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

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

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

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

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

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

Comparison of insulin lispro mixture 25/75 with insulin glargine during a 24-h standardized test-meal period in patients with Type 2 diabetes.

AIM: To compare insulin lispro mixture (25% insulin lispro and 75% NPL; Mix 25/75) twice-daily plus oral glucose-lowering medications (metformin and/or sulphonylurea) with once-daily insulin glargine plus oral agents with respect to postprandial glycaemic control and other glucose and lipid parameters in patients with Type 2 diabetes inadequately controlled with insulin and/or oral glucose-lowering agents. METHODS: This was a randomized, open-label, crossover study. Prestudy oral agents were continued and patients not already on oral agents were treated with metformin. Mix 25/75 and insulin glargine were adjusted over 3 months to attain premeal plasma glucose (PG) < 6.0 mmol/l and were then given during a 24-h in-patient test meal period with frequent PG, serum triglyceride (TG) and free fatty acid (FFA) measurements. RESULTS: Twenty patients (10 F/10 M; mean +/-sd age 54.0 +/- 10.7 years, body mass index 37.0 +/- 8.6 kg/m2, HbA1c 8.4 +/- 1.01%) participated. Mean doses were 23 U before the morning and 37 U before the evening meal for Mix 25/75 and 44 U for insulin glargine. The combined 2-h morning and evening meal postprandial plasma glucose (PPG) was not different between groups (9.2 +/- 2.04 vs. 9.9 +/- 1.66 mmol/l, P = 0.161). Mix 25/75 was associated with a lower mean 2-h PPG for all meals combined (9.0 +/- 1.88 vs. 9.9 +/- 1.80 mmol/l, P < 0.05) and lower mean 24-h PG (6.7 +/- 1.00 vs. 7.5 +/- 1.32 mmol/l, P < 0.01). Eight patients experienced mild hypoglycaemia (PG < 3.5 mmol/l) with Mix 25/75 and 3 with insulin glargine. The endpoint HbA1c was lower with Mix 25/75 (6.9 +/- 0.52% vs. 7.3 +/- 0.81%, P < 0.05). CONCLUSIONS: In a 24-h test-meal setting in 20 patients, Mix 25/75 insulin plus oral glucose-lowering agents was associated with lower mean PPG and 24-h PG, more mild hypoglycaemia and similar TG, FFA and fasting PG concentrations. HbA1c was lower with Mix 75/25 plus oral agents, although it may not have reached steady state due to ongoing dose adjustment.     

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.     

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.     

Effect of a single dose of insulin glargine/lixisenatide fixed ratio combination (iGlarLixi) on postprandial glucodynamic response in Japanese patients with type 2 diabetes mellitus: A phase I randomized trial

This report describes novel clinical data assessing the pharmacodynamics of insulin glargine/lixisenatide (iGlarLixi) compared with placebo and insulin glargine alone, to determine pharmacokinetics of lixisenatide, and to assess safety of iGlarLixi in Japanese people with type 2 diabetes mellitus (T2DM). In a single-centre, open-label, randomized, placebo-controlled cross-over study, participants received subcutaneous iGlarLixi 5 U/5 μg and 10 U/10 μg, placebo, and 5 U insulin glargine. The primary endpoint was area under the postprandial plasma glucose (PPG) curve (AUC_0–2h). A total of 20 participants completed all study periods. iGlarLixi 5 U/5 μg and 10 U/10 μg reduced mean PPG dose-dependently compared with placebo and insulin glargine 5 U. Both combinations significantly reduced PPG-AUC_0–2h dose-dependently compared with placebo (least squares mean difference −7.48 mmol h/L for 5 U/5 μg, −10.75 mmol h/L for 10 U/10 μg; P < 0.0001). iGlarLixi 5 U/5 μg reduced PPG-AUC_0–2h significantly compared with insulin glargine 5 U (−0.76 mmol h/L; P < 0.0001). No symptomatic hypoglycaemia occurred during the study. iGlarLixi single subcutaneous injections significantly and dose-dependently reduced PPG compared to placebo or insulin glargine in Japanese participants with T2DM. iGlarLixi was safe and well tolerated, and would be expected to provide the 24-hour plasma glucose-lowering effects of insulin glargine and the postprandial antihyperglycaemic effects of lixisenatide.     

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.     

