Insulin analogues (insulin detemir and insulin aspart) versus traditional human insulins (NPH insulin and regular human insulin) in basal-bolus therapy for patients with Type 1 diabetes

Aims/hypothesis The aim of the trial was to compare the efficacy and tolerability of two types of basal-bolus therapy, using either the soluble long-acting basal insulin analogue, insulin detemir, in combination with the rapid-acting analogue, insulin aspart, or NPH insulin in combination with mealtime regular human insulin.Methods In this 18-week, 1:1 randomised, open-labelled, parallel trial, 595 patients with Type 1 diabetes mellitus received insulin detemir or NPH insulin in the morning and at bedtime in combination with mealtime insulin aspart or regular human insulin respectively.Results Glycaemic control with insulin detemir/insulin aspart was improved in comparison with NPH insulin/regular human insulin (HbA₁c: 7.88% vs 8.11%; mean difference: –0.22% point [95% CI: –0.34 to –0.10]; p<0.001). Self-measured 8-point plasma glucose profiles differed between the groups (p<0.001), with lower postprandial plasma glucose levels in the insulin detemir/insulin aspart group. Within-person day-to-day variation in plasma glucose was lower with insulin detemir/insulin aspart than with NPH insulin/regular human insulin (SD: 2.88 vs 3.12 mmol/l; p<0.001). Risk of overall and nocturnal hypoglycaemia (23.00–06.00 hours) was, respectively, 21% (p=0.036) and 55% (p<0.001) lower in the insulin detemir/insulin aspart group than in the NPH insulin/regular human insulin group. Body weight (adjusted for baseline and change in HbA₁c) was 1 kg lower with insulin detemir/insulin aspart than with NPH insulin/regular human insulin (p<0.001).Conclusions/interpretation Basal-bolus therapy using insulin detemir/insulin aspart offers a better balance of control and tolerability than with NPH insulin/regular human insulin. The low variability and more physiological action profiles generated with these insulin analogues resulted in improved glycaemic control with lower risk of hypoglycaemia and no concomitant body weight increase.     

Reducing hypoglycaemia with insulin analogues

Numerous studies have demonstrated that tight glycaemic control reduces long-term complications in both Type 1 and Type 2 diabetes. However, current intensive insulin regimens increase the risk of hypoglycaemia, dissuading many attempting this approach. Normal physiological insulin profiles consist of a stable, basal component and meal-related surges in secretion. Conventional insulin regimens cannot mimic this profile accurately due to pharmacokinetic limitations. Human insulin has a slow onset of action, thus patients are advised to inject about 30 min before a meal, ensuring peak insulin concentrations coincide with postprandial glucose excursions. This is clearly impractical for many and can lead to pre-meal hypoglycaemia if the meal is delayed. Furthermore, it only partially overcomes the unphysiological insulin profile and patients experience postprandial hyperglycaemia and are vulnerable to postabsorptive hypoglycaemia. Insulin aspart and insulin lispro are rapid-acting analogues that allow a more physiological replacement of mealtime insulin secretion. They reduce postprandial glucose and usefully reduce the incidence of hypoglycaemia when used in a basal-bolus regimen in tightly controlled patients. Pre-mixed insulins, containing a combination of rapid-acting and intermediate-acting insulin, are widely used, particularly in Type 2 diabetes. They have limitations achieving tight glucose targets but early data suggest that the combination of 30% insulin aspart and 70% protaminated insulin aspart may also reduce severe hypoglycaemia. On-going clinical trials will establish whether they can be used to achieve better glycaemic control with less hypoglycaemia.     

A randomized cross-over trial to identify the optimal use of insulin glargine in prepubertal children using a three-times daily insulin regimen.

