IRMA2 Trial IRbesartan in Micro Albuminuria Type 2

IRMA-2 Trial (IRbesartan in Micro. Albuminuria, 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

Definitions IRMA-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 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).

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

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

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

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

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

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

IRMA-2 Trial Baseline N Mean AER (µG/min) 6 Months N Mean AER 1° endpoint( %) End of study (24 mos) N Mean AER 1° endpoint( %) Irbesartan Placebo 150 mg 300 mg 201 195 194 54 58 53 164 64 7. 5 167 43 4. 0 180 34 1. 0 140 57 15 151 52 9 157 27 5

IRMA-2 Trial Change in Albumin Excretion

IRMA-2 Trial Unadjusted hazard ratio for overt diabetic nephropathy HR 95% CI P irbesartan 150 mg 0. 61 0. 34 -1. 08 <0. 08 irbesartan 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 irbesartan 300 mg 0. 32 0. 15 -0. 65 0. 05 <0. 001

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

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

IRMA-2 Trial Mean 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 dependent 3. This study did not document the longterm 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”

Redefining the Categories of Diabetic Nephropathy 0 30 Normal 300 Microalbuminuria ACEi Normal Overt ARB Early diabetic glomerulopathy New mg/d Therapies Overt