A comparison of intensive mixture therapy with basal insulin therapy in insulin-naïve patients with type 2 diabetes receiving oral antidiabetes agents

Aim: In patients with type 2 diabetes, insulin therapy is commonly initiated with either a single dose of basal insulin or twice‐daily premixed (basal plus prandial) insulin despite no widely accepted recommendation. We compared the glycaemic control, as measured by a change in HbA1c, of intensive mixture therapy (IMT), a basal plus prandial regimen using insulin lispro mixture 50/50 (50% lispro and 50% NPL) before breakfast and lunch and insulin lispro mixture 25/75 (25% lispro and 75% NPL) before dinner, vs. once‐daily insulin glargine therapy, while continuing patients on oral antidiabetes medications. Methods: Following inadequate glycaemic control (HbA1c 1.2–2.0 times the upper limit of normal) and at least 2 months of two or more oral antidiabetes agent therapy, 60 insulin‐naïve patients with type 2 diabetes were randomized to one of the insulin regimens for 4 months with crossover to the alternative regimen for an additional 4 months. Glycaemic goals were preprandial blood glucose <120 mg/dl (6.7 mmol/l) and 2‐h postprandial blood glucose <180 mg/dl (10.0 mmol/l). The insulin dose was optimized by investigators without forced titration. Results: Mean prestudy (baseline) HbA1c for all patients was 9.21 ± 1.33% (±s.d.). IMT compared to glargine resulted in both a lower endpoint in HbA1c (7.08 ± 0.11% vs. 7.34 ± 0.11%; p = 0.003) and a greater change in HbA1c from pretherapy (?1.01 ± 0.10% vs. ?0.75 ± 0.10%; p = 0.0068). Forty‐four per cent of patients receiving IMT and 31% of patients receiving insulin glargine achieved HbA1c ≤ 7%. Two‐hour postprandial glucose values (for all three meals) and predinner glucose values were significantly less with IMT than with insulin glargine (p = 0.0034, 0.0001, 0.0066 and 0.0205). Overall hypoglycaemia throughout the complete treatment period was infrequent (IMT vs. Glargine: 3.98 ± 4.74 vs. 2.57 ± 3.22 episodes/patient/30 days, p = 0.0013), and no severe hypoglycaemia was observed during the study with either therapy. There was no difference in nocturnal hypoglycaemia between the two therapies. The mean insulin dose at the end of therapy was greater for IMT than for once‐daily insulin glargine (0.353 ± 0.256 vs. 0.276 ± 0.207 IU/kg, p = 0.0107). Conclusions: In combination with oral antidiabetes agents, multiple daily injections of a basal plus prandial insulin IMT regimen (using premixed insulin lispro formulations) resulted in greater improvements and a lower endpoint in HbA1c compared with a basal‐only insulin regimen. IMT also resulted in improved postprandial blood glucose control at each meal and enabled administration of a greater daily dose of insulin, which most likely contributed to these lower HbA1c measures. This greater reduction in HbA1c with IMT is accompanied by a small increased occurrence of mild hypoglycaemia but without any severe hypoglycaemia. Greater consideration should be given to initiating insulin as a basal plus prandial regimen rather than a basal‐only regimen.     

Addition of insulin lispro protamine suspension or insulin glargine to oral type 2 diabetes regimens: a randomized trial

