Efficacy and safety of LY2963016 insulin glargine in patients with type 1 and type 2 diabetes previously treated with insulin glargine

The safety and efficacy of LY2963016 insulin glargine (LY IGlar) and Lantus^® insulin glargine (IGlar), products with identical primary amino acid sequences, were assessed in subgroups of patients with type 1 (T1D, n = 452) or type 2 diabetes (T2D, n = 299) reporting prestudy IGlar treatment in 52‐week open‐label (ELEMENT‐1) and 24‐week double‐blind (ELEMENT‐2) studies. At randomization, patients transitioned from their prestudy IGlar to equivalent doses of LY IGlar or IGlar. Primary efficacy (change in glycated haemoglobin from baseline to 24 weeks), other efficacy and select safety outcomes of LY IGlar were compared with those of IGlar. Continuous data were analysed using analysis of covariance, categorical data by Fisher's exact test, and treatment comparisons for hypoglycaemia by Wilcoxon test. No statistically significant treatment differences were identified for efficacy and safety outcomes except for weight change (T1D), overall incidence of detectable insulin antibodies (T2D), and serious adverse events (T2D). These differences were neither consistently observed across both studies nor observed in the total study populations, and their magnitude suggests they were not clinically meaningful. LY IGlar and IGlar show similar efficacy and safety profiles in patients reporting prestudy IGlar treatment.     

Adding insulin glargine vs. NPH insulin to metformin results in a more efficient postprandial β‐cell protection in individuals with type 2 diabetes

Aim: Postprandial release of intact proinsulin (IP) is an independent marker for β‐cell dysfunction in patients with type 2 diabetes. This open‐label, parallel‐group, two‐arm, pilot study compared the β‐cell protective effect of adding insulin glargine (GLA) vs. NPH insulin to ongoing metformin. Material and methods: Overall, 28 insulin‐naive type 2 diabetes subjects (mean ± SD age, 61.5 ± 6.7 years; diabetes duration, 9.8 ± 6.5 years; HbA1c, 7.1 ± 0.5%; BMI, 30.7 ± 4.3 kg/m²) treated with metformin and sulfonylurea were randomized to add once‐daily GLA or NPH at bedtime. At baseline and after 3 months, subjects received a standardized breakfast, lunch and dinner, with pre‐ and postprandial blood sampling to measure plasma IP, total insulin and blood glucose (BG). Results: Insulin dose after 3 months was comparable in both groups (GLA vs. NPH: 23.6 ± 13.4 vs. 23.3 ± 12.7; p = NS ). Both treatments significantly reduced fasting BG levels (GLA: 158 ± 19 to 121 ± 23 mg/dl; NPH: 156 ± 34 to 119 ± 29 mg/dl; both p < 0.01 vs. baseline). Fasting and postprandial BG levels did not differ between groups. IP levels decreased in both groups (p < 0.05 at all timepoints). Although IP release after breakfast did not differ between treatments, GLA induced a greater reduction in IP release after lunch (p = 0.08) and dinner (p = 0.04). Total plasma insulin levels did not differ between groups. Conclusions: Adding basal insulin to metformin reduces postprandial β‐cell load. While GLA and NPH had comparable effects at breakfast, GLA reduces β‐cell stress more effectively at dinner, and with a trend at lunch, most probably because of its longer lasting pharmacodynamic profile.     

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.     

Insulin therapy in elderly patients with type 2 diabetes: the role of insulin glargine

Within the USA, between 1980 and 2005, the prevalence of diagnosed diabetes has increased in all age groups, with the age group 65–74 years having the highest prevalence. The treatment of type 2 diabetes mellitus (T2DM) in elderly people is made more difficult than in their younger counterparts, primarily owing to the impact of co-morbidities, complications and hypoglycaemia as well as technical difficulties with insulin injections. Accordingly, the treatment approach for elderly patients with T2DM may need to be modified to accommodate co-morbidities and illnesses associated with ageing. Risks associated with insulin therapy, particularly hypoglycaemia, have traditionally limited the use of insulin in this patient population. Insulin glargine is associated with a low risk of hypoglycaemia compared with neutral protamine Hagedorn insulin, for example, and could thus provide a treatment of choice for healthcare providers when considering the increasing prevalence of diabetes in the elderly population. A regimen based on insulin glargine plus oral agents provides clinicians with a tool to help meet therapeutic targets in this population without increasing risk of hypoglycaemia.     

