Tolerability and pharmacokinetics of metformin and the dipeptidyl peptidase-4 inhibitor sitagliptin when co-administered in patients with type 2 diabetes

ABSTRACT

Objective: As part of the clinical development of sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of type 2 diabetes, the potential for pharmacokinetic interactions with other antihyperglycemic agents used in managing patients with type 2 diabetes are being carefully evaluated. The purposes of this study were to evaluate the tolerability of co-administered sitagliptin and metformin and effects of sitagliptin on metformin pharmacokinetics as well as metformin on sitagliptin pharmacokinetics under steady-state conditions.

Methods: This placebo-controlled, multiple-dose, crossover study in patients with type 2 diabetes assessed the tolerability of co-administered sitagliptin (50?mg b.i.d.) with metformin (1000?mg b.i.d.). Patients received, in a randomized crossover manner, three treatments (each of 7 days duration): 50?mg sitagliptin twice daily and placebo to metformin twice daily; 1000?mg of metformin twice daily and placebo to sitagliptin twice daily; concomitant administration of 50?mg of sitagliptin twice daily and 1000?mg of metformin twice daily. Following dosing on Day 7 of each treatment period, these pharmacokinetic parameters were determined for plasma sitagliptin and metformin: area under the plasma concentrations–time curve over the dosing interval (AUC_{0–12 h}), maximum observed plasma concentrations (C_max), and time of occurrence of maximum observed plasma concentrations (T_max). Renal clearance was also determined for sitagliptin.

Results: In this study, no adverse experiences were reported by 11 of 13 patients. Two patients had adverse experiences, which were not related to study drugs as determined by the investigators. The mean metformin plasma concentration–time profiles were nearly identical with or without sitagliptin co-administration [metformin AUC_{0–12 h} geometric mean ratio (GMR; [metformin + sitagliptin]/metformin)] was 1.02 (90% CI 0.95, 1.09). Similarly metformin administration did not alter the plasma sitagliptin pharmacokinetics [sitagliptin AUC_{0–12 h} GMR ([sitagliptin + metformin]/sitagliptin)] was 1.02 (90% CI 0.97, 1.08) or renal clearance of sitagliptin. No efficacy measurements (glycosylated hemoglobin or fasting plasma glucose) were obtained during this study. Urinary pharmacokinetics for metformin were not determined due to the lack of effect of sitagliptin on plasma metformin pharmacokinetics.

Conclusions: In this study, co-administration of sitagliptin and metformin was generally well tolerated in patients with type 2 diabetes and did not meaningfully alter the steady-state pharmacokinetics of either agent.     

Sitagliptin attenuates metformin-mediated AMPK phosphorylation through inhibition of organic cation transporters

1. To assess potential interactions between sitagliptin and metformin, we sought to characterize the in vitro inhibitory potency of sitagliptin on the uptake of MPP⁺ and metformin, representative substrates for OCTs, and to evaluate the pharmacological pathways that may be affected by the combination of metformin and sitagliptin.

2. Among the OATs and OCTs screened, OAT3-mediated salicylate uptake and OCT1- and OCT2-mediated MPP⁺ uptake were inhibited by sitagliptin. The K_i values of sitagliptin for OCT1- and OCT2-mediated metformin uptake were 34.9 and 40.8?μM, respectively.

3. As OCT1 is the gate protein for metformin action in the liver, we investigated whether sitagliptin-mediated OCT1 inhibition affected metformin-induced activation of AMPK signalling. Treatment with sitagliptin in MDCK-OCT1 and HepG2 cells resulted in a reduced level of phosphorylated AMPK, with K_i values of 38.8 and 43.3?μM, respectively.

4. These results suggest that the inhibitory potential of sitagliptin on OCT1 may attenuate the first step of metformin action, that is, the phosphorylation of AMPK. Nevertheless, the likelihood of a drug–drug interaction between sitagliptin and metformin is believed to be remote in usual clinical setting.

