death due to renal failure | 4 participants |
| Insulin Glargine | Composite Diabetic Microvascular Outcome (Kidney or Eye Disease) | Endpoint's composition: laser therapy for DR | 57 participants |
| Insulin Glargine | Composite Diabetic Microvascular Outcome (Kidney or Eye Disease) | Endpoint's composition: albuminuria progression | 1153 participants |
| Insulin Glargine | Composite Diabetic Microvascular Outcome (Kidney or Eye Disease) | Participants with a composite endpoint | 1323 participants |
| Standard Care | Composite Diabetic Microvascular Outcome (Kidney or Eye Disease) | Endpoint's composition: albuminuria progression | 1171 participants |
| Standard Care | Composite Diabetic Microvascular Outcome (Kidney or Eye Disease) | Endpoint's composition: dialysis | 28 participants |
| Standard Care | Composite Diabetic Microvascular Outcome (Kidney or Eye Disease) | Endpoint's composition: serum creatinine doubled | 88 participants |
| Standard Care | Composite Diabetic Microvascular Outcome (Kidney or Eye Disease) | Endpoint's composition: vitrectomy | 25 participants |
| Standard Care | Composite Diabetic Microvascular Outcome (Kidney or Eye Disease) | Endpoint's composition: laser therapy for DR | 67 participants |
| Standard Care | Composite Diabetic Microvascular Outcome (Kidney or Eye Disease) | Endpoint's composition: renal transplant | 0 participants |
| Standard Care | Composite Diabetic Microvascular Outcome (Kidney or Eye Disease) | Endpoint's composition: death due to renal failure | 3 participants |
| Standard Care | Composite Diabetic Microvascular Outcome (Kidney or Eye Disease) | Participants with a composite endpoint | 1363 participants |
95% CI: [0.9, 1.047]
Secondary
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).
Time frame: from randomization until the last follow-up visit or last OGTT (median duration of follow-up: 6.2 years)
Population: The analysis was based on the subgroup of the intent-to-treat (ITT) population without diabetes at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Glargine | Incidence of Development of Type 2 Diabetes Mellitus in Participants With IGT and/or IFG | 24.7 percentage of patients |
| Standard Care | Incidence of Development of Type 2 Diabetes Mellitus in Participants With IGT and/or IFG | 31.2 percentage of patients |
95% CI: [0.58, 0.91]
Secondary
Total Mortality (All Causes)
Number of deaths due to any cause
Time frame: from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Population: The analysis was based on the intent-to-treat (ITT) population, which was all randomized participants, regardless of compliance with the protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Glargine | Total Mortality (All Causes) | 951 participants |
| Standard Care | Total Mortality (All Causes) | 965 participants |
95% CI: [0.899, 1.076]
Other Pre-specified
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.
Time frame: from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Population: The analysis was based on the intent-to-treat (ITT) population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Glargine | Number of Patients With First Occurrence of Any Type of Cancer | 559 participants |
| Standard Care | Number of Patients With First Occurrence of Any Type of Cancer | 561 participants |
Other Pre-specified
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.
Time frame: on-treatment period (median duration of follow-up: 6.2 years)
Population: The population analyzed was the safety population consisting of all randomized and treated patients (who received at least one dose of study drug) for the insulin glargine group and of all randomized patients for the standard care group.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Insulin Glargine | Number of Patients With Various Types of Symptomatic Hypoglycemia Events | Patients with hypoglycemia events | 3597 participants |
| Insulin Glargine | Number of Patients With Various Types of Symptomatic Hypoglycemia Events | Patients with non-severe hypoglycemia | 3533 participants |
| Insulin Glargine | Number of Patients With Various Types of Symptomatic Hypoglycemia Events | Patients with confirmed non-severe hypoglycemia | 2581 participants |
| Insulin Glargine | Number of Patients With Various Types of Symptomatic Hypoglycemia Events | Patients with severe hypoglycemia | 352 participants |
| Standard Care | Number of Patients With Various Types of Symptomatic Hypoglycemia Events | Patients with severe hypoglycemia | 113 participants |
| Standard Care | Number of Patients With Various Types of Symptomatic Hypoglycemia Events | Patients with hypoglycemia events | 1624 participants |
| Standard Care | Number of Patients With Various Types of Symptomatic Hypoglycemia Events | Patients with confirmed non-severe hypoglycemia | 904 participants |
| Standard Care | Number of Patients With Various Types of Symptomatic Hypoglycemia Events | Patients with non-severe hypoglycemia | 1582 participants |