AIMS: The long-acting insulin analogue glargine reduces nocturnal hypoglycaemia and stabilizes morning blood glucose levels in patients with Type 1 diabetes (T1DM) on multiple injection therapy. However, young children may not tolerate such intensive insulin regimens. We investigated the effects of glargine in various three-injections-daily insulin combinations on 24-h glucose control in prepubertal children. METHODS: Seventeen T1DM prepubertal children (10 boys), median age 10.2 years (range 6.0-12.4), glycated haemoglobin (HbA(1c)) 8.8% (6.8-11.5) were recruited to a randomized, open-label, cross-over study. After a 2-week run-in period (with NPH pre-bed), every child underwent three different 3-week treatment blocks in random order. All treatment blocks included glargine pre-bed, but used different morning insulins: block 1, soluble only; block 2, soluble + NPH; block 3, aspart + NPH. Continuous glucose monitoring was performed for 3 days at the end of the run-in and each treatment block. RESULTS: Compared with the run-in period on NPH, the three glargine treatment blocks were associated with lower (P < 0.0001) and less variable (P < 0.05) pre-breakfast glucose levels, and with an 8-15% reduction in total daily insulin dose (P < 0.0001). Risk of nocturnal hypoglycaemia detected by continuous glucose monitoring varied significantly between the three glargine treatment blocks, and was lowest when children were given aspart + NPH in the morning (block 3). CONCLUSION: Insulin glargine pre-bed can be used in three-injections-daily regimens in prepubertal children to lower and stabilize pre-breakfast glucose levels. However, to avoid the risk of nocturnal hypoglycaemia, the pre-bed glargine dose should be lowered by giving a further long-acting insulin, such as NPH, in the morning.     

动态血糖监测评价门冬胰岛素30与中性可溶性人胰岛素30R降糖疗效的研究

目的应用动态血糖监测系统(dynamic glucose monitoring system,DGMS)评价门冬胰岛素30(Asp30)的有效性和安全性。方法采用随机交叉试验设计,将2005年12月至2007年12月秦皇岛市第一医院的20例2型糖尿病患者随机分为A、B两组,A、B两组分别交叉应用Asp30和中性可溶性人胰岛素30R(30R)控制血糖,同时应用DGMS监测血糖。结果应用Asp30早餐后血糖、晚餐后血糖、早餐后60min皮下组织葡萄糖浓度、早餐后120min皮下组织葡萄糖浓度、晚餐后60min皮下组织葡萄糖浓度、晚餐后120min皮下组织葡萄糖浓度、平均最大皮下组织葡萄糖浓度、三餐后5h内皮下组织平均葡萄糖曲线下面积、DGMS24h曲线下面积均显著小于应用30R组(P<0.05)。应用Asp30低血糖发生共1例次,应用30R低血糖发生共5例次。结论应用Asp30每日2次皮下注射有效的控制24h血糖,减少了餐后血糖的漂移,很少发生低血糖。     

Biphasic insulin aspart compared to biphasic human insulin reduces postprandial hyperlipidemia in patients with Type 2 diabetes.

BACKGROUND: Premixed insulin analogues reduce postprandial hyperglycemia in patients with Type 2 diabetes in comparison to premixed regular insulin. Insulin also plays an important role in the regulation of postprandial lipid metabolism. It is known that increased levels of postprandial insulin reduce postprandial hyperlipemia but, on the other hand, no information exists with regard to the possible effect of insulin analogues in comparison to human insulin. MATERIALS AND METHODS: 12 subjects (3 men; age 59 +/- 5 years; BMI 30.5 +/- 5.9 kg/m2, duration of diabetes 9 +/- 1 years, HbA1c 8.33 +/- 1.1 %) already on therapy with premixed insulin were treated either with biphasic human insulin (BHI30) or with biphasic insulin aspart (BIAsp30) (1.3 IU fast acting insulin/12 g KH) in the setting of a standardized test meal. Serum levels of glucose, insulin, C-peptide and triglycerides as well as retinylpalmitate in plasma and chylomicron remnants were determined before and up to 8 hours after the meal. RESULTS: As was to be expected, therapy with BIAsp30 reduced the maximum increase of postprandial glucose from 7.10 +/- 2.00 mmol/l to 5.27 +/- 1.83 mmo/l (p = 0.007) compared to BHI30 insulin. In the same way, the maximum increase of triglycerides (from 2.33 +/- 1.03 to 1.65 +/- 0.69 mmol/l, p = 0.014) was reduced. The AUC 0 - 8 for triglycerides was not significantly influenced (34.20 +/- 19.86 vs. 31.46 +/- 16.21 mmol x 8 h/l) but the incremental area over baseline (AOB 0 - 8) was significantly reduced from 8.02 +/- 4.35 to 6.12 +/- 3.94 mmol x 8 h/l (p = 0.024). CONCLUSIONS: Compared to conventional human premixed insulin the prandial therapy with biphasic insulin aspart results not only in an improvement of glucose tolerance but also in a significant reduction of postprandial hyperlipemia.     

