1. ACCORD Microvascular Outcomes
Faramarz Ismail-Beigi, MD, PhD
Case Western Reserve University
For the ACCORD Study Group

2. Outcome Definitions
Nephropathy (5 outcomes) Eye complications (4 outcomes) Neuropathy (4 outcomes) Composite; replicating the UKPDS Composite; replicating the UKPDS plus neuropathy 15 distinct outcomes overall

3. Analysis Technique For each outcome:
Determine whether event has occurred
If no event, censor observation at last surveillance time
If event, assign event time as midpoint between event discovery and most recent prior surveillance time
Pre-transition analyses – use only surveillance prior to 02/05/2008
End of Study analyses – use surveillance through end of trial (June 2009)

4. Analysis Technique
Outcomes analyzed using survival analysis techniques (K-M plots and proportional hazards regression)
Primary efficacy model includes
1. glycemia arm
2. second trial arm (BP intensive/standard; Lipid fibrate/placebo)
3. secondary prevention status
All analyses performed by intention-to-treat (no post-randomization covariates examined)

5. Selected Baseline Characteristics
Characteristic Standard Intensive
BMI (kg/m2)
HbA1c (%)
BP (mm Hg) 135/ /75
Triglycerides (mmol/l)
HDL, men (mmol/l)
HDL, women (mmol/l)

6. Selected Characteristics at Transition (February 2008)
Characteristic Standard Intensive
BMI (kg/m2) *
HbA1c (%) *
BP (mm Hg) / /67*
Triglycerides (mmol/l) *
HDL, men (mmol/l) *
HDL, women (mmol/l) *
* Denotes P<0.05

7. Selected Characteristics at Study End (June 2009)
Characteristic Standard Intensive
BMI (kg/m2) *
HbA1c (%) *
BP (mm Hg) / /68
Triglycerides (mmol/l) *
HDL, men (mmol/l)
HDL, women (mmol/l)
* Denotes P<0.05

8. Composite Microvascular Outcomes
1st Composite Outcome:
Development of renal failure or diabetic eye complications
Renal failure: initiation of dialysis or ESRD, renal transplantation, or irreversible rise of serum creatinine above 3.3 mg/dL
Eye complications: retinal photocoagulation or vitrectomy to treat diabetic retinopathy
Essentially replicates UKPDS composite microvascular outcome

9. Results – Composite Outcome #1
Development of renal failure or retinal photocoagulation or vitrectomy to treat diabetic retinopathy (similar to UKPDS)
Until Transition
Through End of Study
HR (95% CI): (0.88, 1.14)
P = 0.99
HR (95% CI): (0.85, 1.07)
P = 0.42

10. Composite Microvascular Outcomes
2nd Composite Outcome:
Development of renal failure, or retinal photocoagulation or vitrectomy to treat diabetic retinopathy, or development of neuropathy
Adds neuropathy to 1st Composite Outcome
(neuropathy defined as MNSI score ≥ 2.5)

11. Results – Composite Outcome #2
Development of renal failure, or retinal photocoagulation or vitrectomy to treat diabetic retinopathy, or development of neuropathy (MNSI score ≥ 2.5)
Until Transition
Through End of Study
HR (95% CI): (0.89, 1.02)
P = 0.20
HR (95% CI): (0.89, 1.01)
P = 0.12

12. Nephropathy Outcomes 4. Development of any of outcomes 1 to 3, above
1. Development of microalbuminuria
(albumin:creatinine ratio ≥30 and <300 mg/g)
2. Development of macroalbuminuria
(albumin:creatinine ratio ≥ 300 mg/g)
3. Development of renal failure
(initiation of dialysis or ESRD, or renal transplantation, or irreversible rise of serum creatinine above 3.3 mg/dL)
4. Development of any of outcomes 1 to 3, above
5. Doubling of baseline serum creatinine or more than 20 mL/min/1.73 m2 decrease in estimated GFR

13. Results – Nephropathy Outcome #1
Development of microalbuminuria (urine albumin:creatinine ratio ≥ 30 mg/g)
Until Transition
Through End of Study
HR (95% CI): 0.85 (0.77, 0.94) P=0.0012
HR (95% CI):
0.79 (0.69, 0.90) P=

14. Results – Nephropathy Outcome #2
Development of macroalbuminuria (urine albumin:creatinine ratio ≥ 300 mg/g)
Until Transition
Through End of Study
HR (95% CI): (0.54, 0.86) P =
HR (95% CI):
0.71 (0.59, 0.86)
P =

15. Results – Nephropathy Outcome #3
Development of renal failure: initiation of dialysis or ESRD, or renal transplant, or a rise of serum creatinine above 3.3 mg/dL
Until Transition
Through End of Study
HR (95% CI): (0.73, 1.24)
P = 0.71
HR (95% CI): (0.73, 1.16)
P = 0.49

