Bedtime Glargine Research Articles

Long-acting Insulin Analogs Effect on gh/igf Axis of Children with Type 1 Diabetes: a Randomized, Open-label, Two-period, Cross-over Trial.

Growth hormone (GH) secretion is increased in pre-pubertal children with type 1 diabetes and GH excess produces insulin resistance. Early-morning insulinopenia contributes to lower insulin-like growth factor (IGF-I) levels and to GH hypersecretion. To evaluate differences in GH/IGF-I axis of pre-pubertal children with type 1 diabetes treated with glargine or detemir as long-acting insulin analogues, which was the main outcome measure, and to compare insulin effects in obtaining good metabolic control. Children with type 1 diabetes. This was a 32-week, randomized, open-label, two-period, cross-over comparison between bedtime glargine and twice-daily detemir insulin, involving pre-pubertal children in care at a diabetes pediatric centre. After a 8-week-run-in period subjects were randomized to bedtime glargine or twice-daily detemir insulin administration. After a 12-week period treatments were inverted and continued for additional 12 weeks. Overall, 15 pre-pubertal children (53.3% males, mean age 8.6±1.5 years, duration of diabetes 4.2±1.5 years) completed the study. Groups did not differ for GH/IGF axis and HbA1c levels. Treatment with glargine was associated with lower fasting glucose values than treatment with detemir (8.1±1.5 vs. 8.2±1.7 mmol/L, p=0.01). Incidence rate of hypoglycemia was not different between insulin treatments (IRR=1.18, 95%CI 1.00-1.38; p=0.07). Detemir treatment was associated with a higher increase in body weight (p=0.008) and height (p=0.02) when compared with glargine. Detemir and glargine not show significant differential effects on the GH/IGFI axis. The greater weight gain and height associated with detemir treatment, apparently not related to the level of pubertal growth, deserve further investigation.

Once-weekly dulaglutide versus bedtime insulin glargine, both in combination with prandial insulin lispro, in patients with type 2 diabetes (AWARD-4): a randomised, open-label, phase 3, non-inferiority study

For patients with type 2 diabetes who do not achieve target glycaemic control with conventional insulin treatment, advancing to a basal-bolus insulin regimen is often recommended. We aimed to compare the efficacy and safety of long-acting glucagon-like peptide-1 receptor agonist dulaglutide with that of insulin glargine, both combined with prandial insulin lispro, in patients with type 2 diabetes. We did this 52 week, randomised, open-label, phase 3, non-inferiority trial at 105 study sites in 15 countries. Patients (aged ≥18 years) with type 2 diabetes inadequately controlled with conventional insulin treatment were randomly assigned (1:1:1), via a computer-generated randomisation sequence with an interactive voice-response system, to receive once-weekly dulaglutide 1·5 mg, dulaglutide 0·75 mg, or daily bedtime glargine. Randomisation was stratified by country and metformin use. Participants and study investigators were not masked to treatment allocation, but were unaware of dulaglutide dose assignment. The primary outcome was a change in glycated haemoglobin A1c (HbA1c) from baseline to week 26, with a 0·4% non-inferiority margin. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01191268. Between Dec 9, 2010, and Sept 21, 2012, we randomly assigned 884 patients to receive dulaglutide 1·5 mg (n=295), dulaglutide 0·75 mg (n=293), or glargine (n=296). At 26 weeks, the adjusted mean change in HbA1c was greater in patients receiving dulaglutide 1·5 mg (-1·64% [95% CI -1·78 to -1·50], -17·93 mmol/mol [-19·44 to -16·42]) and dulaglutide 0·75 mg (-1·59% [-1·73 to -1·45], -17·38 mmol/mol [-18·89 to -15·87]) than in those receiving glargine (-1·41% [-1·55 to -1·27], -15·41 mmol/mol [-16·92 to -13·90]). The adjusted mean difference versus glargine was -0·22% (95% CI -0·38 to -0·07, -2·40 mmol/mol [-4·15 to -0·77]; p=0·005) for dulaglutide 1·5 mg and -0·17% (-0·33 to -0·02, -1·86 mmol/mol [-3·61 to -0·22]; p=0·015) for dulaglutide 0·75 mg. Five (<1%) patients died after randomisation because of septicaemia (n=1 in the dulaglutide 1·5 mg group); pneumonia (n=1 in the dulaglutide 0·75 mg group); cardiogenic shock; ventricular fibrillation; and an unknown cause (n=3 in the glargine group). We recorded serious adverse events in 27 (9%) patients in the dulaglutide 1·5 mg group, 44 (15%) patients in the dulaglutide 0·75 mg group, and 54 (18%) patients in the glargine group. The most frequent adverse events, arising more often with dulaglutide than glargine, were nausea, diarrhoea, and vomiting. Dulaglutide in combination with lispro resulted in a significantly greater improvement in glycaemic control than did glargine and represents a new treatment option for patients unable to achieve glycaemic targets with conventional insulin treatment. Eli Lilly and Company.