A randomized trial of insulin aspart with intensified basal NPH insulin supplementation in people with Type 1 diabetes.

AIMS: Insulin aspart has been shown to improve post-prandial and overall glycaemic control in people with Type 1 diabetes. We hypothesized that insulin aspart with intensified basal NPH insulin supplementation would result in better overall glycaemic control than human regular insulin with standard basal NPH insulin. METHODS: The trial was conducted in 43 centres in seven countries. People with Type 1 diabetes were randomized to mealtime insulin aspart with up to four daily NPH doses if meals were > 5 h apart and a 25% increase in bedtime NPH dose (n = 187), or to mealtime human unmodified insulin with once or twice daily basal NPH insulin (n = 181). Efficacy and safety were evaluated at 12 weeks (primary evaluation period) and 64 weeks. RESULTS: At 12 and 64 weeks there was no statistically significant difference in HbA1c between the insulin aspart and regular insulin groups: -0.09 (95% confidence interval (CI) -0.23, +0.05)% and -0.14 (-0.32, +0.04)%. Post-prandial glucose values were lower and the area under the 24-h self-monitored blood glucose curve above 7.0 mmol/l was 28% smaller with insulin aspart (35.2 +/- 3.2 vs. 48.9 +/- 3.1 mmol/l h, P = 0.0015). No significant differences were found in mild or severe hypoglycaemia, or adverse event rate. At 64 weeks treatment satisfaction was higher in the insulin aspart group (difference 1.57 (95% CI 0.49, 2.64) points, P = 0.004), while quality of life was not different. CONCLUSIONS: Improved post-prandial glycaemic control and treatment satisfaction with insulin aspart were confirmed. Intensifying basal insulin supplementation resulted in a similar HbA1c decrement as previously found with the use of insulin aspart and standard NPH insulin supplementation. This does not support routinely basal NPH insulin intensification when using rapid-acting insulin analogues in daily practice.     

高血压患者胰岛素抵抗与纤溶系统的关系

目的　研究高血压病 (EH)患者胰岛素抵抗 (IR)与纤溶系统的关系。方法　EH病人 71例 ,采用 75g葡萄糖口服负荷法 (OGTT) ,将EH患者分为糖耐量正常组 (NGT) 44例和糖耐量异常组 (IGT) 2 7例 ,正常对照组 3 1例。测定血浆组织型纤溶酶原激活物活性 (t PA)、纤溶酶原激活物抑制物 -1活性 (PAI 1)、纤溶酶原活性 (PLG) ,在OGTT测定的同时作血胰岛素 (INS)测定 ,并根据Cederholm公式计算出胰岛素敏感指数 (ISIc)。结果　NGT组和IGI组相比t PA无明显差别 (P >0 0 5) ,但两组均较正常对照组降低 (P <0 0 5)。NGT组和IGT组PAI -1与正常对照组比较均无明显差别 (P >0 0 5)。IGT与NGT相比PLG增高 (P <0 0 5) ,与正常对照比较PLG明显增高 (P <0 0 1)。ISIc在NGT组和IGT组较正常对照组明显降低 (P <0 0 5,P <0 0 1) ,且IGT组较NGT组更低 (P <0 0 1)。ISIc与t PA ,PAI 1不相关。结论　高血压病人存在胰岛素抵抗 ,当高血压病合并IGT时 ,胰岛素抵抗更明显。EH病人存在纤溶活性的下降 ,当合并IGT时 ,纤溶活性的降低更为明显。t PA和PAI 1与ISIc无明显相关性     

Mid- and high-ratio premix insulin analogues: potential treatment options for patients with type 2 diabetes in need of greater postprandial blood glucose control

