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

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

Less severe hypoglycaemia, better metabolic control, and improved quality of life in Type 1 diabetes mellitus with continuous subcutaneous insulin infusion (CSII) therapy; an observational study of 100 consecutive patients followed for a mean of 2 years.

AIMS: To compare glycaemic control, occurrence of acute complications, and diabetes-specific quality of life in Type 1 diabetic patients (on intensified conventional insulin treatment (ICT)) before and after initiation of CSII. METHODS: One hundred and three patients (58 women) started CSII between October 1995 and April 1999 in our department. The indication for CSII was optimization of metabolic control and improvement of flexibility of life style (OF group) in 60 patients (58%), and prevention of severe hypoglycaemia (HY group) in 43 patients. Mean age at initiation of CSII was 33 +/- 11 years (OF 33 +/- 10, HY 33 +/- 11 (mean +/- sd)), diabetes duration 18 +/- 9 years (OF 16 +/- 9, HY 20 +/- 9). Three patients stopped CSII, mean duration of CSII of the remaining 100 patients was 1.8 +/- 1.2 years. The occurrence of hypoglycaemia, ketoacidosis and skin abscesses was assessed retrospectively for the 12 months before starting CSII, and recorded continuously during CSII. Quality of life was assessed with a validated, diabetes-specific questionnaire before and after CSII in 50 patients. RESULTS: The incidence of serious hypoglycaemia (any external help) was reduced from 1.23 (OF 0.0; HY 2.93) during ICT to 0.29 cases/patient per year (OF 0.09; HY 0.55) during CSII. The incidence of severe hypoglycaemia (SH) (treated with i.v. glucose or glucagon injection) fell from 0.70 (OF 0.0; SH 1.67) during ICT to 0.06 cases/patient per year (OF 0.02; HY 0.12) during CSII. HbA1c improved from 7.7 +/- 1.1% to 7.2 +/- 1.0% (P < 0.001) (OF 7.8% vs. 7.2%; HY 7.6% vs. 7.2%). During CSII the incidence of abscesses was 0.11 and of ketoacidosis 0.01 cases/patient per year. Quality of life assessments showed significant improvement in all parameters during CSII. CONCLUSIONS: In our cohort of Type 1 diabetic patients, we observed a substantial decrease of hypoglycaemia along with a significant fall of HbA1c. Quality of life on CSII was improved when compared with ICT.     

The effect of an education programme (HyPOS) to treat hypoglycaemia problems in patients with type 1 diabetes

BACKGROUND: In a randomized, prospective multi-centre trial, the effect of a specific training programme (HyPOS) for patients with hypoglycaemia problems was compared with a control group (CG), receiving a standardized education programme aiming at avoidance of hypoglycaemia by optimization of insulin therapy. METHODS: A total of 164 type 1 diabetes patients (age 46.0 +/- 12.5 yrs, HbA(1c) 7.3 +/- 1.0%, 50% male) were randomized. Hypoglycaemia awareness was measured by the hypoglycaemia awareness questionnaire (HAQ) and by a visual analogue scale (VAS). There were no baseline differences. RESULTS: After a 6-month follow-up, hypoglycaemia awareness significantly improved in HyPOS compared to that in the CG (Delta HAQ 0.7 [95% CL 0.1-1.2], p = 0.024, Delta VAS 0.8 [95% CL 0.2 - 1.2], p = 0.015). In HyPOS, the threshold for detection of low blood glucose (Delta 0.2 mmol/L [95% CL 0.03 - 0.04], p = 0.02) and the treatment of low blood glucose (Delta 4.6 g [95% CL 1.6 - 7.6], p = 0.03) increased significantly. The number of undetected hypogylcaemic episodes (Delta - 1.4 episodes per week [95% CL 0.4-2.5], p = 0.01) and the rate of mild hypoglycaemia dropped significantly in HyPOS (Delta 2.1% [95% CL 0.5-5.3], p = 0.015). The numbers of severe (Delta 0.3 events per patient per year [95% CL - 0.04-1.0], p = 0.037) and very severe hypoglycaemic episodes (Delta 0.3 events per patient per year [95% CL - 0.1-0.7], p = 0.09) were lower in HyPOS, but these differences were not significant. CONCLUSION: Compared to the CG, HyPOS demonstrates additional benefits in terms of improving impaired hypoglycaemia awareness, reducing mild hypoglycaemia, detecting low blood glucose, and treating low blood glucose.     

