Effect of the fast-acting insulin analog lispro on the risk of nocturnal hypoglycemia during intensified insulin therapy. U.K. Lispro Study Group. Severe hypoglycaemia in patients with type 1 diabetes and impaired awareness of hypoglycaemia: a comparative study of insulin lispro and regular human insulin. Insulin lispro is as effective as regular insulin in optimising metabolic control and preserving beta-cell function at onset of type 1 diabetes mellitus. Improved postprandial glycemic control during treatment with Humalog Mix25, a novel protamine-based insulin lispro formulation. Humalog Mix25 Study Group. Improved postprandial blood glucose control and reduced nocturnal hypoglycemia during treatment with two novel insulin lispro-protamine formulations, insulin lispro mix25 and insulin lispro mix50. Mix50 Study Group. Comparison of insulin lispro with regular human insulin for the treatment of type 1 diabetes in adolescents. Use of insulin aspart, a fast-acting insulin analog, as the mealtime insulin in the management of patients with type 1 diabetes. A comparison of insulin lispro and buffered regular human insulin administered via continuous subcutaneous insulin infusion pump. Insulin lispro: a potential role in preventing nocturnal hypoglycaemia in young children with diabetes mellitus. Efficacy, safety, and pump compatibility of insulin aspart used in continuous subcutaneous insulin infusion therapy in patients with type 1 diabetes. Use of the short-acting insulin analogue lispro in intensive treatment of type 1 diabetes mellitus: importance of appropriate replacement of basal insulin and time-interval injection-meal. Improved blood glucose variability, HbA1c insuman Infusat and less insulin requirement in IDDM patients using insulin lispro in CSII. The Swedish Multicenter Lispro Insulin Study. Metabolic and immunologic effects of insulin lispro in gestational diabetes. Contribution of postprandial versus interprandial blood glucose to HbA1c in type 1 diabetes on physiologic intensive therapy with lispro insulin at mealtime. Mealtime treatment with insulin analog improves postprandial hyperglycemia and hypoglycemia in patients with non-insulin-dependent diabetes mellitus. Multicenter Insulin Lispro Study Group. Improved mealtime treatment of diabetes mellitus using an insulin analogue. Multicenter Insulin Lispro Study Group. Reduction of postprandial hyperglycemia and frequency of hypoglycemia in IDDM patients on insulin-analog treatment. Multicenter Insulin Lispro Study Group. Treatment with insulin lispro changes the insulin profile but does not affect the plasma concentrations of IGF-I and IGFBP-1 in type 1 diabetes. Health-related quality-of-life results from multinational clinical trials of insulin lispro. Assessing benefits of a new diabetes therapy. Premixed insulin aspart 30 vs. premixed human insulin 30/70 twice daily: a randomized trial in Type 1 and Type 2 diabetic patients. Efficacy of insulin lispro in combination with NPH human insulin twice per day in patients with insulin-dependent or non-insulin-dependent diabetes mellitus. Multicenter Insulin Lispro Study Group. The effect of improved post-prandial blood glucose control on post-prandial metabolism and markers of vascular risk in people with Type 2 diabetes. Use of insulin lispro in continuous subcutaneous insulin infusion treatment. Results of a multicenter trial. German Humalog-CSII Study Group. Insulin lispro therapy in pregnancies complicated by type 1 diabetes mellitus. Metabolic efficacy of preprandial administration of Lys(B28), Pro(B29) human insulin analog in IDDM patients. A comparison with human regular insulin during a three-meal test period. Effect of insulin lispro on glycaemic control in Chinese diabetic patients receiving twice-daily regimens of insulin. Lispro insulin in type 1 diabetic patients on a Mediterranean or normal diet: a randomized, cross-over comparative study with regular insulin. Comparison of insulin aspart with buffered regular insulin and insulin lispro in continuous subcutaneous insulin infusion: a randomized study in type 1 diabetes. 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. Humalog Mix25 improves 24-hour plasma glucose profiles compared with the human insulin mixture 30/70 in patients with type 2 diabetes mellitus. Insulin lispro in CSII: results of a double-blind crossover study. Improved glycemic control with insulin aspart: a multicenter randomized double-blind crossover trial in type 1 diabetic patients. UK Insulin Aspart Study Group. Post-prandial insulin lispro vs. human regular insulin in prepubertal children with Type 1 diabetes mellitus. Effects of a fixed mixture of 25% insulin lispro and 75% NPL on plasma glucose during and after moderate physical exercise in patients with type 2 diabetes. Effect of the rapid-acting insulin analogue insulin aspart on quality of life and treatment satisfaction in patients with Type 1 diabetes. Human insulin analogue [LYS(B28), PRO(B29)]: the ideal pump insulin? Insulin lispro lowers postprandial glucose in prepubertal children with diabetes. Insulin lispro improves postprandial glucose control in patients with diabetes mellitus. Insulin aspart vs. human insulin in the management of long-term blood glucose control in Type 1 diabetes mellitus: a randomized controlled trial. A comparative study of insulin lispro and human regular insulin in patients with type 2 diabetes mellitus and secondary failure of oral hypoglycemic agents. Special management of insulin lispro in continuous subcutaneous insulin infusion in young diabetic children: a randomized cross-over study. Preprandial combination of lispro and NPH insulin improves overall blood glucose control in type 1 diabetic patients: a multicenter randomized crossover trial. Maternal metabolic control and perinatal outcome in women with gestational diabetes treated with regular or lispro insulin: comparison with non-diabetic pregnant women. Comparison of additional metformin or NPH insulin to mealtime insulin lispro therapy with mealtime human insulin therapy in secondary OAD failure. A direct efficacy and safety comparison of insulin aspart, human soluble insulin, and human premix insulin (70/30) in patients with type 2 diabetes. Reduced frequency of severe hypoglycemia and coma in well-controlled IDDM patients treated with insulin lispro. The Benelux-UK Insulin Lispro Study Group.
To measure the effectiveness of insulin lispro, a fast-acting insulin analog, in reducing hypoglycemic episodes when used in a basal bolus regimen by patients with type 1 diabetes using intensive insulin therapy.
                In 11 diabetes outpatient clinics in the U.K., 165 subjects with type 1 diabetes were enrolled in a randomized crossover open-label study with a 2-month run-in period and then treated with a basal bolus regimen. Patients used human NPH insulin at night with either premeal insulin lispro for 4 months followed by human regular insulin for another 4 months or human regular insulin for 4 months followed by insulin lispro for another 4 months. The main outcome measures were the number of hypoglycemic episodes during both treatments and HbA1c level.
                A total of 135 patients were randomized, with 68 receiving insulin lispro and 67 receiving human regular insulin for the first 4 months. The data for the first 4 months of treatment only were compared as two independent groups because of a period effect and a treatment-period interaction. Glycemic control was equally tight during treatment with human regular insulin (HbA1c, 6.2 +/- 0.8%) and insulin lispro (6.0 +/- 0.9%). A total of 1,156 hypoglycemic episodes occurred during treatment with human regular insulin compared with 775 hypoglycemic episodes that occurred during treatment with insulin lispro (P = 0.04). This difference was chiefly because of a reduced number of nocturnal episodes (181 vs. 52, P = 0.001) in the insulin lispro group.
                The use of a fast-acting insulin analog, insulin lispro, as part of a basal bolus regimen reduces nocturnal hypoglycemia in patients with type 1 diabetes who maintain tight glycemic control during intensive insulin therapy. To assess the potential of insulin lispro to limit the frequency of severe hypoglycaemia without compromising glycaemic control in a cohort of patients with type 1 diabetes who are at a high risk of severe hypoglycemia. Research design and methods An open-label, randomised, 12-month comparative crossover study of insulin lispro and regular human insulin was performed in 33 patients with type 1 diabetes with impaired hypoglycaemia awareness. The efficacy of each treatment was evaluated by glycaemic control (HbA(1c)), eight-point home blood glucose profiles, and the frequency and severity of hypoglycaemic episodes and quality of life.
                Eighteen (55%) patients experienced one or more episodes of severe hypoglycaemia in the 48 weeks of study. There was a trend to a lower incidence of severe hypoglycaemia during treatment with insulin lispro in comparison with regular human insulin (55 vs 84 episodes, p=0.087). This resulted principally from a 47% lower incidence of nocturnal severe hypoglycaemia with insulin lispro (25 vs 47 episodes, p=0.11). The lower frequency of severe hypoglycaemia associated with insulin lispro was not explained by differences in glycated haemoglobin between insulin treatments (HbA(1c) 9.1% insulin lispro vs 9.3% regular human insulin).