Some patients with type 2 diabetes continue to have high postprandial blood glucose levels on twice‐daily regimens of ‘low‐ratio’ premix insulin formulations (up to 30% rapid‐acting, with 70% protracted insulin). These patients require intensified insulin therapy, which can be provided by a twice‐ or thrice‐daily regimen of mid‐ratio (50% rapid‐acting and 50% protaminated intermediate‐acting insulin – human or analogue) or high‐ratio (70% rapid‐acting and 30% protaminated insulin – analogue only) premix insulin. Alternatively, a third daily injection of low‐ratio premix insulin can be added to the regimen, with the option of incorporating one or more injections of mid‐ or high‐ratio premix as required, and as an alternative to basal–bolus therapy. How these mid‐ and high‐ratio formulations differ from the low‐ratio premix insulins is reviewed here, with the aim of identifying the role of these formulations in diabetes management. Glucose clamp studies have shown that premix analogues give serum insulin levels proportional to their percentage of rapid‐acting uncomplexed insulin: the higher the proportion, the greater the maximum level reached. Other pharmacokinetic parameters were not always significantly different between the mid‐ and high‐ratio formulations. In clinical trials, postprandial plasma glucose and glycated haemoglobin A1c (HbA_1c) levels were significantly reduced with thrice‐daily mid‐ /high‐ratio premix analogue when compared with twice‐daily low‐ratio biphasic human insulin (BHI) 30/70 or once‐daily insulin glargine. Moreover, glycaemic control with mid‐/high‐ratio premix analogue was found to be similar to that with a basal–bolus therapy. Mid‐ and high‐ratio premix regimens are generally well tolerated. The frequency of minor hypoglycaemia was reportedly higher with mid‐ /high‐ratio premix analogues than with BHI 30, but nocturnal hypoglycaemia was less frequent. Although there is little evidence that clinical outcomes with mid‐ratio premix analogues are different from those with high‐ratio, they are useful additions to the low‐ratio formulations for the management of diabetes, and addressing postprandial hyperglycaemia in particular.     

Practical use of insulin degludec/insulin aspart in a multinational setting: beyond the guidelines

Insulin degludec/insulin aspart (IDegAsp) is a fixed-ratio co-formulation of insulin degludec, which provides long-lasting basal insulin coverage, and insulin aspart, which targets postprandial glycaemia. This review provides expert opinion on the practical clinical use of IDegAsp, including: dose timings relative to meals, when and how to intensify treatment from once-daily (OD) to twice-daily (BID) dose adjustments, and use in special populations (including hospitalized patients). IDegAsp could be considered as one among the choices for initiating insulin treatment, preferential to starting on basal insulin alone, particularly for people with severe hyperglycaemia and/or when postprandial hyperglycaemia is a major concern. The recommended starting dose of IDegAsp is 10 units with the most carbohydrate-rich meal(s), followed by individualized dose adjustments. Insulin doses should be titrated once weekly in two-unit steps, guided by individualized fasting plasma glucose targets and based on patient goals, preferences and hypoglycaemia risk. Options for intensification from IDegAsp OD are discussed, which should be guided by HbA1c, prandial glucose levels, meal patterns and patient preferences. Recommendations for switching to IDegAsp from basal insulin, premixed insulins OD/BID, and basal-plus/basal–bolus regimens are discussed. IDegAsp can be co-administered with other antihyperglycaemic drugs; however, sulphonylureas frequently need to be discontinued or the dose reduced, and the IDegAsp dose may need to be decreased when sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists are added. Considerations around the initiation or continuation of IDegAsp in hospitalized individuals are discussed, as well as in those undergoing medical procedures.     

高血压病患者t－PA及其抑制物与胰岛素抵抗的关系

本文采用发色底物法及放免法检测了４７例老年及老年前期原发性高血压病（ＥＨ）患者和２５例健康老年人血浆组织型纤溶酶原激活物（ｔ－ＰＡ）、纤溶酶原激活的抑制因子（ＰＡＩ）、空腹血浆胰岛素（Ｉｎ）及血糖水平（Ｇ），分析了胰岛素敏感性（ＩＳ）与纤溶活性、体重指数（ＢＭＩ）、血压（ＢＰ）的相关性。结果显示：ＥＨ患者血浆ＰＡＩ活性明显高于对照组，血浆ｔ－ＰＡ活性、ＩＳ明显低于对照组；ＩＳ与ＢＭＩ、ＰＡＩ、ＢＰ呈显著负相关，与ｔ－ＰＡ呈显著正相关。提示纤溶活性异常与胰岛素抵抗共同在高血压病的发生发展中起重要作用。     

Comparison of three multiple injection regimens for Type 1 diabetes: morning plus dinner or bedtime administration of insulin detemir vs. morning plus bedtime NPH insulin.

