Optimal timing of injection of once-daily insulin glargine in people with Type 1 diabetes using insulin lispro at meal-times.

AIMS: To compare blood glucose control when insulin glargine is given at lunch-time, dinner-time, and bed-time in people with Type 1 diabetes using insulin lispro at meal-times. METHODS: In this 16-week, three-way, cross-over study, 23 people with Type 1 diabetes were randomized to insulin glargine injection at lunch-time (L) [mean 12.37 +/- 00.34 (+/- sd) h], dinner-time (D) (18.12 +/- 00.40 h), or bed-time (B) (22.29 +/- 00.40 h), each plus meal-time insulin lispro. Each 4-week treatment period concluded with a 24-h inpatient metabolic profile. RESULTS: Insulin doses, HbA(1c), and fructosamine concentration did not differ between treatment periods. Pre-breakfast self-monitored blood glucose (SMBG) concentration was higher with injection of glargine at lunch-time than at other times [L: 9.2 +/- 0.3 (+/- se) vs. D: 8.2 +/- 0.3 or B: 8.0 +/- 0.3 mmol/l, P = 0.016], as probably was pre-lunch SMBG (L: 8.6 +/- 0.7 vs. D: 6.4 +/- 0.7 or B: 6.4 +/- 0.8 mmol/l, P = 0.051). Pre-dinner SMBG level was higher with dinner-time glargine than other injection times (D: 9.4 +/- 0.9 vs. L: 4.9 +/- 0.9 or B: 7.4 +/- 1.1 mmol/l, P = 0.007). For 22.00 to 02.00 h, mean inpatient plasma glucose concentration was higher with injection of glargine at bed-time than other times (B: 9.1 +/- 0.6 vs. L: 7.8 +/- 0.6 or D: 6.7 +/- 0.6 mmol/l, P = 0.023). Plasma free insulin concentration was lower at the end of the afternoon with dinner-time glargine than other injection times (D: 11.5 +/- 1.4 vs. L: 20.2 +/- 1.3 or B: 16.5 +/- 1.3 mU/l, P < 0.001). Frequency of hypoglycaemia was not different, but timing of hypoglycaemia differed between treatment periods. CONCLUSIONS: Blood glucose levels rise around the time of injection of insulin glargine whether given at lunch-time, dinner-time or bed-time. Bed-time injection leads to hyperglycaemia in the early part of the night which is improved by giving insulin glargine at lunch-time or dinner-time.     

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.     

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.     

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.     

Improvement of blood glucose control in Type 1 diabetic patients treated with lispro and multiple NPH injections.

AIMS: To evaluate a multiple daily injections (MDI) regimen combining lispro with multiple NPH insulin injections in order to replace basal insulin optimally. METHODS: Twenty-five C-peptide negative Type 1 patients already trained to MDI were randomized to lispro (lispro + NPH 5 min before breakfast and lunch, lispro before dinner, NPH at bedtime) or soluble insulin (20-30 min before each meal and NPH at bed-time) for 3 months before crossing over to the other regimen for another 3 months. The mean initial HbA1c level was 8.32+/-1.5%. RESULTS: The variability of capillary blood glucose values was significantly lower with lispro (MAGE 0.75+/-0.36 g/l vs. 0.99+/-0.50, P<0.01; MODD 0.64+/-0.26 g/l vs. 0.80+/-0.40, P<0.05). There was a nonsignificant reduction in HbA1c with lispro: -0.40+/-0.86 vs. -0.08+/-0.71. Mean daily blood glucose levels were significantly lower with lispro (1.53+/-0.48 g/l vs. 1.82+/-0.57 g/l, P<0.05). The frequency of all hypoglycaemic episodes was the same with both regimens but the number of severe hypoglycaemic events was reduced with lispro, P = 0.048. At the end of the study, 75% of the patients chose the lispro associated with multiple NPH regimen for their own treatment. The total insulin doses was the same with both regimens but the proportion of NPH was higher with lispro (53% vs. 34%). CONCLUSIONS: An MDI regimen using lispro combined with multiple NPH compared to a standard MDI regimen using soluble insulin reduced day-to-day blood glucose fluctuations, was generally preferred by patients and was associated with a reduced incidence of severe hypoglycaemia with no loss of overall control.     