     

2型糖尿病患者应用西格列汀的短期疗效及影响因素

目的 分析2型糖尿病患者应用西格列汀的短期疗效及其影响因素,为临床患者的选择及提高疗效提供依据。 方法 收集2012年9月至2014年6月住院并应用西格列汀的2型糖尿病患者86例病例资料。根据患者空腹C肽水平四分位数分为C肽水平最高组和C肽水平最低组,每组12例。采用多元线性逐步回归分析患者临床资料中影响血糖下降水平的因素。 结果 使用西格列汀后,C肽水平最高组与C肽水平最低组空腹血糖(FBG)下降值、餐后2 h血糖(2h-PBG)下降值及百分数差异无统计学意义(P>0.05)。糖化血红蛋白(HbA1c)是影响FBG下降值及下降百分数的独立因素;用药前2h-PBG水平是影响2h-PBG下降值及其下降百分数的独立因素。患者使用西格列汀后,最大日内血糖波动值较使用前减小且低血糖发生显著减少(P<0.05)。 结论 西格列汀可同时降低患者FBG和2h-PBG,且疗效相当;其对FBG和2h-PBG的疗效不完全依赖于C肽水平;可显著减少血糖波动和低血糖事件的发生。     

Efficacy and safety of DPP-4 inhibitors in patients with type 2 diabetes: Meta-analysis of placebo-controlled randomized clinical trials

BackgroundGuidelines for type 2 diabetes (T2D) recommend reducing HbA_1c through lifestyle interventions and glucose-lowering drugs (metformin, then combination with dipeptidyl peptidase-4 inhibitors [DPP-4Is] among other glucose-lowering drugs). However, no double-blind randomized clinical trial (RCT) compared with placebo has so far demonstrated that DDP-4Is reduce micro- and macrovascular complications in T2D. Moreover, the safety of DPP-4Is (with increased heart failure and acute pancreatitis) remains controversial.MethodsA systematic review of the literature (PubMed, Cochrane Library Central Register of Controlled Trials [CENTRAL] and https://clinicaltrials.gov), including all RCTs vs placebo published up to May 2015 and the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), published June 2015, was performed. Primary endpoints were all-cause mortality and death from cardiovascular causes; secondary endpoints were macrovascular and microvascular events. Safety endpoints were acute pancreatitis, pancreatic cancer, serious adverse events and severe hypoglycaemia.ResultsA total of 36 double-blind RCTs were included, allowing analyses of 54,664 patients. There were no significant differences in all-cause mortality (RR = 1.03, 95% confidence interval [CI] = 0.95–1.12), cardiovascular mortality (RR = 1.02, 95% CI = 0.92–1.12), myocardial infarction (RR = 0.98, 95% CI = 0.89–1.08), strokes (RR = 1.02, 95% CI = 0.88–1.17), renal failure (RR = 1.06, 95% CI = 0.88–1.27), severe hypoglycaemia (RR = 1.14, 95% CI = 0.95–1.36) and pancreatic cancer (RR = 0.54, 95% CI = 0.28–1.04) with the use of DPP-4Is. However, DDP-4Is were associated with an increased risk of heart failure (RR = 1.13, 95% CI = 1.01–1.26) and of acute pancreatitis (RR = 1.57, 95% CI = 1.03–2.39).ConclusionThere is no significant evidence of short-term efficacy of DPP-4Is on either morbidity/mortality or macro-/microvascular complications in T2D. However, there are warning signs concerning heart failure and acute pancreatitis. This suggests a great need for additional relevant studies in future.     

Drug interactions of dipeptidyl peptidase 4 inhibitors involving CYP enzymes and P-gp efflux pump

Dipeptidyl peptidase 4 (DPP4) inhibitors are oral antidiabetic drugs approved to manage type 2 diabetes mellitus. Saxagliptin is a substrate of CYP3A4/5 enzymes while other DPP4 inhibitors such as sitagliptin, linagliptin, gemigliptin and teneligliptin are weak substrates of CYP3A4. DPP4 inhibitors have also been identified as substrates of P-gp. Hence, the drugs inhibiting or inducing CYP3A4/5 enzymes and/or P-gp can alter the pharmacokinetics of DPP4 inhibitors. This review is aimed to identify the drugs interacting with DPP4 inhibitors. The plasma concentrations of saxagliptin have been reported to be increased significantly by the concomitant administration of ketoconazole or diltiazem while no significant interactions between various DPP4 inhibitors and drugs like warfarin, digoxin or cyclosporine have been identified.     

