Efficacy and safety of fast‐acting insulin aspart in comparison with insulin aspart in type 1 diabetes (onset 1): A 52‐week,randomized, treat‐to‐target,phase III trial

Aims

To compare the safety and efficacy of fast‐acting insulin aspart (faster aspart) with conventional insulin aspart (IAsp) in adults with type 1 diabetes (T1D).

Materials and methods

onset 1 was a randomized, multicentre, treat‐to‐target, phase III, 52‐week (initial 26 weeks + additional 26 weeks) trial conducted at 165 sites across 9 countries. Adults with T1D were randomly allocated to double‐blind mealtime faster aspart or IAsp, each with once‐ or twice‐daily insulin detemir. The primary endpoint, change in glycated haemoglobin (HbA1c) from baseline after the initial 26 weeks, has been reported previously. In the present paper, we report data from the full 52‐week study period.

Results

Between August 2013 and June 2015, 381 participants were assigned to double‐blind faster aspart and 380 participants to IAsp. After 52 weeks, estimated mean changes from baseline in HbA1c levels were ?0.08% (faster aspart) and +0.01% (IAsp); estimated treatment difference significantly favoured faster aspart (?0.10% [95% confidence interval {CI} ?0.19;?0.00]; P = .0424). Changes from baseline in 1‐hour postprandial plasma glucose (PPG) increment (meal test; faster aspart ?1.05 mmol/L; IAsp ?0.14 mmol/L) also significantly favoured faster aspart (estimated treatment difference ?0.91 mmol/L [95% CI ?1.40;?0.43]; ?16.48 mg/dL [95% CI ?25.17;?7.80]; P = .0002). There was no difference in overall severe or blood glucose‐confirmed hypoglycaemic episodes or treatment‐emergent adverse events between treatments.

Conclusions

At 52 weeks, overall glycaemic control had significantly improved with faster aspart vs IAsp, consistent with the 26‐week study findings. Achieving an insulin profile closer to physiological insulin secretion with faster aspart translates into lower PPG and HbA1c levels compared with those achieved with IAsp in people with T1D.     

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.     

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.     

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。     

Use of fast-acting insulin aspart in insulin pump therapy in clinical practice

Fast-acting insulin aspart (faster aspart) is a novel formulation of insulin aspart (IAsp) containing the additional excipients niacinamide and L-arginine. The improved pharmacological profile and greater early glucose-lowering action of faster aspart compared with IAsp suggests that faster aspart may be advantageous for people with diabetes using continuous subcutaneous insulin infusion (CSII). The recent onset 5 trial was the first to evaluate the efficacy and safety of an ultra-fast-acting insulin in CSII therapy in a large number of participants with type 1 diabetes (T1D). Non-inferiority of faster aspart to IAsp in terms of change from baseline in HbA1c was confirmed, with an estimated treatment difference (ETD) of 0.09% (95% CI, 0.01; 0.17; P < 0.001 for non-inferiority [0.4% margin]). Faster aspart was superior to IAsp in terms of change from baseline in 1-hour post-prandial glucose (PPG) increment after a meal test (ETD [95% CI], −0.91 mmol/L [−1.43; −0.39]; P = 0.001), with statistically significant improvements also at 30 minutes and 2 hours. The overall rate of severe or blood glucose-confirmed hypoglycaemia was not statistically significantly different between treatments, with an estimated rate ratio of 1.00 (95% CI, 0.85; 1.16). A numerical imbalance in severe hypoglycaemic episodes between faster aspart and IAsp was seen in the treatment (21 vs 7) and the 4-week run-in periods (4 vs 0). Experience from clinical practice indicates that all pump settings should be reviewed when initiating faster aspart with CSII, and that the use of continuous glucose monitoring or flash glucose monitoring, along with a good understanding of meal content and bolus type, may also facilitate optimal use. This review summarizes the available clinical evidence for faster aspart administered via CSII and highlights practical considerations based on clinical experience that may help healthcare providers and individuals with T1D successfully initiate and adjust faster aspart with CSII.     

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.     

Post-prandial administration of the insulin analogue insulin aspart in patients with Type 1 diabetes mellitus.

