Ezetimibe/Simvastatin and Rosuvastatin for Oxidative Stress and Mitochondrial Function in Diabetic Polyneuropathy: a Randomized, Double Blinded, Placebo Controlled Clinical Trial

Introduction Nerve dysfunction system in patients with diabetes is known as diabetic neuropathy and is considered as the most prevalent microvascular complication -up to 60%- in type 2 Diabetes Mellitus (T2DM) subjects. Diabetic polyneuropathy (DPN) comprise ≈70% of all cases. Its diagnosis is established by means of validated scores based on clinical features and abnormal nerve conduction studies (NCS). Pathophysiologic findings include loss of multifocal and focal nerve fibers secondary to axonal degeneration an segmental demyelinization, basically due to oxidative stress induced by chronic hyperglycemia, which leads to neural apoptosis. Other mechanisms involved in peripheral nerve injure is nitrosative stress induced by nitric oxide (NO).

Ezetimibe diminishes cholesterol esters content in chylomicrons by reducing liver cholesterol intake which in consequence increases LDL uptake and plasma depuration; as monotherapy it reduces LDL-C by 17%. When combined with simvastatin, cholesterol reduction is potentially increased; furthermore, pleiotropic effects of statins include an increase on nuclear factor kappa B activity and amelioration of superoxide ions after 12 week treatment. Another hydroxy-methyl-glutaryl coenzyme A inhibitor, rosuvastatin, has an antioxidant effect by acting as free radical carrier diminishing mitochondrial and cellular lipid peroxidation (LPO) production.

We conducted this study to evaluate the effect of ezetimibe/simvastatin and rosuvastatin on oxidative stress in patients with DPN.

Methods Study design A randomized, double blinded, placebo controlled phase II clinical trial was performed in the Clinic and Experimental Therapeutics Institute, University of Guadalajara, Mexico. Subjects were assigned to three group treatments in blocks with a parallel sequence 1:1:1 through a randomized computer-based list, generated by a different researcher unaware of drugs given. Patients were divided to: control group that received placebo, ezetimibe/simvastatin and rosuvastatin as a daily single dose for 16 weeks. The selection period was performed from February 2012 to January 2013. We selected 5 non-randomized healthy subjects (HS) from a blood bank to compare the oxidative stress status.

Study population Inclusion criteria were ≥18 years old, T2DM according to American Diabetes Association and DPN by Dyck et. al.3 criteria, HbA1c <12%, and informed consent signed. They were excluded if renal or hepatic failure, pregnant or breastfeeding, other neuropathies (alcohol-induced, radiculopathy, autoimmune, cancer-related), and eliminated if lack treatment adherence (<80% of drug intake), severe adverse drug reaction and/or serious health illness. Patients were selected by invitation in forums; outpatients recruited from primary care clinics; and database collected previously by our Institute from February 2010 to 2012. Patients were instructed to take their drugs only by night at the same time every day, as follows: placebo 100 mg, ezetimibe/simvastatin 10/20 mg, and rosuvastatin 20 mg. All drugs were similar in physical characteristics and presented in dark vials, carefully filled by another group researcher, who placed a respective tag with the patient code. Also, patients were provided with a diary where they would write down the date and time of drug administration, and drug adverse reactions felt. Such information was collected and registered every 4 weeks. Primary outcomes were oxidative stress markers LPO, NO, and TAC before and after 16 week intervention. Secondary outcomes were clinical, NCS and metabolic [fasting glucose, HbA1c, total cholesterol, high and low density lipoproteins (HDL, LDL), and triglycerides] parameters. Safety profile was assessed with drug adverse reactions, renal (urea, creatinin), and hepatic [(alamin- and aspartate-aminotransferase, gama-glutamyltransferase, bilirubins and phosphokinase] laboratory variables.