AIMS: This trial investigated the efficacy and safety of two different administration-time regimens with insulin detemir (IDet) to that of a conventional basal insulin regimen with NPH insulin (NPH). METHODS: This multinational, 16-week, open, parallel group trial included 400 people with Type 1 diabetes mellitus (DM) randomized to IDet either morning and before dinner (IDetmorn+din) or morning and bedtime (IDetmorn+bed), or to NPH morning and bedtime (NPHmorn+bed), all in combination with mealtime insulin aspart (IAsp). RESULTS: HbA1c was comparable between the three groups after 16 weeks (P = 0.64), with reductions of 0.39-0.49% points. Lower fasting plasma glucose (FPG) was observed with IDetmorn+din and IDetmorn+bed compared with NPHmorn+bed (9.8 and 9.1 vs. 11.1 mmol/l, P = 0.006), whereas the IDet groups did not differ (P = 0.15). Within-person variation in self-measured FPG was significantly lower for both IDet regimens (sd IDetmorn+din 2.5, IDetmorn+bed 2.6 mmol/l) than for NPHmorn+bed (sd 3.1 mmol/l, P < 0.001), but was comparable between the IDet groups (P = 0.48). Ten-point plasma glucose profiles were lower between dinner and breakfast in the IDetmorn+din group (P = 0.043), compared with the two other groups. Risk of overall and nocturnal hypoglycaemia was similar for the three groups. Lower mean bodyweight was observed with IDet compared with NPH after 16 weeks (difference: (IDetmorn+din)-1.3 kg, P < 0.001, (IDetmorn+bed)-0.6 kg, P = 0.050). CONCLUSIONS: Both IDet regimens were well tolerated and provided lower and less variable glucose levels with no, or less, weight gain than NPH at comparable HbA1c. IDet can be administered either at dinner or bedtime, with similar glycaemic control according to the need of the individual person.     

The effect of the optimal use of rapid-acting insulin analogues on insulin secretion in Type 2 diabetes

The abnormal glucose tolerance of Type 2 diabetes is characterized by post-prandial hyperglycaemia. We aimed to examine whether the restoration of a more physiological insulin profile using rapid-acting insulin analogues might, through effects on glucose toxicity, improve endogenous insulin secretion rate (ISR) and secondly improve markers of vascular risk. Eighteen people with insulin-treated Type 2 diabetes were recruited into a single centre, cross-over, open-labeled study. The order of pre-meal unmodified human insulin or insulin aspart was randomized: treatment periods lasted at least 8-12 weeks after which ISR was assessed by stepped low-dose glucose infusion and fasting markers of vascular risk measured. Glucose control was good (HbA(1c) 6.94+/-0.12 (+/-S.E.)% versus 7.07+/-0.13%, NS) with insulin aspart and human insulin. Mean post-prandial self-monitored blood glucose concentration was also good particularly with insulin aspart (7.5+/-0.41 mmol/l versus 8.19+/-0.34 mmol/l) but the difference did not reach statistical significance. Over 160 min ISR did not differ between insulin aspart and human insulin and there was also no change in various markers of vascular risk. In conclusion a meal-time+basal insulin regimen gave close to normal post-prandial blood glucose control with both the insulin aspart and human insulin regimens, such that no difference in ISR or markers of vascular risk could be demonstrated.     