AIMS: In intensified insulin therapy, the recent development of short-acting insulin analogues with a very rapid onset of action forces a new discussion in terms of the optimal injection-meal interval. This study evaluated prandial glycaemia in patients with Type 1 diabetes following the subcutaneous injection of soluble human insulin (HI) and the insulin analogue insulin aspart (IAsp) at different injection-meal intervals and investigated whether administration of IAsp after the meal might provide satisfactory metabolic control. METHODS: In a randomized, double-blind, double-dummy, four-period crossover study, 20 Type 1 diabetic patients were investigated. Prandial insulin was administered 15 min before the start of the meal (HI(-15min)), immediately before the meal (HI(0min); IAsp(0min)) and 15 min after the start of the meal (IAsp(+15min)). RESULTS: Plasma glucose excursions from baseline levels during the 4 h (PGexc) were highest with HI(0min) (17.9 mmol.l(-1).h; P < 0.05 vs. other treatments) and were not statistically different for HI(-15min), IAsp(0min) and IAsp(15min) (13.6, 11.9 and 14.2 mmol.l(-1).h, respectively). Maximum concentration of plasma glucose (PGmax) was lowest with IAsp(0min) (11.2 mmol/l; P < 0.05 vs. other treatments). PGmax was comparable with HI(-15min), HI(0min) and IAsp(+15min) (13.3, 14.1 and 13.2 mmol/l, respectively). CONCLUSIONS: With regard to prandial glycaemia IAsp(+15min) is as effective as HI(-5min) and superior to HI(0min). Thus, post-prandial dosing of the insulin analogue IAsp offers an attractive and feasible therapeutic option for well-controlled patients with Type 1 diabetes mellitus.     

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.     

Greater early postprandial suppression of endogenous glucose production and higher initial glucose disappearance is achieved with fast‐acting insulin aspart compared with insulin aspart

Aim

To investigate the mechanisms behind the lower postprandial glucose (PPG) concentrations achieved with fast‐acting insulin aspart (faster aspart) than with insulin aspart (IAsp).

Materials and methods

In a randomized, double‐blind, crossover trial, 41 people with type 1 diabetes received identical subcutaneous single faster aspart and IAsp doses (individualized for each participant), together with a standardized mixed meal (including 75 g carbohydrate labelled with [1‐¹³C] glucose). PPG turnover was determined by the triple‐tracer meal method using continuous, variable [6‐³H] glucose and [6,6‐²H₂] glucose infusion.

Results

Insulin exposure within the first hour was 32% greater with faster aspart than with IAsp (treatment ratio faster aspart/IAsp 1.32 [95% confidence interval {CI} 1.18;1.48]; P < .001), leading to a 0.59‐mmol/L non‐significantly smaller PPG increment at 1 hour (ΔPG_1h; treatment difference faster aspart–IAsp ?0.59 mmol/L [95% CI –1.19; 0.01]; P = .055). The trend towards reduced ΔPG_1h with faster aspart was attributable to 12% greater suppression of endogenous glucose production (EGP; treatment ratio 1.12 [95% CI 1.01; 1.25]; P = .040) and 23% higher glucose disappearance (1.23 [95% CI 1.05; 1.45]; P = .012) with faster aspart than with IAsp during the first hour. Suppression of free fatty acid levels during the first hour was 36% greater for faster aspart than for IAsp (1.36 [95% CI 1.01;1.88]; P = .042).

Conclusions

The trend towards improved PPG control with faster aspart vs IAsp in this study was attributable to both greater early suppression of EGP and stimulation of glucose disappearance.     

Prandial insulin substitution with insulin lispro or insulin lispro mid mixture vs. basal therapy with insulin glargine: a randomized controlled trial in patients with type 2 diabetes beginning insulin therapy

