The effect of ruboxistaurin on nephropathy in type 2 diabetes.
OBJECTIVE
Ruboxistaurin selectively inhibits protein kinase C-beta and ameliorates kidney disease in animal models of diabetes. The purpose of this study was to evaluate the effects of ruboxistaurin on diabetic nephropathy in humans.


METHODS
A randomized, double-blind, placebo-controlled, multicenter, pilot study was performed to evaluate the effects of 32 mg/day ruboxistaurin for 1 year in persons (n = 123) with type 2 diabetes and persistent albuminuria (albumin-to-creatinine ratio [ACR] 200-2,000 mg/g), despite therapy with renin-angiotensin system inhibitors. The primary end point was a change in the ACR. Estimated glomerular filtration rate (eGFR) (four-component equation from the Modification of Diet in Renal Disease study) was also calculated.


RESULTS
At baseline, urinary ACR was 764 +/- 427 mg/g (means +/- SD), and eGFR was 70 +/- 24 ml/min per 1.73 m2. Systolic and diastolic blood pressures were 135 +/- 14 and 75 +/- 9 mmHg, respectively. HbA(1c) was 8.0 +/- 1.2%. After 1 year, urinary ACR decreased significantly (-24 +/- 9%) in participants treated with ruboxistaurin (P = 0.020) and nonsignificantly (-9 +/- 11%) in the placebo group (P = 0.430). The ACR-lowering effect of ruboxistaurin appeared by 1 month. eGFR did not decline significantly in the ruboxistaurin group (-2.5 +/- 1.9 ml/min per 1.73 m2) (P = 0.185), whereas the placebo group lost significant eGFR over 1 year (-4.8 +/- 1.8 ml/min per 1.73 m2) (P = 0.009). Between-group differences for changes in ACR and eGFR were not statistically significant, but this pilot study was underpowered to determine such differences.


CONCLUSIONS
In persons with type 2 diabetes and nephropathy, treatment with ruboxistaurin reduced albuminuria and maintained eGFR over 1 year. Ruboxistaurin may add benefit to established therapies for diabetic nephropathy.
Tuttle
Katherine R
KR
Research Department, The Heart Institute and Sacred Heart Medical Center, Spokane, WA 99204-2340, USA. ktuttle@this.org
Bakris
George L
GL
Toto
Robert D
RD
McGill
Janet B
JB
Hu
Kuolung
K
Anderson
Pamela W
PW
D001741:Black or African American / Q000706:statistics & numerical data; D000368:Aged; D000419:Albuminuria / Q000503:physiopathology / Q000517:prevention & control; D003404:Creatinine / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008301:Maleimides / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D010865:Pilot Projects; D013997:Time Factors; D014481:United States / Q000453:epidemiology / Q000208:ethnology; D044465:White People / Q000706:statistics & numerical data
D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; C099154:ruboxistaurin; D003404:Creatinine