Insulin therapy

Large randomised, controlled clinical trials have clearly shown that, both in type 1 (DCCT) and in type 2 (UKPDS, Kumamoto Study), micro and macrovascular complications are largely preventable with intensive insulin or oral hypoglycemic therapy and optimal metabolic control. Intensive insulin therapy can be performed in selected cases through continuous subcutaneous insulin infusion with a pump. However, almost equally good results can be obtained with a regimen of multiple injections based on a rational association of fast acting and slow acting insulin preparations. The present availability of fast acting insulin analogues (lispro and aspart insulin), characterised by aminoacid substitutions in the C-terminal portion of B-chain and a fast absorption rate from the subcutaneous tissue, is of great advantage in this context. Fast-acting analogues restore prandial insulin peaks while multiple doses of NPH restore basal insulin levels for the control of fasting blood glucose levels. New protracted acting insulin analogues and premixed preparations of fast acting analogues and NPH will soon be available. Pharmcokinetics of the protracted - acting analogue glargine seems particularly satisfactory. Glargine is present in vials in acid solution and has a neutral isoelectric point. Therefore, when injected, glargine precipitated in the subcutaneous tissue and is reabsorbed very slowly in the following 20-24 hours. Moreover, new fatty acid derivatives of insulin analogues are now under experimentation. The protraction of action of this kind of insulin is due to its binding with serum and interstitial albumin and subsequent slow release. Multiple insulin regimens are available for different types of diabetes, different degrees of insulin deficiency and peculiar clinical features of individual patients. However, in any case, insulin therapy should aim to near - normalise not only mean blood glucose and glycated hemoglobin values but also postprandial blood glucose level which represent an independent risk factor an for diabetic complications.     

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.     

初诊2型糖尿病患者短期胰岛素强化治疗后超敏C-反应蛋白的变化

目的观察诺和锐强化治疗后超敏C-反应蛋白(hs-CRP)变化与胰岛素抵抗的关系。方法选择2005年6月至2007年2月在暨南大学医学院第五附属医院暨广东省清远市人民医院对30例初诊2型糖尿病(T2DM)患者进行14d的持续皮下诺和锐输注。分析比较治疗前后空腹(FPG)及餐后血糖(PPG),口服葡萄糖耐量试验时真胰岛素及C肽分泌和真胰岛素及C肽曲线下面积、胰岛素抵抗指数、胰岛素分泌指数、hs-CRP等指标的变化。结果短期诺和锐强化治疗后,FPG、PPG及葡萄糖曲线下面积均较治疗前明显下降(P<0.01);空腹及餐后真胰岛素和C肽的分泌、真胰岛素和C肽曲线下面积、胰岛素分泌指数均较治疗前明显升高(P<0.01)。胰岛素抵抗指数较治疗前明显下降(P<0.05)。hs-CRP明显下降。结论短期诺和锐强化治疗可以迅速降低血糖,改善胰岛B细胞功能,降低胰岛素抵抗,改善炎症,降低hs-CRP。     

Premeal insulin lispro plus bedtime NPH or twice-daily NPH in patients with type 2 diabetes: acute postprandial and chronic effects on glycemic control and cardiovascular risk factors

OBJECTIVE: Two insulin regimens were used to explore acute and chronic postprandial changes in glycemia, lipemia, and metabolic markers associated with increased risk of cardiovascular disease. METHODS: An open-label, randomized, two-period crossover study (12 weeks/period) compared a prandial regimen [premeal insulin lispro+bedtime neutral protamine Hagedorn (NPH)] with a basal regimen (twice-daily NPH). There were 30 patients (12 women and 18 men; mean age=61 years) with type 2 diabetes mellitus (mean duration=16 years) who were randomized after a 2-month lead-in with twice-daily NPH treatment. A standard lunch test meal developed according to each patient's caloric needs was administered at the end of each treatment period. RESULTS: Insulin lispro was associated with significantly lower postprandial glucose (area under the curve0-5 h=43.54 vs. 57.65 mM/h; P<.001), elevated insulin concentrations, and acutely altered lipid fractions that included an early decrease followed by an increase in free fatty acids, lower triglycerides, elevated total cholesterol, elevated low-density lipoprotein cholesterol (LDL), and elevated high-density lipoprotein cholesterol. After 12 weeks of treatment, insulin lispro+bedtime NPH reduced hemoglobin A1c (HbA1c; mean+/-SE=7.6+/-0.2 vs. 8.2+/-0.2%; P<.001) without increasing hypoglycemia or insulin dose as compared with twice-daily NPH. Furthermore, treatment with the prandial insulin regimen resulted in lower total cholesterol, lower LDL cholesterol, and lower oxidized LDL. CONCLUSION: Improved postprandial glycemic control, as observed in a regimen containing both prandial insulin lispro and NPH as the basal insulin, is associated with significantly lower HbA1c and acute modulation of lipid fractions after a test meal. These biochemical modifications may potentially have a favorable impact on cardiovascular risk in patients with type 2 diabetes mellitus.     