Efficacy and safety of replacing sitagliptin with canagliflozin in real-world patients with type 2 diabetes uncontrolled with sitagliptin combined with metformin and/or gliclazide: The SITA-CANA Switch Study

Aim

To analyze the efficacy and safety of replacing sitagliptin with canagliflozin in patients with type 2 diabetes (T2D) and poor metabolic control despite treatment with sitagliptin in combination with metformin and/or gliclazide.

西格列汀对糖尿病肾病患者转化生长因子-β1、血小板源性生长因子BB的影响?

目的：探讨西格列汀对糖尿病肾病患者血糖及转化生长因子-β1(TGF-β1)、血小板源性生长因子 BB (PDGF-BB)的影响。方法82例二甲双胍单药治疗血糖控制不佳的2型糖尿病肾病患者加用西格列汀治疗6个月,观察治疗前后血糖、尿白蛋白排泄率(AER)、血清 TGF-β1和 PDGF-BB 水平,分析西格列汀治疗和 AER、血清TGF-β1、PDGF-BB 的关系。结果加用西格列汀治疗后空腹血浆葡萄糖(fasting plasma glucose,FPG)、餐后血糖(postprandial blood glucose,PPG)、糖化血红蛋白(HbA1c)、胰岛岛素抵抗指数(HOMA-IR)等下降,HOMA-IS 升高(P <0.05);AER 和血清 TGF-β1、PDGF-BB 水平均下降(P <0.05)。结论西格列汀治疗能够降低糖尿病肾病患者的血糖、血清 TGF-β1、PDGF-BB 和 AER 水平。     

