Improved glycaemic control of thrice-daily biphasic insulin aspart compared with twice-daily biphasic human insulin; a randomized, open-label trial in patients with type 1 or type 2 diabetes

Aim:  This trial evaluated the potential for improving glycaemic control by intensifying a conventional twice-daily therapy with premixed human insulin (HI) to a thrice-daily regimen using premixed formulations of biphasic insulin aspart (BIAsp) in patients with type 1 or type 2 diabetes.
Methods:  This was a multicentre, open-label, parallel group trial. After a 4-week run-in period, patients were randomized 1 : 1 to 16 weeks of treatment. A total of 748 patients were screened, 664 were exposed to trial drug and 604 completed the trial.
Results:  Haemoglobin A_1c, the primary efficacy endpoint, was shown to be significantly lower for the BIAsp treatment group compared with the biphasic HI (BHI) 30 group [estimated mean difference: −0.32, 95% confidence interval (CI) (−0.48; −0.16), p = 0.0001]. The average blood glucose level was significantly lower in the BIAsp group [estimated mean difference: −0.79, 95% CI (−1.17; −0.40), p = 0.0001]. There were few major hypoglycaemic episodes, 11 in the BIAsp group and 7 in the BHI 30 group. Although intensification of insulin therapy with BIAsp three times a day was associated with a higher risk of minor hypoglycaemia (relative risk = 1.58, p = 0.0038), the overall rate of minor hypoglycaemia remained low with both the BIAsp and the BHI treatments (13.1 vs. 8.3 episodes/patient year respectively). Overall safety and patient satisfaction were similar with the two insulin therapies.
Conclusions:  This trial confirmed that a thrice-daily BIAsp regimen can safely be used to intensify treatment for patients inadequately controlled on twice-daily BHI. A treat-to-target trial is required to explore the full potential of the BIAsp regimens and evaluate their use as a viable alternative to intensification with a basal-bolus regimen.     

2型糖尿病持续皮下胰岛素输注治疗后应用诺和锐30与诺和灵30R疗效对比

目的：观察比较持续皮下胰岛素输注（CSⅡ）治疗后的2型糖尿病患者改用诺和锐30和诺和灵30R治疗的临床疗效。方法：将60例经CSⅡ治疗后血糖达标（空腹血糖〈7mmol／L，餐后2小时血糖〈10mmol／L）的2型糖尿病患者随机分成诺和锐30组和诺和灵30R组各30例，观察12周内两种不同治疗方案患者空腹血糖（FBG）、早餐后2h血糖（2hPBG）、胰岛素剂量变化及低血糖发生的情况。结果：诺和锐30组全天所需药物的剂量较诺和灵30R减少约10％（P〈0．05）。结论：诺和锐30能减少胰岛素的用量；提高患者的依从性和满意度。     

Assay of insulin-like activity by the isolated fat cell method IV. The biological activity of proinsulin

Summary The effect of bovine proinsulin and related factors on the glucose metabolism of isolated, rat, fat cells was studied. The dose-response curve of proinsulin was parallel to that of insulin and the action of the two proteins showed an identical time course. The activity of single chain proinsulin was about 0.5 U/mg (as estimated from its ability to increase the conversion of¹⁴C-glucose to¹⁴CO₂ or to¹⁴C-glycerides by fat cells) and rose to about 17 U/mg after treatment with trypsin. — The activity of insulin was quantitatively recovered in the presence of proinsulin. Split chain proinsulin showed an activity of 5 U/mg, which rose to about 18 U/mg after treatment with trypsin. Connecting peptide did not influence the glucose metabolism in the absence or presence of insulin. — There was no conversion of proinsulin in the isolated cell incubation medium to insulin or a similar molecule with high biological activity. The activity was the same on rat epididymal fat pads as on isolated fat cells, and there was no significant suppression by Kunitz pancreatic trypsin inhibitor in either system. — The following was concluded: the biological activity of proinsulin on rat isolated fat cells and epididymal fat pads is about 2 per cent of that of insulin, and the effect is caused by the proinsulin molecule itself. The reason for the low biological activity is presumably a smaller affinity for insulin receptors.

