薬理と治療

Abstract

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 diabeticpatients. Sitagliptin acts through increasing incretin（GLP－1 and GIP）hormone concentration,and reduces plasma glucose and HbA1c levels. In addition, DPP－4 inhibitor wasreported to reduce plasma triglyceride（TG）level. Remnant lipoproteins which underlie hypertriglyceridemiaare known to be atherogenic as well as LDL. However, there is little informationabout the effects of long－term sitagliptin therapy on HbA1c, TG and remnant cholesterollevels in Japan. The effects of 10－month add－on therapy with sitagliptin on HbA1c, TG andremnant 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 glycemicresponse to sitagliptin therapy in patients whose type 2 diabetes was not optically controlledwith 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 monthsbefore 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 therapywith sitagliptin. HbA1c was measured by high－performance liquid chromatography. Plasmaremnant cholesterol was determined as RLP－cholesterol（normal range ＜5.2 mg／dL）by themethod of Nakajima et al. Obesity was defined as BMI ≧25 kg／m2 according to the criteriain 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 dura- tion ≧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 signifi- cantly 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 dia- betic 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.