Aims: The addition of basal insulin to existing oral therapy can help patients with type 2 diabetes (T2D) achieve glycaemic targets. This study compares the efficacy and safety of insulin lispro protamine suspension (ILPS) and insulin glargine in insulin‐naive patients with T2D and inadequate control on oral antihyperglycaemic medication (OAM). Materials and Methods: An open‐label, randomized, multicentre, multinational 24‐week study of 471 patients receiving ≥2 OAMs for ≥3 months with a body mass index between 25 and 45 kg/m² and HbA1c 7.5–10.0% was conducted. ILPS was injected once or twice daily vs. glargine injected once daily plus prestudy OAMs. Primary objective compared the HbA1c change from baseline. Results: HbA1c change from baseline to endpoint was similar in both groups [?1.46% (ILPS) and ?1.41% (glargine)]. Least‐squares mean difference (95% CI) for HbA1c (?0.05 [?0.21, 0.11]%), glycaemic variability (0.06 [?0.06, 0.19] mmol/l) and weight change (?0.01 [?0.61, 0.59] kg) showed non‐inferiority (margins of 0.4%, 0.8 mmol/l and 1.5 kg, respectively). Percentages of patients achieving HbA1c <7.0% were 43.8% ILPS and 41.2% glargine. Mean daily insulin dose was 0.39 vs. 0.35 U/kg (p = 0.02) and weight gain was 1.04 vs. 1.07 kg for ILPS vs. glargine (p = 0.98). Overall hypoglycaemia (episodes/patient/year) was similar for ILPS and glargine (24.2 ± 28.8 vs. 23.0 ± 30.9); nocturnal (6.1 ± 10.6 vs. 4.1 ± 9.4, p < 0.001) rates were higher for ILPS. Severe hypoglycaemia was higher for ILPS vs. glargine (n = 9 vs. n = 2; p = 0.04). Conclusions: At endpoint, ILPS was non‐inferior to glargine in HbA1c change from baseline, but associated with increased risk of hypoglycaemia.     

Comparison between a basal-bolus and a premixed insulin regimen in individuals with type 2 diabetes–results of the GINGER study

Aim: To compare the efficacy and safety of an intensified insulin regimen, using insulin glargine (glargine) once daily and pre‐meal insulin glulisine (glulisine) (basal‐bolus), with a conventional therapy, using premixed insulin (premix) twice daily. Methods: This 52‐week, open‐label, randomized, multinational, multicentre trial included 310 subjects with type 2 diabetes (T2D) on premix, with or without metformin, who were randomized to a basal‐bolus regimen with glargine and glulisine (n = 153; mean ± s.d. age 60.2 ± 7.5 years; HbA1c 8.6 ± 0.8%; weight 87.0 ± 15.1 kg; T2D duration 12.8 ± 5.8 years) or twice‐daily premix (n = 157; age 60.9 ± 7.8 years; HbA1c 8.5 ± 0.9%; weight 84.3 ± 15.0 kg; T2D duration 12.5 ± 6.8 years). The primary endpoint was change in HbA1c from baseline to endpoint. Results: Mean decrease in baseline‐to‐endpoint HbA1c for basal‐bolus vs. premix was ?1.31 vs. ?0.80% (difference: ?0.476%; 95% Cl: ?0.714, ?0.238; p = 0.0001, ancova ). More subjects reached HbA1c ≤ 7.0% in the basal‐bolus group than in the premix group [68 (46.6%) vs. 43 (27.9%); p = 0.0004], while they also experienced significantly lower mean ± s.d. daytime (?2.7 ± 2.3 vs. ?2.3 ± 2.5 mmol/l; p = 0.0033) and postprandial (?3.1 ± 2.6 vs. ?2.5 ± 2.8 mmol/l; p < 0.0001) blood glucose. Endpoint daily insulin doses were 98.0 ± 48.7 vs. 91.3 ± 44.3 IU (p = 0.2104); mean weight gain was +3.6 ± 4.0 vs. +2.2 ± 4.5 kg (p = 0.0073). Mean number of overall hypoglycaemic events with basal‐bolus and premix was 13.99 and 18.54 events/patient year, respectively (difference: ?3.90; 95% CI: ?10.40, 2.60; p = 0.2385). Conclusions: An intensified basal‐bolus regimen using glargine/glulisine results in a significantly superior glycaemic control vs. premix therapy in a population with long‐standing insulin‐treated T2D, with no increase in the rates of hypoglycaemia.     

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.     

Effects of insulin glulisine as mono- or add-on therapy in patients with type 2 diabetes mellitus