                In individuals with type 1 diabetes, who have impaired awareness of hypoglycaemia, treatment with insulin lispro may be associated with a lower incidence of severe hypoglycaemia manifested predominantly through less frequent nocturnal episodes. Insulin lispro may have a beneficial role in the management of patients with diabetes at risk of severe hypoglycaemia, although a larger study is required to confirm these findings.
                Copyright 2001 John Wiley & Sons, Ltd. The aim of the study was to examine the effects of intensive insulin therapy using lispro on metabolic control, immunogenicity and beta-cell function of newly diagnosed type 1 diabetic subjects in comparison with intensive insulin therapy using regular insulin. An open study was conducted in 45 newly diagnosed type 1 diabetic subjects. Patients were randomly assigned to intensive insulin therapy using insulin lispro (lispro) (lispro, n=22; 22.8 years) or intensive insulin therapy using regular insulin (regular) (regular, n=23; 24.4 years): three to five injections of subcutaneous rapid-acting insulin before meals and Neutral Protamine Hagedorn (NPH) before dinner/bed-time. GAD, IA2, insulin antibodies, basal and stimulated plasma C-peptide and HbA(1c) were measured initially and at months 1, 4, 8 and 12. Daily blood glucose profiles tended to be lower in the lispro group, particularly values after breakfast, without reaching statistical significance. There were no differences in terms of HbA(1c) throughout the study. The proportion of subjects achieving an HbA(1c)<6% at the end of the study was similar in both groups (regular 73.9%, lispro 68.0%). The number of mild hypoglycemic episodes tended to be lower with lispro, but not significantly. beta-Cell function was not significantly different in both groups. During follow-up there were no differences in antibodies, including IAAb. In summary, insulin lispro used in intensive insulin therapy is as effective as regular insulin in optimizing metabolic control and preserving beta-cell function at diagnosis of type 1 diabetes. Humalog Mix25 is a manufactured premixed insulin formulation containing insulin lispro and a novel insulin lispro-protamine formulation (NPL) in a ratio of 25:75%. The objective of this study was to compare Humalog Mix25 to human insulin 30/70 (30% regular insulin/70% NPH) with respect to glycemic control.
                Humalog Mix25 was compared with human insulin 30/70 in 89 individuals with type 2 diabetes during a 6-month randomized open-label two-period crossover study. Each insulin was administered twice daily, before the morning and evening meals. Information regarding self-monitored blood glucose (BG), hypoglycemic episodes (hypoglycemic signs or symptoms or BG < or = 3.0 mmol/l), insulin dose, and HbA1c was collected.
                Treatment with Humalog Mix25 resulted in better postprandial glycemic control after the morning and evening meals compared with treatment with human insulin 30/70. Overall glycemic control and the incidence of hypoglycemia were comparable between the treatments.
                In comparison to treatment with human insulin 30/70, twice daily administration of Humalog Mix25 resulted in improved postprandial glycemic control, similar overall glycemic control, and the convenience of dosing immediately before meals. The objective of this 6-month, open-label, randomized, two-period crossover study was to compare glycemic control when patients were treated with (1) 2 manufactured premixed insulin formulations containing insulin lispro and a novel insulin lispro-protamine formulation, neutral protamine lispro (NPL), and (2) 2 manufactured premixed human insulin formulations, human insulin 50/50 and human insulin 30/70. One hundred individuals, 37 with type 1 diabetes mellitus (12 females, 25 males; mean age, 39.4 years; mean body mass index [BMI], 24.8; mean duration of diabetes, 12.9 years) and 63 with type 2 diabetes mellitus (33 females, 30 males; mean age, 59.0 years; mean BMI, 28.4; mean duration of diabetes, 12.6 years), were treated with insulin lispro mixtures. Insulin lispro Mix50 (50% insulin lispro/50% NPL) and human insulin 50/50 (50% regular insulin/50% neutral protamine Hagedorn [NPH] insulin) were administered before breakfast; insulin lispro Mix25 (25% insulin lispro/75% NPL) and human insulin 30/70 (30% regular insulin/70% NPH) were administered before dinner. Blood glucose (BG), hypoglycemic episodes (hypoglycemic signs or symptoms or BG <3.0 mmol/L), insulin dose and timing of dose before meals, and hemoglobin A1c were measured. Mean doses of insulin lispro and human insulin mixtures were similar overall and for both diabetes subgroups. However, compared with human insulin mixtures, twice-daily administration of insulin lispro mixtures resulted in improved postprandial glycemic control, similar overall glycemic control, and less nocturnal hypoglycemia, as well as offering the convenience of dosing closer to meals. Although insulin lispro (insulin LP) has been shown to improve postprandial blood glucose (BG) control and reduce hypoglycemic episodes in adult patients with type I diabetes, there appear to have been few clinical studies focusing on its use in adolescents.
                This study compared the effects of insulin LP with those of regular human insulin (insulin R) on postprandial BG control and hypoglycemia in adolescents with type diabetes.
                In this crossover, open-label study, adolescents between the ages of 9 and 18 years who had reached Tanner stage II puberty were randomized to receive either insulin LP immediately before meals or insulin R 30 to 45 minutes before meals, in addition to daily intermediate-acting insulin. After 4 months, patients were switched to the alternate treatment sequence. Eight-point BG profiles, hypoglycemia rate, and glycosylated hemoglobin (HbA1c) were measured at baseline and end point.
                Four hundred eighty-one adolescents participated in the study at 53 investigative sites in 15 countries; 463 were randomized to treatment (228 insulin LP, 235 insulin R), and 457 completed the study. Insulin LP given before breakfast resulted in significantly lower mean (+/-SD) 2-hour postprandial BG levels compared with insulin R (9.7 +/- 4.0 mmol/L vs 10.6 +/- 4.3 mmol/L, respectively; P < 0.001). Insulin LP given before dinner resulted in significantly lower 2-hour postprandial BG levels compared with insulin R (8.6 +/- 3.5 mmol/L vs 9.3 +/- 3.7 mmol/L; P = 0.003). No differences were seen between treatments in 2-hour postprandial BG levels after the midday meal. Mean baseline HbA1c values were similar between sequence groups, and no between-group difference in HbA1c was observed at end point (insulin LP, 8.69% +/- 1.52%; insulin R, 8.70% +/- 1.65%). Treatment with insulin LP resulted in a significantly lower incidence of hypoglycemic episodes per patient per 30 days compared with insulin R (4.02 +/- 4.5 vs 4.37 +/- 4.5, respectively; P = 0.023) and significantly fewer hypoglycemic episodes between midnight and 6 AM (1.0 +/- 1.9 vs 1.7 +/- 2.6; P < 0.001).
                In adolescents with type 1 diabetes, insulin LP significantly improved postprandial glycemic control and reduced episodes of nocturnal hypoglycemia compared with insulin R. Insulin LP was well tolerated and effective as part of an intensified insulin regimen in this study population. To compare long-term glycemic control and safety of using insulin aspart (IAsp) with that of regular human insulin (HI).
                This was a multicenter randomized open-label 6-month study (882 subjects) with a 6-month extension period (714 subjects) that enrolled subjects with type 1 diabetes. Subjects administered IAsp immediately before meals or regular HI 30 min before meals; basal NPH insulin was taken as a single bedtime dose in the majority of subjects. Glycemic control was assessed with HbA1c values and 8-point blood glucose profiles at 3-month intervals.
                Mean postprandial blood glucose levels (mg/dl +/- SEM) were significantly lower for subjects in the IAsp group compared with subjects in the HI group after breakfast (156 +/- 3.4 vs. 185 +/- 4.7), lunch (137 +/- 3.1 vs. 162 +/- 4.1), and dinner (153 +/- 3.1 vs. 168 +/- 4.1), when assessed after 6 months of treatment. Mean HbA1c values (% +/- SEM) were slightly, but significantly, lower for the IAsp group (7.78% +/- 0.03) than for the regular HI group (7.93% +/- 0.05, P = 0.005) at 6 months. Similar postprandial blood glucose and HbA1c values were observed at 12 months. Adverse events and overall hypoglycemic episodes were similar for both treatment groups.
