Pharmacokinetic and pharmacodynamic modelling of the effects of glimepiride on insulin secretion and glucose lowering in healthy humans

Glimepiride is an oral sulfonylurea antihyperglycaemic agent. We used pharmacokinetic-pharmacodynamic (PK-PD) modelling to analyse the relationship between plasma glimepiride concentration, insulin secretion and glucose lowering to determine the effects of the drug in healthy volunteers. A single 2-mg oral dose of glimepiride was administered to six healthy volunteers. The control group received a placebo. All subjects consumed 12 g of sugar immediately after drug administration in order to standardize the initial plasma glucose levels. Serial blood sampling was performed for 9 h after oral dosing. Plasma glimepiride, insulin and glucose levels were determined by validated methods (LC/MS/MS assay, hexokinase method and radioimmunoassay respectively). Time courses of plasma glimepiride concentration, insulin secretion, and glucose lowering effects were analysed by means of PK-PD modelling with the ADAPT II program. The time course of the plasma concentrations followed a two-compartmental model with a lag time. The glimepiride concentration peaked at 191.5 ng/mL at approximately 4 h after administration. The maximal increase in insulin secretion was 9.98 mIU/L and the maximal decrease in plasma glucose was 19.33 mg/dL. Both peak effects occurred at approximately 2.5 h after drug intake. The glucose disappearance model was used to analyse glimepiride's insulin secretion and glucose lowering effects. The PK-PD model described well the relationship between plasma glimepiride and its insulin secretion and hypoglycaemic effects in healthy volunteers.     

Results of VERTIS SU extension study: safety and efficacy of ertugliflozin treatment over 104 weeks compared to glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin

Objective: To assess the safety and efficacy of ertugliflozin over 104?weeks in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin.

Methods: In this double-blind, multicenter, randomized, phase III study (VERTIS SU; NCT01999218), adults with T2DM and glycated hemoglobin (HbA1c) 7.0–9.0% on metformin ≥1500?mg/day received ertugliflozin 5?mg or 15?mg, or glimepiride. The primary efficacy time point was Week 52; double-blinded treatment continued until Week 104.

Results: Baseline characteristics of randomized, treated patients (n?=?1315) were similar across groups (mean age 58.2 years, HbA1c 7.8%); 76.4% completed the study; 61.6% completed on study medication. Mean glimepiride dose at 104?weeks was 3.5?mg/day. At Week 104, least squares mean change from baseline in HbA1c (95% confidence intervals) were ?0.3% (?0.4, ?0.2), ?0.4% (?0.5, ?0.3) and ?0.4% (?0.5, ?0.3) for ertugliflozin 5?mg, 15?mg, and glimepiride, respectively. Ertugliflozin provided sustained reductions in body weight and systolic blood pressure (SBP) over 104?weeks. The incidence of adverse events (AEs) and serious AEs was similar across groups. The incidence of symptomatic hypoglycemia was 3.8%, 6.4% and 22.1% in the ertugliflozin 5?mg, 15?mg, and glimepiride groups, respectively. Genital mycotic infections were reported in 5.3%, 2.6% and 0% of men, respectively, and 9.2%, 12.3% and 1.4% of women, respectively. The incidence of urinary tract infection and hypovolemia AEs was similar across groups.

Conclusions: Ertugliflozin was well tolerated and provided clinically meaningful glycemic control and durable reductions in body weight and SBP over 104?weeks.     

Canagliflozin versus glimepiride treatment in patients with Type 2 diabetes inadequately controlled with metformin (CANTATA-SU trial)

Evaluation of: Cefalu WT, Leiter LA, Yoon KH et al. Efficacy and safety of canagliflozin versus glimepiride in patients with Type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52-week results from a randomized, double-blind, Phase III non-inferiority trial. Lancet 382, 941–950 (2013).

