Comparative pharmacokinetics and pharmacodynamics of the novel rapid-acting insulin analogue, insulin aspart, in healthy volunteers

Objective: The pharmacokinetics of a new insulin analogue, insulin aspart, were compared with unmodified human insulin in a double-blind crossover study of 25 fasting healthy men following a single subcutaneous dose. Methods: Either insulin aspart or human insulin, 0.1 U · kg-body-weight⁻¹, was injected subcutaneously and followed by determination of 8-h profiles of serum insulin and plasma glucose concentrations. Results: The absorption of insulin aspart was, on average, more than twice as fast and reached levels more than twice as high compared with human insulin [t_max(ins) of 52 (23) vs 145 (93) min, P < 0.0001; and C_max(ins) of 41 (11) vs 18 (4) mU · l⁻¹, P < 0.0001; mean with (SD)]. However, total bioavailability did not differ between the insulins, and thus the mean residence time was significantly shorter for insulin aspart [MRT_(ins) of 149 (26) vs 217 (30) min, P < 0.0001]. Plasma glucose (PG) fell more than twice as rapidly [t_min(PG) of 94 (45) vs 226 (120) min, P < 0.0001], to a greater extent [C_min(PG) 2.1 (0.6) vs 1.4 (0.4) mmol · l⁻¹, P < 0.0001], and for a shorter duration with insulin aspart than with human insulin. Conclusion: With improved subcutaneous absorption characteristics, the insulin aspart concentration–time profile resembles physiological meal-stimulated insulin release more closely than that of unmodified human insulin. This significantly alters the pharmacodynamic response in an advantageous manner in the meal-related treatment of diabetes mellitus. Received: 26 October 1998 / Accepted in revised form: 23 January 1999     

预混门冬氨酸胰岛素治疗2型糖尿病临床观察

目的观察预混门冬氨酸胰岛素30/70(降血糖药)对2型糖尿病的疗效与安全性。方法选初诊或单用口服降糖药物治疗血糖控制不佳的2型糖尿病患者116例,随机分为2组:预混门冬氨酸胰岛素30/70(治疗组)60例,精蛋白生物合成人胰岛素30/70(对照组)56例,观察各时段血糖变化。结果2组在强化血糖达标后,早、中、晚餐后30,60,120min血糖比较均有显著性差异(P<0.0001~0.020);且治疗组HbA1C下降更显著(P<0.05)。血糖控制后24h的胰岛素用量,治疗组较对照组减少约20%(P<0.05)。结论预混门冬氨酸胰岛素30/70降餐后血糖和HbA1C明显优于精蛋白生物合成人胰岛素30/70。     

预混门冬胰岛素30和预混人胰岛素30R治疗2型糖尿病疗效比较

目的比较预混门冬胰岛素30和预混人胰岛素30R疗效及安全性。方法采用每天2次的注射方案,选取口服药控制不佳的2型糖尿病患者48例,随机分为预混门冬胰岛素30治疗组和预混人胰岛素30R治疗组进行12周的比较,观察2种不同治疗方案对2型糖尿病患者糖化血红蛋白、4个时点的血糖（空腹及3餐后2h）、低血糖发生的治疗结果。结果预混门冬胰岛素30治疗组的糖化血红蛋白（HbAlc）明显低于预混人胰岛素30R治疗组,预混门冬胰岛素30治疗组早餐、晚餐后2h及空腹血糖低于预混人胰岛素30R治疗组,中餐后2h血糖与预混人胰岛素30R治疗组相似,预混门冬胰岛素30治疗组低血糖发生率低于顸混人胰岛素30R治疗组。结论预混门冬胰岛素30在疗效及安全性更优于预混人胰岛素30R。     

双时相门冬胰岛素30与预混人胰岛素30R治疗2型糖尿病的疗效比较

目的比较分析双时相门冬胰岛素30与预混人胰岛素30R在2型糖尿病的临床治疗效果及安全性。方法选择口服药物降糖效果差的2型糖尿病患者68例作为研究对象,随机分为双时相门冬胰岛素组34例与预混人胰岛素组34例,观察两组别的临床疗效、日均胰岛素用量及低血糖的发生率。结果双时相门冬胰岛素组、预混人胰岛素组治疗前后的FBG、2hPBG、HbA1c经t检验分析,统计学差异均有统计学意义(P<0.001);两组别间治疗后FBG、2hPBG、HbA1c经t检验分析均差异有统计学意义(P<0.05)。两组别的日均胰岛素用量、低血糖的发生次数经t检验分析,差异有统计学意义(P<0.05)。结论双时相门冬胰岛素30相对预混人胰岛素30R速效,日均胰岛素用量比较少,低血糖发生率较少,安全性高。     

