Simultaneous quantitation of metformin and sitagliptin from mouse and human dried blood spots using laser diode thermal desorption tandem mass spectrometry

A simple, rapid and robust high-throughput assay for the simultaneous analysis of metformin and sitagliptin from mouse and human dried blood spot samples using laser diode thermal desorption interfaced with atmospheric pressure chemical ionization tandem mass spectrometry (LDTD-APCI-MS/MS) was developed for use in a pharmaceutical discovery environment as an alternative to traditional plasma analysis. Analytes were extracted from dried blood spots using a simple punch disc and solvent extract procedure. Details of the method development and optimization of the instrumental parameters are presented. The method was successfully applied to spiked mouse and human dried blood spot samples. Analyte stability was determined in dried blood spots on FTA cards and as extracts of dried blood spots. The method was subsequently used to determine the oral pharmacokinetics of metformin and sitagliptin after dosing to male mice. Metformin and Sitagliptin results are compared to data generated by more traditional liquid chromatography-mass spectrometry methods. Intra-assay and inter-assay accuracy and precision across the analytes and species deviated by less than 30% at all calibration levels and less than 20% at all quality control levels.     

西格列汀对2型糖尿病大鼠心肌细胞焦亡的影响及其可能机制

目的:研究西格列汀(sitagliptin,SLT)对2型糖尿病大鼠心肌细胞焦亡的影响,并探讨其抑制糖尿病心肌病可能的作用机制。方法:建立2型糖尿病大鼠模型,并给予(3、10和30 mg/kg)和sirtuin(SIRT)家族抑制剂尼克酰胺(nicotinamide,NAM;500 mg/kg)灌胃4周。检测空腹血糖,采用免疫组织化学法和Western blot法检测心肌组织中相关蛋白表达。结果:与正常对照组相比,糖尿病大鼠心肌组织细胞SIRT3表达下调,而NLRP3表达上调(P0.05),糖尿病大鼠心肌组织发生焦亡的细胞明显增多。灌胃SLT能剂量依赖性地抑制糖尿病大鼠心肌细胞焦亡的发生,并上调SIRT3的表达,下调NLRP3蛋白表达(P0.05);SIRT3非特异性抑制剂NAM(500 mg/kg)能逆转SLT的心脏保护作用,与正常对照组相比,单独给予NAM(500 mg/kg)对正常大鼠心肌细胞SIRT3表达无明显作用,但NLRP3表达上调(P0.05),心肌组织发生焦亡的细胞增多。结论:SLT能抑制糖尿病诱导的心肌细胞焦亡,其作用机制可能涉及SIRT3/NLRP3信号途径。     

Obesity may attenuate the HbA1c‐lowering effect of sitagliptin in Japanese type 2 diabetic patients

Aims/Introduction: The aim of the present study was to assess the independent predictors of the HbA1c‐lowering effect of sitagliptin in Japanese type 2 diabetic patients. Materials and Methods: Data were retrieved from the medical records of 151 type 2 diabetic patients who had been taking sitagliptin 25 or 50 mg once daily for inadequate glycemic control for at least 12 weeks, with or without other oral hypoglycemic agents. Spearman’s rank correlation coefficients were calculated to investigate correlations between two independent continuous variables. Multiple stepwise regression analysis was used to identify independent predictors of reductions in HbA1c levels after 12 weeks of sitagliptin treatment (ΔHbA1c). Results: In all patients combined, Spearman’s rank correlation coefficients showed that ΔHbA1c was significantly correlated with baseline HbA1c alone (r = 0.371, P < 0.0001). However, multiple linear regression analysis among all patients using baseline variables revealed that the independent factors contributing to ΔHbA1c, in order of importance, were method of prescribing (P < 0.0001), baseline HbA1c (P < 0.0001), body mass index (BMI; P = 0.004), and duration of diabetes (P = 0.024). Conclusions: Our analysis may provide novel evidence that increased BMI contributes, in part, to attenuation of the HbA1c‐lowering effect of sitagliptin in Japanese type 2 diabetic patients. Analysis of a larger population over a longer period of time is warranted to confirm these findings. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00156.x, 2011)     

