Effects of Ezetimibe/Simvastatin and Rosuvastatin on Oxidative Stress in Diabetic Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Geannyne Villegas-Rivera, Luis Miguel Román-Pintos, Ernesto Germán Cardona-Muñoz, Oscar Arias-Carvajal, Adolfo Daniel Rodríguez-Carrizalez, Rogelio Troyo-Sanromán, Fermín Paul Pacheco-Moisés, Aldo Moreno-Ulloa, Alejandra Guillermina Miranda-Díaz, Geannyne Villegas-Rivera, Luis Miguel Román-Pintos, Ernesto Germán Cardona-Muñoz, Oscar Arias-Carvajal, Adolfo Daniel Rodríguez-Carrizalez, Rogelio Troyo-Sanromán, Fermín Paul Pacheco-Moisés, Aldo Moreno-Ulloa, Alejandra Guillermina Miranda-Díaz

Abstract

Objective: To evaluate the effects of ezetimibe/simvastatin (EZE/SIMV) and rosuvastatin (ROSUV) on oxidative stress (OS) markers in patients with diabetic polyneuropathy (DPN).

Methods: We performed a randomized, double-blind, placebo-controlled phase III clinical trial in adult patients with Type 2 Diabetes Mellitus (T2DM) and DPN, as evaluated by composite scores and nerve conduction studies (NCS). Seventy-four subjects with T2DM were allocated 1 : 1 : 1 to placebo, EZE/SIMV 10/20 mg, or ROSUV 20 mg for 16 weeks. All patients were assessed before and after treatment: primary outcomes were lipid peroxidation (LPO), and nitric oxide (NO) surrogate levels in plasma; secondary outcomes included NCS, neuropathic symptom scores, and metabolic parameters. Data were expressed as mean ± SD or SEM, frequencies, and percentages; we used nonparametric analysis.

Results: LPO levels were reduced in both statin arms after 16 weeks of treatment (p < 0.05 versus baseline), without changes in the placebo group. NO levels were not significantly affected by statin treatment, although a trend towards significance concerning increased NO levels was noted in both statin arms. No significant changes were observed for the NCS or composite scores.

Discussion: EZE/SIMV and ROSUV are superior to placebo in reducing LPO in subjects with T2DM suffering from polyneuropathy. This trial is registered with NCT02129231.

Figures

Figure 1
Figure 1
Flow diagram of study selection.
Figure 2
Figure 2
Oxidative stress (OS) and vascular function markers. (a) Lipid Peroxidation (LPO) levels in plasma, as assessed by malondialdehyde concentration. (b) Nitric oxide levels in plasma, as assessed by nitrate/nitrite (NOx) concentration. EZE/SIMV, ezetimibe/simvastatin; ROSUV, rosuvastatin. Data is expressed as mean ± SEM, ∗p < 0.05 versus placebo Mann-Whitney U.
Figure 3
Figure 3
Screening levels and changes from screening in (a) neuropathic symptoms score (NSC), (b) neuropathic disability score (NDS), and (c) analog pains scale (APS) score after 16 weeks of treatment. Data is expressed as mean ± SEM, ∗p < 0.05 versus week 0, and ∗∗p < 0.001 versus week 0 (baseline), Wilcoxon matched-pairs signed-rank test.

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