Indications and efficacy of continuous subcutaneous insulin infusion (CSII) therapy in Type 1 diabetes mellitus: a clinical audit in a specialist service.

AIM: To determine if current guidelines correctly identify patients who will benefit from continuous subcutaneous insulin infusion (CSII) therapy by comparing outcomes between Type 1 diabetic patients with recurrent severe hypoglycaemia (SH) indications with those without; and between patients without and with classic contraindications to CSII managed in a single multidisciplinary pump clinic. METHODS: Changes in biomedical outcomes [glycated haemoglobin (HbA1c), hypoglycaemia, diabetic ketoacidosis (DKA) rates], from before CSII to the end of the study (median duration 20.5 months, range 1-192), were analysed retrospectively from data collected from notes and interviews of 40 patients. Quality of life was assessed by three validated questionnaires at study end (33 patients). RESULTS: Twenty-five out of forty patients were started for reasons other than SH and 15 out of 40 had contraindications to CSII. Overall, CSII was associated with a reduction in HbA1c (9.6 +/- 2.7% to 8.3 +/- 1.2%, P = 0.011), SH (6.45 +/- 16.15/year to 0.34 +/- 1.01/year, P = 0.034) and DKA (1.83 +/- 4.48/year to 0.27 +/- 1.12/year, P = 0.036). The fall in SH was greater for patients started for SH (P < 0.001). However, only patients started for other indications showed a fall in HbA1c (P = 0.001). The fall in DKA rate was greater in patients with contraindications (P = 0.042), and they did not lose the other benefits of CSII therapy, including quality of life. CONCLUSIONS: In the setting of a specialist multidisciplinary service, CSII can be an effective and safe therapy. It confers benefit outside the setting of severe hypoglycaemia and can confer benefit in some patients with classic contraindications. This questions the validity of criteria that may exclude these patients in such a service.     

Indications for insulin pump therapy in different age groups: an analysis of 1,567 children and adolescents.

AIMS: The German working group for pump therapy in paediatric patients has defined seven indications for continuous subcutaneous insulin infusion (CSII): dawn phenomenon, reduction of severe hypoglycaemia, improvement of hyperglycaemia, more flexibility, motivation, failure of injection therapy and pregnancy. In this study we analysed age-specific differences for starting CSII in four age groups (group A: 0-4 years; group B: 5-9 years; group C: 10-14 years; group D: 15-19 years). We also investigated whether glycaemic goals could be reached. METHODS: A total of 1567 children and adolescents (mean age 12.4 years, mean diabetes duration 5.2 years) with documented indications for CSII from the DPV-database (December 2005) were included. RESULTS: Dawn phenomenon (27.4%), reduction of hypoglycaemia (20%) and improvement of hyperglycaemia (18.1%) were the commonest indications for starting CSII. Indications differed by age group (P < 0.0001). In infants and toddlers (group A, n = 138) reduction of hypoglycaemia (42.5%) was the commonest indication. For adolescents (group C, n = 789/group D, n = 408) dawn phenomenon (32.1/21.7%) and flexibility (21.7/25.8%) were the main indications. The rate of severe hypoglycaemia with coma in patients commencing CSII in order to reduce hypoglycaemia fell (12.1/100 patient years before CSII vs. 5.8 after 1 year, 4.49 at study end). Glycated haemoglobin (HbA(1c)) in patients with the treatment goal 'improvement of hyperglycaemia' was lowered significantly in the first year of CSII (HbA(1c) start: 8.8%; after 1 year: 8.5%, P < 0.01) and was stable thereafter (8.8% after 36 months). CONCLUSIONS: CSII in children and adolescents is safe and can reduce the rate of severe hypoglycaemia without deterioration in glycaemic control. In patients with poor glucose control, a significant reduction in HbA(1c) can be achieved in the first year.     