                Postprandial glycemic control was significantly better with IAsp compared with HI after 6 and 12 months of treatment. The improvement was not obtained at an increased risk of hypoglycemia. HbA1c was slightly, but significantly, lower for IAsp compared with HI at 6 and 12 months. This study compared glycemic control achieved with insulin lispro or buffered regular human insulin in patients with Type 1 diabetes treated with continuous subcutaneous insulin infusion (CSII) using an external insulin pump. In this 24-week multicenter, randomized, two-way crossover, open-label trial, 58 patients on CSII with adequate glycemic control received either insulin lispro or buffered regular human insulin for 12 weeks, followed by the alternate treatment for another 12 weeks. Efficacy and safety measures included hemoglobin A(1c) (HbA(1c)) at baseline and endpoint, home blood glucose monitoring, hypoglycemia, and frequency of pump catheter occlusion. Patients consumed a standard test meal on three occasions, with determinations of fasting, 1- and 2-h postprandial glucose values. Insulin lispro use was associated with a significantly lower HbA(1c) than was buffered regular human insulin (7.41+/-0.97 vs. 7.65+/-0.85 mmol/l; P=.004). Fasting serum glucose values before the test meal were similar between the two therapies. The 1-h (11.16+/-4.29 vs. 13.20+/-4.68 mmol/l; P=.012) and 2-h (9.64+/-4.10 vs. 12.53+/-4.64 mmol/l; P=.001) postprandial glucose concentrations were significantly lower during treatment with insulin lispro. No differences between treatments were observed in basal or bolus insulin doses, weight gain, or the incidence and rate of hypoglycemia, hyperglycemia, or pump occlusions. When used in external pumps, insulin lispro provides better glycemic control than buffered regular human insulin with a similar adverse event profile. 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.
                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.
                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).
                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. The purpose of this study was to compare the efficacy, safety and pump compatibility of insulin aspart (a rapid-acting insulin analog) and buffered regular human insulin in patients with type 1 diabetes undergoing continuous subcutaneous insulin infusion (CSII) therapy.
                This was a single-center randomized open-label study Patients received CSII therapy with insulin aspart (n = 19) or buffered regular human insulin (n = 10) for 7 weeks. Bolus doses of insulin aspart were administered immediately before meals and buffered regular human insulin 30 min before meals.
                Insulin aspart and buffered regular human insulin were both effective in controlling average daily blood glucose levels (8.2 +/- 1.9 and 8.5 +/- 2.1 mmol/l, respectively) (mean +/- SD) and maintaining serum fructosamine (343 +/- 25.7 and 336 +/- 27.4 micromol/l) and HbA1c (6.9 +/- 0.6 and 7.1 +/- 0.6%) levels. Possible obstructions and set leakages were infrequently reported in both groups. Similar numbers of patients experienced hypoglycemia (blood glucose <2.5 mmol/l): 14 (74%) insulin aspart patients versus 6 (60%) buffered regular human insulin patients. Patients receiving insulin aspart had fewer hypoglycemic events per patient (2.9) than those patients receiving buffered regular human insulin (6.2). There were no differences between the two insulins in the occurrence of hyperglycemic events (blood glucose >19 mmol/l) or in the number and type of adverse events.
                Insulin aspart and buffered regular human insulin were effective and well tolerated and provided similar pump compatibility when used in CSII therapy. To establish whether lispro may be a suitable short-acting insulin preparation for meals in intensive treatment of Type 1 diabetes mellitus (DM) in patients already in chronic good glycaemic control with conventional insulins, 69 patients on intensive therapy (4 daily s.c. insulin injections, soluble at each meal, NPH at bedtime, HbA1c <7.5%) were studied with an open, cross-over design for two periods of 3 months each (lispro or soluble). The % HbA1c and frequency of hypoglycaemia were assessed under four different conditions (Groups I-IV). Lispro was always injected at mealtime, soluble 10-40 min prior to meals (with the exception of Group IV). Bedtime NPH was continued with both treatments. When lispro replaced soluble with no increase in number of daily NPH injections (Group I, n = 15), HbA1c was no different (p = NS), but frequency of hypoglycaemia was greater (p < 0.05). When NPH was given 3-4 times daily, lispro (Group II, n = 18), but not soluble (Group III, n = 12) decreased HbA1c by 0.35 +/- 0.25% with no increase in hypoglycaemia. When soluble was injected at mealtimes, HbA1c increased by 0.18 +/- 0.15% and hypoglycaemia was more frequent than when soluble was injected 10-40 min prior to meals (Group IV, n = 24) (p < 0.05). It is concluded that in intensive management of Type 1 DM, lispro is superior to soluble in terms of reduction of % HbA1c and frequency of hypoglycaemia, especially for those patients who do not use a time interval between insulin injection and meal. However, these goals cannot be achieved without optimization of basal insulin. The aim of the study was to compare lispro (LP) and Insuman(R) (I) insulin in continuous subcutaneous insulin infusion (CSII) therapy with respect to blood glucose control as expressed by the standard deviation of blood glucose (SD(BG) ) and HbA(1c) and to monitor the well-being (WBQ) and treatment satisfaction (DTSQ) parameters during such treatment. Forty-one IDDM patients who had used CSII for at least 6 months participated in an open-label, randomized, cross-over, multicenter study for 4 months (2 months LP and 2 months I or vice versa). Boluses with LP were given 5 min before each meal and with I 30 min before each meal. During LP administration compared with I, the SD(BG) of all blood glucose values (3.6 mmol/l vs. 3.9 mmol/l, p=0.012), as well as the SD(BG) of the postprandial, blood glucose values (3.6 mmol/l vs. 4.0 mmol/l, p=0.006), were significantly reduced. The HbA(1c) was significantly lower during LP administration (7.4% vs. 7.6%, p=0.047). The incidence of hypoglycemic events per 30 days (capillary blood glucose<3.0 mmol/l and/or symptoms) did not significantly differ between LP and I (9.7 vs. 8.0 per month, p=0.23). The total amount of daily insulin was slightly but significantly lower with LP, compared to I (38.0 IU vs. 40.3 IU, p=0.004). There was no treatment effects of LP compared to I concerning WBQ and DTSQ. It is concluded that in CSII therapy LP is superior to I with respect to the stability of blood glucose control, a lower HbA(1c), a less insulin requirement without increasing the frequency of hypoglycemia. To compare the immunologic response to insulin lispro with that to regular human insulin, thereby assuring its safety for use in women with gestational diabetes, and to verify that it is effective.
                We compared the metabolic and immunologic effects of insulin lispro and regular human insulin in 42 women >18 years of age diagnosed with gestational diabetes by oral glucose tolerance testing at 14-32 weeks of gestation. Patients were randomized to receive regular human insulin or insulin lispro before consuming a test meal. Serum insulin, blood glucose, and C-peptide concentrations were measured. Throughout the remainder of gestation, patients received premeal insulin lispro or regular human insulin combined with basal insulin and performed blood glucose self-monitoring before and after each meal. Insulin antibodies and HbA1c were determined at enrollment and 6 weeks later. In addition, 10 patients received continuous intravenous insulin (4 lispro, 6 regular human insulin) and dextrose infusions intrapartum to assess placental insulin transfer.
                Anti-insulin antibody levels were similar in the two groups. Insulin lispro was not detectable in the cord blood. During a meal test, areas under the curve for glucose, insulin, and C-peptide were significantly lower in the lispro group. Mean fasting and postprandial glucose concentrations and end point HbA1c were similar in the two groups. The lispro group demonstrated fewer hypoglycemic episodes (symptoms and blood glucose concentrations <55 mg/dl). No fetal or neonatal abnormalities were noted in either treatment group.
                Insulin lispro may be considered a treatment option for women with gestational diabetes. To quantitate the contribution of postprandial blood glucose, which improves with the short-acting insulin analog lispro [Lys(B28),Pro(B29)] in type 1 diabetes, to the overall 24-h blood glucose concentration and the long-term HbA1c concentration under conditions of different postabsorptive blood glucose.
                A total of 24 type 1 diabetic patients on long-term intensive therapy with premeal human regular insulin (Hum-R) and bedtime NPH were randomly assigned to a continuation of Hum-R (group 1, n = 8), lispro (group 2, n = 8), or lispro + NPH (in variable proportions) administered at mealtime (group 3, n = 8) for 3 months, NPH administered at bedtime was continued in all three groups. Data from home blood glucose monitoring were collected, and a 24-h plasma glucose and insulin profile was obtained during a 2-day hospital visit to calculate areas under the postprandial glucose curve (3.5 h after breakfast, 3.5 h after lunch, and 3.0 h after dinner for a total of 10.0 h) and the postabsorptive blood glucose curve (the remaining 14.0 h out of 24.0 h) (AUC). Eight nondiabetic subjects were also studied.
