The Effects of Transition from Bedtime to Morning Glargine Administration in Patients with Poorly Regulated Type 1 Diabetes Mellitus: Croatian Pilot Study.
ABSTRACT: The objective of this study was to compare differences in glucoregulation, frequency of hypoglycemic episodes, glucose variability and lipid profiles of inpatients with poorly regulated type 1 diabetes mellitus (T1DM) after evening versus morning glargine application.Eighteen patients with poorly regulated T1DM, glycated hemoglobin (Hba1c) levels ?7% and frequent nocturnal and/or morning hypoglycemic episodes were included in this study. There was a 12-week screening phase where patients continued their usual insulin regimen and were encouraged to achieve optimal glycemic control; however, all patients maintained HbA1c values ?7% and continued to have frequent nocturnal and/or morning hypoglycemic events and were therefore transitioned to morning application of insulin glargine for 12 weeks. The primary outcome was to investigate changes in HbA1c values 12 weeks after the transition. The secondary outcome was to evaluate the effect of transition on glucose variability, incidence of hypoglycemic episodes, insulin doses, lipid profile and weight. Data were analyzed using paired Student's t test and Pearson correlation.After the transition, there was no significant change in total daily dose of basal insulin (p 0.114) and the average body weight remained unchanged, while significant reduction of HbA1c was present (8.02 ± 0.5 vs. 7.4 ± 0.3%) (p < 0.01) resulting in a decrease in nocturnal and daytime hypoglycemic episodes per month per person (p < 0.01). Parameters of glucose variability (glycemic standard deviations and J-index) were also improved after transition period (p < 0.01). As for the lipid profile, increase of high-density lipoprotein cholesterol and decrease of triglycerides (p < 0.01) were noticed, while other lipid parameters remained unaffected. Furthermore, insignificant association of basal insulin dose with HbA1c values regardless of the time of administration was observed.In patients with poorly regulated T1DM, transition to morning application of glargine improved glucoregulation (including a decrease in HbA1c, glucose variability and number of nocturnal hypoglycemic episodes), followed by favorable changes in lipid profile without affecting body weight. These effects were associated with the time of application, but not with the insulin dose.
Project description:Introduction:Strict glucose control using multiple doses of insulin is the standard treatment for type 1 diabetes mellitus (T1DM), but increased risk of hypoglycemia is a frequent drawback. Regular insulin in multiple doses is important for achieving strict glycemic control for T1DM, but short-acting insulin analogues may be better in reducing hypoglycemia and postprandial glucose levels. Objective:We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the effects of short-acting insulin analogues vs regular human insulin on hypoglycemia and postprandial glucose in patients with T1DM. Methods:Searches were run on the electronic databases MEDLINE, Cochrane-CENTRAL, EMBASE, ClinicalTrials.gov, LILACS, and DARE for RCTs published until August 2017. To be included in the study, the RCTs had to cover a minimum period of 4 weeks and had to assess the effects of short-acting insulin analogues vs regular human insulin on hypoglycemia and postprandial glucose levels in patients with T1DM. Two independent reviewers extracted the data and assessed the quality of the selected studies. The primary outcomes analyzed were hypoglycemia (total episodes, nocturnal hypoglycemia, and severe hypoglycemia) and postprandial glucose (at all times, after breakfast, after lunch, and after dinner). Glycated hemoglobin (HbA1c) levels and quality of life were considered secondary outcomes. The risk of bias of each RCT was assessed using the Cochrane Collaboration Risk of Bias table, while the quality of evidence for each outcome was assessed using the GRADEpro software. The pooled mean difference in the number of hypoglycemic episodes and postprandial glucose between short-acting insulin analogues vs. regular human insulin was calculated using the random-effects model. Results:Of the 2897 articles retrieved, 22 (6235 patients) were included. Short-acting insulin analogues were associated with a decrease in total hypoglycemic episodes (risk rate 0.93, 95% CI 0.87-0.99; 6235 patients; I2?=?81%), nocturnal hypoglycemia (risk rate 0.55, 95% CI 0.40-0.76, 1995 patients, I2?=?84%), and severe hypoglycemia (risk rate 0.68, 95% CI 0.60-0.77; 5945 patients, I2?=?0%); and with lower postprandial glucose levels (mean difference/MD -?19.44 mg/dL; 95% CI -?21.49 to -?17.39; 5031 patients, I2?=?69%) and lower HbA1c (MD -?0,13%; IC 95% -?0.16 to -?0.10; 5204 patients; I2?=?73%) levels. Conclusions:Short-acting insulin analogues are superior to regular human insulin in T1DM patients for the following outcomes: total hypoglycemic episodes, nocturnal hypoglycemia, severe hypoglycemia, postprandial glucose, and HbA1c.
