Objective　In 2009, sitagliptin became available in Japan. Sitagliptin is an orally active, potent and selective dipeptidyl peptidase-4（DPP-4）inhibitor for the treatment of type 2 diabetic patients. Sitagliptin acts through increasing incretin（GLP-1 and GIP）hormone concentration, and reduces plasma glucose and HbA1c levels. In addition, DPP-4 inhibitor was reported to reduce plasma triglyceride（TG）level. Remnant lipoproteins which underlie hypertriglyceridemia are known to be atherogenic as well as LDL. However, there is little information about the effects of long-term sitagliptin therapy on HbA1c, TG and remnant cholesterol levels in Japan. The effects of 10-month add-on therapy with sitagliptin on HbA1c, TG and remnant cholesterol levels were examined in Japanese type 2 diabetic patients. In addition, obesity and/or disease duration may impact patient therapeutic response to medication. Thus, this study also evaluated the effect of obesity and/or diabetes duration on glycemic response to sitagliptin therapy in patients whose type 2 diabetes was not optically controlled with glimepiride or pioglitazone.
Methods　Sixty four patients with type 2 diabetes and baseline HbA1c（JDS）≧6.2％ to≦7.5％ were studied. Mean age was 63 years. All patients were treated with glimepiride（n＝55, mean dose 1.5±0.1 mg/day）or pioglitazone（n＝9, dose 30 mg/day）at least for 3 months before the study entry. Sitagliptin 50 mg/day was added on after the dose of glimepiride（mean dose 0.6±0.1 mg/day）or pioglitazone（15 mg/day）was reduced to approximately half. Patients were treated with sitagliptin add-on glimepiride or pioglitazone over 10 months. HbA1c and plasma lipid levels were compared before and 10 months after add-on therapy with sitagliptin. HbA1c was measured by high-performance liquid chromatography. Plasma remnant cholesterol was determined as RLP-cholesterol（normal range ＜5.2 mg/dL）by the method of Nakajima et al. Obesity was defined as BMI ≧25 kg/m² according to the criteria in Japanese.
Results　Overall, 10-month add-on therapy with sitagliptin significantly reduced HbA1c level（6.8±0.1％→6.1±0.1％, p＜0.001）. Reduction in HbA1c from baseline at 10 months was significantly（p＜0.01）greater in patients with obesity（7.2±0.2％→6.1±0.1％, percent change −13.0％）than in patients without obesity（6.5±0.1％→6.1±0.1％, percent change -6.8％）. Patients were divided into 4 groups according to BMI and diabetes duration. Group A；24 patients with BMI ＜25 and diabetes duration ＜10 years, Group B；12 patients with BMI ＜25 and diabetes duration ≧10 years, Group C；21 patients with BMI ≧25 and diabetes duration ＜10 years, Group D；7 patients with BMI ≧25 and diabetes duration ≧10 years. Group C showed the greatest reduction in HbA1c level（7.1±0.2％→6.0±0.1％, percent change−13.8％）. Overall, 10-month add-on therapy with sitagliptin significantly reduced TG level（149±8→109±5 mg/dL, p＜0.001）and remnant cholesterol level（7.6±1.0→4.4±0.4 mg/dL, p＜0.05）. There was no significant change in LDL-cholesterol and HDL-cholesterol levels before and after add-on therapy with sitagliptin. Body weight was not significantly changed, and no adverse reactions such as hypoglycemia were observed over the study period.
Conclusion　It is concluded that 10-month add-on therapy with sitagliptin is effective to reduce HbA1c as well as plasma TG and remnant cholesterol levels in Japanese type 2 diabetic patients. In addition, sitagliptin therapy is more effective to reduce HbA1c level in patients with obesity and diabetes duration ＜10 years. This is the first report that DPP-4 inhibitor reduces plasma remnant cholesterol.