                The substitution of Hum-R with lispro (group 2) resulted in lower postprandial blood glucose, but greater postabsorptive blood glucose (P < 0.05 vs. group 1). The postprandial blood glucose AUC was lower (161 +/- 19 vs. 167 +/- 20 mg.100 ml-1.h-1), but the postabsorptive blood glucose AUC was greater (155 +/- 22 vs. 142 +/- 19 mg.100 ml-1.h-1) (P < 0.05). Therefore, the 24-h blood glucose AUC was no different (NS). Consequently, HbA1c was no different (NS). This occurred because in group 2, mealtime lispro resulted in normal prandial plasma insulin, but also resulted in lower interprandial concentration (P < 0.05 vs. group 1). When NPH was added to lispro (30% at breakfast, 40% at lunch, 10% at dinner) in group 3, postabsorptive plasma insulin was similar to group 1 (NS), in group 3, the postprandial blood glucose AUC (153 +/- 17 mg.100 ml-1.h-1) was lower and the postabsorptive blood glucose AUC was no different, as compared with group 1 (NS). Therefore, the 24-h blood glucose AUC was lower (147 +/- 17 vs. 155 +/- 21 and 158 +/- 20 mg.100 ml-1.h-1), and HbA1c was lower (6.41 +/- 0.12 vs. 6.84 +/- 0.2 and 6.96 +/- 0.2% (groups 3, 1, and 2 respectively, P < 0.05). Frequency of hypoglycemia was greater in group 2 (P < 0.05), but not in group 3 (NS) vs. group 1. Insulin lispro is an insulin analog that was recently developed particularly for a mealtime therapy. It has a fast absorption rate and short duration of action. The efficacy of insulin lispro in the clinical therapy of patients with non-insulin-dependent diabetes mellitus (NIDDM) has not been tested.
                To compare insulin lispro and human regular insulin in the mealtime treatment of patients with NIDDM.
                A 6-month, randomized, multinational (16 countries), multicenter (80 sites) clinical trial with an open-label, crossover design was performed in 722 patients with NIDDM. Insulin lispro was injected immediately before and human regular insulin 30 to 45 minutes before the meal.
                Throughout the study, the postprandial rise in serum glucose levels was significantly lower during insulin lispro than human regular insulin treatment. At end point the rise (mean +/- SEM) in serum glucose levels was 30% lower at 1 hour (2.6 +/- 0.1 mmol/L [46.8 +/- 1.8 mg/ dL] for lispro vs 3.7 +/- 0.1 mmol/L [66.6 +/- 1.8 mg/dL] for human regular insulin) and 53% lower 2 hours after the test meal (1.4 +/- 0.1 mmol/L [25.2 +/- 1.8 mg/dL] for lispro vs 3.0 +/- 0.1 mmol/L [54.0 +/- 1.8 mg/dL] for human regular insulin) with insulin lispro compared with human regular insulin therapy (P < .001 for both intervals). During insulin lispro therapy the rate of hypoglycemia overall (P = .01) and overnight (P < .001) was lower and the number of asymptomatic hypoglycemic episodes was smaller (P = .03) than during human regular insulin therapy. Associated with a similar 13% increase (P < .001) in the total daily insulin dose, the glycosylated hemoglobin level decreased (P < .001) equally in both treatment groups. Serum lipid and lipoprotein levels remained unchanged. There were no differences in the adverse events between the 2 treatment groups.
                Compared with human regular insulin therapy, mealtime therapy with insulin lispro reduced postprandial hyperglycemia and may decrease the rate of mild hypoglycemic episodes in patients with NIDDM. The absorption of regular human insulin from subcutaneous injection sites is delayed due to the self-association of insulin to multimeric forms. The insulin analogue insulin lispro has a weak self-association and a fast absorption rate. We examined the safety and efficacy of insulin lispro in the premeal treatment of patients with diabetes mellitus. A 12-month study was performed in 336 patients with insulin-dependent diabetes mellitus (IDDM) and 295 patients with non-insulin-dependent diabetes mellitus (NIDDM). The patients were randomized to inject either regular human insulin 30 to 45 minutes before eating, or insulin lispro immediately before each meal, in addition to basal insulin. The postprandial rise in serum glucose was lower in patients receiving insulin lispro than in those receiving regular human insulin therapy. At end point the increment was significantly lower at 1 hour (35%) and at 2 hours (64%) after the meal in IDDM patients; in NIDDM patients, the increment was nonsignificantly lower at 1 hour (19%) and significantly lower at 2 hours (48%). IDDM patients receiving insulin lispro achieved significantly lower glycated hemoglobin (HbA1c) levels in patients receiving regular human insulin (8.1% vs 8.3%). In NIDDM patients, HbA1c levels decreased equally in both treatment groups. Due to its fast absorption rate, insulin lispro improves postprandial control in diabetes. Insulin lispro can be considered one step toward optimal insulin therapy and improved patient convenience. Insulin lispro, an insulin analog recently developed particularly for mealtime therapy, has a fast absorption rate and a short duration of action. We compared insulin lispro and regular human insulin in the mealtime treatment of 1,008 patients with IDDM. The study was a 6-month randomized multinational (17 countries) and multicenter (102 investigators) clinical trial performed with an open-label crossover design. Insulin lispro was injected immediately before the meal, and regular human insulin was injected 30-45 min before the meal. Throughout the study, the postprandial rise in serum glucose was significantly lower during insulin lispro therapy. At the endpoint, the postprandial rise in serum glucose was reduced at 1 h by 1.3 mmol/l and at 2 h by 2.0 mmol/l in patients treated with insulin lispro (P < 0.001). The rate of hypoglycemia was 12% less with insulin lispro (6.4 +/- 0.2 vs. 7.2 +/- 0.3 episodes/30 days, P < 0.001), independent of basal insulin regimen or HbA1c level. The reduction was observed equally in episodes with and without symptoms. When the total number of episodes for each patient was analyzed according to the time of occurrence, the number of hypoglycemic episodes was less with insulin lispro than with regular human insulin therapy during three of four quarters of the day (P < 0.001). The largest relative improvement was observed at night. In conclusion, insulin lispro improves postprandial control, reduces hypoglycemic episodes, and improves patient convenience, compared with regular human insulin, in IDDM patients. IGF-I levels in patients with type 1 diabetes without endogenous insulin production are low. Our aim was to examine whether the plasma insulin profile obtained by treatment with the insulin analogue lispro has a different effect on plasma concentrations of IGF-I and IGFBP-1 than that seen during treatment with conventional human insulin (regular insulin).
                Twelve patients with type 1 diabetes, age 47.8 +/- 2.4 years (mean +/- SEM), body mass index 26.5 +/- 1.0 kg/m2, diabetes duration 30.5 +/- 3.2 years participated in this open label randomized cross-over study. IGF-I and IGFBP-1 levels were measured at the end of 6 weeks treatment with each insulin being administered by a continuous subcutaneous insulin infusion. IGF-I was measured fasting while IGFBP-1, free insulin and blood glucose were measured fasting and repeatedly after a morning meal preceded by an insulin bolus dose.
                Lispro gave a marked insulin peak of 135 +/- 20 pmol/l 50 minutes after injection. After an initial rapid rise, human regular insulin reached a plateau of approximately 50 pmol/l. The plasma free insulin area under the curve (AUC) from 0710 h to 0910 h was more than twice as large on lispro as on regular insulin (P = 0.01). Plasma IGF-I concentration was 78.8 +/- 10.9 microg/l on lispro and 82.3 +/- 10.5 microg/l on human regular insulin (not significant). AUC for IGFBP-1 did not show a significant difference even when divided from 0710 h to 0910 h and from 0930 h to 1430 h. Blood glucose AUC after administration of the bolus was significantly lower during treatment with lispro (P = 0.006) but glycosylated haemoglobin (HbA1c) was 6.4 +/- 0.2% on both therapies.
                Our results indicate that the effect of lispro on IGF-I and IGFBP-1 in patients with type 1 diabetes does not differ from that of human regular insulin. To compare health-related quality of life (HRQOL) in patients with diabetes receiving insulin lispro with patients receiving regular human insulin (Humulin R).
                We performed two randomized comparative studies over a 6-month period (3 months per treatment). Primary analyses used crossover baseline to 3-month changes in HRQOL scores. Ninety-three principal investigators in Canada, France, Germany, and the U.S. participated in these studies. One HRQOL crossover study included 468 patients with type I diabetes; the other HRQOL crossover study included 474 patients with type II diabetes. In both studies, patients were taking insulin at least 2 months before enrollment. Primary outcomes included two generic HRQOL domains, energy/fatigue and health distress, and two diabetes-specific domains, treatment satisfaction and treatment flexibility. Thirty secondary outcomes included both generic and diabetes-specific measures. Secondary outcome domains were controlled for multiplicity in the analyses.