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Untersuchungen der Insulinähnlichen Aktivität an isolierten Fettzellen. IV. Die biologische Aktivität von Proinsulin

Zusammenfassung Die Wirkung von Rinderproinsulin und verwandter Faktoren auf den Glucosestoffwechsel von isolierten Ratten-Fettzellen wurde untersucht. Die Dosis-Wirkungskurve von Proinsulin verlief parallel zu der von Insulin, und die Einwirkung beider Proteine zeigte einen identischen Zeitablauf. Die Aktivität von einkettigem Proinsulin betrug etwa 0.5 E/mg (wie aus seiner Fähigkeit geschlossen wurde, die Umwandlung von¹⁴C-Glucose in¹⁴CO₂ oder¹⁴C-Glyceride in Fettzellen zu steigern), und erhöhte sich nach Trypsinbehandlung a,uf etwa 17 E/mg. — In Gegenwart von Proinsulin ließ sich die Aktivität von Insulin quantitativ wiederfinden. Proinsulin mit gesprengter Kette wies eine Aktivität von 5 E/mg auf, die nach Trypsinandauung auf 18 E/mg anstieg. C-Peptid beeinflußte den Glucosestoffwechsel weder mit noch ohne Insulinzusatz. — In der Inkubationsflüssigkeit von isolierten Zellen ließ sich keine Umwandlung von Proinsulin in Insulin oder ein ähnliches Molokül mit hoher biologischer Aktivität nachweisen. Aktivitätsmessungen am Ratten-Nebenhoden-Fettgewebsanhang erbrachten die gleichen Resultate wie an isolierten Fettzellen, und der Kunitz-Pankreas-Trypsin-Inhibitor führte in keinem der beiden Systeme zu einer signifikanten Hemmung. — Es wurden folgende Schlüsse gezogen: Proinsulin weist an isolierten Ratten-Fettzellen und am epididymalen Fettgewebsanhang der Ratte etwa 2% der biologischen Aktivität von Insulin auf, und der Effekt wird durch das ProinsuIin-Molekül selbst hervorgerufen. Der Grund für die niedrige biologische Aktivität ist vermutlich in einer geringeren Affinität zu den Insulin-Receptoren zu suchen.

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Dosage de l'activité insulinique par la méthode des cellules adipeuses isolées. IV. L'activité biologique de la proinsuline

Résumé L'effet de la proinsuline bovine et de facteurs analogues sur le métabolisme glucidique de cellules adipeuses isolées de rat a été étudié. La courbe dose-réponse de la proinsuline était paralléle à celle de l'insuline et l'action des deux protéines montrait une évolution dans le temps identique. L'activité de la proinsuline à chaîne unique était d'environ 0.5 U/mg (calculée d'aprés sa capacité à augmenter la conversion de glucose-¹⁴C en¹⁴CO₂ ou en glycérides¹⁴C par des cellules adipeuses) et montait à environ 17 U/mg aprés traitement avec de la trypsine. L'activité de l'insuline a été retrouvée quantitativement en présence de pro insuline. Laproinsuline à chaîne rompue montrait une activité de 5 U/mg qui s'élevait à 18 U/mg aprés traitement par la trypsine. Le polypeptide de connexion n'influençait pas le métabolisme glucidique avec ou sans insuline. Dans le milieu d'incubation, il n'y avait pas de conversion de proinsuline en insuline ou en une molécule comparable avec une activité biologique élevée. L'activité était la même avec du tissu adipeux épididymaire de rat qu'avec des cellules adipeuses isolées et il n'y avait pas de suppression significative par l'inhibiteur de trypsine pancréatique de Kunitz dans aucun des deux systémes. Nous sommes arrivés aux conclusions suivantes: L'activité biologique de la proinsuline sur des cellules adipeuses isolées du rat et sur le tissu adipeux épididymaire correspond à environ 2% de celle de l'insuline et l'effet est causé par la molécule de proinsuline elle-même. La raison pour cette activité biologique basse est probablement une affinité réduite pour les récepteurs de l'insuline.

     

An economic assessment of analogue basal–bolus insulin versus human basal–bolus insulin in subjects with type 1 diabetes in the UK

ABSTRACT

Background: A recent study demonstrated that treatment of type 1 diabetes with an analogue basal–bolus insulin regimen was associated with improved glycaemic control (HbA_1c –0.22% points, p < 0.001), reduced risk of hypo­glycaemic events (–21%, p = 0.036) and reduction in body mass index (–0.30?kg/m², p < 0.001) compared to a human basal–bolus regimen after 18 weeks.

Methods: A published and validated computer simulation model was used to project long-term economic and clinical outcomes in a simulated cohort of type 1 diabetes patients treated with either insulin detemir plus insulin aspart (analogue) or Neutral Protamine Hagedorn plus human soluble insulin (human), in a UK setting. Probabilities of complications and HbA_1c-dependent adjustments were derived from major clinical and epidemiological studies. Complication and treatment costs were projected over patient lifetimes from a National Health Service perspective. Costs and clinical benefits were discounted at 3.5% annually.

