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The ORIGIN Trial (Outcome Reduction With Initial Glargine Intervention)

This study has been completed.
Sponsor:
Collaborator:
Population Health Research Institute
Information provided by (Responsible Party):
Sanofi
ClinicalTrials.gov Identifier:
NCT00069784
First received: October 1, 2003
Last updated: January 24, 2013
Last verified: January 2013
Results First Received: December 18, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Factorial Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Diabetes Mellitus, Non-Insulin-Dependent
Interventions: Drug: insulin glargine (HOE901)
Drug: omega-3 polyunsaturated fatty acids (PUFA)
Drug: placebo
Device: reusable pen device for insulin injection

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups
  Description
Insulin Glargine Treatment with Insulin Glargine with or without omega-3 polyunsaturated fatty acids
Standard Care Standard care with or without omega-3 polyunsaturated fatty acids

Participant Flow:   Overall Study
    Insulin Glargine     Standard Care  
STARTED     6264 [1]   6273 [1]
Safety Population (Treated)     6231 [2]   6273 [3]
COMPLETED     5052 [4]   6273 [5]
NOT COMPLETED     1212     0  
Adverse Event                 105                 0  
Withdrawal by Subject                 1090                 0  
Unknown                 17                 0  
[1] randomized participants = intent-to-treat (ITT) population
[2] randomized patients who received at least one dose of insulin glargine
[3] patients randomized to standard care arm
[4] completed study treatment
[5] not applicable (no treatment)



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Insulin Glargine Treatment with Insulin Glargine with or without omega-3 polyunsaturated fatty acids
Standard Care Standard care with or without omega-3 polyunsaturated fatty acids
Total Total of all reporting groups

Baseline Measures
    Insulin Glargine     Standard Care     Total  
Number of Participants  
[units: participants]
  6264     6273     12537  
Age  
[units: years]
Mean ± Standard Deviation
  63.5  ± 7.8     63.5  ± 7.9     63.5  ± 7.8  
Gender, Customized  
[units: participants]
     
Male     4181     3969     8150  
Female     2082     2304     4386  
Missing value     1     0     1  
Baseline Weight [1]
[units: kg]
Mean ± Standard Deviation
  83.33  ± 16.77     83.13  ± 17.28     83.23  ± 17.03  
Baseline Body Mass Index [2]
[units: kg/m²]
Mean ± Standard Deviation
  29.77  ± 5.17     29.88  ± 5.33     29.82  ± 5.25  
Any previous cardiovascular event  
[units: participants]
     
No     2552     2607     5159  
Yes     3712     3666     7378  
Diabetes diagnosis at time of screening [3]
[units: participants]
     
IFG and/or IGT     735     717     1452  
Newly diagnosed diabetic     365     395     760  
Established diabetes with no OAD treatment     1414     1467     2881  
Established diabetes with one OAD treatment     3748     3692     7440  
Unclear diabetes status     2     2     4  
Duration of diabetes for established diabetes patients [4]
[units: years]
Median ( Inter-Quartile Range )
  3.50  
  ( 1.50 to 7.50 )  
  3.50  
  ( 1.50 to 7.50 )  
  3.50  
  ( 1.50 to 7.50 )  
Glycated Hemoglobin A1c (HbA1c) [5]
[units: percent]
Median ( Inter-Quartile Range )
  6.41  
  ( 5.81 to 7.18 )  
  6.40  
  ( 5.81 to 7.16 )  
  6.40  
  ( 5.81 to 7.18 )  
Fasting Plasma Glucose [6]
[units: mmol/L]
Median ( Inter-Quartile Range )
  6.94  
  ( 6.05 to 8.20 )  
  6.90  
  ( 6.00 to 8.20 )  
  6.94  
  ( 6.05 to 8.20 )  
[1] Due to missing values, N=6256 for insulin glargine and N=6271 for standard care.
[2] Due to missing values, N=6251 for insulin glargine and N=6270 for standard care.
[3]

IFG = Impaired Fasting Glucose defined as a Postprandial Plasma Glucose (PPG) value ≥140 and <200 mg/dL (ie, ≥7.8 and <11.1 mmol/L), with a Fasting Plasma Glucose (FPG) <126 mg/dL (7.0 mmol/L)

IGT = Impaired Glucose Tolerance 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])

OAD = oral antidiabetic drug

[4] Population of patients with established diabetes. Due to missing values, N=5148 for insulin glargine and N=5141 for standard care.
[5] Due to missing values, N=6175 for insulin glargine and N=6189 for standard care.
[6] Due to missing values, N=6248 for insulin glargine and N=6266 for standard care.



