Post‐prandial insulin lispro vs. human regular insulin in prepubertal children with Type 1 diabetes mellitus

Aims To study whether post‐prandial insulin lispro (PL) could be used as a part of insulin therapy instead of premeal human regular insulin (HR) in prepubertal children with Type 1 diabetes mellitus (Type 1 DM). Patients and methods In this open, randomized cross‐over study patients used either PL or HR at breakfast and at dinner. After a 1‐month screening period, patients were randomized to treatment with PL or HR for 3 months and then they crossed over to the other insulin for an additional 3 months. The patients were 24 prepubertal children with Type 1 DM (median age 6.2 years, duration of diabetes 37 months). Home monitoring of 1‐day glucose profiles at meals (premeal, 1 h and 2 h after breakfast and after dinner) and HbA_1c were measured before randomization, before cross‐over, and at the last visit. Data on hypoglycaemic episodes were collected at each of the seven visits. The variables were compared between the two treatments. Results Of the patients 22/24 completed the study. There were no major differences in the glucose excursions between PL and HR after breakfast (mean ± sd : 1‐h PL 3.7 ± 4.7 vs. HR 2.9 ± 3.9 mmol/l, P = 0.3; 2‐h ?0.9 ± 5.4 vs. 0.3 ± 4.5 mmol/l, P = 0.2, respectively) or after dinner (1‐h PL ?2.5 ± 4.8 vs. HR ?0.4 ± 3.7 mmol/l, P = 0.07, 2‐h ?4.1 ± 5.2 vs. ?0.7 ± 5.0 mmol/l, P = 0.05, respectively). Mean change of HbA_1c was similar in both treatment groups (PL 0.2 ± 0.8% vs. HR ?0.4 ± 0.7%, P = 0.1). The frequency of hypoglycaemic episodes was 4.9 per patient per month during treatment with PL, and 4.4 during HR (P = 0.3). Conclusion Treatment with post‐prandial lispro as a meal insulin is as effective and safe as traditional treatment with regular insulin in young children. Diabet. Med. 18, 654–658 (2001)     

Better long-term glycaemic control with the basal insulin glargine as compared with NPH in patients with Type 1 diabetes mellitus given meal-time lispro insulin.

BACKGROUND: Glargine is a long-acting insulin analogue potentially more suitable than NPH insulin in intensive treatment of Type 1 diabetes mellitus (T1 DM), but no study has proven superiority. The aim of this study was to test superiority of glargine on long-term blood glucose (BG) as well as on responses to hypoglycaemia vs. NPH. METHODS: One hundred and twenty-one patients with T1 DM on intensive therapy on four times/day NPH and lispro insulin at each meal, were randomized to either continuation of NPH four times/day (n = 60), or once daily glargine at dinner-time (n = 61) for 1 year. Lispro insulin at meal-time was continued in both groups. In 11 patients from each group, responses to stepped hyperinsulinaemic-hypoglycaemia were measured before and after 1 year's treatment. RESULTS: Mean daily BG was lower with glargine [7.6 +/- 0.11 mmol/l (137 +/- 2 mg/dl)] vs. NPH [8.1 +/- 0.22 mmol/l (146 +/- 4 mg/dl)] (P < 0.05). HbA(1c) at 4 months did not change with NPH, but decreased with glargine (from 7.1 +/- 0.1 to 6.7 +/- 0.1%), and remained lower than NPH at 12 months (6.6 +/- 0.1%, P < 0.05 vs. NPH). Frequency of mild hypoglycaemia [self-assisted episodes, blood glucose < or = 4.0 mmol/l (72 mg/dl)] was lower with glargine vs. NPH (7.2 +/- 0.5 and 13.2 +/- 0.6 episodes/patient-month, P < 0.05). After 1 year, NPH treatment resulted in no change of responses to hypoglycaemia, whereas with glargine plasma glucose, thresholds and maximal responses of plasma adrenaline and symptoms to hypoglycaemia improved (P < 0.05). CONCLUSIONS: The simpler glargine regimen decreases the percentage of HbA(1c) and frequency of hypoglycaemia and improves responses to hypoglycaemia more than NPH. Thus, glargine appears more suitable than NPH as basal insulin for intensive treatment of T1 DM.     