Effects of initiation and titration of a single pre-prandial dose of insulin glulisine while continuing titrated insulin glargine in type 2 diabetes: a 6-month 'proof-of-concept' study

Aim: Stepwise intensification of insulin treatment to match the progressive decline of endogenous insulin secretion has been shown to be an effective management strategy in type 2 diabetes mellitus (T2DM). The efficacy of initiating and titrating a single bolus dose of insulin glulisine to baseline insulin glargine plus oral hypoglycaemic agents (OHAs) was investigated. Methods: This was a 6‐month, parallel‐group, randomized, open‐label, Phase IV study conducted in the US, UK and Russia. People with T2DM (HbA_1c 7.5–9.5%) using any basal insulin underwent a 3‐month run‐in period on insulin glargine titrated to optimize fasting blood glucose (BG) control. Those with HbA_1c >7.0% were randomized to either continue prior therapy (n = 57) or to add a single dose of insulin glulisine (n = 49) immediately prior to the main meal for a further 3 months. Two different titration algorithms were employed for the bolus dose, targeting 2‐h postprandial BG ≤135 mg/dL (≤7.5 mmol/l; Russia and UK) or pre‐meal/bedtime BG 100–120 mg/dl (5.5–6.7 mmol/l; US). Results: HbA_1c and fasting plasma glucose levels decreased during the run‐in period. In the 3 months after randomization, more participants in the basal‐plus‐bolus group reached HbA_1c <7.0% than the basal‐only control group (22.4 vs. 8.8%; p < 0.05), with significantly greater reduction of HbA_1c (?0.37 vs. ?0.11%; p = 0.0290). Rates of hypoglycaemia and mean weight change were comparable between the treatment groups. Conclusions: In people with T2DM inadequately controlled on basal insulin plus OHAs, adding a single injection of insulin glulisine prior to the main meal significantly improves glucose control without undesired side effects.     

In Type 1 diabetic patients with good glycaemic control,blood glucose variability is lower during continuous subcutaneous insulin infusion than during multiple daily injections with insulin glargine

Aims The superiority of continuous subcutaneous insulin infusion (CSII) over multiple daily injections (MDI) with glargine is uncertain. In this randomized cross‐over study, we compared CSII and MDI with glargine in patients with Type 1 diabetes well controlled with CSII. The primary end‐point was glucose variability. Methods Thirty‐nine patients [38.1 ± 9.3 years old (mean ± sd ), diabetes duration 16.6 ± 8.2 years, glycated haemoglobin (HbA_1c) 7.6 ± 0.8%], already on CSII for at least 6 months, were randomly assigned to CSII with lispro or MDI with lispro and glargine. After 4 months they were switched to the alternative treatment. During the last month of each treatment blood glucose variability was analysed using glucose standard deviation, mean amplitude of glycaemic excursions (MAGE), lability index and average daily risk range (ADRR). As secondary end‐points we analysed blood glucose profile, HbA_1c, number of episodes of hypo‐ and hyperglycaemia, lipid profile, free fatty acids (FFA), growth hormone and treatment satisfaction. Results During CSII, glucose variability was 5–12% lower than during MDI with glargine. The difference was significant only before breakfast considering glucose standard deviation (P = 0.011), significant overall using MAGE (P = 0.016) and lability index (P = 0.005) and not significant using ADRR. Although HbA_1c was similar during both treatments, during CSII blood glucose levels were significantly lower, hyperglycaemic episodes were fewer, daily insulin dose was less, FFA were lower and treatment satisfaction was greater than during MDI with glargine. The frequency of hypoglycaemic episodes was similar during both treatments. Conclusions During CSII, glucose variability is lower, glycaemic control better and treatment satisfaction higher than during MDI with glargine.     

Effect of once-weekly dulaglutide versus insulin glargine in people with type 2 diabetes and different baseline glycaemic patterns: A post hoc analysis of the AWARD-2 clinical trial

The long-acting glucagon-like peptide-1 receptor agonist dulaglutide acts by stimulating insulin secretion and reducing glucagon levels in a glucose-dependent manner both in the fasting and postprandial states, resulting in reductions of both fasting glucose (FG) and postprandial glucose (PPG). In contrast, the main mechanism of action of basal insulin is to reduce elevated FG by inhibiting hepatic glucose production. The aim of the present post hoc analysis of the phase 3 AWARD-2 trial was to investigate whether specific baseline glycaemic patterns respond differentially to dulaglutide compared to insulin glargine (glargine). We categorized participants into four subgroups based on prespecified glucose thresholds and their baseline FG and daily 2-hour mean PPG: low FG/low PPG; low FG/high PPG; high FG/low PPG; and high FG/high PPG. Changes in glycaemic measures in response to treatment with dulaglutide or glargine were evaluated in each subgroup. At 52 weeks, significant reductions from baseline in glycated haemoglobin (HbA1c) were observed in all subgroups with dulaglutide 1.5 mg and with glargine (all P < .05), except in patients with low FG/low PPG who received glargine. Greater HbA1c reductions were observed with dulaglutide 1.5 mg compared to glargine in all subgroups (all P ≤ .05), except in the low FG/high PPG subgroup.     