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI) or Nonfatal Stroke   [ Time Frame: from randomization until study cut-off date (median duration of follow-up: 6.2 years) ]

2.  Primary:   Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Revascularization Procedure or Hospitalization for Heart Failure (HF)   [ Time Frame: from randomization until study cut-off date (median duration of follow-up: 6.2 years) ]

3.  Secondary:   Total Mortality (All Causes)   [ Time Frame: from randomization until study cut-off date (median duration of follow-up: 6.2 years) ]

4.  Secondary:   Composite Diabetic Microvascular Outcome (Kidney or Eye Disease)   [ Time Frame: from randomization until study cut-off date (median duration of follow-up: 6.2 years) ]

5.  Secondary:   Incidence of Development of Type 2 Diabetes Mellitus in Participants With IGT and/or IFG   [ Time Frame: from randomization until the last follow-up visit or last OGTT (median duration of follow-up: 6.2 years) ]

6.  Other Pre-specified:   Number of Patients With Various Types of Symptomatic Hypoglycemia Events   [ Time Frame: on-treatment period (median duration of follow-up: 6.2 years) ]

7.  Other Pre-specified:   Number of Patients With First Occurrence of Any Type of Cancer   [ Time Frame: from randomization until study cut-off date (median duration of follow-up: 6.2 years) ]


  Serious Adverse Events
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Time Frame Adverse events (AEs) were assessed through the study. The median duration of follow-up was 6.2 years.
Additional Description Aside from hypoglycemia and cancer, serious AEs were only captured if the event was considered related to a study drug. Non-serious AEs were only captured if the event resulted in some modification (suspension, alteration or cessation) in the dose of a study drug. This creates a bias for the comparison between insulin glargine and standard care.

Reporting Groups
  Description
Insulin Glargine Treatment with Insulin Glargine with or without omega-3 polyunsaturated fatty acids
Standard Care Standard care with or without omega-3 polyunsaturated fatty acids