Project description:Hypoglycemia, a serious risk for insulin-treated patients with type 2 diabetes, negatively affects glycemic control.To test whether treatment with basal insulin degludec is associated with a lower rate of hypoglycemia compared with insulin glargine U100 in patients with type 2 diabetes.Randomized, double-blind, treat-to-target crossover trial including two 32-week treatment periods, each with a 16-week titration period and a 16-week maintenance period. The trial was conducted at 152 US centers between January 2014 and December 2015 in 721 adults with type 2 diabetes and at least 1 hypoglycemia risk factor who were previously treated with basal insulin with or without oral antidiabetic drugs.Patients were randomized 1:1 to receive once-daily insulin degludec followed by insulin glargine U100 (n?=?361) or to receive insulin glargine U100 followed by insulin degludec (n?=?360) and randomized 1:1 to morning or evening dosing within each treatment sequence.The primary end point was the rate of overall symptomatic hypoglycemic episodes (severe or blood glucose confirmed [<56 mg/dL]) during the maintenance period. Secondary end points were the rate of nocturnal symptomatic hypoglycemic episodes (severe or blood glucose confirmed, occurring between 12:01 am and 5:59 am) and the proportion of patients with severe hypoglycemia during the maintenance period.Of the 721 patients randomized (mean [SD] age, 61.4 [10.5] years; 53.1% male), 580 (80.4%) completed the trial. During the maintenance period, the rates of overall symptomatic hypoglycemia for insulin degludec vs insulin glargine U100 were 185.6 vs 265.4 episodes per 100 patient-years of exposure (PYE) (rate ratio?=?0.70 [95% CI, 0.61-0.80]; P?<?.001; difference, -23.66 episodes/100 PYE [95% CI, -33.98 to -13.33]), and the proportions of patients with hypoglycemic episodes were 22.5% vs 31.6% (difference, -9.1% [95% CI, -13.1% to -5.0%]). The rates of nocturnal symptomatic hypoglycemia with insulin degludec vs insulin glargine U100 were 55.2 vs 93.6 episodes/100 PYE (rate ratio?=?0.58 [95% CI, 0.46-0.74]; P?<?.001; difference, -7.41 episodes/100 PYE [95% CI, -11.98 to -2.85]), and the proportions of patients with hypoglycemic episodes were 9.7% vs 14.7% (difference, -5.1% [95% CI, -8.1% to -2.0%]). The proportions of patients experiencing severe hypoglycemia during the maintenance period were 1.6% (95% CI, 0.6%-2.7%) for insulin degludec vs 2.4% (95% CI, 1.1%-3.7%) for insulin glargine U100 (McNemar P?=?.35; risk difference, -0.8% [95% CI, -2.2% to 0.5%]). Statistically significant reductions in overall and nocturnal symptomatic hypoglycemia for insulin degludec vs insulin glargine U100 were also seen for the full treatment period.Among patients with type 2 diabetes treated with insulin and with at least 1 hypoglycemia risk factor, 32 weeks' treatment with insulin degludec vs insulin glargine U100 resulted in a reduced rate of overall symptomatic hypoglycemia.clinicaltrials.gov Identifier: NCT02030600.