A randomized pilot study in Type 1 diabetes complicated by severe hypoglycaemia, comparing rigorous hypoglycaemia avoidance with insulin analogue therapy, CSII or education alone.

AIM: To determine potential for amelioration of recurrent severe hypoglycaemia without worsening in overall control in individuals with long-standing Type 1 diabetes (T1DM). METHODS: Twenty-one people with T1DM characterized by altered hypoglycaemia awareness and debilitating severe hypoglycaemia were randomized in a pilot 24-week prospective study to optimized analogue therapy (ANALOGUE; lispro/glargine); continuous subcutaneous insulin infusion therapy (CSII; lispro); or re-education with relaxation of blood glucose targets on existing conventional insulin regimen (EDUCATION). Glycaemic profiles and duration of biochemical hypoglycaemia were measured by continuous subcutaneous glucose monitoring and self-monitored blood glucose. RESULTS: Further severe hypoglycaemia was prevented in five participants (71%) in each group (P = 0.06). Incidence of severe hypoglycaemia was: 0.6 (ANALOGUE), 0.9 (CSII), and 3.7 (EDUCATION) episodes per patient year. Restoration of hypoglycaemia awareness was confirmed by validated questionnaire in three (43%) ANALOGUE, four (57%) CSII and five (71%) EDUCATION patients. Glycated haemoglobin (HbA1c) was significantly improved in the ANALOGUE group between weeks 0 and 24 (8.6 +/- 1.1 vs. 7.6 +/- 0.8%; P = 0.04 for change). Non-significant improvement was seen in the CSII group (8.5 +/- 1.9 vs. 7.4 +/- 1.0%; P = 0.06). No change in HbA1c was seen in the EDUCATION group (8.5 +/- 1.1 vs. 8.3 +/- 1.0%; P = 0.54). There were no episodes of diabetic ketoacidosis or any other adverse events in any group. CONCLUSIONS: In this pilot randomized trial comparing optimized ANALOGUE, CSII or EDUCATION alone in unselected individuals with recurrent severe hypoglycaemia, we show potential for restoring hypoglycaemia awareness and preventing further severe hypoglycaemia with concomitant improvement in glycaemic control in ANALOGUE and CSII groups.     

Twice-daily pre-mixed insulin rather than basal insulin therapy alone results in better overall glycaemic control in patients with Type 2 diabetes.

AIMS: To compare the glycaemic control of an insulin lispro mixture (25% insulin lispro and 75% NPL) twice daily in combination with metformin to that of once-daily insulin glargine plus metformin in patients with Type 2 diabetes inadequately controlled with intermediate insulin, or insulin plus oral agent(s) combination therapy. RESEARCH DESIGN AND METHODS: Ninety-seven patients were randomized in a multicentre, open-label, 32-week crossover study. Primary variables evaluated: haemoglobin A1c (A1c), 2-h post-prandial blood glucose (BG), hypoglycaemia rate (episodes/patient/30 days), incidence (% patients experiencing > or = 1 episode) of overall and nocturnal hypoglycaemia. RESULTS: At endpoint, A1c was lower with the insulin lispro mixture plus metformin compared with glargine plus metformin (7.54% +/- 0.87% vs. 8.14% +/- 1.03%, P < 0.001). Change in A1c from baseline to endpoint was greater with the insulin lispro mixture plus metformin (-1.00% vs. -0.42%; P < 0.001). Two-hour post-prandial BG was lower after morning, midday, and evening meals (P < 0.001) during treatment with the insulin lispro mixture plus metformin. The fasting BG values were lower with glargine plus metformin (P = 0.007). Despite lower BG at 03.00 hours (P < 0.01), patients treated with the insulin lispro mixture plus metformin had a lower rate of nocturnal hypoglycaemia (0.14 +/- 0.49 vs. 0.34 +/- 0.85 episodes/patient/30 days; P = 0.002), although the overall hypoglycaemia rate was not different between treatments (0.61 +/- 1.41 vs. 0.44 +/- 1.07 episodes/patient/30 days; P = 0.477). CONCLUSION: In patients with Type 2 diabetes and inadequate glucose control while on insulin or insulin and oral agent(s) combination therapy, treatment with a twice-daily insulin lispro mixture plus metformin, which targets both post-prandial and pre-meal BG, provided clinically significant improvements in A1c, significantly reduced post-prandial BG after each meal, and reduced nocturnal hypoglycaemia as compared with once-daily glargine plus metformin, a treatment that targets fasting BG.     