Results: Quality-adjusted life expectancy (QALE) was 0.66 quality-adjusted life years (QALY) higher in the analogue insulin versus the human insulin group (mean ± SD) (7.65 ± 0.09 versus 6.99 ± 0.08). Direct lifetime costs were £1654 greater with analogue versus human insulin treatment (£40?876 ± 1119 versus £39?222 ± 1141), producing an incremental cost effectiveness ratio (ICER) of £2500 per QALY gained. Sensitivity analyses showed the results were robust under a range of plausible scenarios.

Conclusions: Treatment with analogue insulin was associated with a decreased incidence of long-term complications and improved QALE, but slightly higher treatment costs compared to human insulin therapy. Analogue insulin treatment had an ICER within the range generally considered to represent good value for money in the UK.     

预混门冬胰岛素30和预混人胰岛素30R治疗2型糖尿病的临床比较

目的 探讨每日2次注射预混门冬胰岛素30(诺和锐30特充)和预混人胰岛素30R(诺和灵30R)治疗口服降糖药效果不佳的2型糖尿病的疗效及低血糖风险.方法 68例经口服降糖药物控制不佳的2型糖尿病患者,根据入院先后按11比例随机分为诺和锐30组和诺和灵30R组.入选病例在继续服用除胰岛素促泌剂以外的口服降糖药的基础上,分别采用每日早晚餐前注射诺和锐30和诺和灵30R,进行为期12周的观察.比较12周后两组HbA1c、八点血糖及曲线下面积、日均血糖和低血糖发生频率等.结果 ①两组治疗后空腹血糖、HbA1c均显著下降,提示诺和锐30和诺和灵30R治疗2型糖尿病均有效.②诺和锐30组的早晚餐后2 h、中餐前、睡前血糖均显著低于诺和灵30R组(P＜0.01),日均血糖和八点血糖曲线下面积也有所改善.③诺和锐30组低血糖发生次数低于诺和灵30R组,但差异无统计学意义(P＞0.05),诺和锐30组无严重低血糖发生.结论 对于2型糖尿病患者,每日两次注射诺和锐30较诺和灵30R能更明显地降低餐后血糖、日均血糖及减少低血糖风险,同时更易于为患者接受.     

门冬胰岛素注射液强化治疗对急诊经皮冠状动脉介入治疗后急性心肌梗死并应激性高血糖患者的影响

目的探讨门冬胰岛素注射液强化治疗对急诊经皮冠状动脉介入治疗(PCI)后急性心肌梗死(AMI)并应激性高血糖(SHG)患者的影响。方法选取2017年12月—2018年12月河北北方学院附属第二医院心内科收治的急诊PCI后AMI并SHG患者106例,根据胰岛素治疗方案分为对照组和观察组,每组53例。两组患者急诊PCI后均接受标准AMI药物治疗和内科综合治疗,对照组患者PCI后随机血糖>18.0 mmol/L时给予门冬胰岛素注射液皮下注射,观察组患者PCI后立即采用微量泵持续静脉泵注门冬胰岛素注射液,同时每晚睡前给予甘精胰岛素皮下注射;两组患者均连续治疗7 d。比较两组患者PCI后无复流发生情况及心肌灌注情况〔包括ST段抬高总和回落百分比(sumSTR)、TIMI心肌组织灌注分级(TMPG)、肌酸激酶同工酶(CK-MB)峰值〕,PCI前及PCI后7 d炎性因子〔包括白介素16(IL-16)和白介素18(IL-18)〕,PCI前及PCI后7、30 d左心功能指标〔包括左心室射血分数(LVEF)、左心室舒张末容积指数(LVEDVI)、左心室收缩末容积指数(LVESVI)〕,并记录两组患者治疗期间不良心血管事件发生情况。结果观察组患者PCI后无复流发生率低于对照组(P<0.05)。观察组患者PCI后sumSTR>50%者所占比例及CK-MB峰值高于对照组,TMPG优于对照组(P<0.05)。观察组患者PCI后7 d血清IL-16、IL-18水平低于对照组(P<0.05)。时间与方法在LVEF、LVESVI、LVEDVI上无交互作用(P>0.05),时间、方法在LVEF、LVESVI、LVEDVI上主效应显著(P<0.05)。观察组患者PCI后7、30 d LVEF高于对照组,LVESVI、LVEDVI小于对照组(P<0.05)。两组患者治疗期间不良心血管事件发生率比较,差异无统计学意义(P>0.05)。结论门冬胰岛素注射液强化治疗可有效减少急诊PCI后AMI并SHG患者无复流的发生,改善患者心肌灌注及左心功能,减轻炎性反应,且安全性较高。     

Comparison of insulin analogue regimens in people with type 2 diabetes mellitus in the PREFER Study: a randomized controlled trial

