格列美脲联合胰岛素治疗2型糖尿病的多中心临床研究

目的研究在接受胰岛素治疗的2型糖尿病患者中,联合应用格列美脲治疗的疗效及对胰岛素使用剂量的影响.方法为多中心、开放、自身对照的临床研究.100例胰岛素治疗剂量≥50 U/d(胰岛素单用或与≤2种非胰岛素促泌剂联合应用)的2型糖尿病患者,加用格列美脲治疗12周.结果 12周后,糖化血红蛋白(Hh)A1c由基线时的(8.89±1.77)%降至(7.02±0.86)%,下降了(1.86±1.43)%.以HbA1c≤6.5%和<7.0%为目标值,达标率分别为34%和59%,达标率增加31%和50%.胰岛素的剂量由基线时的66.0 U/d降至50.0 U/d,剂量减少26.67%.患者的全天血糖谱均明显改善.治疗期间,30例患者(30%)发生一般性低血糖68件·次,低血糖发生率为2.95次/(患者·年),无严重低血糖事件.受试者体重及体重指数均无明显变化.结论在胰岛素治疗的基础上联合应用格列美脲可有效降低2型糖尿病患者空腹血糖、餐后血糖水平,有利于患者实现HbA1c达标;同时可显著降低胰岛素用量,提高治疗的安伞性和耐受性.     

Blood pressure reactions to insulin treatment in patients with type 2 diabetes

BACKGROUND

The initiation of insulin therapy may be easy and uncomplicated in some patients with type 2 diabetes, but in others, mainly in obese patients, problems often arise (ie, poor compliance, worsening B-cell function and/or insulin resistance).

METHODS

As a substudy of a broader investigation concerning hemorheological effects of insulin treatment in insufficiently controlled type 2 diabetes, blood pressure was recorded in 12 patients at baseline, after two months and after four months on insulin.

RESULTS

After two months on insulin, analyses of triglycerides, high-density lipoprotein cholesterol and total cholesterol indicated metabolic improvement (P<0.05 to 0.001) and a surprisingly uniform increase of blood pressure values (P<0.05 to 0.01) was found. At the same time, the serum sodium concentration increased (P<0.01) and was positively correlated to both systolic and diastolic blood pressure (P<0.01). After four months on insulin, blood pressure returned to pretreatment values or lower (P<0.05 to 0.01). Serum sodium also decreased to pretreatment values. No significant changes of the flow behaviour of blood were seen after the initiation of insulin.

CONCLUSIONS

The number of patients was small and the study was not primarily designed to examine blood pressure. The preliminary conclusion from the present study, however, is that the initiation of insulin treatment in poorly controlled type 2 diabetes causes a temporary and possibly clinically significant elevation of blood pressure. A change in renal treatment of sodium caused by insulin may be one of several possible explanations of the results, but further studies are warranted to confirm the findings.     

Usefulness of the insulin tolerance test in patients with type 2 diabetes receiving insulin therapy

Aims/Introduction

To establish the validity of the plasma glucose disappearance rate (KITT), derived from an insulin‐tolerance test (ITT), for evaluating the insulin sensitivity of patients with type 2 diabetes after insulin therapy.

Materials and Methods

In the first arm of the study, 19 patients with poorly controlled diabetes were treated with insulin and underwent an ITT and a euglycemic clamp test (clamp‐IR). The relationship between the insulin resistance index, as assessed by both the clamp‐IR and KITT tests, was examined. In the second arm of the study, the relationships between KITT values and various clinical parameters were investigated in 135 patients with poorly controlled diabetes, after achieving glycemic control with insulin.

Results

In study 1, a close correlation between KITT and the average glucose infusion rate during the last 30 min of the standard clamp‐IR test (M‐value) was noted (P < 0.001). In study 2, body mass index (P = 0.0011), waist circumference (P = 0.0004), visceral fat area (P = 0.0011) and the log‐transformed homeostasis model assessment of insulin resistance value (P = 0.0003) were negatively correlated with the log‐transformed KITT. High‐density lipoprotein cholesterol (P = 0.0183), low‐density lipoprotein cholesterol (P = 0.0121) and adiponectin (P = 0.0384) levels were positively correlated with the log‐transformed KITT.

