Dual blockade of the renin-angiotensin system in diabetic nephropathy: a randomized double-blind crossover study.
OBJECTIVE
Many patients with diabetic nephropathy (DN) have levels of albuminuria > 1 g/day and blood pressure >135/85 mmHg, despite antihypertensive combination therapy, including recommended doses of ACE inhibitors, e.g., lisinopril/enalapril at 20 mg daily. We tested the concept that such patients might benefit from dual blockade of the renin-angiotensin system (RAS).


METHODS
We performed a randomized double-blind crossover study of 2 months treatment with candesartan cilexetil 8 mg once daily and placebo in addition to previous antihypertensive treatment. We included 18 type 2 diabetic patients with DN fulfilling the above-mentioned criteria. All received recommended doses of ACE inhibitor and, in addition, 15 patients received diuretics, 11 received a calcium channel antagonist, and 3 received a beta-blocker. At the end of each treatment period, we measured the glomerular filtration rate (GFR), 24-h blood pressure, albuminuria, and IgGuria.


RESULTS
The addition of candesartan to usual antihypertensive therapy induced a mean (95% CI) reduction in albuminuria of 25% (2-58), P = 0.036 (geometric mean [95% CI] from 1,764 mg/24 h [1,225-2,540] to 1,334 mg/24 h [890-1,998]). It also produced a mean reduction of 35% (9-53) in the fractional clearance of albumin (P = 0.016), a reduction of 32% (1-54) in fractional clearance of IgG (P = 0.046), a reduction in 24-h systolic blood pressure of 10 mmHg (2-18) (P = 0.019) (mean +/- +/- SE) from 148 +/- 3 to 138 +/- 5 mmHg, and a mean reduction in GFR of 5 ml. min(-1). 1.73 m(-2) (0.1-9) (P = 0.045).


CONCLUSIONS
Dual blockade of the RAS reduces albuminuria and blood pressure in type 2 diabetic patients with DN responding insufficiently to previous antihypertensive therapy, including ACE inhibitors in recommended doses.
Rossing
Kasper
K
Steno Diabetes Center, Gentofte, Denmark. krossing@dadlnet.dk
Christensen
Per K
PK
Jensen
Berit R
BR
Parving
Hans-Henrik
HH
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000419:Albuminuria / Q000517:prevention & control; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D003404:Creatinine / Q000097:blood; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D004232:Diuretics / Q000627:therapeutic use; D004311:Double-Blind Method; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D010349:Patient Compliance; D010919:Placebos; D011355:Prodrugs / Q000627:therapeutic use; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D013777:Tetrazoles
D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002121:Calcium Channel Blockers; D004232:Diuretics; D010919:Placebos; D011355:Prodrugs; D013777:Tetrazoles; D003404:Creatinine; C077793:candesartan cilexetil