Short‐ and long‐term effect of sitagliptin after near normalization of glycemic control with insulin in poorly controlled Japanese type 2 diabetic patients

Aims/Introduction

The aim of the present study was to examine the short‐ and long‐term effect of sitagliptin on glucose tolerance after near normalization of glycemic control with insulin in poorly controlled type 2 diabetic patients.

Materials and Methods

We consecutively enrolled a total of 30 type 2 diabetic patients whose glycated hemoglobin levels (National Glycohemoglobin Standardization Program) were ≥7.4%, stopped all oral antidiabetic drugs and started insulin therapy. When fasting plasma glucose levels became <140 mg/dL, we carried out the first oral glucose tolerance test (OGTT). After 1‐week sitagliptin treatment (50 mg/day), the second OGTT was carried out. Furthermore, we evaluated the long‐term efficacy of sitagliptin on glucose tolerance after near normalization of glycemic control with insulin.

Results

After 1‐week sitagliptin treatment, the area under the curve of insulin was markedly increased, and the area under the curve of glucagon and glucose was markedly decreased. Duration of diabetes and insulin secretory capacity were correlated with the effect of sitagliptin. Furthermore, interestingly, near normalization of glycemic control with insulin therapy for 1–2 weeks brought out the long‐term effectiveness of sitagliptin on glucose tolerance for 24 weeks, which was not observed with other antidiabetic drugs.

Conclusions

These findings suggest that near normalization of glycemic control with insulin improves the clinical response to sitagliptin in poorly controlled type 2 diabetic patients.     

Mechanism-based pharmacokinetic/pharmacodynamic modeling of the effects of sitagliptin on DPP-4 activity,insulin and glucose in diabetic rats

Dipeptidyl peptidase-4 (DPP-4) inhibitors exert their antihyperglycemic effects through repressing inactivation of certain incretin hormones and thus increasing insulin secretion and controlling glucose level. In this study, the plasma concentrations of sitagliptin, a potent DPP-4 inhibitor, after a single oral dose of 300 mg/kg in streptozotocin-induced type 2 diabetic rats were determined by HPLC. A one-compartment pharmacokinetic (PK) model with first order absorption was developed to describe the PK profile of sitagliptin, and the drug concentrations at the doses given in the pharmacodynamic (PD) study were simulated accordingly. The dynamic changes in DPP-4 activity, insulin concentration and blood glucose level in diabetic rats at doses of 1, 5 and 10 mg/kg were measured, and a mechanism-based PK/PD model was established subsequently. In this model, the inhibitory effect of sitagliptin on DPP-4 activity was demonstrated using the Hill’s function with direct link, and the downstream increase in insulin secretion and inhibition of glucose production were characterized using indirect response (IDR) models. This model interpreted the mechanism of antihyperglycemic action of sitagliptin, and may be modified and applied to other species or other agents in this class.     

磷酸西格列汀片处方工艺研究

目的 筛选磷酸西格列汀片的最佳处方工艺。方法 设计不同处方工艺,通过检测溶出曲线及粉体学数据,确定最佳处方工艺。结果 自制片的4个处方中,粉体学数据及压片流畅性均较好,其中湿法制粒工艺两个处方溶出比参比制剂慢,粉末直压工艺中当交联羧甲基纤维素钠为16 mg时溶出曲线与参比制剂拟合较好。结论 通过对磷酸西格列汀片的处方工艺研究,最终确定了磷酸西格列汀片的工艺和崩解剂用量。     

Short-term inhibition of DPP-4 enhances endothelial regeneration after acute arterial injury via enhanced recruitment of circulating progenitor cells

Background

Endothelial injuries regularly occur in atherosclerosis and during interventional therapies of the arterial occlusive disease. Disturbances in the endothelial integrity can lead to insufficient blood supply and bear the risk of thrombus formation and acute vascular occlusion. At present, effective therapeutics to restore endothelial integrity are barely available.We analyzed the effect of pharmacological DPP-4-inhibition by Sitagliptin on endogenous progenitor cell-based endothelial regeneration via the SDF-1α/CXCR4-axis after acute endothelial damage in a mouse model of carotid injury.

