肥胖和非肥胖2型糖尿病患者的代谢状态临床研究

目的 比较肥胖与非肥胖2型糖尿病(T2DM)患者血压及代谢紊乱指标的差异.方法 176例2型糖尿病患者根据体重指数(BMI)分为肥胖和非肥胖两组,肥胖组95例,非肥胖组81例.检测两组的腰围、臀围、血压、空腹血糖(FBG)、餐后2 h血糖(2hBG)、空腹胰岛素(FINS)、餐后2 h胰岛素(2hINS)、空腹C肽(FCP)、餐后2 h C肽(2hCP)、肾功能、糖化血红蛋白(HbA1c)、胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL)、低密度脂蛋白胆固醇(LDL)并进行比较分析.结果 肥胖组的BMI、腰/臀比、血尿酸、FINS、2hINS、FCP和2hCP明显高于非肥胖组(P<0.01),肥胖组收缩压、舒张压较非肥胖组略高(但差异无统计学意义)(P>0.05),肥胖组中合并高血压、高脂血症比例显著高于非肥胖组(P<0.01).结论 T2DM患者中,肥胖患者较非肥胖患者有更严重的代谢紊乱,对肥胖的T2DM患者应采取综合治疗,不仅要控制血糖,还要减肥和减轻胰岛素抵抗.     

Population exposure-response modeling of metformin in patients with type 2 diabetes mellitus

The exposure-response properties of metformin were characterized in 12 subjects with type 2 diabetes mellitus. The time course of drug concentration and effects on fasting plasma glucose and lactic acid concentrations were used from a study in which subjects received 500 mg of metformin twice daily for 5 days followed by 850 mg twice daily for 5 days. Pharmacokinetic sampling included morning trough concentrations obtained on days 7 to 9 and rich sampling (15 time points) on day 10. Fasting plasma glucose and lactic acid concentrations were measured on days 0 to 10 and served as biomarkers of therapeutic effect and tolerability, respectively. A population pharmacokinetic/pharmacodynamic analysis was conducted using nonlinear mixed effects modeling. Metformin pharmacokinetics were described using a 1-compartment model with first-order absorption. Population mean estimates (relative standard error [RSE]) of clearance (CL/F) and volume of distribution were 79.0 L.h(-1) (6.8%) and 648 L (13.8%), respectively. Covariate analyses revealed that creatinine clearance (CL(CR)) significantly influenced metformin CL/F [CL/F = 79.0.(CL(CR)/80)(0.822)]. An indirect response model was applied to describe the antihyperglycemic effect of metformin. Population mean estimates (RSE) of baseline fasting plasma glucose and the drug concentration producing half-maximal effect were 241 mg.dL(-1) (4.6%) and 4.23 mg.L(-1) (31.0%). An empirical linear model was used to describe a slight progressive increase in fasting lactic acid during metformin treatment with an estimated slope coefficient (RSE) of 0.0005 mM.mL.ng(-1) (38.1%). Model evaluation by predictive check and nonparametric bootstrap analysis suggested that the proposed model is robust, and parameter values were estimated with good precision. Simulations suggested that the clinical utility of metformin was maintained over the dose range evaluated with respect to fasting plasma glucose and lactic acid response.     

二甲双胍遗传药理学研究进展

遗传药理学研究发现药物代谢酶、受体和转运体基因遗传多态性是药物作用个体差异的重要决定因素。二甲双胍是治疗2型糖尿病(type2diabetes mellitus,T2DM)的一线药物,同时还可治疗多囊卵巢综合征(polycystic ovary syn-drome,PCOS)等其他与胰岛素抵抗有关的疾病。二甲双胍在临床使用中表现出显著的药物反应个体差异,这种差异性导致药物反应性降低或药物毒副反应的发生。有机阳离子转运体(organiccation transporters,OCTS)遗传多态性对二甲双胍药物反应个体差异有重要影响。本文阐述了OCTS等多个药物相关基因的遗传多态性对二甲双胍药代动力学和药效学的影响,可为临床制定二甲双胍的个体化用药提供参考。     