Project description:Hypoglycemia, common in patients with type 1 diabetes, is a major barrier to achieving good glycemic control. Severe hypoglycemia can lead to coma or death.To determine whether insulin degludec is noninferior or superior to insulin glargine U100 in reducing the rate of symptomatic hypoglycemic episodes.Double-blind, randomized, crossover noninferiority trial involving 501 adults with at least 1 hypoglycemia risk factor treated at 84 US and 6 Polish centers (January 2014-January 12, 2016) for two 32-week treatment periods, each with a 16-week titration and a 16-week maintenance period.Patients were randomized 1:1 to receive once-daily insulin degludec followed by insulin glargine U100 (n?=?249) or to receive insulin glargine U100 followed by insulin degludec (n?=?252) and randomized 1:1 to morning or evening dosing within each treatment sequence.The primary end point was the rate of overall severe or blood glucose-confirmed (<56 mg/dL) symptomatic hypoglycemic episodes during the maintenance period. Secondary end points included the rate of nocturnal symptomatic hypoglycemic episodes and proportion of patients with severe hypoglycemia during the maintenance period. The noninferiority criterion for the primary end point and for the secondary end point of nocturnal hypoglycemia was defined as an upper limit of the 2-sided 95% CI for a rate ratio of 1.10 or lower; if noninferiority was established, 2-sided statistical testing for superiority was conducted.Of the 501 patients randomized (mean age, 45.9 years; 53.7% men), 395 (78.8%) completed the trial. During the maintenance period, the rates of overall symptomatic hypoglycemia were 2200.9 episodes per 100 person-years' exposure (PYE) in the insulin degludec group vs 2462.7 episodes per 100 PYE in the insulin glargine U100 group for a rate ratio (RR) of 0.89 (95% CI, 0.85-0.94; P?<?.001 for noninferiority; P?<?.001 for superiority; rate difference, -130.31 episodes per 100 PYE; 95% CI, -193.5 to -67.16). The rates of nocturnal symptomatic hypoglycemia were 277.1 per 100 PYE in the insulin degludec group vs 428.6 episodes per 100 PYE in the insulin glargine U100 group, for an RR of 0.64 (95% CI, 0.56-0.73; P?<?.001 for noninferiority; P?<?.001 for superiority; rate difference, -61.94 episodes per 100 PYE; 95% CI, -83.85 to -40.03). A lower proportion of patients in the insulin degludec than in the insulin glargine U100 group experienced severe hypoglycemia during the maintenance period (10.3%, 95% CI, 7.3%-13.3% vs 17.1%, 95% CI, 13.4%-20.8%, respectively; McNemar P?=?.002; risk difference, -6.8%; 95% CI, -10.8% to -2.7%).Among patients with type 1 diabetes and at least 1 risk factor for hypoglycemia, 32 weeks' treatment with insulin degludec vs insulin glargine U100 resulted in a reduced rate of overall symptomatic hypoglycemic episodes.clinicaltrials.gov Identifier: NCT02034513.
Project description:INTRODUCTION:To evaluate in an Italian real-world setting the safety and effectiveness of insulin degludec 100 units/mL, given once daily in patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) after switching from other basal insulins. METHODS:ReFLeCT was a multicenter, prospective, observational study conducted across seven European countries which involved adult patients whose physician planned to switch their medication from basal insulin to insulin degludec. The primary outcome was the change in the number of hypoglycemic episodes before and after the switch to insulin degludec. Results are expressed as 12-month follow-up/baseline incidence rate ratios (IRRs) with 95% confidence intervals (95% CIs). RESULTS:The Italian cohort of the ReFLect study comprised 148 patients with T1DM and 311 patients with T2DM. In patients with T1DM, the switch to insulin degludec was associated with significantly lower rates of overall (IRR?0.69, 95% CI 0.57-0.82), non-severe (IRR?0.72, 95% CI 0.60-0.85), and nocturnal hypoglycemia (IRR?0.46, 95% CI 0.31-0.69). Following the switch, hemoglobin A1c (HbA1c) levels decreased significantly by 0.35% (95% CI -?0.50 to ?-?0.20), with no significant changes in fasting plasma glucose (FPG) and basal insulin dose. Body weight increased by 0.83 kg (95% CI 0.16-1.50). In patients with T2DM, significant reductions in the rates of overall (IRR?0.40, 95% CI 0.29-0.55), non-severe (IRR?0.47, 95% CI 0.34-0.63), and nocturnal hypoglycemia (IRR?0.27, 95% CI 0.09-0.86) were documented. HbA1c and FPG decreased significantly by 0.45% (95% CI -?0.58 to?-?0.31) and 0.90 mmol/L (95% CI -?1.21 to?-?0.59], respectively, with no significant changes in basal insulin dose or body weight. Treatment satisfaction significantly improved in both diabetes types. CONCLUSION:In Italian routine clinical practice, switching from other basal insulins to insulin degludec reduced the total episodes of hypoglycemia and improved glycemic control and treatment satisfaction in patients with T1DM and T2DM. TRIAL REGISTRATION:ClinicalTrials.gov NCT02392117.