A randomized, controlled trial comparing insulin lispro with human soluble insulin in patients with Type 1 diabetes on intensified insulin therapy. The UK Trial Group.

AIMS: Despite considerable experience with insulin lispro, few blinded comparisons with soluble insulin are available. This study compared insulin lispro with human soluble insulin in patients with Type 1 diabetes mellitus on multiple injection therapy who inject shortly before meals. METHODS: Glucose control, frequency of hypoglycaemia and patient preference were examined in the course of a prospective, randomized, double-blind, crossover comparison, with a 6-week run-in period and 12 weeks on each therapy. Ninety-three patients took part, all on multiple daily doses of insulin, with soluble insulin before meals and NPH (isophane) insulin at night. The main outcome measures were self-monitored blood glucose profiles, glycated haemoglobin, frequency of hypoglycaemic episodes, patient satisfaction and well-being and patient preference. RESULTS: Blood glucose levels were significantly lower after breakfast and lunch, but higher before breakfast, lunch and supper, in patients taking insulin lispro. Levels of HbA(1c) were 7.4 +/- 1.1% on Humulin S and 7.5 +/- 1.1% on insulin lispro (P = 0.807). The overall frequency of symptomatic hypoglycaemia did not differ, but patients on insulin lispro were less likely to experience hypoglycaemia between midnight and 6 a.m., and more likely to experience episodes from 6 a.m. to midday. Questionnaires completed by 84/87 patients at the end of the study showed that 43 (51%) were able to identify each insulin correctly, nine (11%) were incorrect, and 32 (38%) were unable to tell the insulins apart. No significant preference emerged: 35 (42%) opted for insulin lispro, 24 (29%) opted for Humulin S, while the remainder had no clear preference. CONCLUSIONS: Substitution of insulin lispro for soluble insulin in a multiple injection regimen improved post-prandial glucose control at the expense of an increase in fasting and pre-prandial glucose levels. Patients who already injected shortly before meals expressed no clear preference for the fast-acting analogue, and did not improve their overall control as a result of using it. Nocturnal hypoglycaemia was however, less frequent on insulin lispro, and may emerge as a robust indication for its use.     

Basal-bolus insulin therapy in Type 1 diabetes: comparative study of pre-meal administration of a fixed mixture of insulin lispro (50%) and neutral protamine lispro (50%) with human soluble insulin.

AIMS: To ascertain whether pre-meal administration of 50% insulin lispro and 50% neutral protamine lispro (NPL), given as a fixed mixture (Humalog Mix50, human soluble (regular) insulin as a basal-bolus regimen in people with Type 1 diabetes. Both regimens included bedtime human isophane (NPH) insulin. METHODS: This was a multinational, multicentre, randomized, open-label, two-period crossover comparison of two insulin treatments for two 12-week periods in 109 patients with Type 1 diabetes. The protocol provided preliminary evaluations of dose requirements and recommendations for insulin dose adjustment when switching regimens on the basis of blood glucose (BG) values. Eight-point BG profiles, frequency of hypoglycaemia, HbA1c, insulin dose, time of injection, and frequency of snacking were assessed during each treatment. RESULTS: Total daily insulin dose was similar for both treatments, but the total pre-meal doses were higher (P < 0.001) and the bedtime dose of isophane was lower (P < 0.001) with Mix50. The pre-meal dose before breakfast and lunch, although statistically different (P = 0.006 and P < 0.001, respectively), was of similar magnitude, but the pre-evening meal dose was higher with Mix50 (P < 0.001). Median (interquartile range) time of insulin injection before meals was: Mix50 4.2 (25th percentile = 1.0; 75th percentile = 6.3) min, human soluble insulin 24.6 (25th percentile = 16.6; 75th percentile = 30.0) min. Pre-meal and bedtime BG concentrations did not differ between treatments. The BG 2 h after the evening meal was lower with Mix50 (8.40 +/- 2.95 mmol/l vs. 9.60 +/- 3.47 mmol/l) (P = 0.049). BG after breakfast and lunch, mean HbA1c, frequency of hypoglycaemia, frequency of snacks, and body weight were not different. CONCLUSION: The use of Mix50 in a basal-bolus regimen achieved similar control of pre-meal BG to human soluble insulin, and overall glycaemic control and hypoglycaemia risk were equivalent. This suggests that Mix50 can provide an adequate supply of insulin to control BG between meals while providing the convenience of injecting immediately before meals.     