Initiating insulin therapy in elderly patients with Type 2 diabetes: efficacy and safety of lispro mix 25 vs. basal insulin combined with oral glucose‐lowering agents

Aims To compare starter insulins in the elderly subgroup of the DURABLE trial 24‐week initiation phase. Methods In a post‐hoc analysis of the ≥ 65 years subgroup enrolled in the DURABLE trial, we compared the safety and efficacy of lispro mix 25 (LM25: lispro 25%/insulin lispro protamine suspension 75%), n = 258, vs. glargine, n = 222, added to oral glucose‐lowering agents. Results Baseline glycated hemoglobin (HbA_1c) was similar (LM25 8.7 ± 1.2, glargine 8.8 ± 1.1%, P = 0.612). At 24‐weeks, LM25 patients had lower HbA_1c (7.0 ± 0.9 vs. 7.3 ± 0.9%, P < 0.001), greater HbA_1c reduction (?1.7 ± 1.2 vs. ?1.5 ± 1.1%, P < 0.001), and more patients reaching HbA_1c < 7.0% (55.6 vs. 41.0%, P = 0.005). LM25 patients were on more insulin (0.40 ± 0.19 vs. 0.33 ± 0.19 u/kg/day, P < 0.001) and experienced more weight gain (3.6 ± 3.6 vs. 1.8 ± 3.2 kg, P < 0.001). Additionally, LM25‐treated patients reported a higher mean overall hypoglycaemia rate than glargine patients (40.8 ± 47.6 vs. 31.1 ± 48.5 episodes/patient/year, P = 0.037), while nocturnal hypoglycaemia rates were similar. Over 24 weeks, incidence of severe hypoglycaemia was higher for LM25 (4.3% vs. 0.9%, P = 0.018); however, by 24‐week endpoint incidence was similar (0.8% vs. 0.0%P = 0.125). Conclusions In this elderly subgroup post‐hoc analysis, LM25 demonstrated a lower endpoint HbA_1c and a higher % of patients reaching HbA_1c target of < 7.0%, but with more weight gain and higher rates of hypoglycaemia compared to glargine.     

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.     

A randomized multicentre trial of insulin glargine compared with NPH insulin in people with type 1 diabetes

BACKGROUND: To compare insulin glargine with NPH human insulin for basal insulin supply in adults with type 1 diabetes. METHODS: People with type 1 diabetes (n = 585), aged 17-77 years, were randomized to insulin glargine once daily at bedtime or NPH insulin either once- (at bedtime) or twice-daily (in the morning and at bedtime) according to their prior treatment regimen and followed for 28 weeks in an open-label, multicentre study. Both groups continued with pre-meal unmodified human insulin. RESULTS: There was no significant difference between the two insulins in change in glycated haemoglobin from baseline to endpoint (insulin glargine 0.21 +/- 0.05% (mean +/- standard error), NPH insulin 0.10 +/- 0.05%). At endpoint, self-monitored fasting blood glucose (FBG) had decreased similarly in each group (insulin glargine -1.17 +/- 0.12 mmol/L, NPH insulin -0.89 +/- 0.12 mmol/L; p = 0.07). However, people on >1 basal insulin injection per day prior to the study had a clinically relevant decrease in FBG on insulin glargine versus NPH insulin (insulin glargine -1.38 +/- 0.15 mmol/L, NPH insulin -0.72 +/- 0.15 mmol/L; p < 0.01). No significant differences in the number of people reporting >or=1 hypoglycaemic episode were found between the two groups, including severe and nocturnal hypoglycaemia. Insulin glargine was well tolerated, with a similar rate of local injection and systemic adverse events versus NPH insulin. CONCLUSIONS: A single, bedtime, subcutaneous dose of insulin glargine provided a level of glycaemic control at least as effective as NPH insulin, without an increased risk of hypoglycaemia.     