Conclusions

The ITT is a valid and useful test for evaluating the insulin sensitivity of patients with diabetes, even after treatment with insulin.     

Comparison of insulin monotherapy and combination therapy with insulin and metformin or insulin and rosiglitazone or insulin and acarbose in type 2 diabetes

The aim of this study was to compare the efficacy of treatment with insulin alone, insulin plus acarbose, insulin plus metformin, or insulin plus rosiglitazone in type 2 diabetic subjects who were previously on insulin monotherapy, and to evaluate the effects of these treatments on cardiovascular risk factors including lipid profile, C-reactive protein (CRP) and fibrinogen. Sixty-six poorly controlled type 2 diabetic patients on insulin monotherapy were involved. They were randomized to insulin alone, insulin plus acarbose, insulin plus metformin, or insulin plus rosiglitazone groups for 6 months period. Mean fasting and postprandial glucose values as well as HbA1c levels significantly decreased in all groups. The greatest improvement in HbA1c was observed in insulin plus rosiglitazone (2.4%) and in insulin plus metformin (2%) groups. Daily total insulin dose was increased to 12.7 units/day in insulin alone group, decreased to 4.7 units/day in insulin plus rosiglitazone group, to 4.2 units/day in insulin plus metformin group, and to 2.7 units/day in insulin plus acarbose group. Least weight gain occurred in insulin plus metformin group (1.4 kg) and greatest weight gain occurred in insulin plus rosiglitazone group (4.6 kg). No significant change in lipid levels—except serum triglycerides—was observed in any groups. CRP and fibrinogen levels decreased in all groups, but the decrease in fibrinogen level was significantly greater in insulin plus rosiglitazone group. All groups were comparable in hypoglycemic episodes. No serious adverse event was noted in any group.     

Insulin glargine or NPH combined with metformin in type 2 diabetes: the LANMET study

Aims/hypothesis In type 2 diabetic patients we compared 9 months of combination therapy with insulin glargine and metformin with 9 months of NPH insulin combined with metformin. The primary focus was changes in HbA_1c; secondary focus was diurnal glucose profiles and symptomatic hypoglycaemia. Methods In this investigator-initiated open, parallel-group clinical trial involving seven centres, 110 insulin-naive type 2 diabetic patients with poor glycaemic control (HbA_1c ≥8.0%) on oral hypoglycaemic agents (90% using sulfonylurea plus metformin) were randomised to receive bedtime insulin glargine with metformin (G+MET) or bedtime NPH with metformin (NPH+MET) for 36 weeks. The patients were taught how to self-adjust their insulin dose and use a modem to send the results of home glucose monitoring to treatment centres. The goal was to achieve a fasting plasma glucose (FPG) of 4.0 to 5.5 mmol/l in both groups. Results During the last 12 weeks, FPGs averaged 5.75±0.02 and 5.96±0.03 mmol/l (p<0.001) and insulin doses were 68±5 and 70±6 IU/day (0.69±0.05 and 0.66±0.04 IU kg^–1 day^–1, NS) in the G+MET and NPH+MET groups, respectively. At 36 weeks, mean HbA_1c was 7.14±0.12 and 7.16±0.14%, respectively (NS). Symptomatic, but not confirmed symptomatic, hypoglycaemia was significantly lower during the first 12 weeks in the G+MET group (4.1±0.8 episodes/patient-year) than in the NPH+MET group (9.0±2.3 episodes/patient-year, p<0.05), but not significantly different thereafter. Glucose levels before dinner were higher in the NPH+MET group (10.1±0.3 mmol/l) than in the G+MET group (8.6±0.3 mmol/l, p=0.002) throughout the 36-week study. With regard to baseline characteristics such as initial glycaemia or C-peptide, there was no difference between patients who achieved good glycaemic control (HbA_1c <7.0%) and those who did not. Differences were seen in the following: between study centres, weight gain during the run-in period and insulin therapy, and FPG during the last 12 weeks (5.7±0.2 vs 6.7±0.3 mmol/l for patients reaching vs those not reaching target, p<0.01). Conclusions/interpretation Good glycaemic control can be achieved with both G+MET and NPH+MET. Use of G+MET reduces symptomatic hypoglycaemia during the first 12 weeks and dinnertime hyperglycaemia compared with NPH+MET.     