Starting bedtime glargine versus NPH insulin in poorly controlled type 2 diabetic patients with various hyperglycemia types (fasting type or postprandial type)

Our aim was to compare the effects of an intermediate acting human insulin (NPH) and a long-acting insulin analog, insulin glargine, in insulin naïve type 2 diabetes patients, stratified by the type of hyperglycemia (fasting or postprandial type). Based on different action profiles, we hypothesized that patients having different hyperglycemia types would react differently when treated with these insulins. This is a post hoc analysis of the Lanmet study data. The Lanmet study was a randomized, 36-week controlled insulin initiation study in type 2 diabetes patients. 109 subjects with baseline HbA1c >8.0 % (64 mmol/mol) completed the study. The patients were divided into two groups according to fasting glucose (mmol/l)/HbA1c (%) ratio. Patients with a ratio ≥1.3 were defined as having fasting type and those with a ratio <1.3 as having postprandial type hyperglycemia. The main outcome measures were change in HbA1c and body weight, and final insulin dose. Independently of insulin type, compared to patients with postprandial type hyperglycemia, those with fasting type hyperglycemia had 2.1 kg/m2 greater initial BMI (p = 0.044), gained 2.0 kg more weight (p = 0.020, adjusted for baseline BMI p = 0.035), and had 36 % greater final insulin dose/kg (p = 0.001). With respect to hyperglycemia type, there was no difference between NPH and glargine in their effects on HbA1c. When starting bedtime insulin in type 2 diabetes patients, those with fasting type hyperglycemia are prone to greater weight gain. Hyperglycemia type does not help in identifying patients who would benefit specially from either NPH insulin or insulin glargine.

Insulin glargine compared to NPH among insulin-naïve, U.S. inner city, ethnic minority type 2 diabetic patients

AimsWe compared basal regimens of glargine or NPH among insulin-naïve, U.S. inner city, ethnic minority type 2 diabetic patients who were sub-optimally controlled on maximally tolerated doses of combination oral agents. MethodsEighty-five subjects were randomized to 26 weeks of open-label, add-on therapy using single doses of bedtime NPH, bedtime glargine, or morning glargine; initially through an 8-week dose titration phase, followed by a 16-week maintenance phase during which insulin doses were adjusted only to avoid symptomatic hypoglycemia. ResultsAll three groups were comparable at baseline (mean HbA1c 9.3±1.4%), and improved their HbA1c (to 7.8±1.3%), fasting, and pre-supper glucose readings, with no significant between-group differences. Weight gain was greater with either glargine regimen (+3.1±4.1kg and +1.7±4.2kg) compared to NPH (−0.2±3.9kg), despite comparable total insulin doses. Pre-supper hypoglycemia occurred more frequently with morning glargine, but nocturnal hypoglycemia and improvements in treatment satisfaction did not differ among groups. ConclusionsAmong inner city ethnic minority type 2 diabetic patients in the U.S., we found no differences in basal glycemic control or nocturnal hypoglycemia between glargine and NPH, although glargine precipitated greater weight gain.