The CANTATA-SU study compared two doses of the sodium glucose cotransporter 2 inhibitor canagliflozin (CANA 100 and 300 mg) with the sulfonylurea, glimepiride (6–8 mg) in Type 2 diabetes mellitus patients inadequately controlled on metformin, over 52 weeks. Glimepiride reduced the mean baseline HbA1_C from 7.8–6.99%. CANA 100 mg reduced the baseline HbA1_C from 7.8–6.98% and CANA 300 mg reduced HbA1_C from 7.8–6.87%. Fasting plasma glucose was lowered to a greater extent following CANA 100 mg (1.3 mmol/l) and CANA 300 mg (1.52 mmol/l) as compared to glimepiride (1.02 mmol/l). CANA 100 and 300 mg reduced body weight by 3.7 and 4.0 kg, respectively compared to a 0.7 kg increase with glimepiride. Blood pressure was modestly reduced by both CANA treatments. Both high-density lipoprotein and low-density lipoprotein cholesterol were increased by both doses of CANA compared to glimepiride. Documented hypoglycemia was lower with CANA, but polyuria, pollakiuria, genital mycotic and urinary tract infections were significantly greater in both doses of CANA compared to glimepiride.     

Efficacy and safety of dulaglutide monotherapy compared with glimepiride in East‐Asian patients with type 2 diabetes in a multicentre,double‐blind,randomized, parallel‐arm,active comparator,phase III trial

Aims

To compare the efficacy and safety of once‐weekly glucagon‐like peptide‐1 receptor agonist dulaglutide 1.5 and 0.75 mg with glimepiride in East‐Asian patients with type 2 diabetes (T2D).

Materials and methods

In this phase III, multinational, multicentre, double‐blind, randomized, parallel‐arm, 26‐week study, patients with inadequate glycaemic control were randomized 1:1:1 to once‐weekly dulaglutide 1.5 or 0.75 mg or daily glimepiride (1‐3 mg/d). The primary endpoint was assessment of the non‐inferiority of dulaglutide (1.5 mg), as measured by change in glycated haemoglobin (HbA1c), compared with glimepiride using a 0.4% non‐inferiority margin.

Results

A total of 737 patients were randomized (dulaglutide 1.5 mg, n = 244; dulaglutide 0.75 mg, n = 248; glimepiride, n = 245). At week 26, both doses of dulaglutide were non‐inferior and also superior to glimepiride for HbA1c reduction from baseline with a least squares mean difference of ?6.34 mmol/mol (95% confidence interval [CI] ?8.31, ?4.26) or ‐0.58% (95% CI ?0.76, ?0.39) for dulaglutide 1.5 mg and ?3.50 mmol/mol (95% CI ?5.47, ?1.42) or ?0.32% (95% CI ?0.50, ?0.13) for dulaglutide 0.75 mg (P < .001). A greater proportion of patients in the dulaglutide 1.5 mg group achieved the HbA1c target of <53 mmol/mol (<7.0%) compared with the glimepiride group (74.1% vs 57.4%; P < .001). The mean body weight decreased (P < .005) and total hypoglycaemia rates were lower (P < .001) in the dulaglutide groups compared with the glimepiride group. The most common drug‐related adverse events in both dulaglutide groups (≥5% of patients) included diarrhoea, nausea, increased lipase, decreased appetite, abdominal distension and vomiting.

Conclusions

Dulaglutide (both doses) demonstrated superior glycaemic control vs glimepiride, with a favourable tolerability and safety profile in East‐Asian patients with T2D.     

格列美脲致急性尿潴留1例

导致急性尿潴留的药物很多,如治疗精神病药物奥氮平、度洛西汀[1]和利培酮[2]、钙通道阻滞药齐考诺肽[3]和硝苯地平[4]以及抗生素阿莫西林[5]和林可霉素[6]等,而降糖药格列美脲导致急性尿潴留尚未见文献报道.笔者于2009年4月31日至5月9日收治1例格列美脲致急性尿潴留,现报告如下.     

基于个案报道的格列美脲不良反应/事件分析

目的:探讨格列美脲致药物不良反应/事件的发生特点.方法:计算机检索CNKI、维普、万方、PubMed、Embase等数据库,对有关格列美脲不良反应/事件个案文献报道进行整理和分析.结果:收集文献17篇,获取病例17例.格列美脲不良反应涉及的器官系统较多.药品说明书未提及的严重脱发、眩晕、速发过敏反应、血管炎、支气管哮喘、急性尿潴留等罕见不良反应发生应引起医务人员注意;严重低血糖反应、重症药疹、肝功能损害有报道.结论:格列美脲在临床应用广泛,使用过程中应了解低血糖反应诱发因素,监测不良反应,注意患者用药教育,避免严重不良反应的发生.     

