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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.
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