Insulin Glargine Maintains Equivalent Glycemic Control and Better Lipometabolic Control than NPH Insulin in Type 1 Diabetes Patients Who Missed a Meal

Our goal was to investigate blood glucose and lipometabolism control in type 1 diabetes patients who missed breakfast and the accompanying insulin injection of NPH insulin (NPH) or insulin glargine (glargine) as part of a basal-bolus regimen. This was a multi-center, open-label, controlled study in adults (> or =18 years) with HbA (1c)< or =11.5% on insulin therapy with NPH as basal insulin. Patients were randomized to receive prandial insulin plus either bedtime glargine (n=28) or NPH (n=32). Insulin was titrated to target fasting blood glucose levels 80-130 mg/dl at 06:00-07:00. Patients had no intake of insulin or food between 22:00 and 12:00 the next day. The change in blood glucose levels (07:00-11:00) was similar (27.5 mg/dl vs. 35.4 mg/dl), but the mean blood glucose level was higher with glargine vs. NPH at 22:00 (158.2 mg/dl vs. 130.2 mg/dl). During the period without insulin or food intake, blood glucose decreased with glargine (-25.8 mg/dl) and increased with NPH (+9.1 mg/dl; p=0.0284). Nonesterified fatty acid (07:00 and 09:00-12:00) and beta-hydroxybutyrate (07:00 and 10:00-12:00) levels were lower with glargine vs. NPH (both p<0.05). For patients who miss a morning meal, glargine is associated with maintained glycemic and lipometabolic control compared with NPH insulin.

Continuous Subcutaneous Insulin Infusion Attenuated Glycemic Instability in Preschool Children with Type 1 Diabetes Mellitus

Continuous subcutaneous insulin infusion (CSII) is believed to decrease glycemic instability and hypoglycemia while increasing quality of life compared to insulin injection regimens. To evaluate indices of glycemic control and impact on quality of life, we studied a group of preschool children with type 1 diabetes mellitus (DM) on CSII. Fourteen patients (eight girls and six boys) 3.9 +/- 0.8 years old with DM duration of 2.0 +/- 0.8 years were transitioned from flexible multiple daily insulin (FMDI) (pre-meal aspart and bedtime glargine) to CSII. Patients were evaluated with hemoglobin A(1c) (HbA(1c)) and continuous glucose monitoring quarterly for 1 year. Mean blood glucose (MBG), mean amplitude of glycemic excursion (MAGE), and hypoglycemic events (blood glucose <60 mg/dL) were determined. Patients' parents completed quality of life [TNO-AZL Preschool Children Quality of Life (TAPQoL)] questionnaires for their children at baseline and 1.0 year. The total daily insulin and the bolus:basal ratio did not change during CSII (0.72 +/- 0.21 vs. 0.74 +/- 0.16 U/kg/day and 2.1 +/- 0.61 vs. 2.40 +/- 0.58 U/kg/day, respectively). There was no change in HbA(1c) (8.0 +/- 0.50% vs. 7.8 +/- 0.40%) or frequency of hypoglycemia (moderate, 92.3 vs. 73.1 events/100 patient-years; severe, 22.5 vs. 17.5 events/100 patient-years). The MBG (213 +/- 94 vs. 185 +/- 79 mg/dL) and frequency (1.9 +/- 1.6 vs. 2.1 +/- 2.2) and duration (nocturnal, 135 +/- 141 vs. 120 +/- 103 min; total, 267 +/- 222 vs. 189 +/- 148 min) of hypoglycemic events did not decrease, whereas MAGE was reduced on CSII (210 +/- 31 vs. 168 +/- 22 mg/dL, P < 0.005). The quality of life subscales on the TAPQoL questionnaire did not change on CSII. CSII improved glycemic instability without reducing HbA(1c) or frequency and duration of hypoglycemic events and altering the parent's perception of his or her child's quality of life. CSII improves glycemic instability and is an effective alternative to FMDI therapy in young children with type 1 DM.