Methods and Results

Induction of a defined endothelial injury was performed in the carotid artery of C57Bl/6 mice which led to a local upregulation of SDF-1α expression. Animals were treated with placebo, Sitagliptin or Sitagliptin + AMD3100. Using mass spectrometry we could prove that Sitagliptin prevented cleavage of the chemokine SDF-1α. Accordingly, increased SDF-1α concentrations enhanced recruitment of systemically applied and endogenous circulating CXCR4 + progenitor cells to the site of vascular injury followed by a significantly accelerated reendothelialization as compared to placebo-treated animals. Improved endothelial recovery, as well as recruitment of circulating CXCR4 + progenitor cells (CD133 +, Flk1 +), was reversed by CXCR4-antagonization through AMD3100. In addition, short-term Sitagliptin treatment did not significantly promote neointimal or medial hyperplasia.

Conclusion

Sitagliptin can accelerate endothelial regeneration after acute endothelial injury. DPP-4 inhibitors prevent degradation of the chemokine SDF-1α and thus improve the recruitment of regenerative circulating CXCR4 + progenitor cells which mediate local endothelial cell proliferation without adversely affecting vessel wall architecture.     

A comparative study of the role of crocin and sitagliptin in attenuation of STZ-induced diabetes mellitus and the associated inflammatory and apoptotic changes in pancreatic β-islets

Type 1 diabetes mellitus (T1DM) describes a complex group of metabolic disorders associated with elevated blood glucose levels and increased risks of complications development. Exploring new drug therapies would reduce the increased diabetes-associated morbidity and mortality and will reduce the excessive health care costs. Crocin is the major active ingredient of saffron. In the current study, DM was induced by single intraperitoneal injection of streptozocin (50 mg/kg).DM progression was associated with a significant increase in blood glucose level with reduced insulin and increased glucagon secretion. Pancreatic malondialdehyde (MDA) content significantly escalated, while superoxide dismutase (SOD) activity, reduced glutathione (GSH) concentration, catalase activity, thioredoxin level and serum total antioxidant capacity significantly declined. This was associated with a significant increase in pancreatic caspase-3 contents and pancreatic infiltration with inflammatory cells in β-islets. Both sitagliptin and crocin significantly reduced blood glucose levels, enhanced pancreatic insulin expression and secretion and suppressed glucagon secretion with enhancement of anti-oxidant defenses and reduction of oxidative burden, with evident anti-inflammatory impacts. Interestingly, the effect of crocin on DM indices, inflammatory and apoptotic changes was comparable to that of sitagliptin; the standard oral hypoglycemic agent. Nevertheless, crocin had a superior effect compared to sitagliptin on blood sugar level, β-islets diameter and insulin immune-reactivity. In conclusion, crocin reduced blood glucose level mainly via reduction of oxidative burden, modulation of apoptotic pathway and attenuation of pancreatic inflammation.     

西格列汀联合贝那普利治疗早期糖尿病肾病的效果及对血清IL-6、IL-18、TGF-β1的影响

目的 观察西格列汀联合贝那普利治疗早期糖尿病肾病(diabetic nephropathy,DN)的效果.方法 选取2018年7月—2019年10月在我院就诊的92例早期DN患者,根据治疗方法 不同分为观察组和对照组各46例,对照组采用非二肽基肽酶-4抑制剂类降糖药物联合贝那普利治疗,观察组在对照组基础上加用西格列汀...     