门冬胰岛素30致局限性脂肪萎缩

1例52岁女性2型糖尿病患者，先后用门冬胰岛素和精蛋白锌胰岛素治疗。3个月后，改为门冬胰岛素30皮下注射（剂量不详）。约1个月后，患者的注射部位出现皮疹伴瘙痒，持续2—3h后消退。约2个月后，患者的前臂和腹部注射部位出现局限性脂肪萎缩区，直径1—4cm，停用门冬胰岛素30，改为口服那格列奈60mg，2次／d。1年后，患者的脂肪萎缩区基本消失。     

Predictors of achieving HbA1c <7% and no hypoglycaemia 6 months after initiation of biphasic insulin aspart 30 in patients with type 2 diabetes in the IMPROVE study

Abstract

Background:

Early initiation of insulin therapy has widely been associated with numerous benefits, including improved glycaemic control and reduced long-term risk of developing microvascular diseases. Biphasic insulins offer a convenient option for insulin initiation, addressing both basal and postprandial insulin requirements with one injection, making them relatively simple for patients to dose. Development of biphasic insulin aspart (BIAsp) has further offered improved postprandial glycaemic control and lower rates of nocturnal and major hypoglycaemia than biphasic human insulin.     

门冬胰岛素30与精蛋白生物合成人胰岛素30R对2型糖尿病治疗效果比较

目的研究门冬胰岛素30(诺和锐30)与精蛋白生物合成人胰岛素30R(预混30R)治疗2型糖尿病(T2DM)的效果。方法选取某院T2DM患者92例(2017年1月~2019年1月),按照治疗方法分为A组、B组,各46例。A组采用诺和锐30治疗,B组采用预混30R治疗。比较两组治疗前、治疗3个月后血糖[空腹血糖(FBG)、餐后2 h血糖(2hPBG)、睡前血糖、糖化血红蛋白(HbA1c)]水平、不良反应及低血糖发生率。结果治疗3个月后A组FBG、2hPBG、睡前血糖、HbA1c水平均低于B组(P<0.05);A组不良反应总发生率为8.70%,B组不良反应总发生率为17.39%,组间比较差异无统计学意义(P>0.05);A组低血糖发生率4.35%低于B组17.39%(P<0.05)。结论与精蛋白生物合成人胰岛素30R对比,门冬胰岛素30治疗T2DM能显著降低血糖水平及低血糖发生率,二者安全性高。     

Transferring type 2 diabetes patients with uncontrolled glycaemia from biphasic human insulin to biphasic insulin aspart 30: experiences from the PRESENT study

ABSTRACT

Aim: The Physician's Routine Evaluation of Safety and Efficacy of NovoMix* 30 Therapy (PRESENT) aims to assess the safety and efficacy of biphasic insulin aspart (BIAsp30) used in routine clinical practice.

Methods: This was a large, multi-national, multi-centre, prospective, 6-month study in type 2 diabetes mellitus patients who were prescribed BIAsp30. Efficacy endpoints included changes in HbA_1c, fasting plasma glucose (FPG), postprandial plasma glucose (PPPG), and proportion who achieved target HbA_1c <?7%. Changes from baseline were analysed using paired t-test. Safety endpoints were incidence and rate of hypoglycaemic episodes. A subgroup of patients previously uncontrolled (HbA_1c ≥?7.0%) on biphasic human insulin (BHI) were analysed.

Results: Glycaemia improved significantly (mean ± SD): HbA_1c by 1.58 ± 1.69% points (from 9.32 ± 1.64% to 7.70 ± 1.29%), FPG by 2.92 ± 3.71?mmol/L and PPPG by 4.75 ± 4.87?mmol/L. The incidence of hypoglycaemic episodes decreased over time, from 38.7% (baseline) to 20.8% (6?months). Episodes were mostly minor (reduced from 37.7 to 20.6% at 6?months), occurring during the day (reduced from 31.5 to 17.1% at 6?months). Major episodes were less frequently reported (reduced from 5.0 to 0.4% at 6?months). The rate of hypoglycaemia (episodes/patient year) from baseline to end of study decreased over time for overall (8.9–2.2), major (0.7–0.1), minor (8.2–2.2) and nocturnal (2.9–0.5) episodes.