Serious Adverse Events
    Insulin Glargine     Standard Care  
Total, serious adverse events      
# participants affected / at risk     303/6231 (4.86%)     232/6273 (3.70%)  
Blood and lymphatic system disorders      
Anaemia * 1    
# participants affected / at risk     1/6231 (0.02%)     1/6273 (0.02%)  
Coagulopathy * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Hypochromic anaemia * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Idiopathic thrombocytopenic purpura * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Lymphadenopathy * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Cardiac disorders      
Myocardial infarction * 1    
# participants affected / at risk     10/6231 (0.16%)     9/6273 (0.14%)  
Angina unstable * 1    
# participants affected / at risk     9/6231 (0.14%)     11/6273 (0.18%)  
Acute myocardial infarction * 1    
# participants affected / at risk     8/6231 (0.13%)     4/6273 (0.06%)  
Cardiac failure congestive * 1    
# participants affected / at risk     6/6231 (0.10%)     6/6273 (0.10%)  
Arrhythmia supraventricular * 1    
# participants affected / at risk     3/6231 (0.05%)     1/6273 (0.02%)  
Atrial fibrillation * 1    
# participants affected / at risk     3/6231 (0.05%)     3/6273 (0.05%)  
Angina pectoris * 1    
# participants affected / at risk     2/6231 (0.03%)     3/6273 (0.05%)  
Cardiac arrest * 1    
# participants affected / at risk     2/6231 (0.03%)     1/6273 (0.02%)  
Cardiac failure * 1    
# participants affected / at risk     2/6231 (0.03%)     3/6273 (0.05%)  
Supraventricular tachycardia * 1    
# participants affected / at risk     2/6231 (0.03%)     0/6273 (0.00%)  
Acute coronary syndrome * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Arrhythmia * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Bradycardia * 1    
# participants affected / at risk     1/6231 (0.02%)     1/6273 (0.02%)  
Ventricular extrasystoles * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Ventricular fibrillation * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Ventricular tachycardia * 1    
# participants affected / at risk     1/6231 (0.02%)     1/6273 (0.02%)  
Atrioventricular block * 1    
# participants affected / at risk     0/6231 (0.00%)     3/6273 (0.05%)  
Atrioventricular block second degree * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Cardiac disorder * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Coronary artery disease * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Coronary artery occlusion * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Myocardial ischaemia * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Pericardial disease * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Congenital, familial and genetic disorders      
Skull malformation * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Ear and labyrinth disorders      
Tinnitus * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Vertigo * 1    
# participants affected / at risk     1/6231 (0.02%)     1/6273 (0.02%)  
Inner ear disorder * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Otosclerosis * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Eye disorders      
Vitreous haemorrhage * 1    
# participants affected / at risk     2/6231 (0.03%)     0/6273 (0.00%)  
Retinal haemorrhage * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Retinal oedema * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Visual impairment * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Blindness * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Diabetic retinopathy * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Eversion of lacrimal punctum * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Retinal vein thrombosis * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Gastrointestinal disorders      
Gastrointestinal haemorrhage * 1    
# participants affected / at risk     5/6231 (0.08%)     0/6273 (0.00%)  
Abdominal pain * 1    
# participants affected / at risk     2/6231 (0.03%)     0/6273 (0.00%)  
Pancreatitis * 1    
# participants affected / at risk     2/6231 (0.03%)     0/6273 (0.00%)  
Rectal haemorrhage * 1    
# participants affected / at risk     2/6231 (0.03%)     0/6273 (0.00%)  
Abdominal pain upper * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Abdominal strangulated hernia * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Colitis ulcerative * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Diarrhoea * 1    
# participants affected / at risk     1/6231 (0.02%)     1/6273 (0.02%)  
Duodenal varices * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Gastric ulcer * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Gastrointestinal ulcer haemorrhage * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Oesophagitis * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Pancreatitis acute * 1    
# participants affected / at risk     1/6231 (0.02%)     1/6273 (0.02%)  
Peptic ulcer haemorrhage * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Abdominal distension * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Colitis ischaemic * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Constipation * 1    
# participants affected / at risk     0/6231 (0.00%)     2/6273 (0.03%)  
Dyspepsia * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Gastritis * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Gastrointestinal ulcer * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Lower gastrointestinal haemorrhage * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Pancreatolithiasis * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Upper gastrointestinal haemorrhage * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
General disorders      
Death * 1    
# participants affected / at risk     11/6231 (0.18%)     14/6273 (0.22%)  
Chest pain * 1    
# participants affected / at risk     6/6231 (0.10%)     2/6273 (0.03%)  
Non-cardiac chest pain * 1    
# participants affected / at risk     4/6231 (0.06%)     0/6273 (0.00%)  
Oedema peripheral * 1    