Project description:INTRODUCTION:Insulin degludec (degludec) is a basal insulin with an ultra-long, stable action profile and reduced pharmacodynamic variability. Seven phase 3a trials compared degludec with insulin glargine (glargine). Patient-level meta-analyses were performed to obtain a comprehensive overview of differences between the insulin preparations, possible because consistent outcome definitions were utilized. METHODS:Three categories of trials were analyzed: basal-bolus-treated type 1 diabetes mellitus (T1DMB/B), insulin-naïve type 2 diabetes mellitus (T2DMinsulin-naïve), and basal-bolus-treated T2DM (T2DMB/B). Regression models were adjusted for baseline characteristics. Endpoints analyzed were glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), insulin dose and hypoglycemic rates analyzed in mutually exclusive groups: non-severe nocturnal, non-severe daytime, and severe. RESULTS:As with previous treat-to-target trials, reductions in HbA1c were similar between degludec and glargine. Reductions in FPG were significantly greater with degludec in T1DMB/B and T2DMinsulin-naïve. Total daily insulin dose was significantly lower with degludec in T1DMB/B and T2DMinsulin-naïve. Estimated hypoglycemia rate ratios for degludec/glargine were as follows for T1DMB/B, T2DMinsulin-naïve and T2DMB/B, respectively: non-severe nocturnal 0.83, 0.64, 0.75 (all P < 0.05); non-severe daytime 1.14 [not significant (ns)], 0.89 (ns), and 0.83 (P < 0.05). Rate ratios for severe events were 1.12 (ns) (T1DMB/B); 0.14 (P < 0.05) (T2DMinsulin-naïve); and not analyzed (T2DMB/B) due to too few events. CONCLUSIONS:Compared with glargine, degludec is associated with equivalent HbA1c control and significantly lower nocturnal hypoglycemia rates. In T1DMB/B and T2DMinsulin-naïve, degludec is also associated with significantly greater reductions in FPG and lower total doses of insulin versus glargine.
Project description:Optimal adjustment of basal insulin to overcome hypoglycemia and glycemic variability (GV) depends on its duration of action and peak-less profile. Owing to the ability of long-acting basal insulin to avoid hypoglycemia, we titrated pre-meal glucose to normal fasting blood glucose, 80-110 mg/dL (4.5-6.1 mmol/L), and post-meal glucose to 80-140 mg/dL (4.5-7.8 mmol/L). The purpose of this study was to evaluate two basal insulin analogues degludec (IDeg) and glargine (IGlar), injected in the morning, for GV using continuous glucose monitoring (CGM) in type 1 diabetes (T1DM).In this crossover study, 20 Japanese patients with T1DM (age 54 ± 16 years, disease duration 16 ± 8 years, BMI 24 ± 4 kg/m2, HbA1c 7.4 ± 0.8%) were randomized into one of two different starting regimens, and CGM was conducted on three consecutive days during the last week of each 12-week titration period. Treatment satisfaction was assessed at the end of each treatment period using the Diabetes Therapy-Related Quality of Life Questionnaire (DTR-QOL).There were no differences in HbA1c, total insulin dosage, body weight changes, and basal to bolus ratio between the IDeg and IGlar arms. The day-to-day variability in fasting interstitial GV on the CGM curves was significantly less in the IDeg than IGlar treatment period (25.9 ± 22.0 vs. 43.8 ± 30.1 mg/dl, p = 0.04). Other markers of GV, calculated by the EasyGV software, including mean amplitude of glycemic excursions (MAGE), J-index, total and nocturnal hypoglycemia were not different between the two treatment periods. The score of "satisfaction with treatment", a subdomain of the DTR-QOL system, was higher in the IDeg period.Thus, the morning injection of the two long-acting insulin analogues seemed similar with regard to the magnitude of hypoglycemia in T1DM, but treatment with IDeg was associated with lower day-to-day variation in glucose level. These results suggest that IDeg is safe with minimal morning GV in patients with T1DM.Japanese Clinical Trials Registry, UMIN000012358.