A retrospective review of isolated gliptin-exposure cases reported to a state poison control system

Background. The dipeptidyl peptidase-4 (DPP-4) inhibitors sitagliptin, saxagliptin, and linagliptin are approved by the US Food and Drug Administration in the treatment of type-2 diabetes. Given the limited published information regarding human overdoses to these medications, our goal was to characterize such exposures. Methods. A state poison system database was retrospectively reviewed for all single-agent exposures to sitagliptin, saxagliptin, and linagliptin from 2006 to 2012. Case notes were reviewed and an observational case series was constructed from the data collected including age, weight, gender, circumstances surrounding exposure, symptoms, and outcome. Patients with co-ingestants, confirmed non-exposure, unknown outcomes, or other coding errors were excluded. Results. A total of 197 cases were identified: 135 cases were excluded (123 cases were excluded due to co-ingestants and 12 cases were lost to follow-up); 62 were included for review. No patients experienced hypoglycemia. One of 19 exposed pediatric (0–9 years of age) patients experienced symptoms and was safely managed at home after one episode of emesis. No symptom was experienced following unintentional ingestion by three adolescent (10–18 years of age) patients. Forty single-agent adult exposures to gliptins were included. Thirty-seven involved non-self-harm exposures resulting from double or triple doses; all were safely managed at home without reported symptoms. The majority of these ingestions involved sitagliptin. Three self-harm-adult exposures to gliptins were included for review. All the three were evaluated in a healthcare facility. One patient experienced abdominal discomfort after ingesting 700 mg of sitagliptin and was ultimately discharged from the emergency department. The other two patients experienced no reported symptoms. Conclusion. The majority of gliptin-exposed adult and pediatric/adolescent patients were safely managed at home and when evaluated in a healthcare facility, did not require hospitalization. Intentional self-harm-adult gliptin exposures were managed in a healthcare facility but rarely resulted in hospitalization or serious morbidity at doses up to 18 times the adult therapeutic dose. Additional studies are necessary to determine precise triage guidelines for the management of gliptin overdose.     

Comparative effects of sitagliptin and metformin in patients with type 2 diabetes mellitus: a meta-analysis

Abstract

Background:

Sitagliptin has been widely used in the treatment of type 2 diabetes mellitus (T2DM); however, the therapeutic efficacy of sitagliptin remains inconclusive in randomized controlled studies on T2DM in which metformin has served as a control.     

Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide

ABSTRACT

Objective: To estimate risk and relative risk (RR) of acute pancreatitis among patients using incretin-based diabetes therapies (exenatide or sitagliptin) compared to patients treated with agents with established safety profiles (metformin or glyburide).

Research design and methods: The study population was derived from a large US commercial health insurance transaction database using an active drug safety surveillance system (i3 Aperio^*). This analysis is based on data from June 2005 through June 2008. Cohorts of exenatide and sitagliptin initiators were each matched to an equal number of metformin or glyburide (met/gly) initiators using propensity scores to reduce confounding in the comparison of outcomes during follow-up. Patients with claims suggesting pancreatic disease in the 6 months prior to cohort entry were excluded.

Main outcome measure: Claims for hospitalizations associated with a primary diagnosis of acute pancreatitis (ICD-9 577.0).

Results: There were 27?996 exenatide initiators and 16?276 sitagliptin initiators and approximately equal numbers of matched comparators. During follow-up of up to 1 year, acute pancreatitis occurred among 0.13% of patients treated with exenatide and 0.12% of patients treated with sitagliptin. The risk of acute pancreatitis was comparable for initiators of exenatide (RR 1.0; 95% confidence interval (CI) 0.6–1.7) and sitagliptin (RR 1.0; 95% CI 0.5–2.0) relative to the comparison cohorts.

Conclusions: These data do not provide evidence for an association of acute pancreatitis among initiators of exenatide or sitagliptin compared to met/gly initiators. These results are limited by the data available in an administrative, healthcare database.     

Effects of exenatide versus sitagliptin on postprandial glucose,insulin and glucagon secretion,gastric emptying,and caloric intake: a randomized,cross-over study

ABSTRACT

Background: This study evaluated the effects of exenatide, a GLP-1 receptor agonist, and sitagliptin, a DPP-4 inhibitor, on 2-h postprandial glucose (PPG), insulin and glucagon secretion, gastric emptying, and caloric intake in T2D patients.

