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A 6-Month, Randomized, Double-Masked, Placebo-Controlled Study Evaluating the Effects of the Protein Kinase C-ß Inhibitor Ruboxistaurin on Skin Microvascular Blood Flow and Other Measures of Diabetic Peripheral Neuropathy

¹ Strelitz Diabetes Institutes, Eastern Virginia Medical School, Norfolk, Virginia
² Lilly Research Laboratories, Indianapolis, Indiana
³ Indiana University School of Medicine, Indianapolis, Indiana

Address correspondence and reprint requests to Aaron I. Vinik, MD, PhD, 855 W. Brambleton Ave., Norfolk, VA 23510. E-mail: vinikai{at}evms.edu

OBJECTIVE—Diabetes leads to protein kinase C (PKC)-ß overactivation and microvascular dysfunction, possibly resulting in disordered skin microvascular blood flow (SkBF) and other changes observed in diabetic peripheral neuropathy (DPN) patients. We investigate the effects of the isoform-selective PKC-ß inhibitor ruboxistaurin mesylate on neurovascular function and other measures of DPN.

RESEARCH DESIGN AND METHODS—Endothelium-dependent and C fiber–mediated SkBF, sensory symptoms, neurological deficits, nerve fiber morphometry, quantitative sensory and autonomic function testing, nerve conduction studies, quality of life (using the Norfolk Quality-of-Life Questionnaire for Diabetic Neuropathy [QOL-DN]), and adverse events were evaluated for 20 placebo- and 20 ruboxistaurin-treated (32 mg/day) DPN patients (aged 18 years; with type 1 or type 2 diabetes and A1C 11%) during a randomized, double-masked, single-site, 6-month study.

RESULTS—Endothelium-dependent (+78.2%, P < 0.03) and C fiber–mediated (+56.4%, P < 0.03) SkBF at the distal calf increased from baseline to end point. Significant improvements from baseline within the ruboxistaurin group were also observed for the Neuropathy Total Symptom Score-6 (NTSS-6) (3 months –48.3%, P = 0.01; end point –66.0%, P < 0.0006) and the Norfolk QOL-DN symptom subscore and total score (end point –41.2%, P = 0.01, and –41.0, P = 0.04, respectively). Between-group differences in baseline–to–end point change were observed for NTSS-6 total score (placebo –13.1%; ruboxistaurin –66.0%, P < 0.03) and the Norfolk QOL-DN symptom subscore (placebo –4.0%; ruboxistaurin –41.2%, P = 0.041). No significant ruboxistaurin effects were demonstrated for the remaining efficacy measures. Adverse events were consistent with those observed in previous ruboxistaurin studies.

CONCLUSIONS—In this cohort of DPN patients, ruboxistaurin enhanced SkBF at the distal calf, reduced sensory symptoms (NTSS-6), improved measures of Norfolk QOL-DN, and was well tolerated.

Abbreviations: DPN, diabetic peripheral neuropathy • NIS, Neurologic Impairment Score • NSS, Neuropathy Symptom Score • NTSS-6, Neuropathy Total Symptom Score-6 • PKC, protein kinase C • QOL-DN, Quality-of-Life Questionnaire for Diabetic Neuropathy • QST, quantitative sensory testing • SAE, serious adverse event • SkBF, skin microvascular blood flow • TEAE, treatment-emergent adverse event • VDT, vibration detection threshold

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