Comparison of Glargine Insulin Versus Rosiglitazone Addition in Poorly Controlled Type 2 Diabetic Patients on Metformin Plus Sulfonylurea

We sought to examine the mechanisms by which the addition of glargine insulin or rosiglitazone improves glycemic control in type 2 diabetic subjects poorly controlled on maximally effective doses of metformin plus sulfonylurea. Subjects (aged 47 +/- 11 years, BMI 31 +/- 5 kg/m(2), HbA(1c) [A1C] 9.4 +/- 1.3%) received bedtime glargine insulin (titrated based on the fasting plasma glucose [FPG], n = 10) or rosiglitazone (4 mg twice daily, n = 10). At baseline and after 4 months, A1C was measured and an oral glucose tolerance test and a 3-h euglycemic insulin (80 mU/m(2) per min) clamp with [3-(3)H]glucose were performed. A1C and FPG decreased similarly in the glargine insulin (9.1 +/- 0.4 to 7.6 +/- 0.3% and 212 +/- 14 to 139 +/- 5 mg/dl, respectively, both P < 0.0001) and rosiglitazone (9.4 +/- 0.3 to 7.6 +/- 0.4% and 223 +/- 14 to 160 +/- 19 mg/dl, respectively, both P < 0.005) groups. After 4 months, endogenous glucose production (EGP) declined similarly with glargine insulin (2.27 +/- 0.10 to 1.73 +/- 0.12 mg . kg(-1) . min(-1), P < 0.0001) and rosiglitazone (2.21 +/- 0.12 to 1.88 +/- 0.12 mg . kg(-1) . min(-1), P = 0.01). The hepatic insulin resistance index declined in the rosiglitazone group (32 +/- 3 to 21 +/- 1 mg . kg(-1) . min(-1) x microU/ml, P = 0.03 vs. baseline and P < 0.05 vs. glargine insulin) and did not change in the glargine group (22 +/- 5 to 20 +/- 3 mg . kg(-1) . min(-1) x microU/ml, P = NS). At 4 months, glargine insulin (3.6 +/- 0.5 to 4.2 +/- 0.4 mg . kg(-1) . min(-1), P < 0.01) and rosiglitazone (2.7 +/- 0.3 to 3.8 +/- 0.3 mg . kg(-1) . min(-1), P < 0.0005) increased R(d), but the increment was greater in the rosiglitazone group (P < 0.05). Diastolic blood pressure was reduced only by rosiglitazone (P < 0.01). Triple therapy with glargine insulin or rosiglitazone similarly reduced A1C, primarily by suppressing basal EGP (hepatic). Glargine insulin reduced basal EGP by increasing plasma insulin levels, while rosiglitazone decreased basal hepatic glucose production by improving hepatic insulin sensitivity.

Once-daily Insulin Glargine Administration in the Morning Compared to Bedtime in Combination with Morning Glimepiride in Patients with Type 2 Diabetes: An Assessment of Treatment Flexibility

To compare the incidence of nocturnal hypoglycemia and glycemic control following bedtime or morning insulin glargine (LANTUS; glargine) plus glimepiride. In this 24-week, multinational, open, randomized study, 624 patients with type 2 diabetes poorly controlled on oral therapy received morning or bedtime glargine plus morning glimepiride (2, 3 or 4 mg) titrated to a target fasting blood glucose level < or = 5.5 mmol/l. The incidence of nocturnal hypoglycemia was equivalent between the two groups, with morning glargine non-inferior to bedtime (13.0 VS. 14.9 % of patients; between-treatment difference -1.9 %; one-sided 95 % confidence interval -100 %; 2.84 %). At endpoint, similar improvements in glycemic control were observed with morning compared to bedtime glargine: HbA1c: -1.65 +/- 1.21 VS. -1.57 +/- 1.16 %; p = 0.42; fasting blood glucose: -4.25 +/- 2.82 VS. -4.48 +/- 2.75 mmol/l; p = 0.08. The endpoint mean daily glargine dose was comparable (34.7 +/- 17.4 VS. 32.4 +/- 17.0 IU; p = 0.15), and there was no significant between-treatment difference in the change in body weight (2.1 VS. 1.8 kg; p = 0.39). Once-daily glargine can be administered in a flexible morning or bedtime regimen (plus morning glimepiride) to achieve good glycemic control without any difference in hypoglycemia.