The effects of metformin on adipocyte insulin action and metabolic control in obese subjects with type 2 diabetes

To investigate the mechanisms of action of metformin, insulin receptor binding and the activity of several insulin-controlled metabolic pathways were measured in adipocytes taken from 10 obese Type 2 diabetic patients treated for 4 weeks with either metformin (0.5 g x 3 daily) or matching placebo using a double-blind crossover design. Metformin therapy was associated with a significant fall in serum fructosamine levels (3.1 +/- 0.4 vs 2.8 +/- 0.4 mmol l-1, p less than 0.02) as well as fasting (10.8 +/- 2.4 vs 9.4 +/- 2.1 mmol l-1) and daytime (11.5 +/- 2.4 vs 10.0 +/- 2.2 mmol l-1) plasma glucose concentrations (p less than 0.05). Fasting and postprandial plasma levels of C-peptide and insulin were unchanged. While fasting plasma lactate concentrations remained unaltered after metformin, a rise was noted in response to meals (from 1.4 +/- 0.1 to 1.8 +/- 0.2 mmol l-1, p less than 0.05). Adipocyte insulin receptor binding was unaffected by drug treatment. Moreover, no insulin-like effects or post-binding potentiation of insulin action could be found on adipocyte glucose transport, glucose oxidation, lipogenesis, glycolysis or antilipolysis. A complementary in vitro study using adipocytes from non-obese healthy volunteers failed to show any direct effect of metformin on adipocyte insulin binding or glucose transport and metabolism, at media drug concentrations corresponding to therapeutic plasma levels.     

甘精胰岛素联合赖脯胰岛素强化治疗2型糖尿病临床疗效和安全性观察

目的探讨甘精胰岛素联合赖脯胰岛素强化治疗2型糖尿病的临床疗效和安全性。方法选取确诊为2型糖尿病的患者120例作为研究对象,将患者按照随机数字表法分为对照组和观察组,每组60例,对照组采用诺和灵R联合诺和灵N进行治疗,观察组采用甘精胰岛素联合赖脯胰岛素进行治疗,比较两组患者的临床疗效和安全性。结果观察组患者治疗后的总有效率(90.00%)明显高于对照组(65.00%),观察组患者治疗后低血糖发生率(13.33%)明显低于对照组(41.67%),两组比较差异具有统计学意义(P0.05)。结论对2型糖尿病患者采用甘精胰岛素联合赖脯胰岛素进行强化治疗能够取得较好的临床效果,可以降低患者治疗后低血糖的发生率,值得在临床中推广应用。     

胰岛素联合维格列汀治疗2型糖尿病合并中度肾损伤患者的有效性和安全性

选取2012年12月至2013年11月于天津医科大学代谢病医院和天津滨海新区解放路社区卫生服务中心门诊或住院治疗的胰岛素治疗且血糖控制不佳的中度肾损伤的2型糖尿病（T2DM）患者143例,在现有胰岛素不变的基础上加用维格列汀50 mg每日1次口服治疗12周.比较治疗前后糖化血红蛋白（HbA1c）、空腹血糖（FPG）、预估肾小球滤过率（eGFR）、血红蛋白（Hb）和胰岛素用量变化情况,评估用药后的不良事件以及患者和医师的满意度.132例患者完成12周维格列汀药物治疗.与治疗前相比,治疗后HbA1c降低0.7％,FPG降低了1.8 mmol/L,胰岛素用量减少了8.0U,治疗前后差异具有统计学意义[分别为：（8.4±0.8）％比（7.7±1.2）％,=7.515;（10.6±2.6）比（8.8±1.4） mmol/L,t =9.476;（51 ±16）比（43±15） U/d,t=4.421;均P＜0.05];Hb和eGFR治疗前后无差异（均P ＞0.05）.治疗中无胰腺炎、死亡等严重不良事件的发生.医师对于中度肾损伤患者应用维格列汀治疗的满意度达94.7％,患者自身的满意度为94.0％.胰岛素联合维格列汀50 mg每日1次可改善中度肾损伤患者的血糖水平,同时具有良好的耐受性和安全性.     