# participants affected / at risk     3/6231 (0.05%)     0/6273 (0.00%)  
Sudden death * 1    
# participants affected / at risk     3/6231 (0.05%)     1/6273 (0.02%)  
Cardiac death * 1    
# participants affected / at risk     1/6231 (0.02%)     1/6273 (0.02%)  
Device failure * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Pyrexia * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Sudden cardiac death * 1    
# participants affected / at risk     1/6231 (0.02%)     1/6273 (0.02%)  
Hernia obstructive * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Hepatobiliary disorders      
Cholelithiasis * 1    
# participants affected / at risk     2/6231 (0.03%)     1/6273 (0.02%)  
Hepatic cirrhosis * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Hepatitis * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Cholecystitis * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Cholecystitis acute * 1    
# participants affected / at risk     0/6231 (0.00%)     2/6273 (0.03%)  
Hepatitis toxic * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Liver disorder * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Immune system disorders      
Drug hypersensitivity * 1    
# participants affected / at risk     2/6231 (0.03%)     0/6273 (0.00%)  
Hypersensitivity * 1    
# participants affected / at risk     1/6231 (0.02%)     1/6273 (0.02%)  
Infections and infestations      
Pneumonia * 1    
# participants affected / at risk     5/6231 (0.08%)     6/6273 (0.10%)  
Gastroenteritis * 1    
# participants affected / at risk     2/6231 (0.03%)     3/6273 (0.05%)  
Sepsis * 1    
# participants affected / at risk     2/6231 (0.03%)     0/6273 (0.00%)  
Urinary tract infection * 1    
# participants affected / at risk     2/6231 (0.03%)     1/6273 (0.02%)  
Abdominal abscess * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Anal abscess * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Diverticulitis * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Herpes zoster * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Infective exacerbation of chronic obstructive airways disease * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Respiratory tract infection * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Bronchitis * 1    
# participants affected / at risk     0/6231 (0.00%)     4/6273 (0.06%)  
Cellulitis * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
H1N1 influenza * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Pseudomonas infection * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Rectal abscess * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Wound infection * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Injury, poisoning and procedural complications      
Accidental overdose * 1    
# participants affected / at risk     5/6231 (0.08%)     0/6273 (0.00%)  
Fracture * 1    
# participants affected / at risk     3/6231 (0.05%)     3/6273 (0.05%)  
Toxicity to various agents * 1    
# participants affected / at risk     2/6231 (0.03%)     1/6273 (0.02%)  
Intentional overdose * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Radius fracture * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Splenic rupture * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Subdural haematoma * 1    
# participants affected / at risk     1/6231 (0.02%)     1/6273 (0.02%)  
Wrist fracture * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Fall * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Gun shot wound * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Hip fracture * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Joint dislocation * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Meniscus lesion * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Overdose * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Tendon injury * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Upper limb fracture * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Investigations      
Arteriogram coronary * 1    
# participants affected / at risk     4/6231 (0.06%)     1/6273 (0.02%)  
Weight increased * 1    
# participants affected / at risk     2/6231 (0.03%)     0/6273 (0.00%)  
Arteriogram carotid * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Biopsy lymph gland * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Colonoscopy * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Diagnostic procedure * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Ureteroscopy * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Cystoscopy * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Investigation * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Liver function test abnormal * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Metabolism and nutrition disorders      
Hypoglycaemia * 1    
# participants affected / at risk     36/6231 (0.58%)     15/6273 (0.24%)  
Hypoglycaemic unconsciousness * 1    
# participants affected / at risk     21/6231 (0.34%)     0/6273 (0.00%)  
Hypoglycaemic seizure * 1    
# participants affected / at risk     7/6231 (0.11%)     0/6273 (0.00%)  
Hyperglycaemia * 1    
# participants affected / at risk     2/6231 (0.03%)     0/6273 (0.00%)  
Hypertriglyceridaemia * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Hypokalaemia * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Lactic acidosis * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Cachexia * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Diabetic foot * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Shock hypoglycaemic * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Musculoskeletal and connective tissue disorders      
Arthritis * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Muscle spasms * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Osteoarthritis * 1    