Influence of preprandial vs. postprandial insulin glulisine on weight and glycaemic control in patients initiating basal-bolus regimen for type 2 diabetes: a multicenter, randomized, parallel, open-label study (NCT00135096)

Aim: Insulin therapy is commonly associated with weight gain. The timing of prandial insulin administration may enhance its efficacy/safety and maintain effective weight control. This study examined the effect of postprandial vs. preprandial insulin glulisine on weight gain and glycaemic control in type 2 diabetes patients taking basal insulin. Methods: This was a multicenter, randomized, open‐label trial conducted in 45 centres in the USA. A total of 716 patients with type 2 diabetes and glycated haemoglobin A_1c (HbA_1c) ≥7.5% and ≤10.0% were screened; 345 were randomized and 322 comprised the intent‐to‐treat group (premeal, 163; postmeal, 159). Insulin glargine once daily, ±metformin and subcutaneous injections of premeal or postmeal insulin glulisine were given for 52 weeks. Main outcome measures included changes in HbA_1c, fasting plasma glucose and weight from study baseline to endpoint (week 52). Results: At study end, insulin glulisine achieved similar glycaemic control whether it was administered before or after meals (HbA_1c: 7.04% premeal vs. 7.16% postmeal, p = NS). Overall hypoglycaemia incidence and severe hypoglycaemia rates were not significantly different between premeal and postmeal groups; however, symptomatic and nocturnal hypoglycaemia rates were higher in the postprandial group. Mean body weight was lower in the postmeal group, with the difference between postmeal and premeal weight change from baseline to week 52 of ?0.87 kg (p = 0.243). Conclusion: Postprandial glulisine administration provided similar glycaemic control and was non‐inferior to preprandial administration on weight gain, without additional risk of severe hypoglycaemia, showing dosing flexibility and the feasibility of such approach when clinically indicated.     

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.     

Once-daily insulin detemir is comparable to once-daily insulin glargine in providing glycaemic control over 24 h in patients with type 2 diabetes: a double-blind, randomized, crossover study

Once-daily dosing with insulin detemir and insulin glargine were compared in a double-blind, randomised, crossover study in type 2 diabetes subjects previously treated with other antihyperglycaemic medications. Blood glucose was measured through continuous glucose monitoring (CGM). Insulin dose was adjusted daily during the titration phase to achieve target blood glucose values of (70-120 mg/dL) during the basal period, defined as 2400–0600 hours. The last meal of the day started at 1800 h and basal insulin was injected at 2000 h. The CGM data for a 24-h period on the second consecutive day after achieving target blood glucose levels were compared between treatments. Twenty-nine subjects completed the study. Over a 24-h measurement period, once-daily dosing with insulin detemir provided glycaemic control very similar to that of once-daily insulin glargine in patients with type 2 diabetes after both had been titrated to the same glucose target. Insulin detemir- and insulin glargine-treated subjects had similar mean 24-h glucose values (133 ± 21 mg/dL compared with 126±20 mg/dL respectively, p = 0.385) and similar glucose values during the basal period (105 ± 23 mg/dL compared with 98 ± 19 mg/dL, respectively p = 0.204).Target basal glycaemic control was achieved in all subjects in a mean of 3.8 days for detemir and 3.5 days for glargine (p = 0.360). The mean dose of detemir was similar to that of glargine (26.3 and 26.6 units/day, respectively, p = 0.837). In this study, once-daily dosing of insulin detemir provided 24-h glycaemic control similar to that of insulin glargine in patients with type 2 diabetes.     

Twice-daily compared with once-daily insulin glargine in people with Type 1 diabetes using meal-time insulin aspart.

