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.     

Starting insulin therapy in type 2 diabetes: twice-daily biphasic insulin Aspart 30 plus metformin versus once-daily insulin glargine plus glimepiride.

AIM: To compare the efficacy and safety of two analog insulins as starting regimens in insulin-na?ve Type 2 diabetes patients. METHODS: In this randomized, open-label parallel study, twice-daily biphasic insulin aspart 30 (30% soluble and 70% protaminated insulin aspart; BIAsp 30) plus metformin (met) was compared with once-daily insulin glargine (glarg) plus glimepiride (glim) in 255 insulin-na?ve patients (131 male; mean+/-SD age, 61.2+/-9.1 years). Mean baseline HbA (1c) (+/-SD) was 9.2+/-1.4% and 8.9+/-1.3% for BIAsp 30 plus met ( N=128) and glarg plus glim ( N=127), respectively ( P=0.0747). Primary endpoint was the difference in absolute change in HbA (1c) between groups after 26 weeks of treatment. RESULTS: HbA (1c) change was significantly greater in the BIAsp 30 plus met group than the glarg plus glim group (between-group difference: -0.5% (95% CI: -0.8; -0.2); P=0.0002). Mean prandial plasma glucose increment was significantly lower for BIAsp 30 plus met compared with glarg plus glim: 1.4+/-1.4 mmol/l vs. 2.2+/-1.8 mmol/l; P=0.0002. During the maintenance phase (weeks 6-26), one major hypoglycemic episode occurred in each group; 20.3% and 9% of patients experienced minor hypoglycemic episodes in the BIAsp 30 plus met and glarg plus glim groups, respectively ( P=0.0124). At end-of-trial, mean daily insulin doses were 0.40 U/kg BIAsp 30 and 0.39 U/kg glarg. Glarg plus glim-treated patients experienced significant weight gain of 1.5 kg (95% CI: 0.84; 2.19; P<0.0001). Weight change with BIAsp 30 plus met of +0.7 kg was not statistically significant (95% CI: -0.07; 1.42; P=0.0762). CONCLUSIONS: Starting insulin in Type 2 diabetes patients with twice-daily BIAsp 30 plus met can reduce HbA (1c) and mean prandial plasma glucose increment to a greater extent than once-daily glarg plus glim.     

双时相门冬胰岛素30联合二甲双胍治疗基础胰岛素控制不佳的2型糖尿病患者:疗效及安全性评价

目的 评价既往基础胰岛素联合口服降糖药物(OAD)治疗血糖控制不佳的2型糖尿病患者转用双时相门冬胰岛素30(BIAsp30)联合二甲双胍治疗的疗效及安全性.方法 本试验为多中心、非随机、开放、单组治疗达标研究,包括2周筛选期、4周导入期和16周治疗期.既往使用基础胰岛素联合OAD治疗血糖控制不佳的2型糖尿病患者转用每日两次BIAsp30注射联合口服二甲双胍治疗.收集疗效及安全性数据进行统计学分析.结果 共293例患者(男154,女139)入选,平均年龄(54.0±9.6)岁,平均糖尿病病程(8.54±5.49)年,平均体重指数(24.89±3.28)kg/m2,HbA1c 8.16%±0.89%,122例既往使用基础胰岛素类似物,169例使用人中效胰岛素.经16周的治疗,平均HbA1C降幅达1.30%±0.96%(P＜0.01);HbA1C达到＜7.0%和≤6.5%的患者比例分别为60.4%和38.9%.患者8点血糖谱各点血糖值均有显著降低(P＜0.01),8点血糖均值由基线时的(10.53±2.58)mmol/L降至(7.79±1.58)mmol/L(P＜0.01),降幅为2.76 mmol/L.早餐和晚餐后血糖增幅显著下降,分别下降了1.73 mmol/L(P＜0.01)和1.28 mmol/L(P＜0.01),而午餐后的血糖增幅未发现显著性降低(-0.09 mmol/L,P=0.734 5).研究治疗中无严重不良事件和重度低血糖事件报告,总体低血糖发生率为2.68例/患者年;患者体重平均增加(0.76±0.14)kg(P＜0.01).结论 BIAsp30联合二甲双胍可显著改善基础胰岛素联合OAD血糖控制不佳的2型糖尿病患者的血糖控制,并具有良好的安全性.     