Aims:  Insulin analogues are widely used but few data exist comparing different analogue regimens. We compared two such regimens in type 2 diabetes mellitus (T2DM) uncontrolled by oral antidiabetic agents (OADs) with or without basal insulin.
Methods:  In a 26-week multinational, multicentre, randomized treat-to-target trial, OADs were discontinued and subjects randomized to analogue basal–bolus therapy (insulin detemir once daily and insulin aspart mealtimes) or biphasic insulin aspart 30 (30% rapid-acting insulin aspart), twice daily. Insulin was titrated to targets for fasting, predinner and postprandial plasma glucose (PG), as appropriate.
Results:  Of 719 subjects, 92% completed the study; 58% achieved haemoglobin fraction A_1c (HbA_1c) ≤7.0%, with reductions of 1.56% (to 6.96%) with basal–bolus therapy and 1.23% (to 7.17%) with biphasic insulin aspart. Reduction with basal–bolus therapy was superior in the overall population by 0.23% (p = 0.0052), with no difference between regimens in insulin-naive patients. Major hypoglycaemia occurred in five basal–bolus patients (0.9%) and in no patients with biphasic insulin aspart. Incidence of minor hypoglycaemia was similar in both groups. All insulin doses increased during titration, with increase in lunchtime insulin aspart dose and equal distribution of breakfast and dinner biphasic insulin aspart doses. Insulin detemir remained once daily in 87% of patients.
Conclusions:  Modern insulin analogue regimens, adjusted to PG targets, enable a majority of people with T2DM to reach HbA_1c≤7.0% after failure of OADs and OAD-basal insulin therapy. Insulin-treated patients may benefit more from transfer to analogue basal–bolus therapy, while insulin-naive individuals benefit equally well from the more convenient biphasic analogue regimen.     

2型糖尿病精氨酸刺激后胰岛素原的释放及其与血糖的关系

目的探讨2型糖尿病(T2DM)患者精氨酸刺激后胰岛素原(PI)释放的变化及其与血糖水平的关系。方法选择2001年11月至2003年8月上海交通大学附属第六人民医院的106例T2DM患者及35名正常糖耐量(NGT)健康对照者行精氨酸刺激试验,分析比较精氨酸刺激试验后PI及其增值(ΔPI)和PI/[真胰岛素(TI) PI]的变化。结果(1)T2DM组精氨酸刺激后各时间点PI、PI/(TI PI)值显著高于NGT组(P均<0.01),其PI在2min时达峰值,随后呈逐渐下降趋势。(2)不同空腹血糖(FPG)的T2DM患者各时间点PI、PI/(TI PI)分析显示FPG2组(7mmol/L≤FPG<9mmol/L)和FPG3组(FPG≥9mmol/L)明显高于FPG1组(FPG<7mmol/L,P均<0.05)。结论精氨酸刺激后PI“不成比例”增加是T2DM患者胰岛B细胞功能缺陷的重要表现之一,因此在比较T2DM与NGT人群胰岛B细胞功能时应测定TI以减少PI的干扰。     

血清瘦素水平与胰岛素原、真胰岛素及胰岛素敏感性的关系

目的　研究中国人群空腹瘦素水平与真胰岛素 (TI)、胰岛素原 (PI)、PI/TI比值及胰岛素敏感性之间的关系。方法　 90 2例非糖尿病者均系 2 0 0 0年接受糖尿病流行病学调查者。测定空腹瘦素、TI和PI浓度以及空腹及餐后 2h血糖。瘦素、TI及PI检测采用本室建立的特异的酶联免疫分析法 (ELISA)。胰岛素敏感性以HOMA胰岛素抵抗指数 (HOMA IR)评价。结果　血清瘦素水平女性高于男性。相关分析显示血清瘦素水平与空腹TI、PI及HOMA IR显著正相关 (男性 792例 ,r分别为0 345、0 2 36和 0 364 ;女性 1 1 0例 ,r分别为 0 574、0 375和 0 576 ,P <0 0 0 1 ) ,但与空腹血糖仅在男性呈弱相关 (r=0 1 5 ,P =0 0 1 5) ,与空腹PI/TI比值不相关。在调整年龄、体重指数 (BMI)和腰臀围比(WHR)后 ,尽管相关性减弱 ,瘦素水平仍然与TI、PI以及HOMA IR显著相关。结论　本组的血清瘦素浓度与TI、PI以及胰岛素抵抗显著正相关 ,且在一定程度上独立于肥胖和脂肪分布。瘦素水平高或瘦素抵抗的个体可能存在高胰岛素血症和胰岛素抵抗 ,提示其瘦素 胰岛素轴的调节异常。本研究未发现瘦素水平与空腹PI/TI比值的相关 ,提示瘦素可能与这一反映胰岛 β细胞的功能异常的标志无关。本研究揭示的高瘦素 高胰岛素血症或胰岛素抵抗之间的