What is the role of between meal snacks with intensive basal bolus regimens using preprandial lispro?

AIMS: Hypoglycaemia avoidance for patients on intensive insulin regimens requires the eating of snacks between meals. Insulin lispro with its shorter action profile may permit omitting such snacks. METHODS: Ten Type 1 diabetes mellitus (DM) patients were rendered euglycaemic with a morning intravenous insulin infusion. Each was studied on six afternoons in random order, with previously determined equal doses of Humulin S (HS) injected at -30min, or lispro injected at 0 min before a standard lunch. The snack was either eaten mid-afternoon, combined with the lunch or omitted altogether. RESULTS: Lispro and lunch with a snack combined at 0 min gave equal control to HS at -30 min and lunch at 0 min with a mid-afternoon snack. Lispro and lunch at 0 min with a mid-afternoon snack gave a lower early postprandial glucose. At 120 min glucose (mean mmol/l +/- SEM) were 7.4+/-0.8 vs. 7.0+/-1.0 (P = 1.0) and 3.9+/-0.5 (P = 0.045), respectively. The area under the insulin curve over the whole afternoon was similar for HS and lispro (13193.3+/-974.6 vs. 13193.6+/-809.9 mIU/min, P = 1.0) but with a greater peak for lispro than HS with lispro falling more rapidly. Despite significantly lower lispro levels after 180 min, intermediary metabolites concentrations were similar in all HS and lispro study days. CONCLUSIONS: Lispro injected immediately before combined snack and lunch and with no subsequent snack achieves equivalent control to conventional regimens using HS -30 min before lunch and mid-afternoon snack. Lispro taken with traditional meal patterns without dose reduction risks early postprandial hypoglycaemia and late hyperglycaemia.     

Insulin lispro: a potential role in preventing nocturnal hypoglycaemia in young children with diabetes mellitus.

AIMS: The long duration of action of soluble insulin given in the evening could contribute to the high prevalence of nocturnal hypoglycaemia seen in young children with Type 1 diabetes mellitus (T1DM). We examined whether replacing soluble insulin with insulin lispro reduced this risk in children on a three times daily insulin regimen. METHODS: Open crossover study comparing insulin lispro vs. soluble insulin in 23 (16 boys) prepubertal children (age 7-11 years) with T1DM on three injections/day; long-acting isophane insulin remained identical. At the end of each 4-month treatment arm, an overnight 15-min venous sampled blood glucose profile was performed. RESULTS: Despite similar blood glucose levels pre-evening meal (lispro vs. soluble: mean +/- se 6.5 +/- 1.0 vs. 7.1 +/- 1.1 mmol/l, P = 0.5), post-meal (18.00-22.00 h) blood glucose levels were lower on insulin lispro (area under curve 138 +/- 12 vs. 170 +/- 13 mmol min-1 l-1, P = 0.03). In contrast, in the early night (22.00-04.00 h) the prevalence of low blood glucose levels (< 3.5 mmol/l) was lower on lispro (8% of blood glucose levels) than on soluble insulin (13%, P = 0.01). In the early morning (04.00-07.00 h) mean blood glucose and prevalence of low levels were no different between the two treatment groups, and fasting (07.00 h) blood glucose levels were similar (6.1 +/- 0.8 vs. 6.3 +/- 0.9 mmol/l, P = 0.8). At the end of each treatment arm there were no differences in HbA1c (lispro vs. soluble 8.6% vs. 8.4%, P = 0.3), or in insulin doses (mean, range 0.97, 0.68-1.26 vs. 0.96, 0.53-1.22 U/kg per day, P = 0.2). CONCLUSIONS: The shorter duration of action of insulin lispro given before the evening meal may reduce the prevalence of early nocturnal hypoglycaemia without compromising HbA1c in young children with T1DM.     