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

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

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.     

Preprandial combination of lispro and NPH insulin improves overall blood glucose control in type 1 diabetic patients: a multicenter randomized crossover trial

BACKGROUND AND AIM: While lispro insulin has been reported to lower postprandial blood glucose concentrations, less consistent effects have been shown for glycosylated hemoglobin (HbA1c) levels. Aim of this study was to determine whether pre-meal association of NPH, an intermediate-acting insulin, with lispro improves overall glycemic control in type 1 diabetic patients. METHODS AND RESULTS: Eighty-five type 1 diabetic patients were studied in a multicenter randomized comparative (human regular vs lispro insulin) crossover (3-month) study in which NPH insulin was given as a dinner or bedtime injection and at breakfast and lunch if necessary. The number of injections was kept constant: 42% and 58% of patients injected insulin 3 and 4 times per day, respectively. Fasting and preprandial blood glucose levels were similar, while postprandial levels improved after lispro compared to human regular insulin (breakfast: 8.28 +/- 2.39 vs 9.28 +/- 2.72 mmol/l; lunch: 8.33 +/- 2.67 vs 9.06 +/- 2.67 mmol/l, dinner: 8.06 +/- 2.72 vs 9.28 +/- 2.44 mmol/l, ANOVA: p = 0.003). HbA1c also improved after lispro: 8.1 +/- 0.9 vs 8.3 +/- 0.8%, p < 0.05. The rate of hypoglycemia was similar. Patients showed better acceptance of lispro treatment (p < 0.001). CONCLUSIONS: Lispro improves overall blood glucose control in type 1 diabetic patients without increasing the incidence of hypoglycemia. This can be achieved by an optimal combination of lispro insulin with NPH whenever the time intervals between meals are too long.     

Insulin lispro (Lys(B28), Pro(B29) in the treatment of diabetes during the fasting month of Ramadan. Ramadan Study Group.

AIMS: To compare insulin lispro with soluble human insulin in patients with Type 2 diabetes mellitus fasting during Ramadan, with respect to the rate of hypoglycaemic episodes and postprandial blood glucose values after the main meal after sunset. METHODS: The insulins were compared in an open-label, randomized, cross-over study of 70 outpatients. Hypoglycaemic episodes were recorded by the patients in a self-monitoring diary. Fasting, 1-h and 2-h postprandial blood glucose values were recorded by the patient on three consecutive days at the end of each treatment period. RESULTS: The fasting blood glucose values before sunrise (P>0.4) and after sunset (P>0.6) were similar and did not differ significantly between both treatment groups. The rise in blood glucose after the main meal after sunset was 3.0+/-0.4 mmol/l after 1 h in the insulin lispro treatment group compared to 4.3+/-0.4 mmol/l in the soluble insulin treatment group (P<0.01), and 2.6+/-0.4 mmol/l after 2h with insulin lispro compared to 4.0+/-0.5 mmol/l with soluble insulin (P<0.008). Mean hypoglycaemic episodes per patient over 14 days were 1.3+/-0.1 vs. 2.6+/-0.2, P<0.002, respectively, for insulin lispro and soluble insulin. Most hypoglycaemic episodes occurred during the time period from 6 h after the before sunrise meal until breaking the fast after sunset. CONCLUSIONS: The significantly lower rate of hypoglycaemic episodes combined with better control of postprandial blood glucose suggest insulin lispro may be more suitable prandial insulin for patients treated with Type 2 diabetes who fast during Ramadan.     

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.     

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.     

Efficacy of Humalog injections before an afternoon meal and their acceptance by children and adolescents with type 1 diabetes.