Flexible Insulin Therapy With Glargine Insulin Improved Glycemic Control and Reduced Severe Hypoglycemia Among Preschool-Aged Children With Type 1 Diabetes Mellitus

Insulin replacement regimens now stress the importance of administering throughout the day insulin doses that are based on flexible food choices and focusing on improved metabolic control. A flexible multiple daily insulin (FMDI) regimen (premeal lispro plus bedtime glargine) results in lower hemoglobin A1c (HbA1c) levels and fewer hypoglycemic episodes than does a multiple daily insulin (MDI) regimen among school-aged children and adolescents with type 1 diabetes mellitus (DM). The purpose of this study was to determine the feasibility of FMDI therapy for a group of preschool-aged children with type 1 DM who were transitioned from MDI therapy (premeal lispro plus ultralente insulin twice per day), by comparing BMI, total daily insulin requirements, HbA1c levels, and episodes of severe hypoglycemia. Data were collected over a 2-year period, during quarterly DM clinic visits, from 35 patients (17 female patients and 18 male patients, 4.8 +/- 1.0 years of age) who had received MDI insulin therapy for > or =1 year before being transitioned to a FMDI regimen. Although there was no significant change in BMI with FMDI therapy (17.1 +/- 1.8 kg/m2 vs 17.0 +/- 1.7 kg/m2), 43% of patients (6 female subjects and 9 male subjects) were overweight (BMI of >85th percentile for age) both before and after treatment. The total daily insulin requirement (0.67 +/- 0.13 U/kg per day vs 0.78 +/- 0.14 U/kg per day) and bolus/basal insulin ratio (1.1 +/- 0.4 vs 1.9 +/- 0.6) were significantly increased and overall glycemic control was improved after transition to FMDI therapy (HbA1c levels: 8.8 +/- 0.9% vs 8.3 +/- 0.8%). However, HbA1c levels improved only among normal-weight subjects (9.0 +/- 1.0% vs 8.3 +/- 1.0%) and not among overweight subjects (8.7 +/- 0.7% vs 8.4 +/- 0.6%) after FMDI therapy. The overall rate of severe hypoglycemia was significantly decreased with the FMDI regimen (25.5 events per 100 patient-years vs 10.6 events per 100 patient-years) but again only for normal-weight children (29.7 events per 100 patient-years vs 7.4 events per 100 patient-years). The use of FMDI therapy with glargine among preschool-aged children with type 1 DM was associated with improved overall glycemic control and decreased frequency of severe hypoglycemia. Although our study did not have a control group, these findings suggest that FMDI regimens may be a feasible therapeutic alternative to MDI treatment for preschool-aged children with type 1 DM. However, excess body weight status appeared to preclude a desirable therapeutic response in this group of patients.

Good Glycemic Control With Flexibility in Timing of Basal Insulin Supply

The early initiation of insulin therapy to achieve good metabolic control is being increasingly considered in type 2 diabetes (1), but barriers, including fear of hypoglycemia, need to be overcome to achieve target glycemic control (2). Insulin glargine (glargine; Lantus) is a once-daily, basal human insulin analog. The 24-h duration and flat time-action profile of glargine (3) should give flexibility to patients in terms of the injection time despite targeting fasting blood glucose (FBG) close to normal: administration should be possible at any time of day provided it is at the same time each day. Previously, we have demonstrated similar levels of nocturnal hypoglycemia but better glycemic control with morning versus bedtime glargine plus three milligrams glimepiride (4). The study objective was to compare the frequency of nocturnal hypoglycemia following morning …

Beneficial Effects of Continuous Subcutaneous Insulin Infusion and Flexible Multiple Daily Insulin Regimen Using Insulin Glargine in Type 1 Diabetes