二甲双胍在老年2型糖尿病患者治疗中的作用

二甲双胍(Metformin)自1957年上市以来,已经在治疗糖尿病的征途上风风雨雨走过了50多年.实际上,早在一个世纪前科学研究者就在对山羊豆素样化合物的合成和药理学研究中发现了二甲双胍,但由于胰岛素和磺脲类药物的发现和使用,使二甲双胍的临床应用经历了曲折的道路.并且经受住了历史的考验,其在临床上的应用价值不断被发掘.2007年在美国糖尿病学会(ADA)糖尿病临床指南中,首次在控制高血糖的策略中推荐具体降糖药物使用的前后顺序和路径:生活方式干预的同时应用二甲双胍作为起始治疗,胰岛素强化合并二甲双胍及格列酮作为最终治疗.二甲双胍作为2型糖尿病的一线用药的地位得到了进一步确立和巩固.2008年ADA指南又提出其在预防和延缓2型糖尿病上的作用.     

Contraindications to metformin therapy among patients with type 2 diabetes mellitus

Objective The biguanide, metformin, is a commonly prescribed oral antihyperglycemic agent. However, there are several clinical conditions that are considered as contraindications to the use of metformin among patients with type 2 diabetes mellitus. The aim of this study was to investigate the presence and nature of contraindications to metformin therapy among patients with type 2 diabetes mellitus. Method A retrospective study of the medical files of diabetic patients available at Alwosta clinic, north Palestine was carried out. Information about disease and medication profile of the patients was retrieved and analyzed using SPSS during the study period in 2004/2005. Focus was on metformin users who have contraindications to metfromin therapy. Main outcome measure Presence and number of contraindications to metformin therapy. Results Two hundred and seventy-two type 2 diabetic patients were identified. One hundred and twenty four of those diabetic patients were metformin users. Approximately, 60% of patients in the metformin group had a least one contraindication. Congestive heart failure and renal impairment were the most quantitatively present contraindications. Conclusion Contraindications to metformin therapy are common among type 2 diabetic patients and mostly disregarded. Patients have to be critically assessed before starting therapy and in case of metformin prescribing; dose should be adjusted based on the presence of risk factors for metformin adverse effects.     

腹腔镜下胃旁路术治疗非肥胖2型糖尿病的临床疗效观察

目的观察腹腔镜下胃旁路术（LRYGB）对非肥胖2型糖尿病患者临床疗效。方法对2011年1月-2012年10月间本院实施LRYGB的2型糖尿病病患者中BMI〈28.0 kg/m216例患者的临床资料进行回顾性分析。结果平均手术时间145 min,术中平均出血量35 ml,术后平均9.3 d,术后出现吻合口出血1例,无死亡病例及严重的手术并发症。术后患者1个月空腹血糖及餐后血糖明显下降（P〈0.01）,术后3个月至半年降至正常水平。糖化血红蛋白在术后3个月开始明显下降（P〈0.01）,术后半年降至正常水平。体质量指数在术后1个月有明显下降,术后6个月-12个月期间体质量指数趋于稳定,无明显变化。结论 LRYGB后2型糖尿病患者血糖代谢明显改善,但其远期疗效还需进一步研究。     

Sitagliptin/metformin fixed-dose combination: in patients with type 2 diabetes mellitus