AIM: To compare blood glucose control when using insulin glargine twice daily at breakfast- and dinner-times with insulin glargine once daily at dinner time, in unselected people with Type 1 diabetes using insulin aspart at meal-times. METHODS: In this 8-week, two-way, cross-over study, 20 people with Type 1 diabetes were randomized to insulin glargine injection once daily at dinner-time or twice daily at breakfast- and dinner-times, both plus meal-time insulin aspart. Each 4-week treatment period concluded with a 24-h inpatient metabolic profile. RESULTS: Insulin doses, HbA1c, fructosamine concentration and pre-breakfast self-monitored blood glucose (SMBG) concentration did not differ between treatment periods. SMBG concentrations after breakfast, after lunch and before dinner were lower with twice-daily compared with once-daily dinner-time glargine [9.3 +/- 0.5 (+/- se) vs. 6.7 +/- 0.5 mmol/l, P = 0.003; 10.2 +/- 0.9 vs. 7.0 +/- 0.9 mmol/l, P = 0.024; 9.6 +/- 0.5 vs. 6.6 +/- 0.5 mmol/l, P = 0.001]. Mean 24-h SMBG concentration was lower with twice-daily glargine (7.1 +/- 0.5 vs. 8.8 +/- 0.5 mmol/l, P = 0.031). Within-day variability of SMBG concentration was lower with twice-daily glargine (sd 3.2 +/- 0.2 vs. 4.0 +/- 0.3 mmol/l, P = 0.044). Plasma free insulin concentration was higher in the afternoon with twice-daily glargine (21.9 +/- 1.4 vs. 16.1 +/- 1.3 mU/l, P = 0.009), but lower overnight (12.1 +/- 1.7 vs. 17.8 +/- 1.7 mU/l, P = 0.030), compared with once-daily injection. Plasma glucose concentration overnight was higher with twice-daily compared with once-daily glargine (mean 9.0 +/- 0.4 vs. 6.6 +/- 0.4 mmol/l, P = 0.001). CONCLUSIONS: Blood glucose concentration rises in the late afternoon in association with falling plasma insulin levels towards the end of the 24-h period after insulin glargine injection in some people with Type 1 diabetes using once-daily glargine at dinner-time plus a rapid-acting insulin analogue at meal-times. This is prevented by twice-daily injection of insulin glargine.     

Insulin management in overweight or obese type 2 diabetes patients: the role of insulin glargine

Type 2 diabetes mellitus (T2DM) and obesity commonly co-exist. Improved clinical management of T2DM and improved glycaemic control with traditional therapies including insulin usually result in some weight gain – a frequently perceived barrier to the introduction of insulin by both patient and healthcare professionals. Weight gain of 2.5 kg per 1% change in haemoglobin A_1c (HbA_1c) is common in many studies. Strategies to minimize weight gain, particularly in obese patients, are essential to help patients better manage their diabetes and improve quality of life. Insulin analogues with lower risk of hypoglycaemia and better within-patient variability compared with human insulin may help facilitate reaching treatment goals. Moreover, weight gain can be minimized by earlier insulinization and the use of basal insulin, such as insulin glargine, instead of premixed insulin. Data specific to the obese patient with T2DM are presented; they are currently limited but do indicate that insulin glargine therapy is associated with improved glycaemic control as well as less weight gain than other insulins, such as premixed insulin and prandial insulin regimens. Retrospective subanalyses of earlier trials and ongoing studies would shed further light on the impact of insulin therapy in obese people with T2DM in addition to determination of optimal therapeutic strategies.     

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.     

Nateglinide and acarbose for postprandial glucose control after optimizing fasting glucose with insulin glargine in patients with type 2 diabetes

Aims

Basal insulin treatment is frequently used in type 2 diabetes, but the successful control of postprandial glucose is challenging. We compared the effect of preferential postprandial glucose targeting drugs for postprandial glucose control after optimizing fasting glucose with basal insulin.

Methods

This study was performed in 58, insulin naïve type 2 diabetes. After fasting glucose was optimized by insulin glargine, nateglinide or acarbose was initiated and then crossed over after second wash out period. 75 g oral glucose tolerance test and 7 point self monitoring blood glucose for 3days at the end of each period was performed.

Results

Both drugs effectively reduced postprandial glucose levels compared with the insulin glargine monotherapy. No significant differences were found between nateglinide and acarbose in terms of mean glucose level, standard deviation of glucose levels, mean average glucose excursion and average daily risk range. Homeostasis model analysis (HOMA)% β, corrected insulin response and insulin-to-glucose ratio were significantly higher in the responder group compared with the non-responder. There was no episode of severe hypoglycemia.

Conclusions

Nateglinide and acarbose are equally effective in type 2 diabetes for postprandial glucose excursions during basal insulin treatment. The markers of beta cell function might be used for predicting response. (Clinical trial reg. no. NCT 00437918, clinicaltrail.gov.)     

动态监测甘精胰岛素与预混胰岛素治疗期间老年2型糖尿病患者血糖漂移和低血糖发生率

用动态血糖监测的方法比较甘精胰岛素联合口服瑞格列奈,与每日注射2次预混胰岛素(诺和灵30R)治疗的老年2型糖尿病患者血糖漂移水平和低血糖发生情况.发现甘精组血糖漂移度明显低于预混组;低血糖事件也明显少于预混组.因此,老年2型糖尿病患者每天1次甘精胰岛素加瑞格列奈口服,在血糖达到良好控制时,血糖的漂移程度更低,低血糖发生率低.