A comparison of insulin aspart and regular insulin in elderly patients with type 2 diabetes

AIM: To evaluate the pharmacokinetic and pharmacodynamic properties of insulin aspart in elderly patients with diabetes. METHODS: Studies were conducted in elderly patients with diabetes (n = 19, M/F 10/9, age 72 +/- 1 years, BMI 27 +/- 1 kg/m(2), HbA(1c) 6.4 +/- 0.1%, diabetes duration < 5 years). Nine patients were treated with metformin, and ten with diet. Subjects underwent 2 studies in random order. In one study, 0.1 u/kg of novolin R (Novo Nordisk, Copenhagen, Denmark) was administered at 7:30 am. Thirty minutes later, at time 0, subjects were given 235 ml of ensure with fibre. The other study was identical to the first except that insulin aspart (Novorapid, Novo Nordisk, Copenhagen, Denmark) 0.1 u/kg was given at time zero. Insulin and glucose valuves were measured as at regular intervals. RESULTS: Insulin and glucose profiles were nearly identical with insulin aspart and regular human insulin. The AUC for glucose (aspart: 6.9 +/- 0.1 mM; regular: 7.1 +/- 0.1 mM, p = ns) and insulin (aspart: 335 +/- 30 pM; regular: 330 +/- 25 pM, p = ns) did not differ between groups. CONCLUSIONS: Insulin aspart appears to act similarly to regular human insulin in elderly patients with type 2 diabetes.     

Insulin aspart vs. human insulin in the management of long-term blood glucose control in Type 1 diabetes mellitus: a randomized controlled trial.

AIMS: To compare the efficacy of insulin aspart, a rapid-acting insulin analogue, with that of unmodified human insulin on long-term blood glucose control in Type 1 diabetes mellitus. METHODS: Prospective, multi-centre, randomized, open-labelled, parallel-group trial lasting 6 months in 88 centres in eight European countries and including 1,070 adult subjects with Type 1 diabetes. Study patients were randomized 2:1 to insulin aspart or unmodified human insulin before main meals, with NPH-insulin as basal insulin. Main outcome measures were blood glucose control as assessed by HbA1c, eight-point self-monitored blood glucose profiles, insulin dose, quality of life, hypoglycaemia, and adverse events. RESULTS: After 6 months, insulin aspart was superior to human insulin with respect to HbA1c with a baseline-adjusted difference in HbA1c of 0.12 (95% confidence interval 0.03-0.22) %Hb, P < 0.02. Eight-point blood glucose profiles showed lower post-prandial glucose levels (mean baseline-adjusted -0.6 to -1.2 mmol/l, P < 0.01) after all main meals, but higher pre-prandial glucose levels before breakfast and dinner (0.7-0.8 mmol/l, P < 0.01) with insulin aspart. Satisfaction with treatment was significantly better in patients treated with insulin aspart (WHO Diabetes Treatment Satisfaction Questionnaire (DTSQ) baseline-adjusted difference 2.3 (1.2-3.3) points, P < 0.001). The relative risk of experiencing a major hypoglycaemic episode with insulin aspart compared to human insulin was 0.83 (0.59-1.18, NS). Major night hypoglycaemic events requiring parenteral treatment were less with insulin aspart (1.3 vs. 3.4% of patients, P < 0.05), as were late post-prandial (4-6 h) events (1.8 vs. 5.0% of patients, P < 0.005). CONCLUSIONS: These results show small but useful advantage for the rapid-acting insulin analogue insulin aspart as a tool to improve long-term blood glucose control, hypoglycaemia, and quality of life, in people with Type 1 diabetes mellitus.     