PURPOSE: To compare the effects of prandial insulin therapy focusing on postprandial glucose control vs. basal insulin therapy focusing on fasting glucose control in patients with type 2 diabetes. METHODS: This was an open-label, randomized, parallel, three-arm multicenter trial in patients with type 2 diabetes starting insulin treatment. Patients (n=159) were randomly assigned to 24-week treatment with 3x daily insulin lispro, 3x daily lispro mid mixture (MidMix; 50% lispro, 50% protaminated lispro), or 1x daily insulin glargine; oral antihyperglycemic agents were discontinued. Primary end point was the postprandial glucose excursion 2 h after breakfast at the end of study. Secondary outcomes included HbA1c, self-monitored blood glucose profiles, hypoglycemic episodes, body weight, and patient satisfaction. RESULTS: At the end of study, glucose excursions 2 h after breakfast were significantly lower with lispro and MidMix than with glargine (P<.001 for each vs. glargine): lispro, -0.6+/-2.0 mmol/l; MidMix, +0.8+/-2.4 mmol/l; glargine, +2.5+/-2.4 mmol/l. Fasting glucose decreases were significantly greater with glargine (-2.6+/-2.4 mmol/l) than with lispro or MidMix (-0.9+/-2.2 mmol/l; +0.9+/-1.8 mmol/l). Nevertheless, HbA1c decreased by 1.1% (lispro) and 1.2% (MidMix), vs. 0.3% with glargine. Hypoglycemic episodes were rare with 1-1.5 self-reported episodes per 100 patient-days. CONCLUSIONS: In patients with type 2 diabetes starting insulin, 3x daily prandial treatment with a rapid-acting analog focusing on postprandial glucose values enabled better control of postprandial and circadian blood glucose profiles than once-daily glargine, in spite suboptimal fasting glucose levels, which targets fasting glucose values. These results support studies suggesting that control of postprandial hyperglycemia plays a key role in achieving HbA1c targets.     

Insulin aspart improves meal time glycaemic control in patients with Type 2 diabetes: a randomized, stratified, double-blind and cross-over trial.

AIMS: This randomized, multi-centre, double-blind, stratified, two period, cross-over trial was undertaken to assess the pharmacokinetics and pharmacodynamics of insulin aspart injected immediately before compared with regular human insulin injected 30 min before a Mediterranean-style meal in 37 (23 M, 14 F) patients with Type 2 diabetes. METHODS: Insulin aspart or regular human insulin was given subcutaneously (0.15 U/kg) in random sequence, using a double-dummy technique (at one visit: human regular insulin at t=-30 min and placebo at t=0; at the other visit: placebo at t=-30 min and aspart insulin at t=0). Serum glucose and insulin concentrations (15 points) were measured after each meal for 240 min. RESULTS: Post-prandial glycaemic excursions were 20% lower with insulin aspart (IAsp) compared with regular human insulin (HI) treatment [ratio (Iasp/HI)=0.80, CI=(0.66-0.98), P=0.034]. The maximum serum glucose (SG) concentration was similar for the two treatments (P=NS). The (median) time to maximum SG was 25 min shorter for IAsp compared with HI (P=0.048). Maximum serum insulin concentration was higher after IAsp compared with HI (P=0.023) as well as the area under the 4-h serum insulin curve (P=0.006). Furthermore, the time to maximum serum insulin concentration was 27 min shorter after IAsp (P=0.039), even though IAsp was injected 30 min after HI. No adverse events occurred during the trial. CONCLUSIONS: In patients with Type 2 diabetes a more favourable insulin profile and a better glycaemic control were found with IAsp injected immediately before compared with HI injected 30 min before a Mediterranean-style meal.     

Insulin detemir and insulin aspart: a promising basal-bolus regimen for type 2 diabetes

This trial compared the efficacy and safety of basal-bolus therapy using either the soluble basal insulin analogue insulin detemir (IDet) in combination with meal-time rapid-acting analogue insulin aspart (IAsp), or NPH insulin (NPH) in combination with meal-time regular human insulin (HSI). This was a 22-week, multinational, open-labelled, symmetrically randomised, parallel group trial including 395 people with type 2 diabetes (IDet + IAsp: 195, NPH + HSI: 200). At 22 weeks, HbA1c was comparable between treatments (IDet + IAsp: 7.46%, NPH + HSI: 7.52%, P = 0.515) with decreases from baseline of 0.65% and 0.58%, respectively. Treatment with IDet + IAsp was associated with a significantly lower within-person variation in self-measured fasting plasma glucose (FPG) (SD:1.20 versus 1.54 mmol/L, p < 0.001), as well as a lower body weight gain (0.51 versus 1.13 kg, p = 0.038) than with NPH + HSI. The risk of nocturnal hypoglycaemia was 38% lower with IDet + IAsp than with NPH + HSI, but statistical significance was not attained (P = 0.14). The overall safety profile was similar between the two treatments. Basal-bolus treatment with IDet + IAsp is an effective and well tolerated insulin regimen in people with type 2 diabetes, resulting in glycaemic control comparable to that of NPH + HSI, but with the advantages of less weight gain and a lower day-to-day within-person variation in FPG.     