Preprandial vs. postprandial insulin lispro-a comparative crossover trial in patients with Type 1 diabetes.

AIMS: Administration of bolus insulin after eating may be a useful therapeutic option for some patients. This 6-month, crossover study compared metabolic effects of routine use of preprandial vs. postprandial injection of bolus insulin lispro. METHODS: Thirty-one patients with Type 1 diabetes injected insulin lispro either preprandially or postprandially for a 3-month period followed by the alternate regimen for a further 3 months. HbA1c, fructosamine and eight-point self-determined blood glucose profiles were measured and analysed using an anova model appropriate for a crossover design. RESULTS: Mean HbA1c decreased slightly from baseline with preprandial (-0.15 +/- 0.41%) and increased slightly with postprandial (0.11 +/- 0.48%) insulin lispro so that there was a significant (P = 0.008) difference between treatments in final HbA1c level. Mean fructosamine also decreased slightly with preprandial (-15 +/- 31 micro mol/l) but was almost unchanged (1 +/- 39 micro mol/l) with postprandial insulin lispro. Overall daily blood glucose was not different (P = 0.312) for preprandial compared with postprandial administration. However, mean preprandial glucose was lower (7.5 +/- 2.01 vs. 6.6 +/- 1.22 mmol/l; P = 0.026), whereas mean postprandial glucose was higher (7.7 +/- 1.8 vs. 8.7 +/- 2.1 mmol/l; P = 0.031) with postprandial insulin lispro administration. Mean blood glucose excursions were higher with postprandial compared with preprandial insulin lispro, indicating greater daily fluctuations. No difference in incidence of hypoglycaemia was observed with the two treatment regimens. CONCLUSIONS: Postprandial insulin lispro administration appeared to be an acceptable treatment regimen and may be of benefit in certain situations. However, the benefits of postprandial administration may have to be balanced against poorer glycaemic control with continuous long-term use.     

A 75% insulin lispro/25% NPL mixture provides a longer duration of insulin activity compared with insulin lispro alone in patients with Type 1 diabetes.

AIMS: To compare a new insulin formulation, high mix (HM) [75% lispro (LP) and 25% neutral protamine lispro (NPL)], to regular human insulin (HR) and LP with respect to glucose response and pharmacokinetics following a test meal in patients with Type 1 diabetes. METHODS: After fasting overnight, patients received an intravenous insulin infusion to standardize blood glucose (BG) to 7.5 mmol/l (135 mg/dl). In a randomised, three-way crossover study, HR was injected 30 min before, and LP or HM was injected immediately before the test meal on three separate occasions. For each patient, LP and HR were administered at identical doses; the HM dose was one and one third times that of HR and LP to maintain the same dose of short or rapid-acting insulin. The insulin infusion was stopped 15 min after the insulin injection. Free insulin and BG concentrations were measured frequently for 7 h following the test meal. RESULTS: HM and LP resulted in better glycaemic control than HR during the observation period. BG concentrations during the first 4-5 h did not differ between HM and LP. However, HM exhibited prolonged insulin activity relative to LP beyond 5 h, extending the duration of action by approximately 1 h, and resulting in lower overall BG concentrations when the 0-6- and 0-7-h intervals were considered. CONCLUSIONS: Compared with LP, HM provided similar glycaemic control for up to 5 h and superior glycaemic control from 5 to 7 h following a standard test meal.     