Sitagliptin/metformin is a single-tablet, fixed-dose combination of the dipeptidyl peptidase-4 inhibitor sitagliptin and the biguanide antihyperglycaemic metformin that achieves greater improvements in glycaemic control than either component alone in patients with type 2 diabetes mellitus. Recommended dosages of sitagliptin plus metformin, either as the fixed-dose tablet or a combination of the individual agents, significantly reduced glycosylated haemoglobin (HbA(1c)) levels in two well designed clinical trials in treatment-naive patients with type 2 diabetes. The improvements in glycaemic control seen with sitagliptin plus metformin therapy after 18 or 24 weeks were greater than those observed with the individual components alone and/or placebo, and sustained over treatment durations of up to 2 years. As add-on therapy in treatment-experienced patients with inadequate glycaemic control, the HbA(1c)-lowering efficacy of sitagliptin plus metformin was noninferior to that of glimepiride plus metformin in a 30-week, double-blind trial. Sitagliptin plus metformin and glipizide plus metformin lowered HbA(1c) levels by generally similar magnitudes, with the noninferiority of sitagliptin plus metformin to glipizide plus metformin being established in one 52-week study. As part of triple combination therapy, also in treatment-experienced patients with inadequate glycaemic control, sitagliptin added to ongoing glimepiride with or without metformin or ongoing insulin with or without metformin significantly improved glycaemic control over 24 weeks. Sitagliptin plus metformin, as the fixed-dose tablet or a combination of the individual agents, was generally well tolerated in patients with type 2 diabetes, and was associated with a low risk of hypoglycaemia.     

二甲双胍对肥胖2型糖尿病患者血清C反应蛋白补体C3的影响

目的探讨二甲双胍对肥胖2型糖尿病患者血清C反应蛋白(CRP)和补体C3水平的影响。方法随机将42例肥胖2型糖尿病患者分为二甲双胍组26例,安慰剂组16例,治疗24周。观察治疗前后CRP、补体C3变化情况。结果24周后治疗组血清CRP水平治疗前后比较差异有统计学意义(P<0.05),对照组差异无统计学意义。补体C3水平治疗组治疗前后比较无明显改善。结论二甲双胍治疗肥胖2型糖尿病患者血清CRP水平明显下降。补体C3无明显变化。     

对二甲双胍的再认识

二甲双胍作为最早的口服降糖药物之一,在糖尿病的治疗舞台上经历了50余年的风风雨雨,可以形容为“历久弥新五十年,经典用药谱新篇”。伴随着近年来国际、国内糖尿病预防和治疗观念的不断发展,以及对二甲双胍这一经典药物的临床使用的进一步认识,二甲双胍在2型糖尿病治疗领域的地位得到进一步提升，存预防糖耐量损害（IGT）转变为糖尿病的大型研究中显示了它的良好效果。     

Safety and efficacy of metformin up-titration in Japanese patients with type 2 diabetes mellitus treated with vildagliptin and low-dose metformin

Background: This study investigated the safety and efficacy of metformin up-titration in Japanese patients with type 2 diabetes mellitus treated with vildagliptin (100 mg/day) and low-dose metformin (500 or 750 mg/day).

Research design and methods: Fifty patients were randomly allocated to the control group (maintaining the initial low-dose of metformin) and the dose increase group (up-titrating of metformin to 1,500–2,250 mg/day) for 24 weeks. The primary outcome was change in HbA1c from baseline to 24 weeks.

Results: Among the 25 patients allocated to the dose increase group, four patients were not able to complete the study protocol because of gastrointestinal symptoms. HbA1c in the dose increase group was significantly but modestly lower than in the control group (change in HbA1c: 0.22 ± 0.57 vs. ?0.15 ± 0.58%, group comparison, P < 0.05). The dose increase group did not gain weight during the study period, and no hypoglycemic events were reported in both groups. The rate of gastrointestinal symptoms in the dose increase group was profoundly higher than in the control group (32 vs. 0%, P < 0.01).

Conclusions: In Japanese patients with type 2 diabetes treated with vildagliptin and low-dose metformin, metformin up-titration significantly but modestly improved glycemic control without hypoglycemia and weight gain.     

Economic evaluation of orlistat in overweight and obese patients with type 2 diabetes mellitus