Pre-meal insulin aspart compared with pre-meal soluble human insulin in type 1 diabetes

Insulin aspart has been shown, in medium-term studies, to achieve reductions in HbA(1c) without increasing the risk of major hypoglycaemia compared with pre-meal human insulin. The aim of the present 3-year study was to evaluate the long-term safety and efficacy of insulin aspart in people with type 1 diabetes. This was a 30-month extension of a multinational, multicentre, open-label, parallel-group study of 753 people with type 1 diabetes, originally randomly allocated to treatment with insulin aspart or unmodified human insulin before meals, with NPH insulin as basal insulin. Main outcomes measures were hypoglycaemia (major or minor), adverse events and HbA(1c). As insulin aspart became commercially available in some countries before the end of the trial, analyses of HbA(1c) used 30-month data to maintain statistical power. The relative risk estimate of major hypoglycaemia was similar between treatment groups (relative risk [RR] 1.00 [95% CI 0.72, 1.39]). The risk of having a minor hypoglycaemic episode was higher with insulin aspart than with human soluble insulin (RR 1.24 [1.09, 1.39] p=0.024). Insulin aspart was significantly superior to human insulin with respect to overall glycaemic control, with a baseline-adjusted HbA(1c) difference of -0.16 (-0.32, -0.01)% (p=0.035). Insulin aspart was well tolerated and effective during long-term treatment. The HbA(1c) advantage was maintained with insulin aspart without any adverse impact on the rate of major hypoglycaemia.     

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.     

Efficacy, safety and lack of immunogenicity of insulin aspart compared with regular human insulin for women with gestational diabetes mellitus.

AIM: The efficacy and safety of insulin aspart (IAsp), a rapid-acting human insulin analogue, were compared with regular human insulin (HI) as the bolus component of basal-bolus therapy for subjects with gestational diabetes mellitus (GDM). METHODS: In a randomized, parallel-group, open-labelled trial, 27 women with GDM (age 30.7 +/- 6.3 years, HbA(1c) < 7%) were randomized to receive IAsp (5 min before meal) or HI (30 min before meal). The trial period extended from diagnosis of GDM (18-28 weeks) to 6 weeks postpartum. RESULTS: Both treatment groups maintained good overall glycaemic control during the study (beginning and end of study HbA(1c)< or = 6%). During the meal test, mean glucose at week 6 (IAsp 4.2 +/- 0.57 mmol/l, HI 4.8 +/- 0.86 mmol/l) was slightly lower than at week 0 (IAsp 4.9 +/- 0.59 mmol/l, HI 5.1 +/- 0.36 mmol/l). However, change from baseline values for average glucose (IAsp -1.09 +/- 0.54 mmol/l, HI -0.54 +/- 0.74 mmol/l; P = 0.003) and C-peptide (IAsp -0.50 +/- 0.67 nmol/l, HI -0.30 +/- 0.70 nmol/l; P = 0.027) were significantly lower after IAsp treatment than HI treatment. No major hypoglycaemic events were reported during the study. Cross-reacting insulin antibody binding increased slightly from baseline in both treatments groups (end of study: IAsp 2.1 +/- 5.4%, HI 6.4 +/- 13.9%), whereas antibodies specific to IAsp or HI remained relatively low (< 1% binding). CONCLUSION: IAsp was more effective than HI in decreasing postprandial glucose concentrations. Duration of IAsp injection 5 min before a meal rather than 30 min prior to meals offers a more convenient therapy for subjects with GDM. Overall safety and effectiveness of IAsp were comparable to HI in pregnant women with GDM.     