对2型糖尿病患者启动胰岛素治疗的思考

在2型糖尿病的治疗中尽早启动胰岛素治疗,是血糖达标的需要,也是保护胰岛β细胞、恢复其功能,从而延缓糖尿病进展的需要。初诊2型糖尿病患者经过3个月的生活方式干预和优化的口服降糖药物治疗血糖仍不能达标时,即应启动胰岛素治疗。对代谢紊乱严重、血糖水平较高的患者,应及时启动胰岛素强化治疗。可供选择的胰岛素治疗方案很多,各有优缺点和适应人群,临床上应当因患者而异地选择适宜的起始治疗方案。如何依据糖化血红蛋白（Hb）A1c选择起始治疗方案,目前尚无定论。推荐当HbA1c≤8．5％时主要选择基础胰岛素,HbA1c〉8．5％时选择预混胰岛素或基础—餐时或持续皮下胰岛素输注（CSII）作为起始胰岛素治疗方案。     

Effect of combination therapy with repaglinide and metformin hydrochloride on glycemic control in Japanese patients with type 2 diabetes mellitus

Aims/Introduction

We investigated the efficacy and safety of repaglinide as an add‐on therapy for Japanese patients with type 2 diabetes mellitus receiving metformin monotherapy (at a dose of 1,500 mg/day, mainly) in addition to diet and exercise.

Materials and methods

In the 16‐week multicenter, placebo‐controlled, randomized, double‐blind, parallel‐group trial (the phase III study), patients with type 2 diabetes mellitus with metformin monotherapy were randomly assigned to the repaglinide or placebo group. Thereafter, a 36‐week, multicenter, uncontrolled, dose‐titration method study was extended to a total duration of 52 weeks (the long‐term study). The primary end‐point of each study was a change in glycated hemoglobin (HbA_1c) from baseline.

Results

After 16 weeks, mean reductions in HbA_1c were significantly greater for the repaglinide group than for the placebo group (–0.98 ± 0.72% vs 0.13 ± 0.63%, P < 0.001). In the long‐term study, the mean change in HbA_1c was −0.76 ± 0.83%. The rate of adverse events was 60.6 and 50.0% in the repaglinide and placebo groups, respectively, in the phase III study, and 78.3% in the long‐term study. Hypoglycemia was reported in 11.7, 0 and 13.3% of patients in the repaglinide group, placebo group and long‐term study, respectively.

Conclusions

Combination therapy with repaglinide and metformin resulted in an approximately 1% reduction in HbA_1c at week 16 and in a significant long‐term improvement in HbA_1c at the end of the study. No safety problems were noted during the concomitant use of repaglinide and metformin. These studies were registered with JapicCTI (nos. JapicCTI‐101202 and JapicCTI‐101203).     

肥胖症患者和新诊断的2型糖尿病患者真胰岛素和前胰岛素的改变

目的 了解真胰岛素（ｔｒｕｅ ｉｎｓｕｌｉｎ,ＴＩ）和前胰岛素（ｐｒｏｉｎｓｕｌｉｎ,ＰＩ）在肥胖症和２型糖尿病患者中的改变,了解免疫活性胰岛素（ｉｍｍｕｎｏｒｅａｃｔｉｖｅ ｉｎｓｕｌｉｎ,ＩＲＩ）能否准确反映ＴＩ。方法 ３３例糖耐量正常（ＮＧＴ）,２４例糖耐量减低（ＩＧＴ）和５３例新诊断的２型糖尿病患者行口服葡萄糖耐量实验,并根据体重指数（ＢＭＩ）分为肥胖和非肥胖组;采用ＥＬＩＳＡ方法（其单克     

探讨初诊的老年2型糖尿病患者不同胰岛素治疗方案对远期血糖控制的影响

目的探讨仞诊的老年2型糖尿病不同治疗方案对远期预后的影响。方法选取初诊2型糖尿病患者105例,随机分为3组,即三餐前短效胰岛素加睡前中效胰岛素组、每日两次预混胰岛素加口服药组以及单独应用口服降糖药组。其中95例经过平均2—3W的治疗血糖达标,然后改为口服药治疗,观察1年后这些患者的血糖控制情况、胰腺功能、体重变化等。结果胰岛素治疗结束时三组血糖达标率分别是第1组97．1％;第2组94．3％;第3组80％,组间比较第3组与前两组差异有统计学意义,1年后血糖达标率分别是第1组91．2％,第2组为93．9％,第3组为85．0％,第3组与1、2组之间差异仍有统计学意义。前两组在血糖控制上差异无统计学意义。结论初始应用预混胰岛素或多次胰岛素注射两种方式对近期血糖控制和远期血糖控制效果相当,而预混胰岛素联合口服药组比较适合老年患者在门诊中应用。     