Antibody response to insulin in children and adolescents with newly diagnosed Type 1 diabetes

Aims To compare levels of insulin antibodies in children and adolescents after initiation of insulin therapy using either insulin aspart (IAsp) or human insulin (HI) in combination with Neutral Protamine Hagedorn (NPH) insulin, and to investigate the relationships between insulin antibodies and HbA_1c and insulin dose. Methods IAsp‐specific antibodies (IAsp‐Ab) and antibodies cross‐reacting with HI and IAsp (HI‐cross‐Ab) were analysed by radioimmunoassay at diagnosis of diabetes and every 3–6 months for 30 months. Seventy‐two patients (HI = 30, IAsp = 42) with Type 1 diabetes, aged 2–17 years were included. Data on HbA_1c, insulin dose and serious adverse events (SAEs) were collected retrospectively. Results IAsp‐Ab levels remained low throughout the study. After 9 months, the level of HI‐cross‐Ab increased [mean (sd ) HI, 48.8% (21.53); IAsp, 40.2% (17.92)] and remained elevated. Repeated measurement analysis of HI‐cross‐Ab levels showed no significant difference between treatments (P = 0.16). HI‐cross‐Ab were significantly associated with total insulin dose (U/kg) (P = 0.001) and time (P < 0.0001), but not with HbA_1c (P = 0.24). Mean (± sd ) HbA_1c was similar at diagnosis (HI 9.5 ± 1.97%; IAsp 9.6 ± 1.62%); HbA_1c then decreased and stabilized to about 6.0% in both groups. Few SAEs were reported, the majority being hypoglycaemic episodes. Conclusions Treatment with IAsp and with HI was associated with an increase in HI‐cross‐Ab in insulin‐naive children, but this did not influence treatment efficacy or safety. These results support the safe use of IAsp in children and adolescents with Type 1 diabetes.     

Short-term fully closed-loop insulin delivery using faster insulin aspart compared with standard insulin aspart in type 2 diabetes

We evaluated the efficacy and safety of short-term fully closed-loop insulin delivery using faster versus standard insulin aspart in type 2 diabetes. Fifteen adults with insulin-treated type 2 diabetes underwent 22 hours of closed-loop insulin delivery with either faster or standard insulin aspart in a double-blind randomized crossover design. Basal-bolus regimen was replaced by model predictive control algorithm-directed insulin delivery based on sensor glucose levels. The primary outcome was time with plasma glucose in target range (5.6–10.0 mmol/L) and did not differ between treatments (mean difference [95% CI] 3.3% [−8.2; 1.7], P = 0.17). Mean glucose and glucose variability were comparable, as was time spent below and above target range. Hypoglycaemia (<3.5 mmol/L) occurred once with faster insulin aspart and twice with standard insulin aspart. Mean total insulin dose was higher with faster insulin aspart (mean difference [95% CI] 3.7 U [0.7; 6.8], P = 0.021). No episodes of severe hypoglycaemia or other serious adverse events occurred. In conclusion, short-term fully closed-loop in type 2 diabetes may require higher dose of faster insulin aspart compared with standard insulin aspart to achieve comparable glucose control.     

Insulin detemir lowers the risk of hypoglycaemia and provides more consistent plasma glucose levels compared with NPH insulin in Type 1 diabetes.

