David F. McAuley, Pharm D.
GlobalRPh Inc.
 Nephropathy is one of the most common microvascular complications associated with diabetes and it is currently the leading cause of end-stage renal disease.1,2,3  Diabetic nephropathy accounts for roughly 40% of all new cases seen in the United States each year.1,2  One of the earliest indicators of nephropathy is the presence of microalbuminuria (urinary albumin: 30 to 300 mg/g creatinine or mg/24 h). Several contributing factors have been implicated in the pathogenesis of diabetic nephropathy including dyslipidemia, hypertension, hyperglycemia, and the renin-angiotensin system.2,3  In order to slow the progression of diabetic nephropathy several interventions are required including: 1) Maintaining tight glycemic control (hemoglobin A1c </= 7.0%).  2) Maintaining blood pressure under 130/80 mm Hg. 3) Maintaining the LDL less than 100 mg/dl.2,3,4  Although these therapeutic options may slow the progression of nephropathy, the incidence of end-stage renal disease as a result of diabetes continues to rise in the United States.2,3

It appears that each of these factors (hypertension, hyperglycemia, and activation of the renin-angiotensin system), may be inducing changes in cellular function by a common intracellular signaling pathway: the activation of protein kinase C (PKC)b.3,5 In vascular tissue, the activation of the PKC b isoform is closely linked to diabetes and decreased bioavailability of NO (Nitric Oxide) in endothelial cells leading to impaired endothelial-dependent vasodilatation.2,5  Further, growing evidence from previous animal and human studies have shown that inhibiting the PKC isoform may have renal and vascular protective effects and may reduce albuminuria and mesangial expansion.3,6,7 Consequently, a selective PKC b inhibitor may be beneficial in reducing the microvascular and/or macrovascular complications of diabetes, including nephropathy.3

Ruboxistaurin mesylate (LY333531), a bisindolylmaleimide, shows a high degree of specificity for the inhibition of the PKC isoform (protein kinase C beta).6,8  Release of this mediator, protein kinase C beta (PKC-beta), leads to cell growth, fibrosis, and tissue injury.8 Ruboxistaurin mesylate is currently in phase III trials to determine whether clinical outcomes such as mortality, renal, and cardiovascular events are improved beyond the current standard of care.8

Tuttle KR et al reported on 3 animal models of diabetic nephropathy (preclinical studies) and the impact of ruboxistaurin on the progression of diabetic nephropathy. Summary of the studies: “In the STZ rat, Leprdb/Leprdb mouse, and STZ-Ren 2 rat models, ruboxistaurin normalized glomerular hyperfiltration, decreased urinary albumin excretion, and reduced glomerular TGF-Beta1 levels and extracellular matrix protein production, thus reducing mesangial expansion, glomerulosclerosis, TIF, and loss of renal function.”2

Eli Lilly recently (June 2005) announced the results of a one-year pilot study examining the effect of ruboxistaurin mesylate in persons with type 2 diabetes and diabetic nephropathy. Study design: multicenter, randomized, double-blinded, parallel placebo- controlled trial. n=123. Patients were randomized at 17 clinical sites in the U.S. Treatment: ruboxistaurin 32 mg/day versus placebo. Participants were required to be stabilized on doses of ACE inhibitors, ARBs, or both, for 6 months prior to the study (these agents were continued throughout the trial). Baseline characteristics of the two treatment groups were very similar. Adverse events: no significant differences were found between the ruboxistaurin and placebo treatment groups. Study conclusion: The data showed that ruboxistaurin significantly reduced albuminuria (indicator of diabetic nephropathy) by 24%, compared to a 9% reduction (nonsignificant) in patients taking placebo. The reductions in albuminuria with ruboxistaurin were seen after one month of treatment and remained consistent throughout the study. 1 Additionally, patients taking placebo experienced a significant loss of kidney function after 1 year, however kidney function was stable in patients treated with ruboxistaurin.1


The growth in new cases of renal disease, especially among patients with type 2 diabetes, continues to accelerate and has been described by some as a medical catastrophe of worldwide proportions.1  Utilizing a novel approach, selective inhibition of the PKC
b pathway with an agent such as ruboxistaurin, is an attractive new strategy that could be beneficial in reducing the microvascular and/or macrovascular complications of diabetes, including nephropathy.1,2,8 Ruboxistaurin is also currently being investigated for other diabetic microvascular complications such as diabetic peripheral neuropathy and diabetic retinopathy associated with type 1 and type 2 diabetes.1  The results of the Eli Lilly pilot study showed that ruboxistaurin was well tolerated, however, the small sample size (n=123) and the limited duration of follow-up (</= 1 year) prevents a firm decision about its place in therapy or safety. Further studies are needed in order to determine ruboxistaurin’s final role.

1) Eli Lilly and Company (Lemons M). Pilot Study of Ruboxistaurin Showed Favorable Effects on Kidney Damage and Function in People with Type 2 Diabetes and Nephropathy. June 2005. https://newsroom.lilly.com/ReleaseDetail.cfm?ReleaseID=165871 Accessed: 6/28/2005.
2) Tuttle KR, Anderson PW. A novel potential therapy for diabetic nephropathy and vascular complications: protein kinase C beta inhibition. Am J Kidney Dis. 2003 Sep;42(3):456-65.

3) Kelly DJ, Zhang Y, Hepper C, Gow RM, Jaworski K, Kemp BE, Wilkinson-Berka JL, Gilbert RE. Protein Kinase C B Inhibition Attenuates the Progression of Experimental Diabetic Nephropathy in the Presence of Continued Hypertension. Diabetes 52:512–518, 2003.

4) Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development of progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329. 997–986.

5) Ishii H, Jirousek MR, Koya D, et al. Amelioration of vascular dysfunctions in diabetic rats by an oral PKC inhibitor. Science 1996;272:728-731.

6) Jirousek MR, Gillig JR, Gonzalez CM, et al. (S)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9: 16,21-dimetheno-1H,13H-dibenzo[e,k]pyrrolo[3,4-h] [1,4,13]-oxadiazacyclohexadecene-1,3(2H)-dione (ruboxistaurin) and related analogues: Isozyme selective inhibitors of protein kinase C. J Med Chem 1996;39:2664-2671.

7) Koya D, Haneda M, Nakagawa H, et al. Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes. FASEB J 2000;14:439-447.

8) Williams ME. The next generation of diabetic nephropathy therapies: an update. Adv Chronic Kidney Dis. 01-APR-2005; 12(2): 212-22.

Ruboxistaurin mesylate and its role in treating diabetic nephropathy