Reduction of oxidative stress and inflammation by blunting daily acute glucose fluctuations in patients with type 2 diabetes: role of dipeptidyl peptidase-IV inhibition

Abstract

Objective: Evaluate the effects of two dipeptidyl peptidase-IV (DPP-4) inhibitors, sitagliptin and vildagliptin, known to have different efficacy on mean amplitude of glycemic excursions (MAGE), on oxidative stress, and on systemic inflammatory markers in patients with type 2 diabetes.

Research design and methods: A prospective, randomized, open-label PROBE design (parallel group with a blinded end point) study was performed in 90 patients with type 2 diabetes inadequately controlled by metformin. The study assigned 45 patients to receive sitagliptin (100 mg once daily; sitagliptin group) and 45 patients to receive vildagliptin (50 mg twice daily; vildagliptin group) for 12 weeks. MAGE, evaluated during 48 h of continuous subcutaneous glucose monitoring, allowed an assessment of daily glucose fluctuations at baseline and after 12 weeks in all patients. Assessment of oxidative stress (nitrotyrosine) and systemic levels of inflammatory markers interleukin (IL)-6 and IL-18 was performed at baseline and after 12 weeks in all patients.

Results: HbA(1c), fasting and postprandial glucose, MAGE, and inflammatory and oxidative stress markers were similar between the groups at baseline. After 12 weeks, MAGE (P < 0.01) was lower in the vildagliptin group than in the sitagliptin group. After treatment, HbA(1c) and postprandial glucose evidenced similar changes between the groups (P = NS). Vildagliptin treatment was associated with a stronger decrease in nitrotyrosine (P < 0.01), IL-6 (P < 0.05), and IL-18 (P < 0.05) than sitagliptin treatment. Nitrotyrosine and IL-6 changes significantly correlated with changes in MAGE but not in fasting glucose and HbA(1c).

Conclusions: MAGE reduction is associated with reduction of oxidative stress and markers of systemic inflammation in type 2 diabetic patients. These effects were greater in the vildagliptin group than in the sitagliptin group.

Figure 1

Plasma GLP-1 (A) and glucagon (B) levels are shown during standard meals at baseline in type 2 diabetic patients. Plasma GLP-1 (C) and glucagon (D) levels are shown after 3 months of treatment with vildagliptin (50 mg, twice daily; VILDA) or sitagliptin (100 mg, once daily; SITA) in type 2 diabetic patients. The standardized breakfast contained 419 kcal (57% carbohydrate, 17% protein, and 26% fat), lunch contained 692 kcal (66% carbohydrate, 16% protein, and 18% fat), and dinner contained 507 kcal (41% carbohydrate, 26% protein, and 32% fat). Sample correlation analysis is shown between MAGE and GLP-1 at 30 min changes (E) and between MAGE and ΔAUC glucagon changes (F). Values are the mean ± SD. *P < 0.05 compared with the vildagliptin group.

Figure 2

Changes in MAGE and in plasma nitrotyrosine, IL-6, and IL-18 levels in vildagliptin (VILDA) and sitagliptin (SITA) group are shown after 3 months of therapy. *P < 0.05.