Project description:AIMS:Insulin glargine 300?U/mL (Gla-300) offers a flatter pharmacodynamic profile than insulin glargine 100?U/mL (Gla-100). We have compared these insulins over 1?year in people with type 1 diabetes (T1DM). METHODS:EDITION 4 was a 6-month, multicentre, randomized, open-label phase 3 study. People with T1DM who completed the 6?months continued randomized Gla-300 or Gla-100 once daily, morning or evening, for a further 6?months. RESULTS:Among 549 participants randomized, 444 completed the 12-month study period (Gla-300, 80%; Gla-100, 82%). Mean HbA1c decreased similarly from baseline to month 12 in the 2 treatment groups (difference, 0.02 [95% CI, -0.13 to 0.17]) %-units [0.2 (-1.5 to 1.9) mmol/mol]), to a mean of 7.86 %-units (62.4?mmol/mol) in both groups. For morning vs evening injection, there was no difference in HbA1c change over 12?months for Gla-100, but a significantly larger decrease in HbA1c was observed in the Gla-300 morning group than in the Gla-300 evening group (difference, -0.25 [-0.47 to -0.04] %-units [-2.7 (-5.2 to -0.4) mmol/mol]). Mean glucose from the 8-point SMPG profiles decreased from baseline, and was similar between the 2 treatment groups. Basal insulin dose was 20% higher with Gla-300 than with Gla-100, while hypoglycaemia event rates, analysed at night, over 24?hours, or according to different glycaemic thresholds, did not differ between treatment groups, regardless of injection time. Adverse event profiles did not differ between groups. CONCLUSIONS:In T1DM, Gla-300 provides glucose control comparable to that of Gla-100, and can be given at any time of day.
Project description:We aimed to describe the safety and efficacy of insulin glargine in Chinese paediatric patients with type 1 diabetes mellitus (T1DM). Neutral protamine Hagedorn (NPH) insulin was the reference therapy.This open-label, randomised, Phase III study was conducted at 10 sites in China. Children aged ?6 to <18 years with T1DM were randomised (2:1) to insulin glargine or NPH insulin asbasal insulinfor a 24-week treatment period. For all patients, insulin aspart was given as bolus insulin. The primary endpoint was absolute change in glycated haemoglobin(HbA1c) from baseline to Week 24. Secondary endpoints included the percentage of patients reaching HbA1c <7.5% (<58.5 mmol/mol), and safety. The study was registered at clinicaltrials.gov (NCT01223131).In total,196 patients were screened, and 162 were randomised (107 and 55 patients were randomised to insulin glargine and NPH insulin, respectively). The mean?±?SD of absolute change in HbA1c was-0.25?±?1.68% (-2.69?±?18.32 mmol/mol) in the insulin glargine group and -0.54?±?1.67% (-5.55?±?20.32 mmol/mol) in the NPH insulin group. At Week 24, 18.7 and 21.6% of patients in the insulin glargine and NPH insulin groups achieved HbA1c <7.5% (<58.5 mmol/mol). Both treatments were generally well tolerated. A numerically lower rate of symptomatic hypoglycaemia per patient year was observed for insulin glargine versus NPH insulin (24.3?±?45.8 versus32.3?±?43.2); severe hypoglycaemia was rare (<2%).Initiation of insulin glargine can aid Chinese paediatric patients with T1DM to safely reduce their HbA1c levels.