The effect of improved post-prandial blood glucose control on post-prandial metabolism and markers of vascular risk in people with Type 2 diabetes

A variety of abnormalities of metabolic, haemostatic and endothelial markers are associated with Type 2 diabetes. Evidence suggests that poor post-prandial blood glucose control may contribute to vascular risk. We aimed to examine whether the restoration of a more physiological insulin profile post-prandially would improve these abnormalities. Twenty-one patients with insulin-treated Type 2 diabetes were recruited into a single centre, crossover, double-blind study. Patients were randomized to unmodified human insulin or insulin aspart before main meals for 6-week study periods, both together with NPH insulin. At the end of each study period, pre-breakfast levels of markers of vascular risk were assessed and a test meal performed. There was no significant difference in HbA(1c) (7.04 +/- 0.13% (+/-S.E.) versus 7.15 +/- 0.11%, P = 0.060) with insulin aspart compared to human insulin at the end of each study period. The mean post-prandial blood glucose concentration at 90 min from self-monitored results was lower with insulin aspart than with human insulin (7.9 +/- 0.4 mmol/l versus 9.3 +/- 0.4 mmol/l, P = 0.011) as was study day post-prandial blood glucose at 90 min (8.4 +/- 0.5 mmol/l versus 9.2 +/- 0.6 mmol/l, P = 0.046). No significant differences were found in fasting lipid profile, apolipoproteins, fibrinogen, plasminogen activator inhibitor-1, E-selectin, or homocysteine between the two study periods. Insulin aspart resulted in improved post-prandial glycaemic control when compared to human insulin in Type 2 diabetic patients, but this was not associated with changes in markers of vascular risk.     

Improved glycaemic control with insulin glargine plus insulin lispro: a multicentre, randomized, cross-over trial in people with Type 1 diabetes.

AIMS: To compare blood glucose control using insulin glargine + insulin lispro with that on NPH insulin + unmodified human insulin in adults with Type 1 diabetes managed with a multiple injection regimen. METHODS: In this 32-week, five-centre, two-way cross-over study, people with Type 1 diabetes (n = 56, baseline HbA1c 8.0 +/- 0.8%) were randomized to evening insulin glargine + mealtime insulin lispro or to NPH insulin (once- or twice-daily) + mealtime unmodified human insulin. Each 16-week period concluded with a 24-h inpatient plasma glucose profile. RESULTS: HbA1c was lower with glargine + lispro than with NPH + human insulin [7.5 vs. 8.0%, difference -0.5 (95% CI -0.7, -0.3) %, P < 0.001]. This was confirmed by an 8% lower 24-h plasma glucose area under the curve (AUC) (187 vs. 203 mmol l(-1) h(-1), P = 0.037), a 24% reduction in plasma glucose AUC > 7.0 mmol/l1 (47 vs. 62 mmol l(-1) h(-1), P = 0.017) and a 15% lower post-prandial plasma glucose AUC (75 vs. 88 mmol l(-1) h(-1), P = 0.002). There was no reduction in night-time plasma glucose AUC or increase in plasma glucose area < 3.5 mmol/l. Monthly rate of nocturnal hypoglycaemia was reduced by 44% with glargine + lispro (0.66 vs. 1.18 episodes/month, P < 0.001). CONCLUSIONS: Compared with NPH insulin + unmodified human insulin, the combination of insulin glargine with a rapid-acting insulin analogue as multiple-injection therapy for Type 1 diabetes improves overall glycaemic control as assessed by HbA1c and 24-h plasma glucose monitoring to a clinically significant degree, together with a reduction in nocturnal hypoglycaemia.     

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.     

Biphasic insulin aspart 30 plus metformin: an effective combination in type 2 diabetes