OBJECTIVE: To estimate the economic value of pharmacological treatment of type 2 diabetes mellitus in overweight and obese patients using orlistat in addition to standard diabetes therapy (i.e., a sulphonlyurea, metformin or insulin) and weight management strategies as compared with standard diabetes therapy and weight management strategies alone in a US-based healthcare setting. The perspective of the study was from the viewpoint of a US healthcare provider. DESIGN AND SETTING: Markov state transition model simulating diabetes-related complications and mortality for a period of 11 years. Patients were modelled to continue orlistat therapy for a 52-week period, assuming a 3-year period of weight regain where after 3 years bodyweight would match that of the placebo group. The impact of orlistat on glycosylated haemoglobin (HbA(1c)) values was evaluated directly using data from four randomised, placebo-controlled, 1-year trials of orlistat in overweight or obese adults with type 2 diabetes who also received standard diabetes pharmacotherapy and intensive lifestyle modification. Incidence rates of micro- and macrovascular complications associated with type 2 diabetes and the estimated relative reduction in incidence rates associated with a decrease in mean updated HbA(1C) values were derived from the United Kingdom Prospective Diabetes Study (UKPDS) estimates for a reference population of male patients, 52 years of age. US cost estimates were derived from published sources and presented in 2001 US dollars. Discounting of 3% was applied. Probabilistic sensitivity analysis was applied to evaluate the robustness of the results of the persistence of the effect of orlistat after treatment. MAIN OUTCOME MEASURES: Average costs and event-free life-years gained during the 11-year period expressed as the incremental costs divided by the incremental gain in life expectancy. RESULTS: Treatment with orlistat, 120 mg three times daily, increased event-free life expectancy by 0.13 years over an 11-year period. Average treatment costs were estimated to be 19,987 US dollars in the orlistat group compared with 18,865 US dollars in the group that received diabetes medication and weight management alone. This translated into a cost-effectiveness ratio of 8327 US dollars per event-free life-year gained. CONCLUSION: Adding orlistat as a pharmacological treatment to conventional diabetes and weight management approaches seems to be a cost-effective treatment option for overweight and obese patients with type 2 diabetes.     

Third-line agent selection for patients with type 2 diabetes mellitus uncontrolled with sulfonylureas and metformin

Patients with type 2 diabetes mellitus often begin treatment by taking oral agents, usually metformin or a sulfonylurea, and then progress to the combination of these two agents. Most patients often require three or more agents or a change to an insulin regimen. However, no guidelines are available to aid the clinician in the decision-making process for selecting the third agent. Many options are available for additional therapy, including thiazolidinediones, intermediate- and long-acting insulins, exenatide, and dipeptidyl peptidase-4 inhibitors. Although the American Diabetes Association recommends metformin as first-line therapy, it does not give exact specifications for second- and third-line agents but only summarizes clinical data and options about each therapeutic drug class. Guidelines from the American College of Endocrinology and American Association of Clinical Endocrinologists recommend several options depending on the patient's hemoglobin A(1c) level. Therefore, a standard of care cannot be provided; rather, clinicians must evaluate each patient to ascertain that patient's optimum therapy. In doing so, clinicians need to be familiar with the efficacy, safety, and cost of each agent.     

Combination therapy with metformin plus vildagliptin in type 2 diabetes mellitus

Introduction: Type 2 diabetes mellitus (T2DM) is pathophysiologically characterized by a combination of insulin resistance and beta-cell dysfunction. Consequently, a proper treatment of such a disease should target both of these defects. Dipeptidyl peptidase-4 (DPP-4) inhibitors are among the most recent additions to the therapeutic options for T2DM and are able to increase circulating levels of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), thus stimulating glucose-dependent insulin secretion.

Areas covered: This paper provides an overview of the clinical results of combination therapy with metformin and the DPP-4 inhibitor vildagliptin in T2DM patients.

Expert opinion: Vildagliptin–metformin single-tablet combination is indicated for the treatment of T2DM patients not achieving a sufficient glycemic control at their maximally tolerated dose of metformin. Results from clinical trials provide evidence of vildagliptin efficacy administered in addition to metformin, as either first- or second-line treatment. The vildagliptin–metformin association seems to have favorable effects on beta-cell function and is characterized by good safety and tolerability profiles when compared with other antidiabetic agents. Of note, data available suggest that administration of fixed-dose combination products, together with the low incidence of adverse gastrointestinal events, may improve compliance and adherence of patients to therapy, resulting in an improved metabolic control.     