Pregnancy outcome in Type 1 diabetes mellitus treated with insulin lispro (Humalog).

AIMS: The use of insulin lispro in pregnancy has not been systematically investigated despite its increasing use. Pooled data from seven centres with experience in the use of insulin lispro were accumulated to evaluate pregnancy outcome in women with Type 1 diabetes. METHODS: Seven units with specialist obstetric diabetes services were recruited to describe their total experience with insulin lispro in pregnancy. Outcomes with respect to the rate of miscarriage, congenital abnormality, perinatal mortality and maternal parameters were recorded in a standardized format. RESULTS: Outcomes on 71 babies from 76 pregnancies were documented. There were six (7.8%) early miscarriages. All 71 babies were liveborn with a mean gestational age of 37.2 weeks, and median birthweight of 3230 g. Seven babies weighed > 4 kg. There were four congenital abnormalities (5.6%). There was a 72% increase in the mean insulin dose (0.75-1.29 IU/kg per day). Maternal glycaemic control improved throughout pregnancy. No women developed retinopathy de novo during pregnancy and six with established retinopathy required laser therapy during pregnancy. CONCLUSIONS: The use of insulin lispro in Type 1 diabetes during pregnancy results in outcomes comparable to other large studies of diabetic pregnancy.     

Comparison of insulin detemir and insulin glargine in subjects with Type 1 diabetes using intensive insulin therapy.

AIMS: To compare glycaemic control and risk of hypoglycaemia of twice-daily insulin detemir with once-daily insulin glargine in subjects with Type 1 diabetes. METHODS: In this 26-week, multicentre, open-label, parallel-group trial, 320 subjects with Type 1 diabetes received either insulin detemir twice daily or insulin glargine once daily. each in combination with premeal insulin aspart. RESULTS: After 26 weeks, HbA(1c) had decreased from 8.8 to 8.2% in the insulin detemir group and from 8.7 to 8.2% in the insulin glargine group. Home-measured fasting plasma glucose (PG) was lower with insulin glargine than with insulin detemir (7.0 vs. 7.7 mmol/l, P < 0.001). The overall shape of the home-measured nine-point PG profiles was comparable between treatments (P = 0.125). Overall, there was no significant difference in within-subject variation in PG (P = 0.437). Within-subject variation in predinner PG was lower with insulin detemir than with insulin glargine (P < 0.05). The overall risk of hypoglycaemia was similar with no differences in confirmed hypoglycaemia. However, the risk of severe and nocturnal hypoglycaemia was 72% and 32%, respectively, lower with insulin detemir than with insulin glargine (P < 0.05). Body weight gain was not significantly different comparing insulin detemir and insulin glargine (0.52 kg vs. 0.96 kg, P = 0.193). CONCLUSIONS: Treatment with twice-daily insulin detemir or once-daily insulin glargine, each in combination with insulin aspart, resulted in similar glycaemic control. The overall risk of hypoglycaemia was comparable, whereas the risks of both severe and nocturnal hypoglycaemia were significantly lower with insulin detemir.     

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.     

An estimation of the long‐term clinical and economic benefits of insulin lispro in Type 1 diabetes in the UK

