Ruboxistaurin Mesylate And Its Role In Treating Diabetic Nephropathy

David F. McAuley, Pharm D.
GlobalRPh Inc.

Introduction:

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).² 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

Evidence:

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

Conclusion:

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.

References:

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.