                Primary analyses showed that treatment satisfaction scores (P < 0.001) and treatment flexibility scores (P = 0.001) were higher for insulin lispro in type I diabetic patients. No other significant treatment differences were detected using the data from these 6-month crossover studies.
                Treatment satisfaction and treatment flexibility were significantly improved in patients with type I diabetes using insulin lispro. Other HRQOL findings were comparable for insulin lispro and regular human insulin. Insulin lispro appears to have a measurable impact on lifestyle benefits in patients with type I diabetes, as demonstrated by increased treatment satisfaction and treatment flexibility. To compare the efficacy and safety of premixed insulin aspart (30% free and 70% protamine-bound, BIAsp 30) with human insulin premix (BHI 30) used in a twice-daily injection regimen in people with Type 1 and Type 2 diabetes.
                People with Type 1 and Type 2 diabetes (n = 294) using twice-daily insulin were randomized to a 12-week open-label comparison of BIAsp 30 and BHI 30. Efficacy was assessed by analysis of variance of 12-week data, adjusted for baseline level.
                BIAsp 30 was as effective as BHI 30 based on the primary efficacy measure, HbA1c, mean difference -0.01 (90% confidence interval (CI) -0.14; 0.12) %Hb. Meal-time self-measured blood glucose increment averaged over the three main meals was significantly lower in the BIAsp 30 group than in the BHI 30 group (-0.68 (-1.20; -0.16) mmol/l; P < 0.02). Significant improvements were observed after breakfast, before lunch, after dinner and at bedtime (P < 0.02-0.05), with blood glucose around 1.0 mmol/l lower in the BIAsp 30 group. The number of major hypoglycaemic episodes with BIAsp 30 was half that with BHI 30. However, the overall risk of both minor and major hypoglycaemia did not differ significantly between treatments.
                Post-prandial glycaemic control was significantly improved, without increasing the risk of hypoglycaemia, and overall control was similar when people with Type 1 and Type 2 diabetes were treated on a twice-daily regimen with immediate premeal injections of BIAsp 30 compared with BHI 30. A common treatment regimen for patients with either insulin-dependent diabetes mellitus (IDDM) or non-insulin-dependent diabetes mellitus (NIDDM) is a combination of rapid-acting insulin and intermediate-acting insulin administered twice each day. It is usually recommended that regular human insulin be injected 30 to 45 minutes before a meal. In practice, patients often inject regular human insulin closer to mealtime, causing a higher post-prandial serum glucose level and an increased potential for hypoglycemia in the postabsorptive period. Insulin lispro, a rapid-acting insulin analogue, is best injected just before a meal because of its more rapid absorption and shorter duration of action. In 707 randomized patients, 379 with IDDM and 328 with NIDDM, we studied the effect of twice-daily insulin lispro or regular human insulin in combination with NPH human insulin (isophane insulin) on premeal, 2-hour postprandial, and bedtime glycemic control. Assessments were based on the results of a seven-point blood glucose profile, the insulin dose (by formulation and time of administration), the incidence and frequency of hypoglycemic episodes, and the glycated hemoglobin value. Treatment with insulin lispro resulted in lower postprandial glucose levels and smaller increases in glucose level after the morning and evening meals compared with treatment with regular human insulin. Overall glycemic control, frequency of hypoglycemic events, and total insulin dose were not different between the two groups. Insulin lispro in combination with NPH human insulin in a twice-per-day regimen allows injection closer to mealtime and improves post-prandial glycemic control without increasing the risk of hypoglycemia. A variety of abnormalities of metabolic, haemostatic and endothelial markers are associated with Type 2 diabetes. Evidence suggests that poor post-prandial blood glucose control may contribute to vascular risk. We aimed to examine whether the restoration of a more physiological insulin profile post-prandially would improve these abnormalities. Twenty-one patients with insulin-treated Type 2 diabetes were recruited into a single centre, crossover, double-blind study. Patients were randomized to unmodified human insulin or insulin aspart before main meals for 6-week study periods, both together with NPH insulin. At the end of each study period, pre-breakfast levels of markers of vascular risk were assessed and a test meal performed. There was no significant difference in HbA(1c) (7.04 +/- 0.13% (+/-S.E.) versus 7.15 +/- 0.11%, P = 0.060) with insulin aspart compared to human insulin at the end of each study period. The mean post-prandial blood glucose concentration at 90 min from self-monitored results was lower with insulin aspart than with human insulin (7.9 +/- 0.4 mmol/l versus 9.3 +/- 0.4 mmol/l, P = 0.011) as was study day post-prandial blood glucose at 90 min (8.4 +/- 0.5 mmol/l versus 9.2 +/- 0.6 mmol/l, P = 0.046). No significant differences were found in fasting lipid profile, apolipoproteins, fibrinogen, plasminogen activator inhibitor-1, E-selectin, or homocysteine between the two study periods. Insulin aspart resulted in improved post-prandial glycaemic control when compared to human insulin in Type 2 diabetic patients, but this was not associated with changes in markers of vascular risk. Insulin lispro is an analog of human insulin with a faster onset and a shorter duration of action than regular human insulin. Efficacy and tolerability of insulin lispro in continuous subcutaneous insulin infusion (CSII) treatment were assessed in an open randomized crossover trial comparing insulin lispro and regular human insulin, both applied with insulin pumps.
                A total of 113 type 1 patients (60 male, 53 female, age [mean +/- SD] 37 +/- 12 years, duration of diabetes 19 +/- 9 years) participated in this open, randomized crossover study. Both insulins were applied for 4 months each with the appropriate intervals between the prandial insulin bolus and the meal (human insulin: 30 min; lispro: 0 min). Observation parameters were HbA1c, daily and postprandial blood glucose profiles, adverse events, rate of hypoglycemic and hyperglycemic events, number of catheter obstructions, and treatment satisfaction as assessed with an international validated questionnaire.
                The patients were well controlled with a mean HBA1c of 7.24 +/- 1.0% at baseline. HbA1c decreased in both treatment periods, but it was better during insulin lispro treatment (insulin lispro: 6.8 +/- 0.9%, regular human insulin: 6.9 +/- 1.0%, Friedman's rank-sum test: P < 0.02). In addition, the 1-h and 2-h postprandial rises in blood glucose were significantly lower (P < 0.001 for each meal) with insulin lispro, resulting in smoother daily glucose profiles as compared with regular human insulin. No significant differences were reported for the rate of hypoglycemia (mean +/- SD [median]: insulin lispro 12.4 +/- 13.9 [8], regular human insulin 11.0 +/- 11.2 [8]), for the rate of catheter obstructions (42 events in each treatment arm), and for the number and type of adverse events. No severe case of ketoacidosis was seen during insulin lispro treatment, whereas one case was reported during therapy with regular human insulin. Treatment satisfaction was better when patients were treated with insulin lispro.
                Insulin lispro is a suitable and very convenient pump insulin that may result in an improvement of long-term glucose control during CSII treatment. Its safety profile does not differ from that of regular human insulin. 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.
                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.
                33 pregnant women with type 1 DM were randomised to treatment with lispro insulin (n=16) or regular insulin (n=17).
                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.
                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. The objective of this study was to compare the efficacy of the rapid-acting Lys(B28), Pro(B29) human insulin analog, insulin lispro, with currently available short-acting human insulin in a multiple injection therapy (MIT) regimen with respect to blood glucose and plasma insulin profiles and to serum metabolites (lactate, free fatty acids, glycerol, and beta-hydroxybutyrate) in 12 well-controlled type 1 diabetic subjects (8 male, HbA1c 6.8 +/- 0.9% [mean +/- SD]).
                After a run-in period of 4 weeks, patients were treated with either lispro at mealtime or human insulin 30 min before the meal for two periods of 4 weeks in a randomized open-label crossover study. Intermediate-acting insulin (NPH insulin) was given at bedtime. At the end of both study periods, metabolic profiles were assessed from 10:00 P.M. to 7:00 P.M. the next day.