Conclusions: In this observational study, in the type 2 diabetes mellitus patients who were poorly controlled on BHI, glycaemia improved when transferred to BIAsp30, and a lower incidence or rate of hypoglycaemia was observed in these patients.     

Systematic review of the cost-effectiveness of biphasic insulin aspart 30 in type 2 diabetes

Abstract

Objectives:

To review the cost-effectiveness of biphasic insulin aspart (BIAsp 30) compared to other insulin regimens in the treatment of type 2 diabetes based on published literature.     

Comparative effect of human soluble insulin and insulin aspart upon hypoglycaemia-induced alterations in cardiac repolarization

AIMS: Sudden death in young diabetic patients has been associated with nocturnal hypoglycaemia perhaps as a result of cardiac dysrhythmias following abnormal cardiac repolarization during hypoglycaemia. It was therefore important to compare the effect of soluble human insulin (HI) and a rapid-acting insulin analogue, insulin aspart (IAsp), on these aspects of cardiac function. METHODS: A total of 17 healthy males underwent identical hyperinsulinaemic hypoglycaemic clamps with blood glucose maintained at 5 mm for 30 min and reduced to 2.5 mm after an additional 30 min. Subjects received either HI or IAsp on two different occasions separated by 4-6 weeks. Regular measurements were made of two measures of cardiac repolarization, QT dispersion and QTc as well as of counter-regulatory hormones. RESULTS: The blood glucose lowering effect did not differ between IAsp and HI and the clearance rates were similar (HI mean +/- SD 1.24 +/- 0.12 l h(-1) kg(-1), IAsp mean +/- s.d. 1.22 +/- 0.32 l h(-1) kg(-1)). There were similar significant increases but no difference between treatments in QTc after hypoglycaemia induced by either IAsp or HI (480 +/- 37 ms vs 480 +/- 25 ms; NS). However, QT dispersion during hypoglycaemia was less pronounced with IAsp than with HI (92 +/- 36 ms vs 107 +/- 42 ms; P < 0.05). Plasma adrenaline increased significantly and similarly after both insulins (initial and final concentration, HI, 0.23 +/- 0.01 to 4.87 +/- 0.48 nm, P < 0.001, IAsp, 0.24 +/- 0.01 to 4.99 +/- 0.48 nm, P < 0.001). Serum potassium decreased significantly but by a similar amount between the groups (initial and final concentration, HI, 4.18 +/- 0.3 to 4.2 +/- 0.2 mm, P < 0.001, IAsp, 4.2 +/- 0.3 to 4.2 +/- 0.3 mm, P < 0.001). CONCLUSIONS: Soluble human insulin and insulin aspart had similar effects upon hypoglycaemia-induced alterations in cardiac repolarization, presumably because the effects of both regular insulin and insulin aspart on the sympathoadrenal response and potassium concentration were the same.     

Pharmacokinetics and pharmacodynamics of insulin aspart in patients with Type 2 diabetes: assessment using a meal tolerance test under clinical conditions

1. Few studies have evaluated the pharmacokinetics of rapid-acting insulin analogues in patients with Type 2 diabetes, especially under clinical conditions. The aim of the present study was to assess both the pharmacokinetics and pharmacodynamics of insulin aspart in Type 2 diabetic patients who were being treated with the analogue alone. 2. Meal tolerance tests with and without self-injection of a customary dose of insulin aspart (0.05-0.22 U/kg) were conducted in 20 patients in a randomized cross-over study. 3. The dose of insulin aspart (per bodyweight) was significantly correlated with both the maximum concentration (r(2) = 0.59; P < 0.01) and area under the concentration-time curve for insulin aspart (r(2) = 0.53; P < 0.01). However, the time to maximum concentration (T(max)), which varied widely from < 60 to ≥ 120 min, was not associated with either dosage (r(2) = 0.02; P = 0.51) or body mass index (r(2) = 0.02; P = 0.57). Injection of insulin aspart exacerbated delayed hyperinsulinaemia after meal loading, mainly in patients with T(max) ≥ 120 min. With regard to pharmacodynamics, insulin aspart had favourable effects on postprandial hyperglycaemia, hyperglucagonaemia and hyperlipidaemia. 4. The T(max) for this insulin analogue differed greatly between individuals and delayed hyperinsulinaemia was particularly exacerbated in patients with higher T(max) values. Identification of the factors contributing to interindividual variation in the absorption lag time is essential for improving the efficacy and safety of insulin aspart.     