Project description:INTRODUCTION:The purpose of this study was to compare insulin degludec with insulin glargine in terms of efficacy and safety in patients with type 2 diabetes. METHODS:We systematically searched PubMed, Embase, Web of Science, and Cochrane Library databases for randomized controlled trials published prior to 13 August 2018 (no language restrictions) which compared insulin degludec with insulin glargine. Our main endpoints were glycemic control, hypoglycemic event, weight gain, and serious adverse events (SAEs). We assessed pooled data using random-effects models. RESULTS:A total of 15 studies that included 9619 patients in the insulin degludec arm of the studies and 7075 patients in the insulin glargine arm were identified and subsequently assessed. Our analysis showed that compared with insulin glargine, insulin degludec yielded an improved mean reduction in fasting plasma glucose (FPG) (weighted mean difference [WMD] - 5.20 mg/dL, 95% confidence interval [CI] - 7.34, - 3.07, P < 0.00001) and a lower ratio of participants experiencing ≥ 1 severe hypoglycemic event (relative risk [RR] 0.68, 95% CI 0.50, 0.93, P = 0.01) and nocturnal hypoglycemia (RR 0.81, 95% CI 0.75, 0.88, P < 0.0001); however, in the insulin degludec group there was a lower ratio of participants with glycated hemoglobin (HbA1c) of ≤ 7.0% (RR 0.92, 95% CI 0.86, 0.98, P = 0.01). There was no statistically significant difference between the two treatment groups for HbA1c reduction (WMD 0.03, 95% CI - 0.00, 0.07, P = 0.08), body weight gain (WMD 0.12, 95% CI - 0.19, 0.43, P = 0.46), and proportion of participants with SAEs (RR 0.97, 95% CI 0.92, 1.02, P = 0.20). CONCLUSIONS:Insulin degludec and insulin glargine provide similar glycemic control, but insulin degludec also lowers the risk of hypoglycemia. Consequently, insulin degludec may be an alternative treatment for the management of patients with type 2 diabetes who are prone to hypoglycemia with insulin glargine.
Project description:<h4>Purpose</h4>The efficacy and safety of insulin degludec/insulin aspart (IDegAsp) once daily (OD) compared with insulin glargine U100 (IGlar) OD over 52 weeks in insulin-naïve adults with type 2 diabetes mellitus (T2DM) was investigated.<h4>Methods</h4>In this open-label, parallel-group treat-to-target trial, participants were randomized (1:1) to receive IDegAsp OD (breakfast, n = 266) or IGlar OD (as per label, n = 264). Participants then entered a 26-week extension phase (IDegAsp OD, n = 192; IGlar OD, n = 221). The primary endpoint was change from baseline to Week 26 in HbA1c.<h4>Results</h4>After 26 and 52 weeks, mean HbA1c decreased to similar levels in both groups. After 52 weeks, the mean estimated treatment difference was -0.08% (-0.26, 0.09 95%CI), confirming the non-inferiority of IDegAsp OD versus IGlar OD evaluated at Week 26. After 52 weeks, there was a similar reduction in mean fasting plasma glucose in both treatment groups. The rate of confirmed hypoglycemic episodes was 86% higher (p < 0.0001) whereas the rate of nocturnal hypoglycemia was 75% lower (p < 0.0001) for IDegAsp versus IGlar.<h4>Conclusion</h4>Nocturnal-confirmed hypoglycemia was higher with IGlar whereas overall and diurnal hypoglycemia were higher with IDegAsp dosed at breakfast. These results highlight the importance of administration of IDegAsp with the main meal of the day, tailored to the individual patient's needs.<h4>Trial registration</h4>ClinicalTrials.gov: NCT01045707 [core]) and NCT01169766 [ext].