# participants affected / at risk     1/6231 (0.02%)     1/6273 (0.02%)  
Osteoporotic fracture * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Spinal column stenosis * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Chondrocalcinosis pyrophosphate * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Lumbar spinal stenosis * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Osteoporosis * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Rheumatoid arthritis * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Spinal disorder * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Spinal osteoarthritis * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)      
Lung neoplasm malignant * 1    
# participants affected / at risk     4/6231 (0.06%)     3/6273 (0.05%)  
Pancreatic carcinoma * 1    
# participants affected / at risk     4/6231 (0.06%)     5/6273 (0.08%)  
Prostate cancer * 1    
# participants affected / at risk     4/6231 (0.06%)     5/6273 (0.08%)  
Adenocarcinoma * 1    
# participants affected / at risk     1/6231 (0.02%)     1/6273 (0.02%)  
Adrenal adenoma * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Basal cell carcinoma * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Bladder cancer * 1    
# participants affected / at risk     1/6231 (0.02%)     1/6273 (0.02%)  
Breast cancer * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Chronic lymphocytic leukaemia * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Colon cancer * 1    
# participants affected / at risk     1/6231 (0.02%)     2/6273 (0.03%)  
Colon neoplasm * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Colorectal cancer * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Endometrial cancer * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Gastric cancer * 1    
# participants affected / at risk     1/6231 (0.02%)     1/6273 (0.02%)  
Hepatic neoplasm malignant non-resectable * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Lymphoma * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Malignant melanoma stage I * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Multiple myeloma * 1    
# participants affected / at risk     1/6231 (0.02%)     1/6273 (0.02%)  
Myelodysplastic syndrome * 1    
# participants affected / at risk     1/6231 (0.02%)     1/6273 (0.02%)  
Neoplasm malignant * 1    
# participants affected / at risk     1/6231 (0.02%)     2/6273 (0.03%)  
Non-small cell lung cancer * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Pancreatic neoplasm * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Pituitary tumour benign * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Rectosigmoid cancer stage III * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Renal cell carcinoma * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Salivary gland neoplasm * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Transitional cell carcinoma * 1    
# participants affected / at risk     1/6231 (0.02%)     1/6273 (0.02%)  
Acute myeloid leukaemia * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Brain neoplasm * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Gallbladder cancer * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Hepatic neoplasm malignant * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Lymphoproliferative disorder * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Mediastinum neoplasm * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Metastases to lung * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Metastatic neoplasm * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Metastatic squamous cell carcinoma * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Non-Hodgkin's lymphoma * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Pseudomyxoma peritonei * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Rectal cancer * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Renal cancer * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Uterine cancer * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Nervous system disorders      
Hypoglycaemic coma * 1    
# participants affected / at risk     18/6231 (0.29%)     2/6273 (0.03%)  
Cerebrovascular accident * 1    
# participants affected / at risk     8/6231 (0.13%)     5/6273 (0.08%)  
Syncope * 1    
# participants affected / at risk     4/6231 (0.06%)     1/6273 (0.02%)  
Cerebral haemorrhage * 1    
# participants affected / at risk     3/6231 (0.05%)     0/6273 (0.00%)  
Grand mal convulsion * 1    
# participants affected / at risk     2/6231 (0.03%)     0/6273 (0.00%)  
Cerebral infarction * 1    
# participants affected / at risk     1/6231 (0.02%)     1/6273 (0.02%)  
Cranial nerve palsies multiple * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Dementia * 1    
# participants affected / at risk     1/6231 (0.02%)     3/6273 (0.05%)  
Dizziness * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Ischaemic cerebral infarction * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Neurological symptom * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Subarachnoid haemorrhage * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
VIIth nerve paralysis * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Cerebral artery embolism * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Cerebrovascular disorder * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Cognitive disorder * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Convulsion * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Diabetic neuropathy * 1    
# participants affected / at risk     0/6231 (0.00%)     2/6273 (0.03%)  
Haemorrhagic stroke * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Ischaemic stroke * 1    
# participants affected / at risk     0/6231 (0.00%)     2/6273 (0.03%)  
Lumbar radiculopathy * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Neuropathy peripheral * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Polyneuropathy * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Transient ischaemic attack * 1    
# participants affected / at risk     0/6231 (0.00%)     3/6273 (0.05%)  
Psychiatric disorders      
Abnormal behaviour * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Hypomania * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Major depression * 1    