                During the treatment periods, glycemic control was stable during lispro but improved during human insulin (delta HbA1c lispro 0.1 +/- 0.48, NS; human insulin -0.41 +/- 0.34%, P < 0.05). Glucose excursions, as measured by the incremental AUC, during the day and for the 2-h postprandial periods, were lower, although not significantly, for lispro. Insulin profiles demonstrated a faster rise after administration of lispro as compared with human insulin, peaking at 61 +/- 11.9 and 111 +/- 48.1 min (P < 0.01). Glycerol levels showed a slight increase before lunch and dinner, suggestive of enhanced lipolytic activity and compatible with the lower insulin levels.
                Lispro insulin applied in an MIT regimen creates more physiologic insulin profiles and tends to lower the glycemic excursions during the day compared with short-acting insulin. The analog can be applied safely in an MIT regimen, with mealtime intervals up to 5 h. nan Lispro (LP) and regular human (HR) insulins were compared in Type 1 diabetic (T1DM) patients on either a Mediterranean diet or normal diet. Twelve T1DM patients were recruited and randomized into two groups of 6, groups A and B. They were treated in different sequences (in 3-month intervals for 1 year). Group A: LP insulin and normal diet, LP insulin and Mediterranean diet, regular insulin and Mediterranean diet, regular insulin and normal diet. Group B: regular insulin and normal diet, regular insulin and Mediterranean diet, LP insulin and Mediterranean diet, LP insulin and normal diet. Each patient was treated with rapid acting insulin, either LP insulin or HR insulin, before each main meal and a dose of slow acting insulin at bedtime. Every 15 days the glycemic control, the incidence and frequency of hypoglycemic episodes, and any adverse events were evaluated. Every 3 months, hematology and a chemistry panel, pre- and post-prandial glycemic and insulinemic profiles were evaluated in all patients. HbA1c levels significantly decreased in LP patients on normal diet, post-prandial glycemic levels were significantly lower in LP than in HR patients from 30 min onwards, 15-min post-prandial insulin levels higher in LP- than in HR-treated patients, and hypoglycemic episodes were significantly less in LP- than in HR-treated patients. LP insulin, irrespective of the type of diet, results in more effective glycemic control, significantly reduces hypoglycemic episodes as opposed to traditional insulin therapy and seems to be more effective with a normal diet than with a Mediterranean diet. To compare the safety and efficacy of insulin aspart (IAsp), buffered regular insulin (BR), and insulin lispro administered by continuous subcutaneous insulin infusion (CSII) in patients with type 1 diabetes.
                After completing a 4-week run-in period with BR, 146 adult patients with type 1 diabetes (with pretrial CSII experience) were randomly assigned (2:2:1) to CSII treatment with IAsp, BR, or lispro for 16 weeks in a multicenter, open-label, randomized, parallel-group study. Bolus insulin doses were administered 30 min before meals (BR) or immediately before meals (IAsp or lispro).
                Treatment groups had similar baseline HbA(1c) (7.3% +/- 0.7 for IAsp, 7.5% +/- 0.8 for BR, and 7.3% +/- 0.7 for lispro). After 16 weeks of treatment, HbA1c values were relatively unchanged from baseline, and the mean changes in baseline HbA1c values were not significantly different between the three groups (0.00 +/- 0.51, 0.15 +/- 0.63, and 0.18 +/- 0.84 for the IAsp, BR, and lispro groups, respectively). The rates of hypoglycemic episodes (blood glucose <50 mg/dl) per patient per month were similar (3.7, 4.8, and 4.4 for the IAsp, BR, and lispro groups, respectively). Clogs/blockages in pumps or infusion sets were infrequent; most subjects (76, 83, and 75% in the IAsp, BR, and lispro groups, respectively) had < or = 1 clog or blockage per 4 weeks during the trial.
                Insulin aspart in CSII was as efficacious and well tolerated as BR and lispro and is a suitable insulin for continuous subcutaneous insulin infusion using external pumps. 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.
                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.
                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.
                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. To compare the effects of Humalog Mix25 (Humalog Mix75/25 in the USA) (Mix25) and human insulin 30/70 (30/70) on the 24-hour inpatient plasma glucose (PG) profile in patients with type 2 diabetes mellitus (T2DM).
                A randomised, open-label, 8-week crossover study. Study insulins were injected twice daily, 5 minutes before breakfast and dinner.
                Four-week outpatient (dose-adjustment) treatment phase, and 3-day inpatient (test) phase.
                Twenty-five insulin-treated patients with T2DM (ages 40-66 years), mean (+/- standard error of the mean) (SEM) HbA1c 7.7% +/- 0.23%, and body mass index (BMI) 29.3 +/- 0.83 kg/m2.
                24-hour PG profiles, PG excursions after meals, PG area under the curve (AUC), and 30-day hypoglycaemia rate.
                The 2-hour PG excursions following breakfast (5.5 +/- 0.34 v. 7.2 +/- 0.34 mmol/l, p = 0.002) and dinner (2.4 +/- 0.27 v. 3.4 +/- 0.27 mmol/l, p = 0.018) were smaller with Mix25 than with 30/70. PG AUC between breakfast and lunch was smaller with Mix25 than with 30/70 (77.6 +/- 3.8 v. 89.5 +/- 4.3 mmol/h/ml, p = 0.001). PG AUC between lunch and dinner, dinner and bedtime, and bedtime and breakfast did not differ between treatments. Pre-meal and nocturnal PG were comparable. The postprandial insulin requirement for lunch meals was supplied equally by the two insulin treatments. The thirty-day hypoglycaemia rate was low (Mix25 0.049 +/- 0.018 v. 30/70 0.100 +/- 0.018 episodes/patient/30 days, p = 0.586) for both treatments.
                In patients with T2DM, Mix25 improved the 24-hour PG profile with lower postprandial PG excursions than with human insulin 30/70. Insulin lispro is a human insulin analog that dissociates more rapidly than human regular insulin after subcutaneous injection, resulting in higher insulin levels at an earlier point in time and a shorter duration of action. The aim of the study was to evaluate if this pharmacokinetic difference would translate into better postprandial and overall control in 30 IDDM patients (age, 35.1 +/- 1.5 years; male-female ratio, 17:13; BMI, 24.8 +/- 0.5 kg/m2; HbA1c, 8.03 +/- 0.13% at baseline) treated with continuous subcutaneous insulin infusion (CSII; Disetronic H-TRON V100) in a double-blind crossover clinical study. Patients were randomized to insulin lispro or human regular insulin for 3 months before crossing over to the other insulin for another 3 months. All meal boluses were given immediately before breakfast, lunch, and supper. An eight-point blood glucose profile was measured once weekly, and HbA1c levels were measured monthly. At the end of the 3-month treatment period, HbA1c levels were significantly lower with insulin lispro, compared with human regular insulin: 7.66 +/- 0.13 vs. 8.00 +/- 0.16% (P = 0.0041). While preprandial, bedtime, and 2:00 A.M. values for blood glucose were not significantly different, 1-h postprandial blood glucose was significantly improved after breakfast, lunch, and dinner with insulin lispro, compared with human regular insulin: 8.35 vs. 9.79 mmol/l (P = 0.006), 7.58 vs. 8.74 mmol/l (P = 0.049), and 7.85 vs. 9.01 mmol/l (P = 0.03). The incidence of hypoglycemia per 30 days (blood glucose levels, <3.0 mmol/l) was 8.4 +/- 1.3 before randomization, decreasing to 6.0 +/- 0.9 for insulin lispro and to 7.6 +/- 1.3 for regular insulin during the last month of the study. Two patients in each group reported insulin precipitation. We conclude that insulin lispro improves glycemic control in CSII without increasing the risk of hypoglycemia. To compare glycemic control obtained with the new rapid-acting insulin analog insulin aspart with that obtained with unmodified human insulin using algorithm-driven dosage adjustment.
                This was a multicenter randomized double-blind crossover study of 90 male subjects with type 1 diabetes. Insulin aspart or soluble human insulin was administered before meals, and NPH insulin was administered at bedtime as basal therapy. Each 4-week study period ended with a 24-h inpatient serum insulin and plasma glucose profile.
                The 24-h plasma glucose control obtained with insulin aspart, as assessed by excursions of blood glucose outside a predefined normal range (4.0-7.0 mmo/l), was superior (22% reduction in excursion, P < 0.01). Fructosamine levels remained unchanged with insulin aspart, with daytime glycemic control superior but nighttime glycemic control inferior. Eight-point home blood glucose profiles confirmed that insulin aspart significantly improved postprandial blood glucose control after lunch and dinner (P < 0.05) without deterioration of preprandial blood glucose control. Hypoglycemic episodes requiring third-party intervention were significantly fewer with insulin aspart than with human insulin (20 vs. 44 events, P < 0.002). Insulin aspart was well tolerated.
