Treatment of Diabetic Nephropathy and Proteinuria Background End stage renal disease is a major cause of death and disability among diabetics BP reduction is important to slow the progression of diabetic nephropathy Outcomes trials that demonstrate a clear renoprotective benefit of ACE inhibitors in diabetes have been conducted primarily in type 1 diabetics Three recently completed randomized blinded trials address the previously unanswered questions of whether ARBs delay the progression of diabetic nephropathy (RENAAL, IDNT) or reduce proteinuria (IRMA II) in patients with type 2 diabetes 1 RENAAL, IRMA-2 and IDNT Three featured trials linking a disease spectrum IRMA 2 Study of irbesartan to assess it s effect on slowing of the progression to overt nephropathy in hypertensive patients with type 2 diabetes and microalbuminuria IDNT RENAAL Study of irbesartan/losartan to assess it s protective effects in hypertensive patients with type 2 diabetes and proteinuria Microalbuminuria Proteinuria ESRD Cardiovascular Morbidity and Mortality Death Early Stage Late Stage End Stage Lewis EJ et al. N Engl J Med 21;34:81-86. 2 1
IRMA 2: Study Design 9 patients with hypertension, type 2 diabetes, microalbuminuria (albumin excretion rate 2 2 µg/min), and normal renal function Double-blind Treatment Screening/Enrollment Up to weeks Placebo/ group* Irbesartan 1 mg* Irbesartan 3 mg* Follow-up: 2 years * Adjunctive antihypertensive therapies (excluding ACE inhibitors, angiotensin II receptor antagonists, and dihydropyridine calcium channel blockers) could be added to all groups to help achieve equal blood pressure levels. IRMA 2: Blood Pressure Response mmhg 2 18 16 14 12 1 8 6 4 2 13 13 13 14 143 142 9 84 9 84 91 Irbesartan 1mg 84 Irbesartan 3mg N=21 N=19 N=194 Baseline On Treatment 4 2
IRMA 2 Primary Endpoint Time to Overt Proteinuria Subjects (%) 2 1 1 Irbesartan 1 mg Irbesartan3 mg RRR=39% P=.8 RRR=7% P<.1 3 6 12 18 22 24 Follow-up (mo) IRMA 2 Normalization of Urinary Albumin Excretion Rate Subjects (%) 4 4 3 3 2 2 1 1 21 (n=21) P=.6 24 1 mg (n=19) Irbesartan 34 3 mg (n=194) 6 3
Angiotensin II Receptor Blockers in Type 2 Diabetics Progression of Microalbuminuria Primary Outcome: Development of clinical proteinuria Duration IRMA II (n=9) Irbesartan 1mg vs placebo* Irbesartan 3mg vs placebo* 39% (P=.8) 7% (P<.1) 2 yrs Albumin excretion rate of 2 to 2 µg per minute in 2 of 3 consecutive, sterile, overnight urine samples Urinary albumin excretion rate >2 µg per minute and at least 3% higher than baseline in at least 2 consecutive measurements *In combination with conventional antihypertensive therapy (excluding ACE inhibitors) IRMA II=The Irbesartan Microalbuminuria Type 2 Diabetes in Hypertensive Patients Study 7 Parving HH, et al. N Engl J Med. 21;34(12):87-878. RENAAL Randomized Double-blind PL controlled study of 131 type 2 diabetics enrolled for mean of 3.4 yrs Patients initiated on Losartan mg; elective titration up to 1mg (based on BP target) and then additional therapy as needed 27.8% patients on losartan mg, 71.2% on 1mg los. most common other agent- CCBs ~9% in both groups Results: 16% RR reduction in losartan group vs. PL for morbidity and mortality from CV causes, proteinuria and rate of progression of renal disease. Brenner B et al. N Engl J Med 21;34:861-869. 8 4
IDNT: Study Design 1,71 patients with hypertension, type 2 diabetes, and proteinuria ³ 9 mg/day Double-blind Treatment Screening/Enrollment Up to weeks * Adjunctive antihypertensive therapies (excluding ACE inhibitors, angiotensin II receptor antagonists, and calcium channel blockers) could be added to all groups to help achieve equal blood pressure levels. Irbesartan* Placebo/ group* Amlodipine* Minimum follow-up: approximately 2 years (average follow-up 2.6 years) Lewis EJ et al. N Engl J Med 21;34:81-86. IDNT: Blood Pressure Response Irbesartan and Amlodipine had equivalent BP lowering mmhg 2 18 16 14 12 1 8 6 4 2 18 16 18 144 14 141 87 8 87 N=69 N=79 N=67 Irbesartan Amlodipine Avg dose: 269mg/d Avg dose: 9.1mg/d (3. add. med) (3. add. med) Lewis EJ et al. N Engl J Med 21;34:81-86. 77 87 77 Baseline On Treatment 1
Angiotensin II Receptor Blockers in Type 2 Diabetics With Nephropathy Progression of Renal Insufficiency Primary Endpoint: Composite of doubling of serum creatinine, end stage renal disease, or death Average Duration RENAAL (n=1,14) Losartan -1 mg vs placebo* 16% (p=.2) 3.4 yrs IDNT (n=1,71) Irbesartan 1-3mg vs placebo* Irbesartan 1-3 mg vs Amlodipine* 2% (p=.2) 23% (p=.6) 2.6 yrs *In combination with conventional antihypertensive therapy (excluding ACE inhibitors) RENAAL=The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study IDNT=The Irbesartan in Diabetic Nephropathy Trial Brenner BM, et al. N Engl J Med. 21;34(12):861-869. Lewis EJ, et al. N Engl J Med. 21;34(12):81-86. 11 Angiotensin II Receptor Blockers (ARBs) in Type 2 Diabetes and Nephropathy Summary of Findings (I) RENAAL, IDNT and IRMA II present the strongest evidence to date for the efficacy of specific types of treatment to slow the progression of nephropathy in type 2 diabetes The ARBs losartan and irbesartan compared to placebo* have been shown to reduce the progression of renal insufficiency beyond the benefit of similarly achieved blood pressures Irbesartan compared to placebo* has been shown to reduce the progression of microalbuminuria to diabetic nephropathy *In combination with conventional antihypertensive therapy (excluding ACE inhibitors) Brenner BM, et al. N Engl J Med. 21;34(12):861-869. Lewis EJ, et al. N Engl J Med. 21;34(12):81-86. Parving HH, et al. N Engl J Med. 21;34(12):87-878. 12 6