1. (IRbesartan in MicroAlbuminuria, Type 2 Diabetic Nephropathy Trial)
IRMA-2 Trial
(IRbesartan in MicroAlbuminuria, Type 2 Diabetic Nephropathy Trial)
HH Parving et al
N Eng J Med 345: , 2001
Edmund J. Lewis, M.D.
Muehrcke Family Professor of Nephrology
Section of Nephrology
Rush University Medical Center
Chicago, IL

2. Definitions IRMA-2 Measure of Albuminuria:
Overnight urine albumin for 3 consecutive days
AER µG/min in 2 of 3 consecutive overnight urine samples
Urine albumin determined by nephelometry
Primary efficacy measure:
Time to event from baseline visit to overt nephropathy (AER >200 µG/min and at least 30% higher than baseline on 2 consecutive visits).

3. Secondary Outcomes IRMA-2
Changes in level of albuminuria
Restoration of normal albumin excretion rate AER <20 µG/min) by the time of the last visit

4. Some relevant points about studying microalbumunuria.
(CSG: Pilot trial of sulodexide in microalbuminuria associated with type 2 diabettes)

5. 24 Hr Albumin Excretion vs Mean Albumin/Creatinine Ratio (MACR) (3 Consecutive First Morning Voids)

6. 24 Hr Albumin/Creatinine Ratio vs Mean Albumin/Creatinine Ratio (MACR) (3 Consecutive First Morning Voids)

7. Variance in Albumin Parameters
24 Hr Albumin
mg/24 Hr
24 Hr ACR
mg/G
MACR
MACR /24hr Albumin (%)
MACR /24hr
24hr ACR(%)
Median
116 79 67
58%
85%
Mean
232
163
132
57%
81%
S.D.
±361
±250
±200

8. Within Patient Variation in MACR (3 Consecutive First Morning Voids)
Average CV of 3 consecutive voids = 33%

9. IRMA-2 Trial Irbesartan Baseline Placebo 150 mg 300 mg N 201 195 194
Mean AER (µG/min) 54 58 53
6 Months
164
167
180
Mean AER 64 43 34
1° endpoint( %)
7.5
4.0
1.0
End of study (24 mos)
140
151
157 57 52 27 15 9 5

10. Change in Albumin Excretion
IRMA-2 Trial
Change in Albumin Excretion

11. IRMA-2 Trial Unadjusted hazard ratio for overt diabetic nephropathy
HR 95% CI P
irbesartan 150 mg <0.08
irbesartan 300 mg <0.001
Adjusted hazard ratio (baseline AER, BP)
irbesartan 150 mg
irbesartan 300 mg <0.001

12. IRMA-2 Trial H.H.Parving et al, NEJM 345:870-878, 2001

13. IRMA-2 Trial 95% CI Placebo 21% 15-26% 150 mg 24% 18-30% 300 mg 34%
Restoration of Normoalbuminuria
95% CI
Placebo
21%
15-26%
150 mg
24%
18-30%
300 mg
34%
26-40%

14. Mean Arterial Blood Pressure
IRMA-2 Trial
Mean Arterial Blood Pressure

15. Conclusions IRMA-2
Irbesartan was effective in diminishing the rate of progression from “microalbuminuria” to “overt nephropathy”
This effect was dose dependent
This study did not document the long-term durability of the result.
Taken with the results of IDNT, this effect appeared to be a valid surrogate in this patient population.

16. Potential End Points For Study of Microalbuminuria in Type 1 or Type 2 diabetes mellitus
decreased albumin excretion rate
decreased progression from “microalbuminuria” (albumin excretion <300 mg/day) to overt nephropathy (>300 mg/day)
regression of albuminuria (normalize or “significantly reduce”

17. Redefining the Categories of Diabetic Nephropathy30
300
mg/d
Normal
Microalbuminuria
Overt
ACEi
ARB
Normal
Early
diabetic glomerulopathy
Overt
New
Therapies