Aim: To evaluate the safety and efficacy of insulin glulisine (glulisine) with and without oral antidiabetic drugs (OAD; sulphonylurea or sulphonylurea + biguanide) relative to that of OAD alone in Japanese and Korean patients with inadequately controlled type 2 diabetes mellitus (T2DM). Methods: In an open, randomized, parallel‐group, comparative, controlled trial, 387 patients were randomized and treated with glulisine + OAD (n = 130), glulisine monotherapy (n = 127) or OAD only (n = 130) for 16 weeks. Glulisine was self‐injected subcutaneously three times daily (0–15 minutes before meals) at a starting dose of ≥0.2 U/kg/day. Patients titrated the glulisine dose to achieve a 2‐h postprandial plasma glucose (2h‐PPG) level of 7.1–9.5 mmol/l (128–172 mg/dl) by administering at least one additional unit at each appropriate meal time if the 2h‐PPG level was > 9.5 and < 11.1 mmol/l (> 172 and < 200 mg/dl) and by administering at least two additional units if the 2h‐PPG level was ≥ 11.1 mmol/l (≥ 200 mg/dl). Therapy with OAD was continued at the stable baseline regimen. The primary efficacy endpoint was change in haemoglobin A_1c (HbA_1c) from baseline to endpoint in the intention‐to‐treat population. Results: At baseline, therapy with OAD was a sulphonylurea only and a sulphonylurea + a biguanide in approximately 24 and 76% of patients respectively. Both glulisine groups had larger reductions in adjusted mean HbA_1c than the OAD‐only group (glulisine + OAD, ?2.07%; glulisine monotherapy, ?1.25%; OAD only, ?0.61%). Superiority of glulisine + OAD and glulisine monotherapy vs. OAD only was shown by differences in adjusted mean HbA_1c change from baseline values of ?1.46% (p < 0.0001) and ?0.64% (p < 0.0001) respectively. Both glulisine groups had better 2h‐PPG control than the OAD‐only group. Mean daily glulisine doses increased from baseline to endpoint (glulisine + OAD, 13.3–22.5 U; glulisine monotherapy, 14.2–38.0 U). The rate of all symptomatic hypoglycaemia events per patient‐year in the entire treatment phase was 11.9 in the glulisine + OAD group, 8.8 in the glulisine monotherapy group and 1.7 in the OAD‐only group. There was only one event of severe hypoglycaemia, which occurred in the glulisine + OAD group. Efficacy and safety were similar in Japanese and Korean subpopulations. Conclusions: Both glulisine + OAD and glulisine monotherapy were well tolerated and effective for Japanese and Korean patients with T2DM mellitus inadequately controlled by OAD therapy alone.     

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.     

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.     

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 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.     

Insulin glulisine imparts effective glycaemic control in patients with Type 2 diabetes

INTRODUCTION: Insulin glulisine (glulisine) was evaluated versus regular human insulin (RHI) in Type 2 diabetes (T2DM) patients. METHODS: Patients previously on >6 months' continuous insulin treatment aged >or=18 years in a randomized, multinational, controlled, open-label, parallel group, 26-week study received twice-daily NPH insulin and either glulisine (0-15 min before breakfast and dinner; n=448) or RHI (30-45 min before breakfast and dinner; n=442) at least twice daily. RESULTS: Mean baseline characteristics were similar between groups. There were no differences in baseline to endpoint HbA(1c) reductions (glulisine: -0.32%; RHI: -0.35%; p=0.5726), and the non-inferiority of glulisine versus RHI was demonstrated (difference in adjusted mean change 0.03%; 95% CI: -0.07, 0.13). Postprandially, glulisine lowered plasma glucose significantly more versus RHI at 2h (14.14 mmol/L versus 15.28 mmol/L; p=0.0025) and excursions at 1h (3.99 versus 4.59; p=0.0151) and 2h (4.87 versus 6.03; p=0.0002). No between-group differences occurred in the frequencies and monthly rates of all symptomatic hypoglycaemia; nocturnal hypoglycaemia from Month 4 to treatment end was less frequent with glulisine versus RHI (9.1% versus 14.5%; p=0.029). CONCLUSION: Glulisine was non-inferior to RHI in reducing HbA(1c) in T2DM. Glulisine demonstrated superior postprandial glucose control and was associated with fewer nocturnal hypoglycaemic episodes, indicating clinical benefits.     

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.     