西格列汀联合二甲双胍对2型糖尿病伴骨质疏松症患者骨代谢的影响

目的探讨西格列汀联合二甲双胍对2型糖尿病伴骨质疏松患者骨转换标志物和骨密度的影响。方法选取2015年1月至2016年1月在本院明确诊断的2型糖尿病合并骨质疏松患者95例,随机分为3组,二甲双胍(metformin,M)+阿卡波糖组(acarbose,A)(M+A组)32例、西格列汀(sitagliptin,S)+阿卡波糖组(S+A组)31例、西格列汀+二甲双胍+阿卡波糖组(S+M+A组)32例,治疗随访48周。治疗前及治疗48周后测定体质量指数(body mass index,BMI)、血清空腹血糖(fasting plasma glucose,FPG)、餐后2小时血糖(2-hour postprandial plasma glucose,2h PG)、糖化血红蛋白(glycated hemoglobin A1c,Hb A1c)、25-羟基维生素D[25-hydroxyvitamin D,25(OH)D]、骨钙素(osteocalcin,OC)、I型胶原羧基端肽β特殊系列(β-cterminal cross-linked telpeptide,β-CTX)、骨特异碱性磷酸酶(bone specific alkaline phosphatase,b-ALP)。采用双能X线吸收测定法(dual energy X-ray absorptiometry,DXA)测定患者腰椎2~4及股骨颈的骨密度(bone mineral density,BMD)。比较各组治疗前后BMI、生化指标、骨转换指标和BMD的变化。结果 5例患者因药物不耐受而脱落,90例患者完成治疗随访,3组各30例。M+A组、S+A组、S+M+A组患者治疗前BMI[(25.1±1.5、25.2±1.6、25.1±1.7)kg/m2]、FPG[(8.45±0.81、8.43±0.83、8.46±0.91)mmol/L]、2h PG[(11.54±1.58、11.68±1.61、11.72±1.70)mmol/L]、Hb A1c[(7.92±0.71、7.95±0.73、7.94±0.75)%]比较差异无统计学意义(均P0.05);治疗后BMI[(24.2±1.6、24.1±1.5、23.5±1.4)kg/m2]、FPG[(6.51±0.69、6.49±0.67、6.15±0.71)mmol/L]、2h PG[(9.10±0.72、9.18±0.89、8.11±0.51)mmol/L]、Hb A1c[(6.71±0.51、6.74±0.53、6.18±0.58)%]均较治疗前显著下降,差异有统计学意义(均P0.05);治疗后S+M+A组与M+A组和S+A组BMI、FPG、2h PG、Hb A1c比较下降更显著,差异有统计学意义(均P0.05);M+A组与S+A组BMI、FPG、2h PG、Hb A1c比较差异无统计学意义(均P0.05)。M+A组、S+A组、S+M+A组患者治疗前b-ALP[(12.5±1.9、12.6±2.1、12.4±2.4)U/L]、OC[(14.2±1.8、14.3±1.7、14.1±1.9)μg/L]、β-CTX[(413.5±65.3、420.4±70.5、428.1±69.6)ng/L]和腰椎2~4的BMD[(0.417±0.091、0.415±0.086、0.419±0.095)g/cm2]及股骨颈的BMD[(0.483±0.086、0.492±0.092、0.487±0.094)g/cm2]比较差异无统计学意义(均P0.05);治疗后b-ALP[(15.8±2.4、16.1±2.5、20.4±2.9)U/L]、OC[(16.9±2.2、17.2±2.4、20.5±2.6)μg/L]明显升高,β-CTX[(351.7±45.8、352.9±47.9、319.5±50.9)ng/L]明显下降,腰椎2~4的BMD[(0.552±0.087、0.572±0.079、0.632±0.084)g/cm2]及股骨颈BMD[(0.617±0.073、0.621±0.073、0.715±0.083)g/cm2]增加,与治疗前比较差异有统计学意义(均P0.05);治疗后S+M+A组与M+A组和S+A比较,b-ALP、OC、BMD升高更显著,β-CTX下降更显著,差异有统计学意义(均P0.05);M+A组与S+A组b-ALP、OC、β-CTX、BMD比较差异无统计学意义(均P0.05)。3组患者治疗前、后25(OH)D变化无统计学意义(均P0.05)。结论西格列汀和二甲双胍除了具有降低血糖的作用外,还能够促进骨形成、抑制骨吸收,增加糖尿病合并骨质疏松患者骨密度,且两药联合应用有叠加增强作用。     

西格列汀单用或联合厄贝沙坦对早期糖尿病肾病白细胞介素18等指标的影响

目的 观察西格列汀单用或联合厄贝沙坦对早期2型糖尿病肾病患者血清胱抑素C(cystatin C,CysC)、白细胞介素18(interleukin-18,IL-18)和24 h尿白蛋白排泄率(urine albumin emission rate,UAER)水平的影响.方法 90例早期糖尿病肾病患者随机分为3组,每组30例.在原治疗方案及生活方式的基础上,西格列汀组予以西格列汀片100 mg,口服,1次/d;厄贝沙坦组予以厄贝沙坦片150 mg,口服,1次/d;联合用药组予以西格列汀和厄贝沙坦片,用法和剂量同前;3组疗程均为12周.观察各组治疗前后糖化血红蛋白(glycosylated hemoglobin,HbAlc)、血清CysC、IL-18和UAER水平的变化.结果 治疗后,3组患者血清CysC、IL-18和UAER水平均较治疗前下降(P＜0.05),联合用药组下降幅度大于其他两组(P＜0.05),西格列汀组与厄贝沙坦组间变化差异无统计学意义(P＞0.05).西格列汀组、联合用药组患者治疗后HbAlc降低(P＜0.05),组间差异无统计学意义(P＞0.05),厄贝沙坦组患者HbAlc治疗前后无明显变化(P＞0.05).结论 西格列汀单用或联合厄贝沙坦均可改善早期2型糖尿病肾病患者的血糖与肾功能,联合用药效果更佳,血清CysC和IL-18的下降可有效反应肾功能的改善,西格列汀有可能通过减轻炎症因子、抗氧化应激作用而发挥肾脏保护作用.