AIM: This study compared glycaemic control achieved with biphasic insulin aspart 30 (BIAsp 30) monotherapy, BIAsp 30 plus metformin and glibenclamide plus metformin in patients with type 2 diabetes not adequately controlled with metformin. METHODS: In this multinational, open-labelled, parallel group, 16-week trial, 341 patients (patients not adequately controlled with metformin for at least 1 month) with type 2 diabetes were studied. Patients were randomized to receive BIAsp 30, twice daily (n = 107 exposed to treatment), or BIAsp 30, twice daily, plus metformin (n = 108) or glibenclamide plus metformin (n = 114). The primary endpoint was HbA(1c) at end of trial; adverse events, hypoglycaemia episodes, blood lipids and weight were also monitored. RESULTS: In the total population (HbA(1c) 7.5-13.0% at screening), end-of-trial HbA(1c) levels were lower in patients receiving BIAsp 30 plus metformin compared with those receiving BIAsp 30 only [mean treatment difference (+/-s.e.m), 0.39 +/- 0.15%, p = 0.007]. In a subpopulation (HbA(1c) > or = 9.0% at baseline, n = 193), patients receiving BIAsp 30 plus metformin had significantly lower HbA(1c) levels at the end of the trial compared with those receiving glibenclamide plus metformin (treatment difference, 0.46 +/- 0.21%, p = 0.027). Mean body weight (+/-s.d) at the end of the trial was significantly lower in patients receiving glibenclamide plus metformin compared with those receiving BIAsp 30 only (84.3 +/- 13.3 kg vs. 88.9 +/- 16.9 kg, p < 0.001). No major hypoglycaemic episodes were recorded during the trial, and incidence rates for minor and symptoms-only hypoglycaemia were low and similar between treatment groups (0.03-0.04 events/patient/week). CONCLUSION: BIAsp 30 added to metformin could be an appropriate therapeutic option for achieving good glycaemic control, compared with the addition of a second oral agent, particularly where HbA(1c) > or = 9%.     

用诺和锐和诺和灵R持续皮下输注治疗2型糖尿病的疗效对比

目的　比较速效胰岛素类似物 (诺和锐 )和短效人胰岛素 (诺和灵R)用外置的胰岛素泵持续皮下输注 (CSⅡ )治疗 2型糖尿病 (T2DM )的疗效。　方法　该研究为持续 2 4周随机、开放、交叉实验 ,2 9例T2DM患者 ,随机分为诺和锐组和诺和灵R组 ,诺和锐为餐前即刻输注 ,诺和灵R为餐前 30min输注 ,12周治疗后两组交换用药。观察两种不同治疗方式患者糖化血红蛋白 (HbA1c)、8个时点 (3餐前后、睡前、凌晨 2点 )血糖、低血糖及胰岛素泵的安全性的差异。　结果　接受诺和锐治疗组的患者HbA1c指标好于诺和灵R组 (P <0 0 1)。 8个时点血糖检测显示诺和锐组三餐后及睡前血糖水平均低于诺和灵R组 (P <0 0 1～ 0 0 5 )。两组患者胰岛素用量、低血糖发生率及胰岛素泵的安全性均无差异。　结论　诺和锐与诺和灵R均可安全有效的降低血糖及HbA1c ,诺和锐用于CSⅡ控制餐后血糖更具优点。     

A double-blind randomized study comparing the effects of continuing or not continuing rosiglitazone + metformin therapy when starting insulin therapy in people with Type 2 diabetes.

AIMS: To compare the efficacy and safety of either continuing or discontinuing rosiglitazone + metformin fixed-dose combination when starting insulin therapy in people with Type 2 diabetes inadequately controlled on oral therapy. METHODS: In this 24-week double-blind study, 324 individuals with Type 2 diabetes inadequately controlled on maximum dose rosiglitazone + metformin therapy were randomly assigned to twice-daily premix insulin therapy (target pre-breakfast and pre-evening meal glucose < or = 6.5 mmol/l) in addition to either rosiglitazone + metformin (8/2000 mg) or placebo. RESULTS: Insulin dose at week 24 was significantly lower with rosiglitazone + metformin (33.5 +/- 1.5 U/day, mean +/- se) compared with placebo [59.0 +/- 3.0 U/day; model-adjusted difference -26.6 (95% CI -37.7, -15,5) U/day, P < 0.001]. Despite this, there was greater improvement in glycaemic control [HbA(1c) rosiglitazone + metformin vs. placebo 6.8 +/- 0.1 vs. 7.5 +/- 0.1%; difference -0.7 (-0.8, -0.5)%, P < 0.001] and more individuals achieved glycaemic targets (HbA(1c) < 7.0% 70 vs. 34%, P < 0.001). The proportion of individuals reporting at least one hypoglycaemic event during the last 12 weeks of treatment was similar in the two groups (rosiglitazone + metformin vs. placebo 25 vs. 27%). People receiving rosiglitazone + metformin in addition to insulin reported greater treatment satisfaction than those receiving insulin alone. Both treatment regimens were well tolerated but more participants had oedema [12 (7%) vs. 4 (3%)] and there was more weight gain [3.7 vs. 2.6 kg; difference 1.1 (0.2, 2.1) kg, P = 0.02] with rosiglitazone + metformin. CONCLUSIONS: Addition of insulin to rosiglitazone + metformin enabled more people to reach glycaemic targets with less insulin, and was generally well tolerated.     