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

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

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

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

谷赖胰岛素或赖脯胰岛素联合甘精胰岛素对糖尿病的有效性及安全性

目的 比较谷赖胰岛素和赖脯胰岛素联合甘精胰岛素对糖尿病的有效性、安全性.方法 本研究为多中心、随机、对照研究,包括4周的导人期和12周的治疗期.2007年2月至2008年6月共人选糖尿病患者484例（1型34例,2型450例）,患者糖化血红蛋白（HbA1c）为6.5％～11.0％,之前已接受连续3个月的胰岛素治疗.按3：1随机给予谷赖胰岛素（363例）或赖脯胰岛素（121例）每日3次联合甘精胰岛素每日1次治疗,比较两组治疗12周后HbA1c、血糖变化及低血糖发生情况和治疗满意度.组间数据比较采用ANOVA方法.结果 治疗12周后,谷赖胰岛素和赖脯胰岛素组HbA1c分别由8.7％±1.2％降至7.9％±1.0％及由8.8％±1.2％降至7.9％±1.0％（组内治疗前后比较,t=- 12.55、-8.88,均P＜0.05）.两组空腹血糖（FPG）分别由（8.6±2.8）mmol/L降至（7.7±2.5）mmol/L及由（8.6±2.5） mmol/L降至（7.8±2.2）mmol/L（组内治疗前后比较,t=-6.55、-2.98,均P＜0.05）.谷赖胰岛素组标准餐后2h血糖（2 h PPG）由（10.6±3.8） mmol/L降至（ 10.2±3.7） mmol/L（t=-2.07,P＜0.05）;赖脯胰岛素组2 h PPG治疗前后差异无统计学意义[由（ 10.9±4.0）mmol/L降至（10.4±3.5） mmol/L,t=-1.37,P＞0.05].治疗12周期间,谷赖胰岛素组和赖脯胰岛素组低血糖事件发生率分别为33.9％ （123/363）和34.7％ （42/121）.治疗前后谷赖胰岛素组和赖脯胰岛素组治疗满意度总评分分别由29±5升至31±5及由29±5升至31±4（组内治疗前后比较,t =6.81、4.21,均P＜0.05）.结论 谷赖胰岛素和赖脯胰岛素联合甘精胰岛素治疗糖尿病的临床疗效、安全性及治疗满意度相似.     

A comparison of insulin lispro Mix25 and human insulin 30/70 in the treatment of type 2 diabetes during Ramadan

OBJECTIVE: To compare insulin lispro Mix25 and human insulin 30/70 with regard to their effect on morning and evening postprandial glucose (PPG) control, and on average daily blood-glucose (BG), in patients with Type 2 diabetes who wish to fast during Ramadan. METHOD: Insulin lispro Mix25 and human insulin 30/70 were compared in an open-label, multicenter, randomised, crossover study involving 151 patients. Each treatment period had a duration of 14 days during which the patients self-monitored their BG before and 2 h after the main meals on any 3 days within the last 5 days of each treatment period. RESULTS: The 2 h PPG excursion following the main evening meal after sunset was significantly lower with insulin lispro Mix25 (3.4+/-2.9 mmol/l) compared with human insulin 30/70 (4.0+/-3.2 mmol/l, P=0.007). The evening pre-meal fasting BG values were also lower with insulin lispro Mix25 (7.1+/-2.2 mmol/l) versus human insulin 30/70 (7.5+/-2.6 mmol/l, P=0.034). The average daily BG concentration was 9.5+/-2.4 mmol/l during treatment with insulin lispro Mix25 versus 10.1+/-2.5 mmol/l with human insulin 30/70 given in identical doses (P=0.004). CONCLUSION: When compared with human insulin 30/70, treatment of insulin-requiring Type 2 patients with insulin lispro Mix25 during Ramadan resulted in better average daily glycaemia, and better BG control before and after the evening meal. Insulin lispro Mix25 should be considered as a therapeutic option during Ramadan.     

Safety and efficacy of insulin glargine (HOE 901) versus NPH insulin in combination with oral treatment in Type 2 diabetic patients

Aims A European, randomized, 29‐centre, open‐label study compared the safety and efficacy of two formulations of insulin glargine and neutral protamine Hagedorn (NPH) human insulin, in combination with oral agents, in patients with Type 2 diabetes mellitus (DM). Methods Two‐hundred‐and‐four patients with Type 2 DM, in whom oral treatment alone was inadequate, were randomized to insulin glargine with 30 µg/ml zinc [insulin glargine (30)], or insulin glargine with 80 µg/ml zinc [insulin glargine (80)] or NPH insulin subcutaneously once daily. Insulin was titrated to aim for fasting blood glucose (FBG) values between 4 and 7 mmol/l. All participants received oral therapy during the 3‐week titration phase and 1‐week maintenance phase of the trial. Results No differences between treatment groups were observed in adjusted mean fasting plasma glucose; significant decreases of 3.4 mmol/l, 3.5 mmol/l and 3.1 mmol/l were observed within the insulin glargine (30), insulin glargine (80) and NPH insulin groups, respectively (P < 0.0001 in each case). No differences between groups, but significant changes within groups, were observed in self‐monitored FBG, mean FBG, blood glucose profile, stability of FBG, nocturnal blood glucose, fasting serum C‐peptide, non‐esterified fatty acids, haemoglobin A_1c, fructosamine and fasting serum insulin. A significantly greater proportion of NPH insulin patients experienced symptomatic nocturnal hypoglycaemia (19.1 NPH group vs. 7.3% glargine groups; P = 0.0123). Both insulins were well tolerated; one patient in each group experienced an injection site reaction. Conclusions Insulin glargine is as safe and effective as NPH insulin given once daily and in this study caused fewer episodes of nocturnal hypoglycaemia. Diabet. Med. 20, 545–551 (2003)