Methods: This double-blind, randomized cross-over, multi-center study was conducted in metformin-treated T2D patients: 54% female; BMI: 33?±?5?kg/m²; HbA_1c: 8.5?±?1.2%; 2-h PPG: 245?±?65?mg/dL. Patients received exenatide (5?µg BID for 1 week, then 10?µg BID for 1 week) or sitagliptin (100?mg QAM) for 2 weeks. After 2 weeks, patients crossed-over to the alternate therapy. Postprandial glycemic measures were assessed via standard meal test; caloric intake assessed by ad libitum dinner (subset of patients). Gastric emptying was assessed by acetaminophen absorption (Clinicaltrials.gov Registry Number: NCT00477581).

Results: After 2 weeks of therapy, 2-h PPG was lower with exenatide versus sitagliptin: 133?±?6?mg/dL versus 208?±?6?mg/dL, p?<?0.0001 (evaluable, N?=?61). Switching from exenatide to sitagliptin increased 2-h PPG by +73?±?11?mg/dL, while switching from sitagliptin to exenatide further reduced 2-h PPG by ?76?±?10?mg/dL. Postprandial glucose parameters (AUC, C_ave, C_max) were lower with exenatide than sitagliptin (p?<?0.0001). Reduction in fasting glucose was similar with exenatide and sitagliptin (?15?±?4?mg/dL vs. ?19?±?4?mg/dL, p?=?0.3234). Compared to sitagliptin, exenatide improved the insulinogenic index of insulin secretion (ratio exenatide to sitagliptin: 1.50?±?0.26, p?=?0.0239), reduced postprandial glucagon (AUC ratio exenatide to sitagliptin: 0.88?±?0.03, p?=?0.0011), reduced postprandial triglycerides (AUC ratio exenatide to sitagliptin: 0.90?±?0.04, p?=?0.0118), and slowed gastric emptying (acetaminophen AUC ratio exenatide to sitagliptin: 0.56?±?0.05, p?<?0.0001). Exenatide reduced total caloric intake compared to sitagliptin (?134?±?97?kcal vs. +130?±?97?kcal, p?=?0.0227, N?=?25). Common adverse events with both treatments were mild to moderate in intensity and gastrointestinal in nature.

Conclusions: Although this study was limited by a 2-week duration of exposure, these data demonstrate that, exenatide had: (i) a greater effect than sitagliptin to lower postprandial glucose and (ii) a more potent effect to increase insulin secretion and reduce postprandial glucagon secretion in T2D patients. In contrast to sitagliptin, exenatide slowed gastric emptying and reduced caloric intake. These key findings differentiate the therapeutic actions of the two incretin-based approaches, and may have meaningful clinical implications.     

二甲双胍分别联合西格列汀与吡格列酮治疗2型糖尿病的效果观察

目的观察并分析二甲双胍分别联合西格列汀、吡格列酮治疗2型糖尿病（T2DM）的临床效果及安全性。方法将2011年1月至2012年12月我院收治的76例T2DM患者随机分为A（n=40）、B（n=36）两组,A组患者予二甲双胍＋西格列汀方案,B组予二甲双胍＋吡格列酮方案,疗程12周。12周后对比两组患者血糖浓度、临床疗效及药物不良反应。结果（1）服药12周后,A、B两组空腹血糖[（6．4±1．8）、（7．0±1．9）mmolfL]、餐后2h血糖[（8．1±2．7）、（9．5±2．8）mmol／L]及糖化血红蛋白[（6．2±2．1）％、（7．1±2．2）％]均较治疗前明显下降[（9．4±2．4）、（9．1±2．5）mmol／L与（13．6±4．5）、（13．3±4．9）mmol／L与（9．2±2．4）％、（8．9±2．6）％,t值分别为6．325、4．013、6．628、4．040、5．950、3．171,P均〈0．05]。A组患者餐后2h血糖浓度（8．1±2．7）mmolfL明显低于B组（9．5±2．8）mmol／L（t=2．214,P=0．030）。（2）A组患者总有效率90．0％（36／40）略高于B组83．3％（30／36）,差异无有统计学意义（x2=0．269,P：0．604）。（3）A、B两组用药期问分别发生药物不良反应10例（25．O％）、11例（30．6％）,两组不良反应发生率比较差异无统计学意义（x2=0．292,P=0．589）。结论二甲双胍分别联合西格列汀、吡格列酮方案均是治疗T2DM的有效方案,前者临床效果具有优势,尤其是对降低餐后血糖优势明显。     