# participants affected / at risk     1/6231 (0.02%)     1/6273 (0.02%)  
Confusional state * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Renal and urinary disorders      
Nephrolithiasis * 1    
# participants affected / at risk     2/6231 (0.03%)     0/6273 (0.00%)  
Renal failure * 1    
# participants affected / at risk     2/6231 (0.03%)     1/6273 (0.02%)  
Urinary tract obstruction * 1    
# participants affected / at risk     2/6231 (0.03%)     0/6273 (0.00%)  
Haematuria * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Renal failure acute * 1    
# participants affected / at risk     1/6231 (0.02%)     2/6273 (0.03%)  
Nephropathy * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Renal failure chronic * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Ureteric obstruction * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Urethral stenosis * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Urinary retention * 1    
# participants affected / at risk     0/6231 (0.00%)     2/6273 (0.03%)  
Reproductive system and breast disorders      
Postmenopausal haemorrhage * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Prostatism * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Respiratory, thoracic and mediastinal disorders      
Chronic obstructive pulmonary disease * 1    
# participants affected / at risk     4/6231 (0.06%)     2/6273 (0.03%)  
Acute pulmonary oedema * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Asphyxia * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Epistaxis * 1    
# participants affected / at risk     1/6231 (0.02%)     4/6273 (0.06%)  
Pleural effusion * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Pulmonary oedema * 1    
# participants affected / at risk     1/6231 (0.02%)     1/6273 (0.02%)  
Respiratory failure * 1    
# participants affected / at risk     1/6231 (0.02%)     1/6273 (0.02%)  
Acute respiratory failure * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Bronchospasm * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Pulmonary embolism * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Skin and subcutaneous tissue disorders      
Diabetic ulcer * 1    
# participants affected / at risk     1/6231 (0.02%)     1/6273 (0.02%)  
Erythema * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Erythema multiforme * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Ecchymosis * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Surgical and medical procedures      
Cardiac pacemaker insertion * 1    
# participants affected / at risk     2/6231 (0.03%)     1/6273 (0.02%)  
Coronary artery bypass * 1    
# participants affected / at risk     2/6231 (0.03%)     1/6273 (0.02%)  
Cholecystostomy * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Hip arthroplasty * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Intestinal resection * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Urethral dilation procedure * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Vitrectomy * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Abdominal hernia repair * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Angioplasty * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Cholecystectomy * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Colporrhaphy * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Hospitalisation * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Parotidectomy * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Percutaneous coronary intervention * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Vascular disorders      
Hypotension * 1    
# participants affected / at risk     3/6231 (0.05%)     0/6273 (0.00%)  
Aortic aneurysm * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Embolism * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Femoral artery occlusion * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Hypertension * 1    
# participants affected / at risk     1/6231 (0.02%)     3/6273 (0.05%)  
Hypertensive emergency * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Iliac artery stenosis * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Intermittent claudication * 1    
# participants affected / at risk     1/6231 (0.02%)     1/6273 (0.02%)  
Ischaemia * 1    
# participants affected / at risk     1/6231 (0.02%)     0/6273 (0.00%)  
Accelerated hypertension * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Arterial occlusive disease * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Deep vein thrombosis * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Orthostatic hypotension * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Peripheral vascular disorder * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
Thrombosis * 1    
# participants affected / at risk     0/6231 (0.00%)     1/6273 (0.02%)  
* Events were collected by non-systematic assessment
1 Term from vocabulary, MedDRA 14.0




  Other Adverse Events
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Time Frame Adverse events (AEs) were assessed through the study. The median duration of follow-up was 6.2 years.
Additional Description Aside from hypoglycemia and cancer, serious AEs were only captured if the event was considered related to a study drug. Non-serious AEs were only captured if the event resulted in some modification (suspension, alteration or cessation) in the dose of a study drug. This creates a bias for the comparison between insulin glargine and standard care.

Frequency Threshold
Threshold above which other adverse events are reported   5%  

Reporting Groups
  Description
Insulin Glargine Treatment with Insulin Glargine with or without omega-3 polyunsaturated fatty acids
Standard Care Standard care with or without omega-3 polyunsaturated fatty acids

Other Adverse Events
    Insulin Glargine     Standard Care  
Total, other (not including serious) adverse events      
# participants affected / at risk     0/6231     0/6273  



  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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