16. Results – Nephropathy Outcome #4
Development of any of the following nephropathy outcomes
(Doubling of serum creatinine or more than 20 mL/min/1.73 m2 decrease in estimated GFR or development of macroalbuminuria, or development of renal failure)
Until Transition
Through End of Study
HR (95% CI):
1.07 (1.02, 1.13)
P =
HR (95% CI): (0.99, 1.10)
P = 0.11

17. Mean Serum Creatinine Levels
Intensive
Standard ________
Until Transition
Through End of Study
HR (95% CI): (1.02, 1.13) P = 0.02
HR (95% CI): (0.99, 1.10)
P = 0.11

18. Results – Nephropathy Outcome #5
Doubling of baseline serum creatinine or more than 20 mL/min/1.73 m2 decrease in estimated GFR
Until Transition
Through End of Study
HR (95% CI): (0.70, 0.94)
P = 0.005
HR (95% CI): 1.03 (0.98, 1.08) P=0.270
HR (95% CI): 1.05 (1.00, 1.11) P=0.067

19. Diabetic Eye Complications
1. Retinal photocoagulation or vitrectomy to treat diabetic retinopathy
2. Eye surgery for cataract extraction
3. Three-line change (i.e., worsening) in visual acuity
4. Severe vision loss
(Snellen fraction <20/200)

20. Results – Diabetic Eye Complication Outcome #1
Retinal photocoagulation or vitrectomy for retinopathy
Until Transition
Through End of Study
HR (95% CI): (0.87, 1.17)
P = 0.90
HR (95% CI): (0.85, 1.10)
P = 0.62

21. Results – Diabetic Eye Complication Outcome #2
Eye surgery for cataract extraction
Until Transition
Through End of Study
HR (95% CI): (0.79, 1.02)
P = 0.105
HR (95% CI): (0.80, 0.99) P =

22. Results – Diabetic Eye Complication Outcome #3
Three line change in visual acuity (using Log MAR visual acuity chart)
Until Transition
Through End of Study
HR (95% CI):
0.91 (0.84, 0.98)
P = 0.012
HR (95% CI):
0.94 (0.89, 1.00) P = 0.050
HR (95% CI):
0.84 (0.73, 0.97)
P =
HR (95% CI):
0.94 (0.89, 1.00)
P =

23. Results – Diabetic Eye Complication Outcome #4
Severe vision loss (Snellen fraction <20/200)
Until Transition
Through End of Study
HR (95% CI): (0.80, 1.13)
P = 0.57
HR (95% CI): (0.88, 1.16)
P = 0.91

24. Neuropathy Outcomes
1. Score of ≥ 2.5 on the Michigan Neuropathy Screening Instrument (MNSI)
2. Loss of vibratory sensation
3. Loss of ankle jerk during Jendrassic maneuver
4. Loss of pressure sensation
(measured by 10 gm force monofilament test)

25. Results – Neuropathy Outcome #1
Score of ≥ 2.5 on the Michigan Neuropathy Screening Instrument (MNSI)
Until Transition
Through End of Study
HR (95% CI):
0.92 (0.86, 0.99)
P =
HR (95% CI): (0.87, 1.01)
P = 0.08

26. Results – Neuropathy Outcome #2
Loss of vibratory sensation using 128 Hz tuning fork
Until Transition
Through End of Study
HR (95% CI): (0.86, 1.05)
P = 0.29
HR (95% CI): (0.85, 1.01)
P = 0.080

27. Results – Neuropathy Outcome #3
Loss of ankle jerk during Jendrassic maneuver
Until Transition
Through End of Study
HR (95% CI): (0.87, 1.01)
P = 0.10
HR (95% CI): (0.84, 0.97) P =

28. Results – Neuropathy Outcome #4
Loss of pressure sensation by 10 gm force monofilament test
Until Transition
Through End of Study
HR (95% CI): (0.77, 1.00) P =
HR (95% CI): (0.75, 0.95) P =

29. Summary of Microvascular Results
Up to Transition
Pr(≥ 1 significant test) = 0.54

30. Summary of Microvascular Results
Through End of Study
P (≥ 1 significant test) = 0.54

31. Conclusions
Intensive treatment of glycemia in the ACCORD cohort did not reduce the risk of composite measures of advanced microvascular outcomes
Intensive therapy delayed the onset of albuminuria and some measures of eye complications and neuropathy
Microvascular benefits of intensive therapy should be weighed against increase in total and CVD-related mortality, increased weight gain, and high risk for severe hypoglycemia