AIMS: To evaluate the acceptability and efficacy of an injection of insulin lispro, before an afternoon meal. METHODS: The subjects, 43 patients with Type 1 diabetes, 16 boys and 27 girls, aged 12.4 +/- 2.4 years, were randomly assigned to the treatment (n = 20) or the untreated control group (n = 23). The treatment was an injection of insulin lispro immediately before the afternoon meal. The control group had no injection. The treatment and the control group consumed identical types of meals for 2 months. The mean before-dinner blood glucose was measured during the last 2 weeks of the study. RESULTS: Injection of insulin lispro resulted in a significant reduction in the before-dinner blood glucose compared with the untreated control group (10.4 +/- 3.8 mmol/l vs. 14.7 +/- 3.9 mmol/l, respectively). The number of days on which the blood glucose was > 10 mmol/l was reduced by half in the insulin lispro group. The difference in HbA1c between baseline and endpoint differed slightly but significantly between the two groups, in boys. Treated patients ate the meal less frequently (11.4 +/- 3.0 times per 15 days) than the control patients (14.4 +/- 0.6 times per 15 days) and injected themselves with insulin 8.9 +/- 3.6 times per 15 days. The HbA1c increased significantly with the number of meals taken without injection. There was no statistically significant difference in the frequency of hypoglycaemia or changes in weight between the two groups. CONCLUSIONS: We conclude that an injection of insulin lispro before the afternoon meal can effectively lower the before-dinner blood glucose, and in boys also lowers the HbA1c. Patients were satisfied with the lower blood glucose before dinner, and did not find the insulin lispro injection difficult. However, compliance with the protocol procedures decreased during a subsequent 6-month period.     

Insulin lispro therapy in pregnancies complicated by type 1 diabetes mellitus

OBJECTIVE: To compare the efficacy and safety of preprandial administration of rapid-acting lispro analogue with regular short-acting insulin to pregnant women with type 1 diabetes. STUDY DESIGN: Open randomised multicentre study. Women were treated with multiple insulin injections aiming at normoglycaemia. Blood glucose was determined six times daily, HbA(1c) every 4 weeks. Diurnal profiles of blood glucose were analysed at gestational week 14 and during the study period at weeks 21, 28 and 34. PARTICIPANTS: 33 pregnant women with type 1 DM were randomised to treatment with lispro insulin (n=16) or regular insulin (n=17). RESULTS: Blood glucose was significantly lower (P<0.01) after breakfast in the lispro group, while there were no significant group differences in glycemic control during the rest of the day. Severe hypoglycaemia occurred in two patients in the regular group but biochemical hypoglycaemia (blood glucose <3.0 mmol/l) was more frequent in the lispro than in the regular group (5.5 vs. 3.9%, respectively). HbA(1c) values at inclusion were 6.5 and 6.6% in the lispro and regular group respectively. HbA(1c) values declined during the study period and were similar in both groups. There was no perinatal mortality. Complications during pregnancy, route of delivery and foetal outcome did not differ between the groups. Retinopathy progressed in both groups, one patient in the regular group developed proliferative retinopathy. CONCLUSION: The results suggest that it is possible to achieve at least as adequate glycemic control with lispro as with regular insulin therapy in type 1 diabetic pregnancies.     

Glargine is superior to neutral protamine Hagedorn for improving glycated haemoglobin and fasting blood glucose levels during intensive insulin therapy

AIM: To compare glycaemic control and symptomatic hypoglycaemia rates with glargine versus neutral protamine Hagedorn (NPH) in poorly controlled type 1 diabetes patients. METHODS: Patients (n = 125) received preprandial insulin lispro and either glargine (n = 62) or NPH (n = 63) at bedtime for 30 weeks in a multicentre, randomized, single-blind (a blinded investigator made titration decisions) study. Basal insulin dosage was titrated to achieve fasting blood glucose (FBG) values < 5.5 mmol/L. RESULTS: Baseline characteristics were similar for the two groups (mean diabetes duration 17.5 +/- 10.1 years) except mean glycated haemoglobin (HbA(1c)), which was lower in the glargine versus NPH group (9.2 +/- 1.1% vs 9.7 +/- 1.3%; P < 0.02). At end-point, mean HbA(1c) was 8.3 versus 9.1% for the glargine versus NPH groups. Adjusted least-squares mean (LSM) change from baseline was -1.04 versus -0.51%, a significant treatment benefit of 0.53% for HbA(1c) in favour of glargine (P < 0.01). Mean baseline FBG were similar for the glargine and NPH groups (11.2 vs 11.4 mmol/L). The means for end-point FBG were 7.9 versus 9.0 mmol/L. Adjusted LSM change from baseline was -3.46 versus -2.34 mmol/L, with a significant difference of 1.12 mmol/L in favour of glargine (P < 0.05). There were similar total numbers of daytime mild, moderate or severe hypoglycaemia episodes in the two treatment arms. However, significantly fewer moderate or severe nocturnal hypoglycaemic episodes were observed in the glargine group (P = 0.04 and P = 0.02). CONCLUSION: Glargine is superior to NPH for improving HbA(1c) and FBG levels during intensive insulin therapy in patients with type 1 diabetes, and is associated with less severe nocturnal hypoglycaemia.     