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.     

Insulin-pump use in everyday practice: data from an exhaustive regional registry in France

AIM: The aim of this study is to evaluate the effectiveness and safety of continuous subcutaneous insulin infusion (CSII) under real-life conditions among all patients treated with CSII in the south of Paris. METHODS: The 42 diabetologists practising in the region enrolled all patients treated with CSII or admitted for CSII initiation. During the study visit, the data for pump use and clinical results were recorded. RESULTS: Data were obtained for 424 patients, mean age 44.2+/-15.6 years, disease duration 18.7+/-10.6 years, including 339 treated with CSII for longer than three months (mean duration: 3.5+/-3.5 years; range: 3-258 months). Most of the patients (N=285, 84.8%) had type 1 diabetes; 44 (13.1%) had type 2 diabetes. In patients treated for more than three months, HbA1c decreased significantly between CSII initiation (9.1+/-1.9%) and the study visit (7.8+/-1.4%; P<0.0001). Patients with HbA1c >9%, using the pump, experienced a significant 0.9% improvement in their HbA1c levels with CSII versus multiple daily injections (P=0.001). The number of episodes of moderate hypoglycaemia was 2.7+/-2.5 per patient per week; of severe hypoglycaemia, 0.34 per patient per year and of ketoacidosis, 0.11 per patient per year. Factors significantly associated with HbA1c levels included amount of physical activity, pregnancy, HbA1c at CSII initiation and number of glucose self-determinations. Those associated with the number of moderate hypoglycaemia episodes were basal rate number, female gender and HbA1c level. HbA1c was negatively correlated with moderate hypoglycaemia (P<0.001), but not with severe hypoglycaemia. CONCLUSION: This 'pump' registry establishes the effectiveness of CSII in everyday practice, yet underscores the risks of severe hypoglycaemia and ketosis episodes. It could help diabetologists to improve patient training programmes and follow-up.     

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.     

Cognitive function, insulin-dependent diabetes and hypoglycaemia.

A series of seven psychometric tests, to evaluate mental concentration and the ability to retain selective attention, lexical fluency, wordlist memorizing and psychomotor speed, was performed on 25 non-diabetic control subjects and 55 insulin-dependent diabetes (IDD) patients of similar social background and professional status. When tested, none of the diabetics was hypoglycaemic and these patients were divided into two groups: Group I: 30 IDD patients unaware of hypoglycaemia, and experiencing frequent and severe episodes of hypoglycaemia. Group II: 25 IDD patients aware of hypoglycaemia. Groups I and II had experienced the disease for the same period of time (17 +/- 13 vs. 14 +/- 11 years, respectively) and they had similar HbA1c levels (7.14 +/- 1.25% vs. 8.6 +/- 1.88%, respectively) and degenerative complications. Compared with the scores of the controls, the Group I scores were lower in four tests: trail-making part A (psychomotor speed; P less than 0.001) and part B (retaining selective attention; P less than 0.01), lexical fluency (P less than 0.01) and Rey auditory-verbal learning test (wordlist learning; P less than 0.05). Group II scores were lower in two tests: trail-making part A (P less than 0.01) and part B (P less than 0.05). In word memorizing, the performance of Group I was inferior to that of Group II (P less than 0.05). In general, these psychometric tests showed that IDD scores were lower than those of the controls, with an average of 67% for Group II and 80% for Group I. Chronic hyperglycaemia and severe hypoglycaemia may have a deleterious effect on cognitive performance. In particular, several severe episodes of hypoglycaemia could be responsible for permanent memory impairment.     

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.     

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.     

Comparison of the effects of continuous subcutaneous insulin infusion (CSII) and NPH-based multiple daily insulin injections (MDI) on glycaemic control and quality of life: results of the 5-nations trial.