门冬胰岛素治疗妊娠糖尿病的临床效果观察

目的观察门冬胰岛素治疗妊娠糖尿病的临床效果。方法选取60例妊娠糖尿病患者,随机分为对照组与观察组,每组各30例。对照组给予常规人胰岛素三餐前30min皮下注射治疗;治疗组给予门冬胰岛素早晚餐前5min皮下注射治疗。比较两组的FPG、2hPG、HbA1c的控制情况及血糖达标时间、胰岛素日用量、低血糖发生率。结果治疗后,两组的FPG、2hPG、HbA1c均较治疗前明显降低;治疗组FPG、2hPG、HbA1c均低于对照组（P〈0．05）;治疗组血糖达标时间明显短于对照组,胰岛素用量较对照组低,且低血糖发生率较对照组低（P〈0．05）;两组的母婴结局比较,差异无统计学意义（P〉0．05）。结论门冬胰岛素治疗妊娠糖尿病,疗效确切,安全性可靠,对母婴结局有重要的意义。值得临床推广。     

Cost-effectiveness of insulin aspart versus human soluble insulin in type 2 diabetes in four European countries: subgroup analyses from the PREDICTIVE study

ABSTRACT

Objectives: To evaluate the long-term health economic outcomes associated with insulin aspart (IAsp) compared to human soluble insulin (HI) in type 2 diabetes patients on basal-bolus therapy in Sweden, Spain, Italy and Poland.

Methods: A published computer simulation model of diabetes was used to predict life expectancy, quality-adjusted life expectancy and incidence of diabetes-related complications. Baseline cohort characteristics (age 61.6 years, duration of diabetes 13.2 years, 45.1% male, HbA_1c 8.2%, BMI 29.8?kg/m²) and treatment effects were derived from the PREDICTIVE observational study. Country-specific complication costs were derived from published sources. The analyses were run over 35-year time horizons from third-party payer perspectives in Spain, Italy and Poland and from a societal perspective in Sweden. Future costs and clinical benefits were discounted at country-specific discount rates. Sensitivity analyses were performed.

Results: IAsp was associated with improvements in discounted life expectancy and quality-adjusted life expectancy, and a reduced incidence of most diabetes-related complications versus HI in all four settings. IAsp was associated with societal cost-savings in Sweden (SEK 2470), direct medical cost-savings in Sweden and Spain (SEK 8248 and €1382, respectively), but increased direct costs in Italy (€2235) and Poland (€743). IAsp was associated with improved quality-adjusted life expectancy in Sweden (0.077 QALYs), Spain (0.080 QALYs), Italy (0.120 QALYs) and Poland (0.003 QALYs).

Conclusions: IAsp was dominant versus HI in both Sweden and Spain, would be considered cost-effective in Italy with an incremental cost-effectiveness ratio of €18?597 per QALY gained, but would not be considered cost-effective in Poland.     

Once-daily initiation with biphasic insulin aspart 30 versus insulin glargine in patients with type 2 diabetes inadequately controlled with oral drugs: an open-label,multinational RCT

Abstract

Objectives:

To assess the efficacy and safety of biphasic insulin aspart 70/30 (BIAsp 30) and insulin glargine, administered once daily in subjects with type 2 diabetes inadequately controlled with oral anti-diabetic drugs.     