Aims To determine the long‐term health economic benefits associated with lispro vs. regular human insulin (RHI) in UK Type 1 diabetic (T1DM) patients using the previously published and validated CORE Diabetes Model. Methods A literature review designed to capture clinical benefits associated with lispro and T1DM cohort characteristics specific to UK was undertaken. Clinical benefits were derived from a Cochrane meta‐analysis. The estimated difference (weighted mean) in glycated haemoglobin (HbA_1c) was ?0.1% (95% confidence interval ?0.2 to 0.0%) for lispro vs. RHI. Severe hypoglycaemia rates for lispro and RHI were 21.8 and 46.1 events per 100 patient years, respectively. Costs and disutilities were accounted for severe hypoglycaemia rates. All costs were accounted in 2007 £UK from a National Health Service (NHS) perspective. Future costs and clinical benefits were discounted at 3.5% annually. Results In the base‐case analysis, lispro was projected to be dominant compared with RHI. Lispro was associated with improvements in quality‐adjusted life expectancy (QALE) of approximately 0.10 quality‐adjusted life years (QALYs) vs. RHI (7.60 vs. 7.50 QALYs). Lifetime direct medical costs per patient were lower with lispro treatment, £70 576 vs. £72 529. Severe hypoglycaemia rates were the key driver in terms of differences in QALE and lifetime costs. Sensitivity analyses with assumptions around time horizon, discounting rates and benefits in terms of glycaemic control or hypoglycaemic event rates revealed that lispro remained dominant. Conclusions Our findings suggest that lispro is likely to improve QALE, reduce frequency of diabetes‐related complications and lifetime medical costs compared with RHI.     

The importance of the initial period of basal insulin titration in people with diabetes

Achieving target glycaemic control is essential in people with diabetes to minimize the risk of long-term complications, and many people with type 2 diabetes will ultimately require basal insulin (BI) therapy to achieve their individualized glycaemic targets. Usually, the first 12 weeks following initiation of BI therapy represents the period when the greatest dose increases and glycaemic reductions occur. Effective glycaemic control combined with minimizing the risk of hypoglycaemia is important to enable the achievement of glycaemic control in the longer term. However, substantial therapeutic inertia exists in clinical practice, both in initiation and up-titration of BI, owing to patient-, physician- and healthcare system-related barriers, including fear of hypoglycaemia and the perception of a burdensome regimen. The more prolonged duration of action, reduced glycaemic variability and lower risk of hypoglycaemia seen with second-generation versus first-generation BI analogues may help alleviate patients’ and physicians’ concerns and facilitate titration. In turn, optimal BI titration and subsequent metabolic benefits may help improve therapy adherence and self-management. This review details the clinical implications of prompt titration of BI to achieve early glycaemic control, and the importance of minimizing hypoglycaemia risk within the initial titration period. Facilitation of patients’ self-management of BI is also addressed.     

Spontaneous hypoglycaemia after pancreas transplantation in Type 1 diabetes mellitus

Hypoglycaemia is an important complication of insulin treatment in Type 1 diabetes mellitus (DM). Pancreas transplantation couples glucose sensing and insulin secretion, attaining a distinctive advantage over insulin treatment. We tested whether successful transplantation can avoid hypoglycaemia in Type 1 DM. Combined kidney and pancreas transplanted Type 1 DM who complied with good function criteria (KP-Tx, n = 55), and isolated kidney or liver transplanted non-diabetic subjects on the same immunosuppressive regimen (CON-Tx, n = 14), underwent 1-day metabolic profiles in the first 3 years after transplantation, sampling plasma glucose (PG) and pancreatic hormones every 2 hours. KP-Tx had lower PG than CON-Tx in the night and in the morning and higher insulin concentrations throughout the day. KP-Tx had lower PG nadirs than CON-Tx (4.40 ± 0.05 vs 4.96 ± 0.16 mmol l⁻¹, ANOVA p = 0.001). Nine per cent of KP-Tx had hypoglycaemic values (PG ≤3.0 mmol l⁻¹) in the profiles, both postprandial and postabsorptive, whereas none of CON-Tx did (p < 0.02). In conclusion, after pancreas transplantation, mild hypoglycaemia is frequent, although its clinical impact is limited. Compared to insulin treatment in Type 1 DM, pancreas transplantation improves but cannot eliminate hypoglycaemia. Copyright © 1998 John Wiley & Sons, Ltd.     