AIMS: The goal of the study was to determine whether continuous subcutaneous insulin infusion (CSII) differs from a multiple daily injection (MDI) regimen based on neutral protamine hagedorn (NPH) as basal insulin with respect to glycaemic control and quality of life in people with Type 1 diabetes. METHODS: The 5-Nations trial was a randomized, controlled, crossover trial conducted in 11 European centres. Two hundred and seventy-two patients were treated with CSII or MDI during a 2-month run-in period followed by a 6-month treatment period, respectively. The quality of glycaemic control was assessed by HbA(1c), blood glucose values, and the frequency of hypoglycaemic events. For the evaluation of the quality of life, three different self-report questionnaires have been assessed. RESULTS: CSII treatment resulted in lower HbA(1c) (7.45 vs. 7.67%, P < 0.001), mean blood glucose level (8.6 vs. 9.4 mmol/l, P < 0.001) and less fluctuation in blood glucose levels than MDI (+/- 3.9 vs. +/- 4.3 mmol/l, P < 0.001). There was a marked reduction in the frequency of hypoglycaemic events using CSII compared with MDI, with an incidence ratio of 1.12 [95% confidence interval (CI): 1.08-1.17] and 2.61 (95% CI: 1.59-4.29) for mild and severe hypoglycaemia, respectively. The overall score of the diabetes quality of life questionnaire was higher for CSII (P < 0.001), and an improvement in pump users' perception of mental health was detected when using the SF-12 questionnaire (P < 0.05). CONCLUSION: CSII usage offers significant benefits over NPH-based MDI for individuals with Type 1 diabetes, with improvement in all significant metabolic parameters as well as in patients' quality of life. Additional studies are needed to compare CSII with glargine- and detemir-based MDI.     

Continuous intraperitoneal insulin infusion partly restores the glucagon response to hypoglycaemia in type 1 diabetic patients

The glycaemic and hormonal responses to a hypoglycaemic event induced by an i.v. bolus of insulin was studied in seven type 1 diabetic patients treated first with continuous subcutaneous insulin infusion (CSII) and subsequently with continuous intraperitoneal insulin infusion (CIPII). Arterialised blood glucose and venous hormonal responses were analyzed. HbA1c was improved by CIPII. Although a regimen of a higher basal insulin infusion rate was applied during CIPII the basal peripheral venous insulin levels were lower. The i.v. bolus of insulin resulted in hypoglycaemia in both tests but was more pronounced during the CSII test expressed as a smaller area under the curve (AUC) for the first hour (13.0 +/- 2.3 vs. 13.7 +/- 1.2 mmol l(-1) h(-1), p=0.016, CSII vs. CIPII). The hypoglycaemia resulted in a significant and similar increase in the plasma levels of adrenaline, cortisol and growth hormone in both experiments. A significant increase in the glucagon level was only observed during CIPII. The incremental glucagon response was also significantly more pronounced in the CIPII test expressed as maximal responses (7.5 +/- 3.0 vs. 17.0 +/- 3.1 pg ml(-1), p =0.048, CSII vs. CIPII) as well as incremental AUC (5.1 +/- 12.0 vs. 44.4 +/- 13.2 pg ml(-1) h(-1), p =0.027, CSII vs. CIPII). It seems that CIPII in type 1 diabetic patients could improve the glucagon release to hypoglycaemia. This observation may contribute in explaining why CIPII is associated with a lower incidence of hypoglycaemia in spite of an improvement in metabolic control.     

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.     

Assessment of hypoglycaemia awareness using continuous glucose monitoring.

AIMS: To investigate the possibility of assessing hypoglycaemia awareness in patients with Type 1 diabetes using continuous glucose monitoring. METHODS: Twenty patients with Type 1 diabetes were investigated. Ten patients with Type 1 diabetes and strongly impaired hypoglycaemia awareness were compared with 10 patients with intact hypoglycaemia awareness regarding quality of hypoglycaemia perception (number of undetected hypoglycaemic episodes per 24 h, glucose level < 3.3 mmol/l). Hypoglycaemia detection was assessed using the event function of the Continuous Glucose Monitoring System (CGMS; Medtronic MiniMed, Northridge, CA, USA). Patients were instructed to enter an event upon suspecting being hypoglycaemic. RESULTS: Satisfactory CGMS performance could be achieved [mean r = 0.893 between calibration measurements and CGMS data, mean absolute difference (MAD) = 20.6%], although artefacts were observable and had to be controlled. Hypoglycaemia unaware patients showed a significantly higher total number of hypoglycaemic episodes (P < 0.05), number of undetected hypoglycaemic episodes (P < 0.01), and mean glucose levels (P < 0.05). Even in aware patients, undetected hypoglycaemia was observable. No significant differences regarding occurrence of nocturnal hypoglycaemia were observable. CONCLUSIONS: The possibility of direct assessment of hypoglycaemia awareness using continuous glucose monitoring was demonstrated. Its application in clinical practice could be of use for assessing hypoglycaemia perception and evaluating the impact of treatment changes on hypoglycaemia awareness.     