2种口服降糖药物联合胰岛素治疗初诊2型糖尿病的临床对比研究

目的：探讨2种口服降糖药物分别联合人工合成胰岛素对初诊2型糖尿病（T2DM）的患者血糖指标、胰岛β细胞功能及低血糖发生率的影响。方法：研究对象选取某院2013年4月-2015年12月收治初诊T2DM患者共120例,以随机数字表法分为A组（60例）和B组（60例）,分别在甘精胰岛素应用基础上加用罗格列酮和格列美脲辅助治疗;比较2组患者血糖达标时间,胰岛素用量,治疗前后BMI水平、血糖指标水平、胰岛β细胞功能指标水平、低血糖及心血管疾病发生率等。结果：2组患者血糖达标时间和胰岛素用量比较差异无显著性意义（P>0.05）;B组患者治疗后BMI水平显著低于A组（P<0.05）;2组患者治疗后血糖和胰岛β细胞指标水平组间比较差异无显著性意义（P>0.05）;同时B组患者低血糖发生率显著低于A组（P<0.05）;2组患者心血管疾病发生率比较差异无显著性意义（P>0.05）。结论：罗格列酮和格列美脲分别联合人工合成胰岛素治疗初诊T2DM临床疗效接近,但格列美脲口服可有效减少体质量增加量,降低低血糖发生风险,更具临床应用价值。     

格列美脲治疗2型糖尿病安全性和有效性的多中心临床研究

目的 评价格列美脲对单纯饮食或用二甲双胍和/或阿卡波糖治疗控制不满意的2型糖尿病治疗的安全性、耐受性和有效性。方法 用多中心、开放性、非对照性临床研究,入选患者给予格列美脲1～4 mg,每日早餐前顿服,疗程16周。试验前后测定血糖、糖化血红蛋白、血脂和肝肾功能。结果129例患者人选,122例患者完成试验,格列美脲治疗16周空腹和餐后2h血糖平均分别下降1.3和1.8 mmol·L~(-1),糖化血红蛋白平均下降1.8％。治疗后空腹血浆胰岛素水平无变化,HOMA胰岛素抵抗指数明显下降,患者体重指数平均增加0.3 kg·m~(-2)。与格列美脲治疗有关的主要不良事件为低血糖反应和消化道症状,16例次与药物有关的低血糖反应均为轻度,进食后可自行缓解。对血脂和血压无不良影响。结论 格列美脲可以进一步降低单纯饮食控制或应用二甲双胍和/或阿卡波糖治疗的2型糖尿病患者的空腹和餐后2h时血糖以及糖化血红蛋白,且不增加空腹胰岛素水平,副作用小,耐受性好,使用较安全。     

Vascular effects of glibenclamide vs. glimepiride and metformin in Type 2 diabetic patients.

AIMS: Glibenclamide attenuates the protective responses to opening of vascular ATP-sensitive potassium (K(ATP)) channels during ischaemia. Therefore, glibenclamide treatment of Type 2 diabetes mellitus may have hazardous cardiovascular effects when used under conditions of ischaemia. Glimepiride and metformin seem to lack such characteristics. Based on these data, we hypothesized that, in contrast to glibenclamide, chronic treatment of Type 2 diabetic patients with glimepiride or metformin will not impair the vasodilator function of K(ATP) opening in vivo. METHODS: Two groups of 12 Type 2 diabetes mellitus patients participated in a double-blind randomized cross-over study consisting of two 8-week periods, in which treatment with orally administered glibenclamide (15 mg/day) was compared with either glimepiride or metformin (6 mg and 1500 mg/day, respectively). At the end of each treatment period, the increase in forearm blood flow (FBF, venous occlusion plethysmography) in response to intra-arterial administered diazoxide (K(ATP) opener), acetylcholine (endothelium-dependent vasodilator) and dipyridamole (adenosine-uptake blocker) and to forearm ischaemia was measured. RESULTS: There were no significant differences in vasodilator responses to diazoxide, acetylcholine, dipyridamole and forearm ischaemia after glibenclamide compared with glimepiride and metformin. CONCLUSIONS: Chronic treatment of Type 2 diabetes mellitus with glimepiride or metformin has similar effects on vascular K(ATP) channels compared with chronic glibenclamide treatment.