磷酸西格列汀干预糖尿病大鼠肾脏中VEGF的表达

①目的研究磷酸西格列汀（sitagliptin phosphate,SP）对糖尿病（diabetes mellitus,DM）大鼠肾脏中血管内皮生长因子（VEGF）表达的影响。②方法用50只雄性健康SD大鼠随机分为正常对照组（Normal control,NC组）、糖尿病对照组（DM组）和糖尿病sP治疗组（SP组）,除NC组外,其余两组经腹腔注射链脲佐菌素（str eptozotocin,STZ剂量65mg／kg）制备糖尿病大鼠模型。成功后治疗组每日灌胃给予磷酸西格列汀10mg／（kg·d）,分别采集各组大鼠3、6、8周后的尿液、血液标本,通过酶联免疫吸附法（ELISA）检测肾脏中血管内皮生长因子的表达;取一侧肾组织经HE染色,光镜下观察肾脏组织的病理变化,利用全自动生化仪检测血糖、肌酐、尿素氮及24h尿蛋白。③结果与NC组比较,造膜后大鼠的血糖、血肌酐、尿素氮、24h尿蛋白定量及肾脏组织中VEGF的表达明显升高（P〈0．01）有统计学意义;SP组血肌酐、尿素氮、24h尿蛋白定量及肾脏组织VEGF的表达与DM组比较明显降低（P〈0．01）。④结论磷酸西格列汀这类新型降糖药物对肾脏有一定的保护作用,可延缓糖尿病肾病的发展。     

Box-Behnken效应面法优化磷酸西格列汀片处方设计

目的：筛选磷酸西格列汀片直接压片法的最佳处方。方法：采用Box-Behnken效应面法（BBD）优化磷酸西格列汀片的处方设计,以原料药粒径、MCC占填充剂比例及崩解剂用量为考察因素,以休止角、均匀度、溶出度为评价指标,制备样品作质量考察。结果：最优处方原药粒径100 nm,MCC占填充剂比例为45%,崩解剂用量为2.7%。根据最优处方制备的小试样品,均匀度为（2.53±0.18）%,休止角为（38.9±0.5）°,10 min溶出度为（82.3±2.2）%,与理论值的差距＜10%。3批中试样品,各评价指标与理论值的差距均＜10%,符合质量要求。结论：通过BBD法优化的磷酸西格列汀片处方,具有良好的流动性、混合均匀度,制得片剂具有快速溶出特征。     

Clinical Effects of Exposure to DPP-4 Inhibitors as Reported to the National Poison Data System

DPP-4 inhibitors (sitagliptin, saxagliptin, and linagliptin) are approved for the treatment of diabetes. They are considered safe due to their hyperglycemia dependent mechanism of action. We examined all isolated exposures to DPP-4 inhibitors reported to the National Poison Database System since 2006 to determine if significant toxicity occurs after exposure with attention to pediatric and intentional overdoses. NPDS data regarding DPP-4 ingestions in all age groups between January 2006 and March 2013 was collected. Cases were reviewed, and the following inclusion criteria applied: (1) reported ingestion of a DPP-4 inhibitor and (2) known clinical outcome. Exclusion criteria included the following: (1) exposure to more than a single substance, (2) no known outcome, and (3) clinical outcome judged to be unrelated to the exposure. One thousand four hundred seventy-six cases were reviewed while 826 were excluded. Of 650 included cases, 562 developed no clinical effects. Mild effects were noted in 77. There were no deaths. Moderate/major effect cases were investigated: two medication-naive nondiabetic individuals with accidental exposures developed clinically significant hypoglycemia requiring treatment. One diabetic patient on a DPP-4 inhibitor developed prolonged hypoglycemia requiring admission and continuous exogenous dextrose. Of 650 included exposures to DPP-4 inhibitors, 639 (98.3%) had either no or minor clinical effects. Three resulted in clinically significant hypoglycemia requiring intervention. None of the moderate or major clinical outcomes were the result of intentional overdoses for the purpose of self-injury. No exploratory ingestions resulted in moderate or major effects. Based on this data, exposure to DPP-4 inhibitors may rarely result in clinically significant hypoglycemia.