Combination therapy with metformin plus vildagliptin in type 2 diabetes mellitus

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is pathophysiologically characterized by a combination of insulin resistance and beta-cell dysfunction. Consequently, a proper treatment of such a disease should target both of these defects. Dipeptidyl peptidase-4 (DPP-4) inhibitors are among the most recent additions to the therapeutic options for T2DM and are able to increase circulating levels of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), thus stimulating glucose-dependent insulin secretion. AREAS COVERED: This paper provides an overview of the clinical results of combination therapy with metformin and the DPP-4 inhibitor vildagliptin in T2DM patients. EXPERT OPINION: Vildagliptin-metformin single-tablet combination is indicated for the treatment of T2DM patients not achieving a sufficient glycemic control at their maximally tolerated dose of metformin. Results from clinical trials provide evidence of vildagliptin efficacy administered in addition to metformin, as either first- or second-line treatment. The vildagliptin-metformin association seems to have favorable effects on beta-cell function and is characterized by good safety and tolerability profiles when compared with other antidiabetic agents. Of note, data available suggest that administration of fixed-dose combination products, together with the low incidence of adverse gastrointestinal events, may improve compliance and adherence of patients to therapy, resulting in an improved metabolic control.     

Aliskiren exhibits similar pharmacokinetics in healthy volunteers and patients with type 2 diabetes mellitus

BACKGROUND: The renin system is an attractive target for antihypertensive therapy in patients with diabetes mellitus. However, diabetes is associated with changes in gastrointestinal, renal and hepatic function that may affect the absorption and disposition of oral drugs. This study compared the pharmacokinetics and pharmacodynamics of the orally active direct renin inhibitor, aliskiren, in healthy volunteers and patients with type 2 diabetes. METHODS: This was an open-label study conducted in 30 patients with type 2 diabetes and 30 healthy volunteers matched for age, bodyweight and race. Following a 10-hour fast, all participants received a single oral dose of aliskiren 300mg. Blood samples were taken at frequent intervals for 96 hours post-dose for determination of plasma concentrations of aliskiren (using a high-performance liquid chromatography-tandem mass spectroscopy method). Plasma renin activity (PRA) and renin concentration (RC) were also measured for 24 hours after dosing. RESULTS: Aliskiren exhibited similar pharmacokinetics in patients with type 2 diabetes and healthy volunteers. Exposure to aliskiren was slightly higher in patients with type 2 diabetes compared with healthy volunteers (mean area under the plasma concentration-time curve from 0 to 24 hours 1859 vs 1642 ng . h/mL; maximum observed plasma drug concentration 394 vs 348 ng/mL), while apparent clearance corrected for bioavailability was slightly lower (205 vs 234 L/h) and elimination half-life slightly longer (44 vs 39.9 hours), but there were no statistically significant differences for any pharmacokinetic parameters. There was no significant correlation between glycaemic control (% glycosylated haemoglobin) and any of the measured pharmacokinetic parameters in patients with type 2 diabetes. Aliskiren caused sustained suppression of PRA for at least 24 hours after dosing despite increasing RC; there were no major differences in the pharmacodynamic effects of aliskiren between patients with type 2 diabetes and healthy volunteers. Aliskiren was well tolerated in both patient groups, with no clinically significant changes in laboratory values and a low risk of adverse events. CONCLUSION: Aliskiren showed a similar pharmacokinetic profile in healthy volunteers and patients with type 2 diabetes, and administration of a single oral 300 mg dose of aliskiren was well tolerated by both patients and healthy volunteers. The pharmacodynamic effects of aliskiren were also similar in healthy volunteers and diabetic patients, with sustained inhibition of renin system activity observed for at least 24 hours after dosing.     