A randomized controlled trial examining combinations of repaglinide, metformin and NPH insulin.

AIMS: To compare combination use of repaglinide, metformin and bedtime Neutral Protamine Hagedorn (NPH) insulin with conventional approaches of insulin initiation in patients with Type 2 diabetes (T2DM). METHODS: Eighty-two patients with T2DM with suboptimal glycaemic control on oral glucose-lowering agents were randomized to one of three treatment regimens for 4 months. Group 1 received metformin and twice daily biphasic 30/70 human insulin mixture (n = 27), group 2 metformin and bedtime NPH insulin (n = 26) and group 3 metformin, bedtime NPH insulin and mealtime repaglinide (n = 25). RESULTS: Seventy-five patients completed the study. Baseline and end-point mean HbA1c levels fell from 9.0 +/- 1.1 to 7.9 +/- 1.1% in group 1, 10.0 +/- 2.2 to 9.2 +/- 1.4% group 2 and 10.0 +/- 1.7 to 8.1 +/- 1.5% in group 3, respectively. All groups showed improvements in HbA1c. There was no significant difference between groups in the proportions of patients experiencing hypoglycaemia (29.6, 25.0 and 16.7%, respectively; P = 0.55) or in mean weight gain (2.9, 0.7 and 2.2 kg, respectively; P = 0.06). By 4 months, insulin doses were 0.63 +/- 0.32 IU/kg in group 1, 0.58 +/- 0.21 IU/kg in group 2 and 0.37 +/- 0.22 IU/kg in group 3 (group 3 vs. groups 1 and 2: P < 0.002). CONCLUSIONS: The approach using repaglinide, metformin and NPH insulin improved glycaemic control with a similar safety profile to conventional insulin initiation in T2DM and produced final glycaemic control similar to metformin and a twice daily biphasic insulin mixture.     

