Effects of Epalrestat as Aldose Reductase Inhibitor (ARI), Sitagliptin as Incretin-Based Therapy (IBT), or Combined Epalrestat and Sitagliptin on Cardiac Vagal Neuropathy (CVN) in Patients with Type 2 Diabetic Mellitus

Abstract

Background: Aldose reductase inhibitor (ARI) partially ameliorates cardiac vagal neuropathy (CVN) in patients with diabetes mellitus. Incretin-based therapy (IBT) has neuroprotective properties for neuropathy in mice and rat. Materials and Methods: Effects of epalrestat as ARI, sitaglipitin as IBT, or combined ARI and IBT on CVN were examined in 42 patients with CVN and type 2 diabetes mellitus. Subjects were divided into 3 groups; group A (n =12) was treated with add-on oral epalrestat; group B (n =18) was treated with addon oral sitaglipitin; and group C (n = 12) with CVN despite treatment with epalrestat (n=6) for 1 year in group A , sitagliptin (n=5) for 1 year in group B and subcutaneously injected exenatide (n = 1) as IBT for 1 year was treated with add-on combined epalrestat and sitaglipitin, although there were no placebo in all patients with CVN. CVN was defined as maximal coefficient of variance in electrocardiographic beatto-beat interval (max CV. R-R) of three measurements during deep breathing at rest on ≤2.00%. Since disease duration was ≥20 years in each group, patient had various chronic complications and various treatments. Results: Mean duration of treatment was 1 year. Max CV.R-R after treatment was significantly (P<0.001) increased after treatment in each group. Nevertheless, 8 (67%) and 5 patients (28%) still had CVN after treatment in groups A and B, respectively, whereas no patients had CVN after treatment in group C. There was significant difference (P <0.002) in magnitude increase of max CV. R-R after treatment between groups using ANOVA with multiple comparison test. No significant differences were observed in other variables before and after treatment between groups. Conclusion: Sitagliptin may be more effective than epalrestat for CVN in type 2 diabetic patients, and combined epalrestat and sitagliptin may be haven a synergistic effect. Effects of Epalrestat as Research ArticleOpen Access IntroductionMost common peripheral neuropathies (PN) in patients with diabetes mellitus (DM) are chronic sensorimotor distal symmetric polyneuropathy (DPN) and autonomic neuropathy (AN) [1][2][3][4][5][6]. The autonomic nervous system modulates electrical and contractile activity of the myocardium via interplay of sympathetic and parasympathetic activities.The cardiac autonomic neuropathy (CAN) of patients with DM is associated with an increased risk of mortality [1][2][3][4][5][6]. Therefore, it is most studied and is a clinically important form of diabetic AN [1,[5][6]. The American Diabetes Association (ADA) highlighted its significance and addressed it in its guidelines [1,5]. A recent review suggests that R-R interval as Cardiac Vagal Neuropathy (CVN) may be useful for CAN [6]. It is known that pharmacological interventions included anti-hyperglycemic drugs, anti-oxidants, or anti-hypertensive drugs, as well as aldose reductase inhibitor (ARI) drugs that reduce the activity of polyol pathway of nerves [7][8][9][10] hyperglycemic effect, IBT has neurotropic actions and neuroprotective p...