1

Appendix A

Table 1: Summary results from the ACCORD trial publications on major, macro- and micro-vascular outcomes

Reference / Focus / Outcomes / HR: CI
NEJM: 2011;364:818-28 / Glycemia Treatment Strategy:
Macrovascular and major outcomes,
Intensive vs. Standard / Primary outcome a / 0.91:0.81-1.03
Non fatal myocardial infarction / 0.82:0.70-0.96b
Non fatal stroke / 0.87:0.65-1.17
Deaths from cardiovascular causes / 1.29:1.04-1.60 b
Deaths from any cause / 1.19:1.03-1.38 b
Revascularization, or hospitalization or congestive heart failure (CHF) / 0 93:0 86-1 01
Fatal or non fatal myocardial infarction, or unstable angina / 0.90:0.81-1.01
Fatal or non fatal stroke
nonfatal myocardial infarctions / 0.86:0.65-1.13
Fatal or nonfatalCHF / 1.09:0.91-1.32
Lancet, 2010;376(9739):419-30 / Glycemia treatment strategy: intensive vs. standard
Microvascular outcomes / Composite outcome 1c / 0.95: 0.85-1.07
Composite outcome 2d / 0.95:0.89-1.01
Development of microalbuminuriae / 0.85:0.77-0.94 b
Development of macroalbuminuriaf / 0.71:0.59-0.86 b
Development of renal failure,
end stage renal disease (ESRD)g / 0.92:0.86-0.99 b
Doubling of baseline serum creatinine or more than 20 ml/min per 1.73 m² decrease in estimated GFRh / 1.04:0.99-1.10
Retinal photocoagulation or vitrectomy to treat retinopathy / 0.97:0.85-1.10
Eye surgery for cataract extraction / 0.89:0.80-0.99 b
Worsened visual acuity / 0.91:0.83-1.00
Severe loss of vision / 1.01:0.88-1.16
Neuropathy (MNSI score 2.0)i / 0.92:0.86-0.99 b
New loss of vibratory sensationj / 0.93:0.85-1.01
New loss of ankle jerkk / 0.90:0.84-0.97 b
New loss of sensation to light touchl / 0.85:0.76-0.95 b
NEJM 2010;362:1575-85. / Blood Pressure Strategy: Intensive vs. Standard
Macrovascular and major outcomes, / Primary outcomea / 0.88: 0.73-1.06
Non fatal myocardial infarction / 0.87: 0.68-1.10
Non fatal stroke / 0.63: 0.41-0.96b
Any stroke / 0.59: 0.39-0.89b
Deaths from cardiovascular causes / 1.06: 0.74-1.52
Death from any cause / 1.07: 0.85-1.35
Fatal or non fatal CHF / 0.95: 0.84-1.07
NEJM: 2010;362:1563-74 / Lipid Treatment Strategy: fenofibrate vs. placebo / Primary outcomea / 0.92:0.79-1.08
Non fatal myocardial infarction / 0.91:0.74-1.12
Non fatal stroke / 1.17:0.76-1.78
Any stroke / 1.05:0.71-1.56
Deaths from cardiovascular causes / 0.91:0.75-1.10
Death from any cause / 0.68:0.66-1.12
Fatal or non fatal CHF / 0.82:0.65-1.05
NEJM:2010;363:233-44 / Retinopathy in each of the treatment strategies: glycemia, lipid, blood pressure / Incidence of diabetic retinopathy
Glycemia treatment strategy: intensive vs. standard / 0.67: 0.51-0.87b
Lipid treatment strategy: fenofibrate vs. placebo treatment / 0.60: 0.42-0.87b
Blood pressure treatment strategy: intensive vs. standard: / 1.23:0.84- 1.79

a A composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes

bStatistically significant at p<0.05

cDevelopment of renal failure defined as initiation of dialysis or ESRD, renal transplantation, or rise of serum creatinine >291·72 μmol/L, or retinal photocoagulation or vitrectomy to treat retinopathy

dComposite outcome 1 (see above) and a score of >2·0 on Michigan Neuropathy Screening Instrument (MNSI)

eUrine albumin:creatinine ratio ≥3·4 mg/mmol

fUrine albumin:creatinine ratio ≥33·9 mg/mmol

gDefined as initiation of dialysis or ESRD, or renal transplantation, or rise of serum creatinine >291·72 μmol/L in absence of an acute reversible cause

hGlomerular Filtration Rate estimation is done on the basis of the four variable Modification of Diet in Renal Disease (MDRD) Glomerular Filtration Rate (GFR) equation

iMichigan Neuropathy Screening Instrument (MNSI)

jTested with 128 Hz tuning fork

kJendrassik manoeuvre

lTested using 10 g force monofilament

Appendix B.