Long-term efficacy and safety of insulin detemir compared to Neutral Protamine Hagedorn insulin in patients with Type 1 diabetes using a treat-to-target basal–bolus regimen with insulin aspart at meals: a 2-year,randomized, controlled trial

Aims This 24-month, multi-national, open-label, parallel group trial investigated the long-term efficacy and safety of insulin detemir and Neutral Protamine Hagedorn insulin in combination with mealtime insulin aspart in patients with Type 1 diabetes using a treat-to-target concept. Methods Patients were randomized 2 : 1 to detemir (n = 331) or NPH (n = 166) groups. Basal insulin was initiated once daily (evening) and titrated individually based on self-measured plasma glucose (PG) levels, aiming for pre-breakfast and pre-dinner targets ≤ 6.0 mmol/l. A second basal morning dose could be added according to pre-defined criteria. Results After 24 months, superiority of glycated haemoglobin (HbA_1c) was achieved with detemir compared to NPH (detemir 7.36%, NPH 7.58%, mean difference −0.22% points) [95% confidence interval (CI) −0.41 to −0.03%], with reductions of 0.94% and 0.72% points, respectively. Fasting PG (FPG_lab) was also lower with detemir (detemir 8.35 mmol/l, NPH 9.43 mmol/l; P = 0.019). Twenty-two per cent of patients treated with detemir reached an HbA_1c ≤ 7.0% in the absence of confirmed hypoglycaemia during the last month of treatment vs. 13% on NPH (P = 0.019). Risk of major and nocturnal hypoglycaemia was 69% and 46% lower with detemir than with NPH (P < 0.001), respectively; patients treated with detemir gained less weight (detemir 1.7 kg, NPH 2.7 kg; P = 0.024). The overall safety profile was similar in the two groups and treatment with detemir did not result in any unexpected findings. Conclusions Long-term treatment with the insulin analogues detemir + aspart was superior to NPH + aspart in reducing HbA_1c, with added benefits of less major and nocturnal hypoglycaemia and less weight gain.     

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.     

Comparison of insulin lispro protamine suspension versus insulin glargine once daily in basal-bolus therapies with insulin lispro in type 2 diabetes patients: a prospective randomized open-label trial

Aims: To compare the efficacy and safety of insulin lispro protamine suspension (ILPS) versus insulin glargine once daily in a basal‐bolus regimen in type 2 diabetes mellitus (T2DM) patients. Methods: Three hundred eighty‐three insulin‐treated patients were randomized to either ILPS plus lispro or glargine plus lispro in this open‐label 24‐week European study. Insulin doses were titrated to predefined blood glucose (BG) targets. Non‐inferiority of ILPS versus glargine was assessed by comparing the upper limit of the 95% confidence interval (CI) for the change of HbA1c from baseline to week 24 (adjusted for country and baseline HbA1c) with the non‐inferiority margin of 0.4%. Secondary endpoints included HbA1c categories, BG profiles, insulin doses, hypoglycaemic episodes, adverse events and vital signs. Results: Non‐inferiority of ILPS versus glargine in the change of HbA1c from baseline was shown: least‐square mean between‐treatment difference (95% CI) was 0.1% (?0.11; 0.31). Mean changes at week 24 were ?1.05% (ILPS) and ?1.20% (glargine). HbA1c <7.0% was achieved by 21.7 versus 29.4% of patients. Mean basal/mealtime insulin doses at week 24 were 29.6/36.2 IU/day (ILPS) versus 32.8/42.2 IU/day (glargine); the difference was not statistically significant for total dose (p = 0.7). In both groups, 56.1/25.7% versus 63.6/19.3% of patients experienced any/nocturnal hypoglycaemia (p = 0.2 for both). No relevant differences were noted in any other variables. Conclusions: A basal‐bolus regimen with ILPS once daily resulted in non‐inferior glycaemic control compared to a similar regimen with glargine, without statistically significant or clinically relevant differences in hypoglycaemia. ILPS‐based regimens can be considered an alternative to basal‐bolus regimens with glargine for T2DM patients.