Biphasic insulin aspart given thrice daily is as efficacious as a basal-bolus insulin regimen with four daily injections: a randomised open-label parallel group four months comparison in patients with type 2 diabetes.

AIMS: To show that a thrice daily meal-time biphasic insulin aspart (BIAsp) treatment regimen is as efficacious as a 4 times daily basal-bolus regimen with human isophane insulin (NPH) and insulin aspart (IAsp). METHODS: A multinational, randomised, open-label parallel-group trial in 394 patients with type 2 diabetes on a once or twice daily insulin regimen. Patients were randomised 1:1 to BIAsp or IAsp+NPH for 16 weeks. The BIAsp group was treated according to individual needs using BMI as a surrogate index of insulin resistance. Subjects administered BIAsp 70 (BMI< or =30 kg/m (2)) or BIAsp 50 (BMI>30 kg/m (2)) with breakfast and lunch and BIAsp 30 with dinner. The IAsp+NPH group injected IAsp at meals and NPH at bedtime as basal insulin. HbAlc levels after 16 weeks were compared between treatments using a predefined non-inferiority criterion of 0.4%. The incidence of hypoglycaemic episodes and adverse events was evaluated. RESULTS: Mean HbAlc (+/-SD) decreased from 9.1+/-0.7% to 7.8+/-1.0% with both treatments. Glycaemic control provided by BIAsp was non-inferior to that obtained by the IAsp+NPH (intention to treat ITT) population: diff, HbAlc -0.05%; 95% CI (-0.24; 0.14); per protocol (PP) population: diff, HbAlc -0.03%; 95% CI (-0.23; 0.16). Similar improvements in glycaemic control in both groups were confirmed by self-measured 8-point plasma glucose (PG) profiles, average and fasting PG concentrations, and average prandial PG increments. The incidence of adverse events and hypoglycaemic episodes was similar in the two treatment groups. CONCLUSIONS: A thrice daily meal-time BIAsp regimen is a suitable alternative to an intensified insulin regimen in people with inadequately controlled type 2 diabetes mellitus, and requires fewer daily injections than a basal-bolus therapy without compromising efficacy and safety.     

Insulin detemir compared with NPH insulin in children and adolescents with Type 1 diabetes.

AIMS: This study compared the effect of insulin detemir on glycaemic control (HbA(1c), fasting plasma glucose and variability thereof) with that of Neutral Protamine Hagedorn human isophane (NPH) insulin, both combined with insulin aspart, in children with Type 1 diabetes mellitus, and compared the safety of these treatments. METHODS: In this 26-week, open-label, randomized (2 : 1), parallel-group study, 347 (140 prepubertal and 207 pubertal) children with Type 1 diabetes, aged 6-17 years, received insulin detemir (n = 232) or NPH insulin (n = 115) once or twice daily, according to the prestudy regimen, plus premeal insulin aspart. RESULTS: The mean HbA(1c) decreased by approximately 0.8% with both treatments. After 26 weeks, the mean difference in HbA(1c) was 0.1% (95% confidence interval -0.1, 0.3) (insulin detemir 8.0%, NPH insulin 7.9%). Within-subject variation in self-measured fasting plasma glucose was significantly lower with insulin detemir than with NPH insulin (SD 3.3 vs. 4.3, P < 0.001), as was mean fasting plasma glucose (8.4 vs. 9.6 mmol/l, P = 0.022). The risk of nocturnal hypoglycaemia (22.00-07.00 h) was 26% lower with insulin detemir (P = 0.041) and the risk of 24-h hypoglycaemia was similar with the two treatments (P = 0.351). The mean body mass index (BMI) Z-score was lower with insulin detemir (P < 0.001). CONCLUSIONS: Basal-bolus treatment with insulin detemir or NPH insulin and premeal insulin aspart in children and adolescents with Type 1 diabetes mellitus improved HbA(1c) to a similar degree. The lower and more predictable fasting plasma glucose, lower risk of nocturnal hypoglycaemia and lower BMI observed with insulin detemir are clinically significant advantages compared with NPH insulin.     