二甲双胍和西格列汀对绝经后2型糖尿病患者骨代谢的影响

目的探讨二甲双胍和西格列汀对绝经后2型糖尿病合并骨量减少或骨质疏松患者骨代谢及骨密度的影响。方法选择接受治疗的绝经后2型糖尿病合并骨量减少或骨质疏松患者129例,采用随机数字表法分为磺脲类促泌剂治疗组（格列吡嗪组,G组）、二肽基肽酶-4抑制剂联合磺脲类促泌剂治疗组（西格列汀+格列吡嗪组,S+G组）、双胍类联合磺脲类促泌剂治疗组（二甲双胍+格列吡嗪组,M+G组）3组,随访48周,治疗前后测定患者空腹血糖（FBG）、糖化血红蛋白（HbA1C）、LDL-C、碱性磷酸酶（ALP）、骨钙素（OC）、Ⅰ型胶原羧基端肽β特殊序列(β-CTX),采用双能X线骨密度仪测定所有患者股骨颈和髋关节骨密度,对比治疗前后一般生化指标、骨转换指标及骨密度变化。结果129例中有122例完成48周随访,其中G组40例,S+G组41例,M+G组41例。3组患者治疗后BMI、OC、β-CTX、股骨颈和髋关节骨密度比较差异均有统计学意义（均P＜0.05）。3组患者治疗后FBG、HbA1C均较治疗前显著下降（均P＜0.01）。M+G组治疗后BMI较治疗前显著下降（P＜0.01）,G组和S+G组治疗后OC均较治疗前显著下降（均P＜0.01）,S+G组治疗后β-CTX较治疗前显著下降（P＜0.01）,G组治疗后股骨颈和髋关节骨密度均较治疗前显著下降（均P＜0.01）。结论西格列汀主要通过抑制骨吸收,并可能有部分促进成骨发挥其减少骨丢失的作用,二甲双胍可能通过促进成骨发挥其减少骨丢失的作用,两者均可作为绝经后女性2型糖尿病合并骨量减少或骨质疏松患者降糖的一线用药选择。     

西格列汀对妊娠期糖尿病患者餐后血糖异常的控制效果

目的 研究西格列汀对妊娠期糖尿病患者餐后血糖(2hPG)异常的控制效果.方法 选取本院2013年6月至2015年6月80例妊娠期糖尿病患者为研究对象,抽签随机分为观察组与对照组,每组40例.观察组采用西格列汀治疗,对照组单用胰岛素治疗,比较两组治疗前后空腹血糖(FPG)、餐后血糖水平及治疗期间的不良反应发生率.结果 观察组与对照组治疗前FPG、2 hPG比较差异无统计学意义(P＞0.05),治疗后2、4、6周观察组2 hPG分别为(10.16±1.58) mmol/L、(9.23±1.78)mmol/L、(8.86±1.25)mmol/L,显著低于对照组的(12.25±1.66)mmol/L、(11.44±1.79)mmol/L、(10.13±1.44)mmol/L (P＜0.05).治疗后2、4、6周观察组FPG分别为(8.06±0.85) mmol/L、(7.63±0.59) mmol/L、(6.78±0.43) rnmol/L,显著低于对照组的(9.81±0.36) mmol/L、(8.02±0.49) mmol/L、(7.01±0.37)mmol/L (P＜0.05).治疗过程观察组低血糖2例,恶心1例;对照组低血糖1例,眩晕1例,两组比较差异无统计学意义(P＞0.05).结论 西格列汀可以有效地控制妊娠期糖尿病患者的餐后血糖水平,不良反应率低,值得临床应用和推广.