(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 345:870-878, 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 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

Within Patient Variation in MACR (3 Consecutive First Morning Voids) 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 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

Change in Albumin Excretion 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 0.05 irbesartan 300 mg 0.32 0.15-0.65 <0.001

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

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%

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

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.

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”

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