Enhanced renoprotective effects of ultrahigh doses of irbesartan in patients with type 2 diabetes and microalbuminuria.
BACKGROUND
The purpose of this study was to evaluate the renoprotective effect as reflected by short-term changes in albuminuria of ultrahigh doses of irbesartan in type 2 diabetic patients with microalbuminuria.


METHODS
This double-masked randomized crossover trial included 52 (41 males) hypertensive type 2 diabetic patients with microalbuminuria on ongoing antihypertensive medication. At inclusion, previous antihypertensive treatment was discontinued and replaced with bendroflumethiazide, 5 mg once daily, for the entire study. Following 2 months wash-out (baseline), patients were treated randomly with irbesartan 300, 600, and 900 mg once daily, each dose for 2 months. End points evaluated at the end of each study period included urinary albumin excretion rate (UAE) (mean of three 24-hour collections), 24-hour ambulatory blood pressure, and glomerular filtration rate (GFR) [chromium 51 ethylenediaminetetraacetic acid (51Cr-EDTA)].


RESULTS
Baseline values were: 24-hour UAE [geometric mean (95% CI)] 134 (103 to 170) mg/24 hours, ambulatory blood pressure [mean (SD)] 140 (10)/77 (7) mm Hg, and GFR 103 (19) mL/min/1.73 m2. All doses of irbesartan significantly reduced UAE, ambulatory blood pressure, and GFR from baseline. Reductions in UAE from baseline were 52% (46% to 57%), 49% (43% to 54%), and 59% (54% to 63%) with increasing doses of irbesartan (P < 0.01). UAE was reduced significantly more by irbesartan 900 mg compared with lower doses with an additional reduction in UAE of 15% (2% to 26%) by irbesartan 900 mg compared with 300 mg (P = 0.02). The greater reduction in albuminuria by irbesartan 900 vs. 300 mg was more pronounced in patients with UAE during irbesartan 300 mg above vs. below the median [31% (18% to 42%) vs. -9% (-25% to 6%), respectively (P < 0.05)]. With increasing doses systolic ambulatory blood pressure was reduced from baseline by 8 (4 to 12), 9 (5 to 13), and 9 (5 to13) mm Hg, and diastolic ambulatory blood pressure by 6 (4 to 7), 7 (6 to 9), and 7 (6 to 9) mm Hg (NS between doses).


CONCLUSIONS
Ultrahigh dosing of irbesartan (900 mg once daily) is generally safe and offers additional renoprotection independent of changes in systemic blood pressure and GFR in comparison to the currently recommended dose of 300 mg.
Rossing
Kasper
K
Steno Diabetes Center, Gentofte, Denmark. krossing@dadlnet.dk
Schjoedt
Katrine J
KJ
Jensen
Berit R
BR
Boomsma
Frans
F
Parving
Hans-Henrik
HH
D000368:Aged; D000419:Albuminuria / Q000188:drug therapy*; D000450:Aldosterone / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage* / Q000009:adverse effects; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D000077405:Irbesartan; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D012083:Renin / Q000097:blood; D012964:Sodium / Q000097:blood; D013777:Tetrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
D000450:Aldosterone; D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D006442:Glycated Hemoglobin; D000077405:Irbesartan; D008055:Lipids; D012083:Renin; D012964:Sodium; D013777:Tetrazoles