                In comparison with human insulin, insulin aspart can improve postprandial glycemic control as assessed by a reduction in hyper- and hypoglycemic excursions in people with type 1 diabetes. For its full potential to be realized, it will need to provide better control of nighttime hyperglycemia. 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).
                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 HbA1c 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.
                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 HbA1c 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).
                Treatment with post-prandial lispro as a meal insulin is as effective and safe as traditional treatment with regular insulin in young children. To compare the plasma glucose (PG) response with a fixed mixture of 25% insulin lispro and 75% NPL (Mix25), prior to a meal and 3 h before exercise, to human insulin 30/70 (30/70) in patients with type 2 diabetes.
                Thirty-seven patients were treated in a randomized, open-label, 8-week, two-period crossover study. Mix25 was injected 5 min before breakfast and dinner throughout the study, as was 30/70 on inpatient test days and on outpatient dose titration days. Following the 4-week outpatient phase, patients were hospitalized, and exercised at a heart rate of 120 beats/min on a cycle ergometer two times for 30 min, separated by 30 min rest, starting 3 h after a 339 kcal breakfast.
                The 2-h postprandial PG was significantly lower with Mix25 ((mean +/- SEM) 10.5 +/- 0.4 mmol/l vs 11.6 +/- 0.4 mmol/l; p = 0.016). Maximum decrease in PG from onset of exercise to end of exercise was significantly less with Mix25 (-3.6 +/- 0.29 mmol/l vs -4.7 +/- 0.31 mmol/l; p = 0.001). The maximum decrease in PG over 6 h, after exercise onset, was significantly less with Mix25 (-4.3 +/- 0.4 mmol/l vs -5.9 +/- 0.4 mmol/l; p < 0.001). The frequency of hypoglycemia (blood glucose (BG) < 3 mmol/l or symptoms) during the inpatient test was not different between treatments. During the outpatient phase, the frequency of patient-recorded hypoglycemia was significantly lower with Mix25 (0.7 +/- 0.2 episodes/30 d vs 1.2 +/- 0.3 episodes/30 d; p = 0.042).
                Mix25 resulted in better postprandial PG control without an increase in exercise-induced hypoglycemia. The smaller decrease in PG during the postprandial phase after exercise may suggest a lower risk of exercise-induced hypoglycemia with Mix25 than with human insulin 30/70, especially for patients in tight glycemic control. 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).
                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.
                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.
                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. The short-acting insulin analogue lispro ([LYS(B28), PRO(B29)] is absorbed from the subcutis more rapidly than soluble insulin (S). To compare the clinical effectiveness of lispro vs S, 11 Type 1 patients using continuous subcutaneous insulin infusion (CSII) therapy (6 F, 5 M, age 30 +/- 2.5 years, diabetes duration 14 +/- 1.0 years, BMI 24.0 +/- 0.8 kg m(-2), HbA1c 6.5 +/- 0.2%) were studied in an open, randomized, crossover study for 6 months (3 months lispro and 3 months S or vice versa). During lispro treatment mean fasting and 2 h postprandial blood glucose were lower compared to the S phase (fasting 6.5 +/- 0.4 vs 7.5 +/- 0.4 mmol l(-1) (NS), postprandial 6.8 +/- 0.3 vs 8.3 +/- 0.3 mmol l(-1), p = 0.03). In patients treated first with lispro HbA1c levels improved from 6.3 +/- 0.2% to 5.7 +/- 0.3%; On reversion to S HbA1c increased to 6.2 +/- 0.2%. In the group treated first with S, HbA1c fell (6.7 +/- 0.4% vs 6.5 +/- 0.3%) and then improved further to 6.3 +/- 0.3% with lispro. None of these changes were significant. There was no significant difference with respect to hypoglycaemic or other adverse events. It can be concluded that lispro in CSII therapy is safe and may improve postprandial glucose excursions. This study compared the glucose-lowering effect of insulin lispro, given before or after meals, with regular human insulin given before meals in prepubertal children with diabetes.
                A 3-way crossover, open-label study involving 61 prepubertal children (ages 2.9-11.4 years) with type 1 diabetes. The children were randomly assigned to receive regular human insulin 30 to 45 minutes before meals, insulin lispro within 15 minutes before or immediately after meals, combined with basal insulin. Each treatment lasted 3 months. Hemoglobin A(1c) levels and home glucose monitoring profiles were measured at the end of each treatment period.
                Treatment with insulin lispro before breakfast resulted in lower 2-hour postprandial glucose values than regular human insulin (11.7 +/- 4.4 mmol/L vs 15.0 +/- 5.4 mmol/L). Similarly, insulin lispro given before dinner resulted in lower blood glucose values 2 hours postprandially (8.8 +/- 5.0 mmol/L vs 10.8 +/- 5.4 mmol/L) than regular human insulin. When insulin lispro was administered after meals, the 2-hour glucose levels were between those seen with either insulin lispro or regular human insulin given before meals. The number and types of adverse events, the rates of hypoglycemia, and the HbA(1c) levels did not differ among the 3 therapies.
                In prepubertal children, insulin lispro given before meals is safe and significantly lowers postprandial glucose levels after breakfast and dinner compared with regular human insulin, and insulin lispro given after the meal provides similar benefits as regular human insulin before the meal. Insulin lispro was compared with regular human insulin with respect to glycaemic control in patients with diabetes mellitus on intensive insulin treatment. Sixty-two patients (55 type 1; 7 type 2) from eight study centres in the Czech Republic, Slovenia and the Slovak Republic participated in a 4-month, open-label, randomized, crossover study. Patients administered insulin lispro immediately before meals or regular human insulin 30 min before meals. A test meal (220-400 kcal), based on local and individual dietary habits and consistent for each patient throughout the study was given at baseline and at the end of each treatment. At each test meal visit HbA1c, fasting blood glucose, 1-hour and 2-hour postprandial blood glucose levels were measured. The level of HbA1c (7.6% +/- 1.5% versus 7.4% +/- 1.5%), incidence of hypoglycaemia (41-66% of patients--versus 39-63%) and daily insulin dose (0.67 +/- 0.11 U/kg versus 0.65 +/- 0.11 U/kg) did not differ between treatment groups at endpoint (insulin lispro versus regular human insulin, respectively). Mean 2-hour postprandial blood glucose excursion for the insulin lispro group (0.0 +/- 3.7 mmol/L) was significantly lower (p = 0.035) when compared with the regular human insulin group (1.3 +/- 3.7 mmol/L) at endpoint. Therapy with insulin lispro was therefore associated with a significant improvement in postprandial blood glucose excursion control when compared with regular human insulin, without an increase in rate of hypoglycaemia. 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.
                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.
                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).
                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. To compare the effects of insulin lispro (LP) and human regular insulin (HR) when given twice daily with NPH insulin on glycemic control (HbA1c), daily blood glucose profiles and rates of hypoglycemia in patients with type 2 diabetes mellitus after failure to respond to sulfonylurea drugs.
                A 5.5-month randomized, open-label, parallel study of 148 patients receiving either LP (n = 70) or HR (n = 78). Eight-point blood glucose profiles and HbA1c measurements were collected at baseline, 1.5, 3.5 and 5.5 months.
                Two-hour post-breakfast and 2-hour post-supper blood glucose levels (means [and standard errors]) were significantly lower for LP than for HR at the end point (9.5 [0.4] mmol/L v. 10.9 [0.4] mmol/L and 8.4 [0.4] mmol/L v. 9.7 [0.4] mmol/L, respectively, p = 0.02 in both cases). HbA1c improved from 10.5% (0.2%) (LP) and 10.3% (0.2%) (HR) to 8.0% (0.1%). Hypoglycemia rates were similar during the day; however, there was an overnight trend to reduced rates with LP (0.08 [0.03] episodes/30 d v. 0.16 [0.04] episodes/30 d, p = 0.057). Quality-of life assessment showed significant improvement (p < 0.05) in the diabetes-related worry scale for LP subjects whereas HR subjects slightly worsened.
                With traditional twice-daily insulin administration algorithms, LP improves 2-hour postprandial glucose levels, quality of life and overnight hypoglycemia rates while delivering an equivalent level of glycemic control (HbA1c) compared with HR to insulin-naïve patients with type 2 diabetes who require insulin. To compare the safety, efficacy and management of insulin lispro (LP) with regular human insulin (RH) in young diabetic children treated with continuous subcutaneous insulin infusion (CSII).