Spotlight on Insulin Aspart in Type 1 and 2 Diabetes Mellitus

Insulin aspart (NovoLog, NovoRapid), a rapid-acting human insulin analog, provides more rapid absorption than regular human insulin after subcutaneous administration. In most randomized, nonblind clinical trials in patients with type 1 diabetes mellitus, insulin aspart administered immediately before meals resulted in significantly lower mean glycosylated hemoglobin (HbA1c) levels than regular human insulin (usually administered 30 minutes before a meal). Insulin aspart also significantly improved postprandial glycemic control compared with regular human insulin. The efficacy of insulin aspart was similar to that of insulin lispro when administered to patients with type 1 diabetes mellitus via continuous subcutaneous infusion in a randomized, nonblind trial. Preliminary data from randomized, nonblind trials suggest insulin aspart had a trend towards lower HbA1c levels compared with regular human insulin in patients with type 2,diabetes mellitus. Biphasic insulin aspart (30% soluble [rapid-acting] and 70% protamine-bound insulin aspart [BIAsp30]) [NovoLog Mix 70/30, NovoMix 30(2)] generally provided significantly better postprandial glucose control than a similar mixture of biphasic regular human insulin (BHI30) in a randomized, nonblind trial in patients with type 1 or 2 diabetes mellitus. However, the long-term efficacy of BIAsp30 was similar to that of BHI30 after 2 years in a randomized, nonblind trial in patients with type 2 diabetes mellitus. Patients with type 1 or 2 diabetes mellitus reported greater treatment satisfaction with insulin aspart or BIAsp30 than with regular human insulin or BHI30. The overall incidence of hypoglycemia with insulin aspart was lower than, or similar to, that of regular human insulin. Moreover, insulin aspart tended to be associated with a lower occurrence of nocturnal hypoglycemia and severe hypoglycemic events than regular human insulin. Conclusion: The standard preparation of insulin aspart has the potential to better mimic the physiological response to meals than regular human insulin. Insulin aspart when combined with a suitable basal insulin improved overall glycemic control and led to a similar or lower number of hypoglycemic episodes compared with a similar regular human insulin regimen. Insulin aspart was generally as effective and well tolerated as insulin lispro when administered by continuous subcutaneous infusion in a single comparative trial. The efficacy of biphasic insulin aspart has been documented in a small number of trials. Both insulin aspart and biphasic insulin aspart provide for flexible and convenient administration. Insulin aspart is now well established as an effective and convenient means of providing glycemic control which offers clinical and practical advantages over regular human insulin.     

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.     

An exploratory study of the effect of using high-mix biphasic insulin aspart in people with type 2 diabetes

Objective: To compare blood glucose control when using biphasic insulin aspart (BIAsp) three times a day (using 70/30 high‐mix before breakfast and lunch), with biphasic human insulin (BHI, 30/70) twice daily in adults with type 2 diabetes already treated with insulin. Research design and methods: In a 60‐day, open‐label, crossover study, people with insulin‐treated type 2 diabetes [n = 38, baseline haemoglobin A1c 8.3 ± 0.9 (s.d.) %] were randomized to BIAsp three times a day before meals, as BIAsp 70 (70% insulin aspart and 30% protamine‐complexed insulin aspart) before breakfast and lunch and BIAsp 30 (30/70 free and protamine‐complexed insulin aspart) before dinner, or to human premix insulin (BHI) 30/70 twice a day before meals. A 24‐h in‐patient plasma glucose profile was performed at the end of each 30‐day treatment period. The total daily insulin dose of BIAsp regimen was 110% of BHI and the doses were not changed during the study. Results: There was no difference between BIAsp and BHI in geometric weighted average serum glucose over 24 h [7.3 vs. 7.7 mmol/l, BIAsp/BHI ratio 0.95 (95% CI 0.88–1.02), not significant (NS)], but daytime geometric weighted average glucose concentration was significantly lower with the BIAsp regimen than with BHI [8.3 vs. 9.2 mmol/l, BIAsp/BHI ratio 0.90 (0.84–0.98), p = 0.014]. The mealtime serum glucose excursion was also lower with BIAsp than with BHI with statistically significant differences at lunchtime [difference ?4.9 (?7.0 to ?2.7) mmol/l, p = 0.000); the difference in glucose excursions above 7.0 mmol/l was also significant [?5.8 (?8.3 to ?3.2) mmol/l, p = 0.000). The proportion of participants experiencing confirmed hypoglycaemic episodes was similar between regimens (42 vs. 43%, NS). Conclusions: An insulin regimen using high‐mix BIAsp (BIAsp 70) before breakfast and lunch and BIAsp 30 before dinner can achieve lower blood glucose levels during the day through reduced mealtime glucose excursions in particular at lunchtime than a twice‐daily premix regimen.     

Comparison of insulin lispro mixture 25/75 with insulin glargine during a 24-h standardized test-meal period in patients with Type 2 diabetes.

