IRMA-2 Trial

(IRbesartan in MicroAlbuminuria, Type 2 Diabetic Nephropathy Trial)

HH Parving et al

N Eng J Med 345:870-878, 2001

Edmund J. Lewis, M.D.

Muehrcke Family Professor of Nephrology

Section of Nephrology

Rush University Medical Center

Chicago, IL

DefinitionsIRMA-2

Measure of Albuminuria:- Overnight urine albumin for 3 consecutive days- AER 20-200 µG/min in 2 of 3 consecutive

overnight urine samples- Urine albumin determined by nephelometryPrimary 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).

Secondary OutcomesIRMA-2

- Changes in level of albuminuria

- Restoration of normal albumin excretion rate AER <20 µG/min) by the time of the last visit

Some relevant points about studying microalbumunuria.

(CSG: Pilot trial of sulodexide in microalbuminuria associated with type 2 diabettes)

24 Hr Albumin Excretionvs

Mean Albumin/Creatinine Ratio (MACR) (3 Consecutive First Morning Voids)

y = 0.8584x + 0.202

R2 = 0.7501

0

2

4

6

8

10

12

0 2 4 6 8 10 12

(Log2) 24 Hr. Albumin

(Lo

g2)

MA

CR

24 Hr Albumin/Creatinine Ratiovs

Mean Albumin/Creatinine Ratio (MACR) (3 Consecutive First Morning Voids)

y = 0.9269x + 0.1728

R2 = 0.8407

0

2

4

6

8

10

12

0 2 4 6 8 10 12

(Log2) 24 Hr ACR

(Lo

g2)

MA

CR

Variance in Albumin Parameters

24 Hr Albumin

mg/24 Hr

24 Hr ACR

mg/G

MACR

mg/G

MACR /24hr Albumin (%)

MACR /24hr

24hr ACR(%)

Median 116 79 67 58% 85%

Mean 232 163 132 57% 81%

S.D. ±361 ±250 ±200

Within Patient Variation in MACR

(3 Consecutive First Morning Voids)

% CV of 3 ACR Spec.

0.0%5.0%

10.0%15.0%20.0%25.0%30.0%35.0%

0-10 I0-20 20-30

30-40

40-50

50-60

60-70

70-80

80-90

90-100

>100

% CV

% o

f Spe

c.

Average CV of 3 consecutive voids = 33%

IRMA-2 Trial Irbesartan

Baseline Placebo 150 mg 300 mg

N 201 195 194

Mean AER (µG/min) 54 58 53

6 Months

N 164 167 180

Mean AER 64 43 34

1° endpoint( %) 7.5 4.0 1.0

End of study (24 mos)

N 140 151 157

Mean AER 57 52 27

1° endpoint( %) 15 9 5

IRMA-2 Trial Change in Albumin Excretion

IRMA-2 Trial

Unadjusted hazard ratio for overt diabetic nephropathyHR 95% CI P

irbesartan 150 mg 0.61 0.34-1.08 <0.08irbesartan 300 mg 0.30 0.14-0.61 <0.001

Adjusted hazard ratio (baseline AER, BP)irbesartan 150 mg 0.56 0.31-0.99 0.05irbesartan 300 mg 0.32 0.15-0.65 <0.001

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

IRMA-2 Trial Restoration of Normoalbuminuria

95% CI

Placebo 21% 15-26%

150 mg 24% 18-30%

300 mg 34% 26-40%

IRMA-2 TrialMean Arterial Blood Pressure

Conclusions IRMA-2

1. Irbesartan was effective in diminishing the rate of progression from “microalbuminuria” to “overt nephropathy”

2. This effect was dose dependent3. This study did not document the long-

term durability of the result.4. Taken with the results of IDNT, this effect

appeared to be a valid surrogate in this patient population.

Potential End Points For Study of Microalbuminuria in Type 1 or Type

2 diabetes mellitus

1. decreased albumin excretion rate

2. decreased progression from “microalbuminuria” (albumin excretion <300 mg/day) to overt nephropathy (>300 mg/day)

3. regression of albuminuria (normalize or “significantly reduce”

Normal Microalbuminuria Overt

0 30 300 mg/d

NormalOvert

Early diabetic glomerulopathy

ACEi ARB

Redefining the Categories of Diabetic Nephropathy

New Therapies