Glargine versus NPH insulin: efficacy in comparison with insulin aspart in a basal bolus regimen in type 1 diabetes--the glargine and aspart study (GLASS) a randomised cross-over study

The aim of the study was to compare the efficacy of insulin glargine and aspart with NPH insulin and aspart in a basal bolus regimen in type 1 diabetes. In this 36-week randomised open-label two-period cross-over trial, subjects received 16 weeks' treatment with either once-daily insulin glargine or twice-daily NPH insulin after 4-week run-in. Primary outcome was HbA1c and secondary outcomes were fasting plasma glucose (FPG), weight change, incidence of hypoglycaemia, effect on lipid profile and patient satisfaction. Sixty patients with type 1 diabetes were recruited (33 male, mean age 42.7 years, mean HbA1c 8.53%) with 53 completing the study. At completion, HbA1c was lower with glargine and aspart than with NPH and aspart (8.07% versus 8.26%, difference -0.19 [95% CI 0.37-0.01]%, p=0.04). FPG was significantly different between glargine and NPH (p=0.002), with mean FPG on glargine 3mmol/L lower than on NPH at the end of the study. There were no differences in hypoglycaemia rate (p=0.63), weight (p=0.45) or lipid profile (p=0.18). Patient satisfaction was greater with glargine (DTSQ, p=0.001). Three patients discontinued as they wished to remain on glargine. We suggest that glargine combined with aspart is an effective basal bolus regimen in type 1 diabetes.     

Exenatide compared with long-acting insulin to achieve glycaemic control with minimal weight gain in patients with type 2 diabetes: results of the Helping Evaluate Exenatide in patients with diabetes compared with Long-Acting insulin (HEELA) study

Aim: The Helping Evaluate Exenatide in overweight patients with diabetes compared with Long-Acting insulin (HEELA) study was designed to examine whether the glucagon-like peptide-1 (GLP-1) receptor agonist, exenatide, could improve HbA1c (≤7.4%) with minimal weight gain (≤1 kg) compared with insulin glargine.
Methods: Patients [body mass index (BMI) >27 kg/m²] with elevated cardiovascular risk and type 2 diabetes inadequately controlled on two or three oral antidiabetes drugs (OADs) were randomized to add-on exenatide 5–10 μg b.i.d. (n = 118) or insulin glargine o.d. (titrated to target fasting plasma glucose ≤5.6 mmol/l; n = 117) for 26 weeks.
Results: The study population had baseline mean (s.d.) age of 56.5 (9.1) years and BMI of 34.1 (5.3) kg/m², and 58.5% of patients were taking two OADs. Mean baseline HbA1c was 8.65 (0.68)% in the exenatide group and 8.48 (0.66)% in the insulin glargine group. The proportions of patients achieving the composite endpoint of HbA1c ≤7.4% with weight gain ≤1 kg were 53.4% for the exenatide group and 19.8% for the insulin glargine group (p < 0.001 for exenatide vs. insulin glargine). Exenatide and insulin glargine did not demonstrate a significant difference in HbA1c improvements [least square (LS) mean [s.e.m.]: −1.25 [0.09]% and −1.26 [0.09]% respectively; p = 0.924], but had divergent effects on body weight (−2.73 [0.31] vs. +2.98 [0.31] kg respectively, p < 0.001) after 26 weeks. There were more treatment-related adverse events with exenatide but a lower incidence of nocturnal hypoglycaemia, with no differences in overall or severe hypoglycaemia.
Conclusions: Additional treatment with exenatide resulted in significantly more overweight and obese patients with an elevated cardiovascular risk and type 2 diabetes achieving better glycaemic control with minimal weight gain compared with insulin glargine.     

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.     

Clinical outcomes in real‐world patients with type 2 diabetes switching from first‐ to second‐generation basal insulin analogues: Comparative effectiveness of insulin glargine 300 units/mL and insulin degludec in the DELIVER D+ cohort study

Aims

To compare clinical outcomes in patients with type 2 diabetes (T2D) switching from insulin glargine 100 units/mL (Gla‐100) or insulin detemir (IDet) to insulin glargine 300 units/mL (Gla‐300) or insulin degludec (IDeg).

Materials and Methods

We conducted a retrospective, observational study of electronic medical records for Gla‐300/IDeg adult switchers (March 1, 2015 to January 31, 2017) with active records for 12‐month baseline (glycated haemoglobin [HbA1c] used a 6‐month baseline period) and 6‐month follow‐up periods. Gla‐300 and IDeg switchers were propensity score‐matched using baseline demographic and clinical characteristics. Outcomes were HbA1c change and goal attainment (among patients with HbA1c captured at follow‐up), and hypoglycaemia with fixed follow‐up (intention‐to‐treat [ITT]; 6 months) and variable follow‐up (on‐treatment [OT]; to discontinuation or 6 months).