AIM: To compare insulin lispro mixture (25% insulin lispro and 75% NPL; Mix 25/75) twice-daily plus oral glucose-lowering medications (metformin and/or sulphonylurea) with once-daily insulin glargine plus oral agents with respect to postprandial glycaemic control and other glucose and lipid parameters in patients with Type 2 diabetes inadequately controlled with insulin and/or oral glucose-lowering agents. METHODS: This was a randomized, open-label, crossover study. Prestudy oral agents were continued and patients not already on oral agents were treated with metformin. Mix 25/75 and insulin glargine were adjusted over 3 months to attain premeal plasma glucose (PG) < 6.0 mmol/l and were then given during a 24-h in-patient test meal period with frequent PG, serum triglyceride (TG) and free fatty acid (FFA) measurements. RESULTS: Twenty patients (10 F/10 M; mean +/-sd age 54.0 +/- 10.7 years, body mass index 37.0 +/- 8.6 kg/m2, HbA1c 8.4 +/- 1.01%) participated. Mean doses were 23 U before the morning and 37 U before the evening meal for Mix 25/75 and 44 U for insulin glargine. The combined 2-h morning and evening meal postprandial plasma glucose (PPG) was not different between groups (9.2 +/- 2.04 vs. 9.9 +/- 1.66 mmol/l, P = 0.161). Mix 25/75 was associated with a lower mean 2-h PPG for all meals combined (9.0 +/- 1.88 vs. 9.9 +/- 1.80 mmol/l, P < 0.05) and lower mean 24-h PG (6.7 +/- 1.00 vs. 7.5 +/- 1.32 mmol/l, P < 0.01). Eight patients experienced mild hypoglycaemia (PG < 3.5 mmol/l) with Mix 25/75 and 3 with insulin glargine. The endpoint HbA1c was lower with Mix 25/75 (6.9 +/- 0.52% vs. 7.3 +/- 0.81%, P < 0.05). CONCLUSIONS: In a 24-h test-meal setting in 20 patients, Mix 25/75 insulin plus oral glucose-lowering agents was associated with lower mean PPG and 24-h PG, more mild hypoglycaemia and similar TG, FFA and fasting PG concentrations. HbA1c was lower with Mix 75/25 plus oral agents, although it may not have reached steady state due to ongoing dose adjustment.     

Hypoglycaemia with insulin aspart: a double-blind, randomised, crossover trial in subjects with Type 1 diabetes.

AIMS: To compare the effects of the rapid-acting insulin analogue insulin aspart and soluble human insulin on hypoglycaemia and glycaemic control in patients with Type 1 diabetes when injected immediately before meals as part of intensive insulin therapy. METHODS: In this multinational, double-blind, randomised, crossover trial, 155 patients with Type 1 diabetes (HbA(1c) < 8.0%) were symmetrically randomised to two 16-week treatment periods on either type of insulin, both injected 0-5 min before meals. NPH insulin was given as basal insulin once or twice daily as needed, and insulin dosages were regularly adjusted using pre-defined algorithms to maintain tight glycaemic control. Treatment periods were separated by a 4-week washout. RESULTS: The rate of major nocturnal (24.00-06.00 h) hypoglycaemic episodes was 72% lower with insulin aspart than with human insulin (0.067 vs. 0.225 events/month; P = 0.001). Total rate of major hypoglycaemia did not differ significantly between treatments (insulin aspart/human insulin relative risk 0.72; 95% CI 0.47-1.09, P = 0.12). The rate of minor events was significantly reduced by 7% with insulin aspart (P = 0.048). Reductions in rate of hypoglycaemia were achieved with maintained overall glycaemic control: Mean HbA(1c) remained constant, slightly below 7.7% on both treatments. CONCLUSIONS: The use of insulin aspart in an intensive insulin regimen in patients with tightly controlled Type 1 diabetes led to clinically significant reductions in major nocturnal hypoglycaemia with no deterioration in glycaemic control. Major nocturnal hypoglycaemia appears to be a strong clinical indication for the use of rapid-acting insulin analogues during intensive insulin therapy.