AIMS: Hypoglycaemia remains a major barrier preventing optimal glycaemic control in Type 1 diabetes due to the limitations of conventional insulin preparations. We investigated whether basal-bolus therapy with insulin detemir (detemir), a new soluble basal insulin analogue, was more effective in reducing the risk of hypoglycaemia compared with NPH insulin (NPH). METHODS: In this multinational, open-label, cross-over trial, 130 individuals with Type 1 diabetes received detemir and NPH twice daily in a randomized order in combination with premeal insulin aspart (IAsp) during two 16-week treatment periods. Risk of hypoglycaemia was based on self-measured plasma glucose (SMPG) and self-reported episodes during the last 10 weeks of each period. RESULTS: Risk of nocturnal and overall hypoglycaemia was, respectively, 50% and 18% lower with detemir than with NPH (P < 0.001). A total of 19 severe hypoglycaemic episodes occurred during treatment with detemir compared with 33 with NPH (NS). HbA(1c) decreased by 0.3% point with both treatments and was comparable at 7.6% (+/- sem 0.06%, 95% confidence interval -0.106, 0.108) after 16 weeks with similar doses of basal insulin. Within-person variation in mean plasma glucose was lower with detemir than with NPH (sd 3.00 vs. 3.33, P < 0.001), as was prebreakfast SMPG (P < 0.0001). CONCLUSIONS: Detemir was associated with a significantly lower risk of hypoglycaemia compared with NPH at similar HbA1c when used in combination with mealtime IAsp. The more consistent plasma glucose levels observed with detemir may allow people to aim for tighter glycaemic control without an increased risk of hypoglycaemia.     

Effect of the rapid-acting insulin analogue insulin aspart on quality of life and treatment satisfaction in patients with Type 1 diabetes.

AIMS: To compare quality of life (QoL) and treatment satisfaction in patients with Type 1 diabetes receiving the rapid-acting insulin analogue, insulin aspart (IAsp), with that in patients receiving soluble human insulin (HI). METHODS: In this 6-month, multinational, randomized, open-label trial, 424 patients from German-speaking countries were subjected to psychometric assessment before and after randomization (ratio 2 : 1) to basal-bolus treatment with either IAsp (n = 283) or HI (n = 141). Patients on HI were advised to keep an injection-meal interval of 30 min, whereas patients on IAsp were advised to inject immediately before meals. Treatment satisfaction and diabetes-related QoL were assessed using validated instruments to measure the domains of patients' individual treatment goals, physical complaints, worries about the future, social relations, leisure time flexibility, daily hassles, diet restrictions, burdens and fear of hypoglycaemia, blood glucose fluctuations, self-efficacy, and fear of insulin analogues. RESULTS: After 6 months, IAsp was associated with significantly greater improvement in treatment satisfaction than HI in two different scales (P < 0.01), and in QoL with respect to diet restrictions (P < 0.01). Improved satisfaction was mainly due to increased dietary and leisure time flexibility (P < 0.0001). Twenty-three percent of the IAsp group vs. 14% of the HI group achieved small but important improvements of total QoL (between-group difference, P < 0.06). The number needed to treat (NNT) with IAsp for an important increase in QoL was calculated to be 10. Regression analyses of potential predictors of improvement in QoL highlighted patients intensely striving for physical strength (P < 0.01; NNT = 7) and patients feeling less protected against hypoglycaemia (P < 0.005; NNT = 8) as being the most likely to benefit from IAsp. CONCLUSIONS: Under these study conditions, IAsp improved treatment satisfaction and quality of life regarding diet restrictions when compared with human insulin. The 'numbers needed to treat' for important quality of life benefits indicate that the effect of IAsp in this regard is not trivial.     

A comparison of mealtime insulin aspart and human insulin in combination with metformin in type 2 diabetes patients

This randomized, open-label, cross-over study compares the efficacy of mealtime rapid-acting analog insulin aspart with human insulin, in combination with metformin. A total of 30 patients with type 2 diabetes, inadequately controlled (HbA(1c)>7.5%) with oral hypoglycemic agents (OHAs), were assigned to human insulin 30 min before meals or aspart immediately before meals, both with metformin 500 mg t.i.d. for 90 days. Patients then switched to the alternate insulin. At 90 and 180 days, blood glucose and lipids were measured at baseline and every 30 min after test meals, for 3h. HbA(1c) and hypoglycemic events were also assessed. After 3 months, HbA(1c) was significantly reduced with aspart, but not human insulin (-0.4+/-0.7% versus +0.1+/-0.7%, p<0.05). During meal tests, blood glucose area under the curve (AUC) was significantly lower with aspart than human insulin (1240+/-476 min/mmol/l versus 1588+/-766 min/mmol/l, p<0.01). AUCs for lipids were similar for both treatments. Neither group experienced serious hypoglycemic events. These results encourage treatment with mealtime insulin aspart plus metformin, in type 2 diabetes patients with postprandial hyperglycemia inadequately controlled by OHAs alone.     