The aim of this study was to evaluate the metabolic effects of continuous subcutaneous insulin infusion (CSII) with flexible multiple daily insulin (FMDI; premeal lispro + bedtime glargine) therapy as determined by glycosylated hemoglobin (HbA1c), body mass index (BMI), and hypoglycemic episodes in a group of patients who made the transition from multiple daily insulin (premeal lispro + bid ultralente) to either CSII or FMDI therapy. Data from 40 (27 female and 13 male) patients (10.1-17.8 years of age) who were on CSII and 40 age- and gender-matched (27 female and 13 male) patients (10.3-17.3 years of age) who were on FMDI were collected during regularly scheduled visits at a similar frequency over a 1-year period. The total daily insulin dose did not change in CSII (0.97 +/- 0.24 vs 0.91 +/- 0.22 U/kg) and FMDI (0.98 +/- 0.21 vs 0.97 +/- 0.21 U/kg) patients, whereas the bolus:basal insulin ratio was significantly increased in both CSII (1.01 +/- 0.43 vs 1.32 +/- 0.52) and FMDI (1.07 +/- 0.0.41 vs 1.29 +/- 0.47) patients. The total cohort of CSII patients showed a decrease in HbA1c from 8.4 +/- 1.0% to 7.8 +/- 0.8%, whereas the FMDI cohort did not show a significant change in HbA1c (8.5 +/- 1.1% to 8.2 +/- 0.9%). However, 40% of the CSII group and 22.5% of the FMDI group showed > or =1.0% improvement in HbA1c. Also, a similar number of patients in CSII (52.5%; 8.0 +/- 1.1 to 7.2 +/- 0.5%) and FMDI (47.5%; 8.0 +/- 0.5% to 7.5 +/- 0.4%) maintained or achieved target HbA1c values <8.0%. The BMI increased significantly in the CSII group (21.6 +/- 3.2 vs 23.0 +/- 3.0 kg/m2) but did not change in the FMDI group (21.9 +/- 3.9 vs 22.6 +/- 3.8 kg/m2). There was a significant reduction in the rate of severe hypoglycemia (events/100 patient-years) in both cohorts: 20.6 to 8.2 in the CSII and 18.8 to 7.5 in the FMDI. Similarly, the rate of moderate hypoglycemia decreased in both CSII (68.3-35.4) and FMDI (56.3-30.4). CSII therapy resulted in a significant improvement in HbA 1c in the entire group, whereas FMDI therapy improved HbA1c in only a subgroup of patients. However, almost half of the patients in each of the treatment groups maintained or achieved target glycemic control. Both CSII and FMDI treatment groups demonstrated a decreased rate of hypoglycemia without an abnormal increase in BMI. Although the design of this study does not allow direct comparison of the metabolic effects of CSII and FMDI therapies, both regimens seem to be superior to basal ultralente and lispro multiple daily insulin regimen and offer desirable therapeutic alternatives in pediatric diabetes care.

The Treat-to-Target Trial

To compare the abilities and associated hypoglycemia risks of insulin glargine and human NPH insulin added to oral therapy of type 2 diabetes to achieve 7% HbA(1c). In a randomized, open-label, parallel, 24-week multicenter trial, 756 overweight men and women with inadequate glycemic control (HbA(1c) >7.5%) on one or two oral agents continued prestudy oral agents and received bedtime glargine or NPH once daily, titrated using a simple algorithm seeking a target fasting plasma glucose (FPG) <or=100 mg/dl (5.5 mmol/l). Outcome measures were FPG, HbA(1c), hypoglycemia, and percentage of patients reaching HbA(1c) <or=7% without documented nocturnal hypoglycemia. Mean FPG at end point was similar with glargine and NPH (117 vs. 120 mg/dl [6.5 vs. 6.7 mmol/l]), as was HbA(1c) (6.96 vs. 6.97%). A majority of patients ( approximately 60%) attained HbA(1c) <or=7% with each insulin type. However, nearly 25% more patients attained this without documented nocturnal hypoglycemia (<or=72 mg/dl [4.0 mmol/l]) with glargine (33.2 vs. 26.7%, P < 0.05). Moreover, rates of other categories of symptomatic hypoglycemia were 21-48% lower with glargine. Systematically titrating bedtime basal insulin added to oral therapy can safely achieve 7% HbA(1c) in a majority of overweight patients with type 2 diabetes with HbA(1c) between 7.5 and 10.0% on oral agents alone. In doing this, glargine causes significantly less nocturnal hypoglycemia than NPH, thus reducing a leading barrier to initiating insulin. This simple regimen may facilitate earlier and effective insulin use in routine medical practice, improving achievement of recommended standards of diabetes care.

Summaries for patients. A comparison of three insulin regimens (morning glargine, bedtime glargine, or bedtime neutral protamine Hagedorn) in addition to a pill for treating type 2 diabetes.

Summaries for patients. A comparison of three insulin regimens (morning glargine, bedtime glargine, or bedtime neutral protamine Hagedorn) in addition to a pill for treating type 2 diabetes.