Pleiotropic Effects of Linagliptin Monotherapy on Levels of Nitric Oxide, Nitric Oxide Synthase, and Superoxide Dismutase in Hemodialysis Patients with Diabetes

Linagliptin is an anti-diabetic drug and the only bile-excreted dipeptidyl peptidase-4 inhibitor. Malnutrition-inflammation-atherosclerosis syndrome is an important prognostic factor for hemodialysis patients, and we previously reported anti-inflammatory effects of linagliptin in hemodialysis patients with diabetes. Inflammation can accelerate oxidative stress, vasoconstriction, and platelet aggregation. However, few studies have investigated the pleiotropic effects of linagliptin treatment on inflammation in hemodialysis patients. In this study, we have extended our previous investigations of these effects in a longer and more thorough follow-up of hemodialysis patients with diabetes. We examined 20 hemodialysis patients with diabetes who were not receiving oral diabetes drugs or insulin therapy and who exhibited inadequate glycemic control (glycated albumin levels＞20%). Linagliptin (5mg) was administered daily, and we evaluated the patients’ superoxide dismutase, 8-hydroxydeoxyguanosine, nitric oxide, nitric oxide synthase, and asymmetric dimethylarginine levels in serum at baseline and after 1, 3, and 6 months of treatment. After 6 months of treatment, superoxide dismutase levels had significantly decreased from 8.8±0.5U/ml to 7.0±0.5U/ml. Nitric oxide synthase levels were significantly increased at 3 and 6 months (maximum, 94.2±13.2µg/ml; baseline, 31.6±5.5µg/ml). After 3 months of treatment, nitric oxide levels had significantly increased from 64.5±6.6µmol/l to 104±15.4µmol/l, and remained significantly elevated at 6 months. Asymmetric dimethylarginine and 8-hydroxydeoxyguanosine levels did not change during the 6-month treatment course, and no patients exhibited hypoglycemia or other significant adverse effects. Linagliptin treatment significantly changed various markers of inflammation relevant to the atherosclerosis in malnutrition-inflammation-atherosclerosis syndrome. Therefore, linagliptin monotherapy has pleiotropic effects on inflammation in hemodialysis patients with diabetes, and may improve their prognosis.