Inclusion and Exclusion Criteria for the ACCORD trial.

(Excerpt from the ACCORD manual of protocol.)

Inclusion Criteria

1)Type 2 diabetes mellitus defined according to the 1997 ADA criteria

  1. Fasting plasma glucose >126 mg/dl (>7.0 mmol/l), or
  2. Symptoms of hyperglycemia with casual plasma glucose > 200 mg/dl (>11.1

mmol/l), or

  1. 2 hour plasma glucose > 200 mg/dl (>11.1 mmol/l) after a 75 gram oral

glucose load

2)HbA1c (obtained within 3 months prior to anticipated date of randomization)

  1. 7.5 to 11%
  2. if on insulin, < 1 u/kg plus on 0 or 1 oral agent, or
  3. if not on insulin, on 0, 1, or 2 oral agents
  4. 7.5 to 9%
  5. if on insulin < 1 u/kg plus on 2 oral agents, or
  6. if not on insulin plus on 3 oral agents, or
  7. if on insulin > 1 u/kg plus 0 oral agents

3)Known diabetes duration > 3 months

  1. Stable diabetes therapy for > 3 months (dose of any 1 antihyperglycemic drug has

not changed by more than two-fold and new agents have not been added within

the previous 3 months)

4) Age at Randomization

  1. 40 to 79 years (inclusive) for anyone with a history of clinical cardiovascular

disease, or

  1. 55 to 79 years (inclusive) for anyone without a history of clinicalcardiovascular disease

5)At high risk of CVD events, defined as

  1. Presence of clinical cardiovascular disease
  2. previous myocardial infarction (MI)
  3. previous stroke
  4. history of coronary revascularization (e.g., coronary artery bypass graft

surgery, stent placement, percutaneous transluminal coronary angioplasty,

or laser atherectomy)

  1. history of carotid or peripheral revascularization (e.g., carotid

endarterectomy, lower extremity atherosclerotic disease atherectomy,

repair of abdominal aorta aneurysm, femoral or popliteal bypass)

  1. angina with ischemic changes (resting ECG), ECG changes on a graded
  2. exercise test (GXT), or positive cardiac imaging study

OR

  1. If no clinical cardiovascular disease, evidence in the last 2 years suggesting ahigh likelihood of cardiovascular disease. Specifically, the presence of oneof the following
  2. Microalbuminuria
  3. Ankle brachial index < 0.9
  4. LVH by ECG or ECHO
  5. > 50% stenosis of a coronary, carotid, or lower extremity artery
  6. The presence of at least 2 of the following factors that increase CVD risk
  7. On lipid lowering medication or untreated LDL-C >130 mg/dl (3.38

mmol/l)

  1. Low HDL-C (< 40 mg/dl (1.04 mmol/l) for men and < 50 mg/dl (1.29

mmol/l) for women)

  1. On BP lowering medication or untreated SBP >140 mm Hg or DBP > 95

mm Hg

  1. Current cigarette smoking
  2. Body mass index > 32 kg/m2

Exclusion Criteria

Exclusion criteria were selected to enhance safety and adherence

1. History of hypoglycemic coma/seizure within last 12 months

2. Hypoglycemia requiring 3rd party assistance in last 3 months with concomitant

glucose < 60 mg/dl (3.3 mmol/l)

3. History consistent with type 1 diabetes

4. Unwilling to do frequent capillary blood glucose self-monitoring or unwilling to

inject insulin several times a day

5. BMI > 45 kg/m2

6. Serum Creatinine > 1.5 mg/dl (132.6 umol/l) obtained within the previous 2 months

7. Transaminase >2 times upper limit of normal or active liver disease

8. Any ongoing medical therapy with known adverse interactions with the glycemic

interventions (e.g., corticosteroids, protease inhibitors)

9. Cardiovascular event or procedure (as defined for study entry) or hospitalization for

unstable angina within last 3 months

10. Current symptomatic heart failure, history of NYHA Class III or IV congestive heart

failure at any time, or ejection fraction (by any method) < 25%

11. A medical condition likely to limit survival to less than 3 years or a malignancy other

than non-melanoma skin cancer within the last 2 years

12. Any factors likely to limit adherence to interventions. For example,dementia, alcohol or substance abuseplans to move in the next 2 years.

13. Failure to obtain informed consent from participant

14. Currently participating in another clinical trial. Note: Patient must wait until the

completion of his/her activities or the completion of the other trial before being

screened for ACCORD

15. Living in the same household as an already randomized ACCORD participant.

16. Any organ transplant

17. Weight loss > 10% in last 6 months

18. Pregnancy, currently trying to become pregnant, or of child-bearing potential and not

practicing birth control

19. Participants with recurrent requirements for phlebotomy or transfusion of red blood

cells.