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.     

Efficacy and safety of insulin glulisine in Japanese patients with type 1 diabetes mellitus

Aim: The rapid‐acting insulin analogue insulin glulisine (glulisine) was compared with insulin lispro (lispro) for efficacy and safety in Japanese patients with type 1 diabetes mellitus (T1DM), using insulin glargine (glargine) as basal insulin. Methods: This was an open, randomized, parallel‐group, comparative non‐inferiority study. The primary efficacy measure was change in adjusted mean haemoglobin A1c (HbA1c) from baseline to endpoint. Safety and treatment satisfaction using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) were also assessed. Patients were treated for 28 weeks with either glulisine or lispro administered 0–15 min before a meal. Doses were titrated to obtain 2‐h postprandial plasma glucose (2h‐PPG) of 7.11–9.55 mmol/l (128–172 mg/dl). All patients were concomitantly treated with glargine at bedtime, titrated to obtain a fasting (prebreakfast) plasma glucose level of 5.27–7.11 mmol/l (95–128 mg/dl). Results: Baseline mean HbA1c values were similar for the glulisine (n = 132) and lispro (n = 135) groups (7.44 and 7.50% respectively). From baseline to endpoint, adjusted mean HbA1c increased by 0.10% in the glulisine group and by 0.04% in the lispro group. Non‐inferiority of glulisine compared with lispro was shown. There were no significant differences between glulisine and lispro in adjusted mean 2h‐PPG [glulisine, 9.06 mmol/l (163 mg/dl) vs. lispro, 8.13 mmol/l (146 mg/dl); p = 0.065] and change in adjusted mean daily rapid‐acting insulin dose (glulisine, 0.26 U vs. lispro, 0.26 U; p = 0.994) at study endpoint. There was a significant difference for change in adjusted mean daily basal insulin dose from baseline to study endpoint (glulisine, –0.54 U vs. lispro, 0.26 U; p = 0.013). The most common serious adverse events were hypoglycaemia‐related events (hypoglycaemia, hypoglycaemic seizure and hypoglycaemic coma) with no difference observed between the two groups [glulisine, 6.8% (9/132) vs. lispro, 4.4% (6/135); p = 0.437]. No noteworthy differences were observed for change in insulin antibodies from baseline to endpoint. Assessment of treatment satisfaction score and perceived frequency of hyperglycaemia and hypoglycaemia by DTSQ showed no changes from baseline in either group. Conclusions: Glulisine was as effective as lispro with respect to change in HbA1c and was well tolerated when used in combination with glargine in Japanese patients with T1DM.     

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.     

A novel insulin formulation with a more rapid onset of action

AIMS/HYPOTHESIS: This study evaluates the pharmacodynamic and pharmacokinetic properties of the novel ultra-fast insulin product VIAject, a formulation of human soluble insulin and generally recognised as safe ingredients designed to increase the rate of absorption. METHODS: We performed five euglycaemic glucose clamps (Biostator; target blood glucose 5 mmol/l) in ten healthy volunteers. Using a crossover design with a fixed treatment order, 12 IU human soluble insulin, 12 U insulin lispro and 12 IU ultra-fast insulin were injected s.c. in the abdominal region on three study days. On the other two study days, 6 and 3 IU ultra-fast insulin were injected. RESULTS: Subcutaneous injection of 12 IU ultra-fast insulin resulted in a time-action profile characterised by an even more rapid onset of action and maximal metabolic activity than insulin lispro: time to early half-maximal activity was 33 +/- 17 min (mean +/- SD) vs insulin lispro 51 +/- 13 min vs human soluble insulin 66 +/- 15 min (p < 0.05 ultra-fast insulin相似文献