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.     

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.     

A repeated cross-sectional survey of severe hypoglycaemia in 178 Type 1 diabetes mellitus patients performed in 1984 and 1998.

AIMS: To study the prevalence of severe hypoglycaemia (SH) in relation to risk factors in Type 1 diabetic (T1 DM) patients over a period of 14 years. METHODS: We performed a cross-sectional survey of a cohort of 178 T1 DM patients registered at our out-patient clinic in 1984 to be repeated in 1998. An identical questionnaire was sent to the patients in the beginning of 1985 and 1999, respectively, regarding the problem of SH in the preceding year. Additional clinical data were obtained from the patients' medical records on insulin treatment, long-term complications, morbidity, and co-medication. RESULTS: At follow up, the use of multiple insulin injection therapy had increased from 71% to 98% (P < 0.001) and daily self-monitoring of blood glucose (SMBG) from 17% to 48% (P < 0.001). Twenty-seven percent were treated with direct-acting insulin analogues in 1998. An increasing number of patients reported unawareness of hypoglycaemia, 54% vs. 40% (P < 0.01), and nocturnal events were more frequent, 83% vs. 76% (P < 0.05). The prevalence of SH had increased from 17% to 27% (P < 0.05) and a slight decrease of HbA1c, 7.6% to 7.4% (P < 0.05) was documented. CONCLUSION: We conclude that despite more frequent use of multiple injection therapy and SMBG, the prevalence of SH has increased by > 50% over 14 years. A multiple logistic regression analysis of risk factors for SH explained less than 10% of the variance, implicating only unawareness of hypoglycaemia and HbA1c.     

Substitution of night-time continuous subcutaneous insulin infusion therapy for bedtime NPH insulin in a multiple injection regimen improves counterregulatory hormonal responses and warning symptoms of hypoglycaemia in IDDM

Summary In patients with insulin-dependent diabetes mellitus (IDDM) good glycaemic control confers an enhanced risk of hypoglycaemia. Nocturnal hypoglycaemia occurs frequently and contributes to the syndrome of hypoglycaemia unawareness. In order to avoid nocturnal hypoglycaemia we substituted night-time continuous subcutaneous insulin infusion (CSII) therapy in 14 patients with well-controlled IDDM using a multiple injection regimen for the more variable bedtime NPH insulin. During a stepwise hypoglycaemic clamp we studied the effect of this regimen on counterregulatory hormonal responses, warning symptoms and cognitive function. In addition, we investigated the incidence of daytime hypoglycaemia and the acceptability of night-time CSII treatment. CSII was associated with a lower frequency of hypoglycaemia (mean ± SEM): 16.1 ± 3.1 vs 23.6 ± 3.3) episodes during the last 6 weeks of treatment, p = 0.03 (CSII vs NPH)) with maintenance of good glycaemic control (HbA_1c 7.2 ± 0.2 vs 7.1 ± 0.2 %, p = 0.2). Hypoglycaemic thresholds for the growth hormone response and for autonomic symptoms were lower for CSII treatment than for NPH treatment. Of 14 patients 6 decided to continue with the nocturnal CSII treatment. In conclusion, nocturnal CSII improves warning symptoms and counterregulatory hormonal responses to hypoglycaemia and is an acceptable treatment strategy for patients suffering from hypoglycaemia unawareness, as demonstrated in this acute feasibility study. [Diabetologia (1998) 41: 322–329] Received: 21 July 1997 and in revised form: 7 October 1997     

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.