Insulin aspart: a novel rapid-acting human insulin analogue

In order to improve therapy and increase the quality of life for diabetic patients, it has been of significant interest to develop rapid-acting insulin preparations that mimic the physiological meal-time profile of insulin more closely than soluble human insulin. Insulin aspart (B28Asp human insulin) is a novel rapid-acting insulin analogue that fulfils this criterion. The B28Asp modification weakens the self-association of the insulin molecule and provides a more rapid absorption from the sc. injection site. The preclinical evaluation in vitro and in vivo demonstrates that apart from the more rapid absorption, insulin aspart is equivalent to human insulin. Thus, insulin aspart is equivalent to human insulin on key in vitro parameters such as insulin receptor affinity, insulin receptor dissociation rate, insulin receptor tyrosine kinase activation, IGF-I receptor binding affinity, metabolic and mitogenic potency. In accordance with the equivalent in vitro profiles, the toxico-pharmacological properties of insulin aspart and human insulin are also identical. The available data for insulin aspart and other rapid-acting insulin analogues supports that in vitro assays are sensitive and valuable in the preclinical evaluation of insulin analogues. Clinical studies demonstrate that insulin aspart has a pharmacokinetic and pharmacodynamic profile superior to that of soluble human insulin. In Type 1 diabetic patients on a basal-bolus injection regimen, insulin aspart given immediately before the meals provides an improved postprandial glycaemic control and an improved long-term metabolic control, as compared to soluble human insulin given 30 min before the meals, without increasing the risk of hypoglycaemia. Taken together, the data support the hope that insulin aspart will allow the diabetic patient to combine a more flexible lifestyle with better glycaemic control, without any increased safety risk.     

甘精胰岛素联合格列美脲与诺和锐30治疗2型糖尿病的疗效比较

目的比较甘精胰岛素联合格列美脲与诺和锐30治疗口服降糖药未达标的2型糖尿病患者的疗效。方法135例血糖控制未达标的2型糖尿病患者。随机分为甘精胰岛素联合格列美脲组（68例）与诺和锐30治疗组（67例）,观察两组治疗前后血糖及HbA1c变化,以及低血糖的发生率。结果两组各监测点血糖及HbA1c治疗后与治疗前比较均明显下降（P〈0．01）,治疗后两组间比较无明显差异;低血糖发生无明显差异（P〉0．05）。结论甘精胰岛素联合格列美脲与诺和锐30都能有效控制血糖,两组低血糖发生率低且相近。     

125I used for labelling of proteins in an absorption model changes the absorption rate of insulin aspart

The aim of this study is to validate the ability of the disappearance model to predict absorption rates of insulin aspart in pigs. The disappearance model is used as a screening tool to estimate absorption rates after subcutaneous injections in humans or pigs especially of insulin and insulin analogues. The disappearance model measures remaining radioactivity at the injection site and therefore radioactive labelling of the insulin analogue is necessary. The labelling is done with ¹²⁵I. One of the assumptions for the disappearance model to be reliable is that absorption rates of the labelled and non-labelled molecules are comparable. In this study, we compared disappearance data with absorption calculated from plasma samples of insulin aspart. The calculated absorption is based on non-labelled insulin aspart. The absorption rate from the disappearance data was statistical significant (p = 0.0028) different from the absorption rate based on plasma samples. A control study was carried out where ¹²⁵I labelled insulin aspart was compared to ¹²⁷I (the natural non-radioactive isotope) insulin aspart. In this study, absorption rate from the disappearance data and absorption rate based on plasma samples were similar (p = 0.63). Conclusion: Iodination of insulin aspart changes the subcutaneous absorption rate.     

诺和锐30对初诊2型糖尿病的疗效观察

目的观察每日3次诺和锐30对初诊2型糖尿病的疗效。方法选择许昌市中心医院2009年10月至2010年10月新诊断的T2DM住院患者(诊断按WTO1999年标准)60例,随机分为MDI组及诺和锐30组治疗两周,比较PG、c肽、血糖达标时间、胰岛素日用量和低血糖发生人数。结果两组组内比较均有明显改善,差异具有统计学意义(P<0.01)。两组间无统计学意义(P>0.05)。结论每日3次诺和锐30能有效降低血糖,改善β细胞功能,有效降低低血糖事件的发生,可作为初诊2型糖尿病的强化治疗方案。     

门冬胰岛素30联合口服降糖药治疗老年糖尿病的成本-效果分析

目的评价门冬胰岛素30联合口服降糖药的3种不同方案用于治疗老年人糖尿病的成本-效果。方法将90例老年糖尿病患者随机分A、B、C3组,每组30例。A组给予门冬胰岛素30(诺和锐30);B组予诺和锐30+二甲双胍(格华止);C组予诺和锐30+阿卡波糖。治疗后比较分析3组的疗效、不良反应及成本-效果。结果 3组临床疗效及低血糖发生率比较差异均无统计学意义(P>0.05);A、B、C3组药物总成本分别为1517.0元、2010.0元和2271.4元。成本-效果比分别为28.5、30.1和32.4;B、C组对于A组对降血糖的增量成本比为36.8元、45.2元。结论 3种治疗疗效均较好,从成本-效果比分析A组更符合药物经济学原则。