格列美脲治疗肥胖2型糖尿病的临床观察

目的观察肥胖T2DM患者联合应用格列美脲的临床疗效。方法选取76例血糖控制不佳的肥胖T2DM患者随机分为对照组和治疗组（联用格列美脲）,进行12周临床观察。结果两组平均HbA1c及空腹血糖、餐后血糖均显著下降,治疗组下降更为显著;治疗组空腹胰岛素（Fins）和HO—MA-IR较治疗前下降,体重、BMI及胰岛素用量均显著减少;治疗组有1例患者发生一般性低血糖事件1次,无其他不良反应。结论对于血糖控制不佳的肥胖T2DM患者早期联用格列美脲,可有效降低患者空腹血糖及餐后血糖水平,有利于患者实现HbA1c达标;同时可显著降低胰岛素用量,提高治疗安全性和耐受性。     

Starting patients with type 2 diabetes on insulin therapy using once-daily injections of biphasic insulin aspart 70/30, biphasic human insulin 70/30, or NPH insulin in combination with metformin

Transitioning safely to insulin therapy when oral antidiabetic agents fail to provide adequate glycemic control is a critical aspect of care for the patient with type 2 diabetes mellitus (T2DM). We evaluated the clinical effectiveness of starting patients on a relatively simple regimen of once-daily injections of either biphasic insulin aspart 70/30 (10 min before dinner), NPH insulin (at 10 p.m.), or biphasic human insulin 70/30 (30 min before dinner) in combination with metformin. Enrolled patients had T2DM and inadequate glycemic control (AlC≥7.5%) on a previous regimen of metformin as monotherapy or in combination with a sulphonylurea. One hundred and forty (140) patients received metformin monotherapy for 4 weeks followed by 12 weeks of combination treatment with metformin and once-daily insulin injections. AlC levels decreased from baseline by 1.1–1.3% for patients in each of the three treatment groups. Overall, FPG values decreased from baseline by 31% (biphasic insulin aspart), 37% (NPH insulin), and 28% (biphasic human insulin). Subjects whose final FPG level was <126 mg/dl experienced the largest decreases in AlC values (−2.3%, −1.9%, −1.8%, respectively). All three treatment regimens were well tolerated. The results indicate that patients with T2DM can safely and effectively begin insulin therapy using once-daily injections of biphasic insulin aspart 70/30, biphasic human insulin 70/30, or NPH insulin in combination with metformin.     

达格列净联合短期胰岛素强化治疗对初治2型糖尿病患者代谢指标的影响

目的探讨新诊断2型糖尿病（T2DM）患者在短期胰岛素强化治疗的基础上联用达格列净对代谢指标的影响。 方法入选2018年5月至2020年8月于东莞东华医院内分泌科住院的新诊断T2DM患者60例,随机分为试验组（短期胰岛素强化+达格列净）和对照组（短期胰岛素强化）,收集治疗前（d0）、血糖达标后14天（D14）及停药后随访第12周（W12）的资料,分析两组患者的代谢指标的变化。 结果两组患者的体重、体质量指数（BMI）及腰围在W12时仍出现明显下降,且试验组下降更显著;试验组的血尿酸（UA）在D14出现明显下降,但停药后明显回升,而对照组的UA治疗前后无明显变化;两组患者的甘油三酯（TG）、总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-C）在治疗后均出现明显下降,试验组高密度脂蛋白胆固醇（HDL-C）在停药后明显升高,而对照组治疗前后无明显变化。 结论对于新诊断的T2DM患者,在早期胰岛素强化降糖的同时加用达格列净治疗,可更显著减少体重、BMI、腰围,改善患者HDL-C等代谢指标。