地特胰岛素与门冬胰岛素30起始治疗老年2型糖尿病伴轻度认知障碍患者的疗效比较

目的比较地特胰岛素与门冬胰岛素30起始治疗老年2型糖尿病伴轻度认知障碍(mild cognitive impairment,MCI)患者的有效性、安全性及对认知功能的影响。方法采用随机数字表法将100例老年2型糖尿病伴MCI患者分为地特胰岛素组和门冬胰岛素30组,每组50例。地特胰岛素组继续口服降糖药治疗,予地特胰岛素睡前注射;门冬胰岛素30组停用口服降糖药,予门冬胰岛素30早餐前和晚餐前皮下注射。治疗24周,观察空腹血糖(FPG)、餐后2 h血糖(2hPG)、糖化血红蛋白(HbA1c)、胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL-C)、血压、体重、体重指数(BMI)及蒙特利尔认知评估(MoCA)量表评分的变化,并记录血糖达标、低血糖及痴呆发生情况。结果两组治疗后FPG、2hPG、HbA1c、LDL-C均显著降低(P<0.05),且地特胰岛素组2hPG、HbA1c降低程度大于门冬胰岛素30组(P<0.05)。两组治疗前后TC、TG、血压、体重、BMI比较差异均无统计学意义(P>0.05)。地特胰岛素组血糖达标率高于门冬胰岛素30组(P<0.05)。两组患者治疗后低血糖发生少而轻微,不良反应发生率比较,差异无统计学意义(P>0.05),两组治疗前后MoCA量表评分比较,差异无统计学意义(P>0.05)。结论地特胰岛素与门冬胰岛素30起始治疗老年2型糖尿病伴MCI患者均安全、有效,可作为胰岛素起始治疗的首选用药。     

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.     

Twice-daily compared with once-daily insulin glargine in people with Type 1 diabetes using meal-time insulin aspart.

AIM: To compare blood glucose control when using insulin glargine twice daily at breakfast- and dinner-times with insulin glargine once daily at dinner time, in unselected people with Type 1 diabetes using insulin aspart at meal-times. METHODS: In this 8-week, two-way, cross-over study, 20 people with Type 1 diabetes were randomized to insulin glargine injection once daily at dinner-time or twice daily at breakfast- and dinner-times, both plus meal-time insulin aspart. Each 4-week treatment period concluded with a 24-h inpatient metabolic profile. RESULTS: Insulin doses, HbA1c, fructosamine concentration and pre-breakfast self-monitored blood glucose (SMBG) concentration did not differ between treatment periods. SMBG concentrations after breakfast, after lunch and before dinner were lower with twice-daily compared with once-daily dinner-time glargine [9.3 +/- 0.5 (+/- se) vs. 6.7 +/- 0.5 mmol/l, P = 0.003; 10.2 +/- 0.9 vs. 7.0 +/- 0.9 mmol/l, P = 0.024; 9.6 +/- 0.5 vs. 6.6 +/- 0.5 mmol/l, P = 0.001]. Mean 24-h SMBG concentration was lower with twice-daily glargine (7.1 +/- 0.5 vs. 8.8 +/- 0.5 mmol/l, P = 0.031). Within-day variability of SMBG concentration was lower with twice-daily glargine (sd 3.2 +/- 0.2 vs. 4.0 +/- 0.3 mmol/l, P = 0.044). Plasma free insulin concentration was higher in the afternoon with twice-daily glargine (21.9 +/- 1.4 vs. 16.1 +/- 1.3 mU/l, P = 0.009), but lower overnight (12.1 +/- 1.7 vs. 17.8 +/- 1.7 mU/l, P = 0.030), compared with once-daily injection. Plasma glucose concentration overnight was higher with twice-daily compared with once-daily glargine (mean 9.0 +/- 0.4 vs. 6.6 +/- 0.4 mmol/l, P = 0.001). CONCLUSIONS: Blood glucose concentration rises in the late afternoon in association with falling plasma insulin levels towards the end of the 24-h period after insulin glargine injection in some people with Type 1 diabetes using once-daily glargine at dinner-time plus a rapid-acting insulin analogue at meal-times. This is prevented by twice-daily injection of insulin glargine.