                27 very young diabetic children (age 4.6 +/- 2.2 years) treated with CSII participated in an open-label, randomized cross-over multicenter study comparing 2 periods of 16 weeks of CSII with LP or RH.
                Mean daily basal rate was significantly higher during the LP period (p = 0.04). No differences were seen in changes in HbA1c levels, number of hypoglycemic events, cutaneous infections and catheter occlusions. There was no significant difference between the two treatments for preprandial and postprandial glucose values, although prandial glucose excursions tended to be lower with LP (significant at dinner, p = 0.01). Mean blood glucose levels were significantly higher at 0.00 and 3.00 a.m. during LP therapy (p < 0.05). No episode of ketoacidosis occurred during LP treatment. More parents indicated that LP made their own and the child's daily life easier (p = 0.02) and preferred LP (p = 0.01).
                LP in CSII therapy in children is safe, as effective as RH, improved postprandial excursions, met the needs of young children in their daily life well, and gained their parents' satisfaction and preference. However, a shorter duration of LP resulted in hyperglycemia during the first part of the night, which must be compensated for by increasing nocturnal basal rates during this time. 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.
                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).
                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. To compare maternal glucose levels and neonatal outcome, achieved in women with gestational diabetes (GDM) receiving either regular insulin or insulin lispro, with those of a control group of non-diabetic pregnant women.
                We enrolled 49 pregnant women with GDM, randomly allocated to the treatment with either insulin lispro (n=25) or regular insulin (n=24), and 50 pregnant women with normal GCT, matched for age, parity, pre-pregnancy weight and BMI, who formed the control group. All the women were caucasian, non-obese, with a singleton pregnancy and delivered term live born infants. Women of both groups were requested to perform a blood glucose profile (consisting of nine determinations: fasting/pre-prandial, 1 and 2h post-prandial) every week from the time of diagnosis to 38 weeks (study subgroups) or every 2 weeks from 28 to 38 weeks' gestation (control group).
                Overall pre-prandial blood glucose values in diabetic women were significantly higher than those of controls; at the 1h post-prandial time point, blood glucose values of GDM women receiving insulin lispro were similar to those of controls, whereas in the regular group they were significantly higher. Overall, both the lispro and regular insulin obtained optimal metabolic control at the 2h post-prandial time point, although near-normal blood glucose levels 2h after lunch could be observed only in the lispro group. There were no statistically significant differences between the groups in neonatal outcome and anthropometric characteristics; however, the rate of infants with a cranial-thoracic circumference (CC/CT) ratio between the 10th and the 25th percentile was significantly higher in the group treated with regular insulin in comparison to the lispro and control groups.
                Fasting/pre-prandial and 1h post-prandial maternal blood glucose levels in non-diabetic pregnant women fell well below the currently accepted criteria of glycemic normality in diabetic pregnancies. In women with GDM, the use of insulin lispro enabled the attainment of near-normal glucose levels at the 1h post-prandial time point and was associated with normal anthropometric characteristics; the use of regular insulin was not able to blunt the 1h peak post-prandial response to a near-normal extent and resulted in infants with a tendency toward the disproportionate growth. Insulin lispro can be regarded as a valuable option for the treatment of gestational diabetes. It has been found that non-fasting plasma glucose is a better marker of diabetic control than fasting plasma glucose in type 2 diabetes. The main aim of treatment of type 2 diabetic patients is to control plasma glucose and HbA1c levels. In this study, we aimed to assess the effects of three different insulin regimens (group I: lispro insulin + NPH insulin, group II: lispro insulin + metformin and group III: regular insulin + NPH insulin) on overall glycaemic control and metabolic parameters in type 2 diabetic patients with secondary oral anti-diabetic drug failure.
                Sixty type 2 diabetic patients with secondary OAD failure were randomly allocated into three different treatment groups equally. There were no significant differences between groups concerning age, body mass index, diabetes duration, HbA1c and serum lipid levels at the beginning of the study. During the 6-month treatment period, blood glucose levels were determined 10 times during 24 h at pre-meal, post-prandial 1 and 2 h and at bedtime.
                Group I was found to be the most effective treatment regimen in controlling HbA1c levels (group I vs. group II, p = 0.013; group I vs. group III, p = 0.001; group II vs. group III, p > 0.05). When the comparison was made in each group, change in HbA1c was statistically significant for all groups (-3.18%, p = 0.001; -2.02%, p = 0.043 and -2.66%, p = 0.008 respectively). Group I was found to be more effective in controlling fasting and post-prandial plasma glucose levels measured at all times during the day when compared with group II and group III. In group II triglyceride levels were found to be significantly reduced, whereas other groups had no effect on lipids. No serious hypoglycaemic episodes were observed in any of the cases, whereas in group I hypoglycaemic episode rates were increased (chi2 = 8.843, p = 0.012).
                Lispro insulin plus NPH insulin regimen is more effective in controlling both pre- and post-prandial glucose levels and HbA1c when compared to regular insulin plus NPH insulin combination. Mealtime lispro insulin plus metformin combination therapy should also be seriously considered as an effective and alternative treatment regimen. It is worthy of attention that insulin lispro plus metformin lowered triglyceride levels. Because there are limited data on the comparison of insulin aspart and mixed insulin in type 2 diabetes, this trial was performed to compare the efficacy and safety of preprandial insulin aspart with human soluble insulin (HI) and human premix (70% NPH/30% regular) insulin (MIX).
                A total of 231 type 2 diabetic patients were randomized to insulin aspart (n = 75), HI (n = 80), or MIX (n = 76) for 3 months. Insulin aspart and HI were administered with or without bedtime NPH insulin. A total of 204 patients completed the trial according to protocol. HbA1c, 7-point blood glucose, insulin dosage, and hypoglycemic episodes were recorded. The primary end point was "change of HbA1c" from baseline to last visit. Analysis for equivalence was performed by t tests with three subtests.
                HbA1c decreased 0.91 +/- 1.00 for insulin aspart, 0.73 +/- 0.87 for HI, and 0.65 +/- 1.10 for MIX with the following confidence intervals: insulin aspart HI (-0.21 to 0.57, P = 0.025), insulin aspart MIX (-0.17 to 0.69, P = 0.092), and HI-MIX (-0.33 to 0.48, P = 0.006). Postprandial blood glucose decreased in the insulin aspart group: 0.44 mmol/l to >1.67 mmol/l compared with HI and 1.1 mmol/l to >1.67 mmol/l compared with MIX. Preprandial insulin doses were similar in the insulin aspart and HI groups (10-14.5 U). Hypoglycemic events per month were 0.56 HI, 0.40 insulin aspart, and 0.19 MIX.
                Statistically, insulin aspart was not equivalent to another treatment in terms of HbA1c reduction. Insulin aspart treatment resulted in improved HbA1c and postprandial blood glucose. The application of insulin aspart was safe and well tolerated. Several studies have suggested that use of the short-acting insulin analog, insulin lispro, in multiple injection therapy may reduce the risk of hypoglycemia in comparison with regular insulin. This effect might be more pronounced in well-controlled patients, since intensive treatment of IDDM increases the rate of severe hypoglycemic events. This study evaluated the effects of insulin lispro on glycemic control and hypoglycemia rates in well-controlled IDDM patients.
                This was an open, randomized, 6-month crossover study of 199 IDDM patients. Glycemic control was evaluated by HbA1c, home blood glucose measurements, and rate and timing of hypoglycemic events. At the end of the study, patients completed an evaluation form regarding therapy-related quality of life.
                HbA1c remained constant at approximately 7.3% throughout the study. Meal-related glucose excursions were significantly lower with insulin lispro compared with regular insulin (mean -0.8 +/- 1.7 vs. 1.1 +/- 1.6 mmol/l, P < 0.001), as was the within-day variability (M value 27.7 +/- 19.7 vs. 30.2 +/- 23.1, P = 0.007). The incidence of severe hypoglycemic events (58 vs. 36, P = 0.037) including coma (16 vs. 3, P = 0.004) was significantly lower with insulin lispro than with regular insulin. Patients felt that insulin lispro increased flexibility and freedom of lifestyle.
                In well-controlled IDDM patients, insulin lispro is associated with a lower risk of severe hypoglycemia and coma.
Our analysis suggests only a minor benefit of short acting insulin analogues in the majority of diabetic patients treated with insulin. Until long term efficacy and safety data are available we suggest a cautious response to the vigorous promotion of insulin analogues. For safety purposes, we need a long-term follow-up of large numbers of patients and well designed studies in pregnant women to determine the safety profile for both the mother and the unborn child.