利拉鲁肽治疗肥胖2型糖尿病患者临床观察

目的应用利拉鲁肽治疗肥胖T2DM患者,观察有效性及安全性。方法应用二甲双胍或二甲双胍＋胰岛素血糖仍控制不佳的肥胖T2DM患者,加用利拉鲁肽0．6～1．2mg／d,观察3个月,比较治疗前后FPG、2hPG、HBAlC-、BMI、C肽的变化。观察并记录不良反应。结果治疗后患者上述指标均比治疗前有所下降,C肽水平有所恢复,对比差异有统计学意义（P〈0．01）,应用胰岛素的患者胰岛素用量均有不同程度减少,部分患者停用胰岛素。部分患者出现一过性恶心症状。无严重低血糖发生。结论胰岛功能轻度受损的肥胖T2DM患者应用利拉鲁肽治疗不仅可以良好的控制血糖、减少血糖的波动、减少胰岛素用量,而且能够改善患者BMI。     

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.     

双时相门冬胰岛素联用二甲双胍治疗2型糖尿病的成本-效果分析

目的:利用经济学模型,评价应用基础胰岛素治疗的中国2型糖尿病(T2DM)患者转换为双时相门冬胰岛素30(BIAsp30)联用二甲双胍治疗的长期经济与健康产出,证明BIAsp30的成本效果价值,旨在为临床医生和患者合理用药提供参考依据。方法:应用糖尿病CORE模型,计算患者长期(30年)的糖尿病治疗总成本、期望寿命和质量调整生命年。CORE模型是一项已发表的、经过验证和专家评审的、计算机模拟的糖尿病模型。293例中国T2DM患者的临床基线和治疗数据来自于一项16周、多中心和非随机无对照的用于评价基础胰岛素转用BIAsp30联合二甲双胍(MET)治疗的安全性与有效性的临床试验(NCT00614120)。其中基础胰岛素分为2个亚组,甘精胰岛素(IGla)联合MET组和中性鱼精蛋白锌胰岛素(NPH)联合MET组。药物和血糖检测的成本以市场价格计算,并发症及其管理成本是基于2008年已发表文献中的中国三级医院的糖尿病及其并发症成本数据进行CPI调整至2009年。本研究中的成本以直接医疗成本计算,包括降糖药物、血糖检测和糖尿病并发症的成本。直接医疗成本和质量调整生命年的年贴现率根据2006年中国药物经济学指南设定为3%。...     

度拉糖肽联合二甲双胍对肥胖型2型糖尿病患者机体代谢、体脂成分及血清脂肪因子的影响

目的 探究度拉糖肽联合二甲双胍在肥胖型2型糖尿病（T2DM）患者治疗中的临床疗效。方法 将2021年1月至2023年1月在上海市嘉定区安亭医院接受治疗的200例符合本课题筛选条件的肥胖型T2DM患者,随机分为利拉鲁肽组（n＝100）和度拉糖肽组（n＝100）。利拉鲁肽组给予利拉鲁肽联合二甲双胍治疗,度拉糖肽组给予度拉糖肽联合二甲双胍治疗,2组均治疗3个月。比较治疗前及治疗3个月机体代谢指标[空腹血糖（FBG）、餐后2 h血糖（2 h PBG）、血红蛋白（HbA1c）、总胆固醇（TC）、甘油三酯（TG）]、体脂成分（体脂肪率、体重指数、四肢皮下脂肪率、内脏脂肪指数）及血清脂肪因子[脂联素（adiponectin）、神经肽Q（NPQ）、白脂素（asprosin）、鸢尾素（irisin）]水平;观察2组临床疗效及不良反应发生情况。结果 治疗3个月,2组FBG、2 h PBG、HbAlc、TC、TG、体脂肪率、体重指数、四肢皮下脂肪率、内脏脂肪指数、asprosin均较治疗前降低,且度拉糖肽组低于利拉鲁肽组（P<0.05）。治疗3个月后,2组血清adiponectin、NPQ、irisin水平均较治疗前升高,且度拉糖肽组升高幅度大于利拉鲁肽组（P<0.05）。度拉糖肽组有效率98.00%高于利拉鲁肽组91.00%（P<0.05）。2组不良反应发生率（11.00%、14.00%）相比,无统计学差异（P>0.05）。结论 度拉糖肽联合二甲双胍可改善肥胖型T2DM患者机体代谢状态,调节机体体脂成分及血清脂肪因子,临床疗效显著,安全性高。