The Effect of Ruboxistaurin on Nephropathy in Type 2 Di...

The Effect of Ruboxistaurin on Nephropathy in Type 2 Diabetes

The Effect of Ruboxistaurin on Nephropathy in Type 2 Diabetes
Received for publication February 18, 2005. Accepted for publication June 14, 2005.
Katherine R. Tuttle, MD1, George L. Bakris, MD2, Robert D. Toto, MD3, Janet B. McGill, MD4, Kuolung Hu, MS5 and Pamela W. Anderson, MD5
Diabetes Care
© 2005 by the American Diabetes Association, Inc.

Kuolung Hu, MS5 and Pamela W. Anderson, MD5

1 The Heart Institute and Sacred Heart Medical Center, Spokane, Washington
2 Rush University Medical Center, Chicago, Illinois
3 University of Texas-Southwestern Medical School, Dallas, Texas
4 Washington University School of Medicine, St. Louis, Missouri
5 Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana

Address correspondence and reprint requests to Katherine R. Tuttle, MD, Research Department, 122 W. 7th Ave., Suite 230, Spokane, WA 99204-2340. E-mail: ktuttle@this.org

ABSTRACT

OBJECTIVE—Ruboxistaurin selectively inhibits protein kinase C-ß 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.

RESEARCH DESIGN AND 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. HbA1c 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.

Abbreviations: ARB, angiotensin receptor blocker • ACR, albumin-to-creatinine ratio • eGFR, estimated glomerular filtration rate • PKC, protein kinase C

INTRODUCTION

Nephropathy develops in ~40% of people with type 2 diabetes and is the leading cause of end-stage renal disease in the U.S. and the developed world (1,2). Established therapies include antihypertensive treatment (particularly with ACE inhibitors or angiotensin receptor blockers [ARBs]), glycemic control, and limitation of dietary protein (3–9). Many persons with diabetes have progressive nephropathy even with these therapies. Therefore, treatments targeting novel pathogenic mechanisms may be beneficial. Preclinical studies have shown an important role for protein kinase C (PKC)-ß in the pathogenesis of diabetic nephropathy. This signal transduction mediator induces a number of processes leading to kidney injury that can be prevented by ruboxistaurin, a selective PKC-ß inhibitor, in diabetic animals (10,11). The effect of ruboxistaurin on diabetic nephropathy in humans has not been previously evaluated. The purpose of this study was to determine whether treatment with ruboxistaurin in persons with type 2 diabetes and persistent albuminuria, despite therapy with renin-angiotensin system inhibitors, would improve indicators of nephropathy after 1 year.

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