Lower within-subject variability of fasting blood glucose and reduced weight gain with insulin detemir compared to NPH insulin in patients with type 2 diabetes

AIM: The aim of this study was to compare the efficacy and safety of a basal-bolus insulin regimen comprising either insulin detemir or neural protamine hagedorn (NPH) insulin in combination with mealtime insulin aspart in patients with type 2 diabetes. METHODS: This was a 26-week, multinational, open-label, parallel group trial with 505 patients with type 2 diabetes (mean age, 60.4 +/- 8.6 years; mean BMI, 30.4 +/- 5.3 kg/m(2); mean HbA(1c), 7.9 +/- 1.3%). Patients, randomized 2:1 to insulin detemir or NPH insulin, received basal insulin either once or twice daily according to their pretrial insulin treatment and insulin aspart at mealtimes. RESULTS: After 26 weeks of treatment, significant reductions in HbA(1c) were observed for insulin detemir (0.2%-points, p = 0.004) and NPH insulin (0.4%-points; p = 0.0001); HbA(1c) levels were comparable at study end (insulin detemir, 7.6%; NPH insulin, 7.5%). The number of basal insulin injections administered per day had no effect on HbA(1c) levels (p = 0.50). Nine-point self-measured blood glucose (SMBG) profiles were similar for the two treatment groups (p = 0.58), as were reductions in fasting plasma glucose (FPG) (insulin detemir, 0.5 mmol/l; NPH insulin, 0.6 mmol/l). At study end, FPG concentrations were similar for the two treatment groups (p = 0.66). By contrast, within-subject day-to-day variation in fasting SMBG was significantly lower with insulin detemir (p = 0.021). Moreover, patients receiving insulin detemir gained significantly less body weight than those who were administered NPH insulin (1.0 and 1.8 kg, respectively, p = 0.017). The frequency of adverse events and the risk of hypoglycaemia were comparable for the two treatment groups. CONCLUSIONS: Patients with type 2 diabetes, treated for 26 weeks with insulin detemir plus insulin aspart at mealtimes, experienced comparable glycaemic control but significantly lower within-subject variability and less weight gain compared to patients treated with NPH insulin and insulin aspart. Insulin detemir was well tolerated and had a similar safety profile to NPH insulin.     

Less weight gain and hypoglycaemia with once‐daily insulin detemir than NPH insulin in intensification of insulin therapy in overweight Type 2 diabetes patients—The PREDICTIVE™ BMI clinical trial1

Objective To assess weight change when once‐daily insulin detemir (detemir) or neutral protamine Hagedorn insulin (NPH) are used in already overweight Type 2 diabetes patients requiring intensified insulin therapy. Research design and methods This 26‐week randomized, controlled trial included adults with Type 2 diabetes [glycated haemoglobin (HbA_1c) 7.5–11.0%, body mass index (BMI) 25–40 kg/m²] who had received two daily doses of insulin (at least one a premix) for ≥ 3 months. Subjects received either detemir (n = 125) or NPH (n = 146) once daily in the evening and insulin aspart at main meals. Concomitant treatment with metformin was allowed. Basal insulin was titrated to a pre‐breakfast plasma glucose target of 6.1 mmol/l without unacceptable hypoglycaemia. Insulin aspart was also titrated (target, postprandial glucose ≤ 10.0 mmol/l without unacceptable hypoglycaemia). Results At 26 weeks, weight had increased significantly less with detemir (0.4 kg) than with NPH (1.9 kg; difference 1.5 kg, P < 0.0001). BMI increase was also less with detemir than with NPH (difference 0.6 kg/m², P < 0.0001). HbA_1c decreased from 8.9 to 7.8% (detemir) and from 8.8 to 7.8% (NPH; not significant for between‐treatment difference). Incidence of hypoglycaemia was lower with detemir [relative risks 0.62 (all events) and 0.43 (nocturnal); P < 0.0001 for both]. Conclusions PREDICTIVE? BMI was the first study to examine the effect of once‐daily detemir with weight as the primary endpoint in a large population of overweight Type 2 diabetes patients. Use of once‐daily detemir for intensification of insulin therapy resulted in less weight gain, less hypoglycaemia and equivalent glycaemic control compared with NPH.