Results

Each matched cohort comprised 1592 patients. The mean decrease in HbA1c and HbA1c goal (<7.0% [53 mmol/mol] and <8.0% [64 mmol/mol]) attainment rates were similar for Gla‐300 (n = 742) and IDeg (n = 727) switchers. Using fixed follow‐up (ITT method), hypoglycaemia incidence decreased significantly from baseline with Gla‐300 (all hypoglycaemia: 15.6% to 12.7%; P = .006; hypoglycaemia associated with inpatient/emergency department [ED] encounter: 5.3% to 3.5%; P = .007), but not with IDeg. After adjusting for baseline hypoglycaemia, no significant differences in hypoglycaemia incidence and event rate were found at follow‐up (ITT) for Gla‐300 vs IDeg. Using variable follow‐up (OT), hypoglycaemia incidence was similar in both groups, but Gla‐300 switchers had a lower inpatient/ED hypoglycaemia event rate at follow‐up (adjusted rate ratio 0.56; P = .016).

Conclusions

In a real‐world setting, switching from Gla‐100 or IDet to Gla‐300 or IDeg was associated with similar improvements in glycaemic control and hypoglycaemia in adult patients with T2D.     

Treatment satisfaction and psychological well-being with insulin glargine compared with NPH in patients with Type 1 diabetes.

AIMS: To assess satisfaction with treatment and psychological well-being associated with insulin glargine and Neutral Protamine Hagedorn (NPH). Insulin glargine, a new long-acting insulin analogue, provides constant, peakless insulin release following once-daily administration and is associated with fewer hypoglycaemic episodes, despite metabolic control equivalent to that achieved with NPH human basal insulin. METHODS: The Diabetes Treatment Satisfaction Questionnaire (DTSQ) and Well-being Questionnaire (W-BQ) were completed at baseline and at weeks 8, 20 or 28 by 517 patients with Type 1 diabetes participating in a randomized, controlled European trial comparing insulin glargine and NPH. Analysis of covariance was performed on change from baseline scores (main effects: treatment and pooled site; covariate: baseline scores). RESULTS: Treatment satisfaction improved with insulin glargine at all time points, including endpoint, but deteriorated slightly with NPH. These differences were significant throughout the study (change from baseline to endpoint: +1.27 vs. -0.56; P = 0.0001). Outcomes were better with insulin glargine for the DTSQ items, Perceived Frequency of Hyperglycaemia and Hypoglycaemia, with statistically significant differences at week 28 and endpoint for hyperglycaemia (P = 0.0373 and 0.0379) and at week 20 for hypoglycaemia (P = 0.0024). There was no difference in psychological well-being between the treatment groups, with mean scores increasing in both. CONCLUSIONS: Study participants had treatment-independent improvements in General Well-being. Advantages for insulin glargine were seen in significantly improved Treatment Satisfaction throughout the study, together with lower Perceived Frequency of Hyperglycaemia than for patients on NPH, without a significant increase in Perceived Frequency of Hypoglycaemia.     

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

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

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

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

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.     

Improving metabolic control in sub-optimally controlled subjects with Type 1 diabetes: comparison of two treatment algorithms using insulin glargine

This study assessed the incidence of severe hypoglycaemia with two insulin glargine titration algorithms: Algorithm 1 (increments of at least 10%, but not exceeding 4U) versus Algorithm 2 (1-6U increments). In this multicenter (n=409), multinational (n=54), open-label, 24-week randomized trial in 2442 subjects with sub-optimally controlled Type 1 diabetes (T1DM), mean prior insulin therapy duration was 14.6+/-10.3 years. The incidence of severe hypoglycaemia was similar with Algorithms 1 and 2 (16.6events/100 patient-years versus 14.4events/100 patient-years). There were similar rates of both symptomatic and nocturnal hypoglycaemia. HbA(1c) and fasting blood glucose (FBG) decreased significantly (baseline to endpoint; p<0.001), and comparably with Algorithms 1 and 2 (HbA(1c): -0.64% versus -0.72%; FBG: -57mg/dL versus -59mg/dL). Mean basal insulin dose increased with both algorithms (+5.7U versus +5.9U). In a diverse population with longstanding T1DM, transfer from any insulin regimen, including basal-bolus or premixed insulin to an insulin glargine-based regimen resulted in significant improvements in glycaemic control, with low rates of severe hypoglycaemia, irrespective of the titration algorithm used.