Pre-breakfast Plasma Glucose Research Articles

Pharmacokinetic and pharmacodynamic properties of once-weekly insulin icodec in individuals with type 2 diabetes.

To characterize the pharmacokinetic and pharmacodynamic properties of once-weekly insulin icodec in type 2 diabetes (T2D). In an open-label trial, 46 individuals with T2D (18-75 years; body mass index 18.0-38.0 kg/m2 ; glycated haemoglobin ≤75 mmol/mol [≤9%]; basal insulin-treated) received subcutaneous once-weekly icodec for ≥8 weeks at individualized doses, aiming at a pre-breakfast plasma glucose concentration of 4.4 to 7.0 mmol/L (80-126 mg/dL) on the last three mornings of each weekly dosing interval. Frequent blood sampling to assess total serum icodec concentration (ie, albumin-bound and unbound) occurred from first icodec dose until 35 days after last dose. Icodec trough concentrations following initiation of once-weekly dosing were predicted by pharmacokinetic modelling. During the final 3 weeks of icodec treatment, while at steady state, the icodec glucose-lowering effect was assessed in three glucose clamps (target 7.5 mmol/L [135 mg/dL]): 0 to 36, 40 to 64 and 144 to 168 h post-dose, thus covering the initial, middle and last part of the 1-week dosing interval. Glucose-lowering effect during a complete dosing interval was predicted by pharmacokinetic-pharmacodynamic modelling. Model-predicted icodec steady state was attained after 3 to 4 weeks. At steady state, model-predicted daily proportions of glucose-lowering effect on days 1 to 7 of the 1-week dosing interval were 14.1%, 16.1%, 15.8%, 15.0%, 14.0%, 13.0% and 12.0%, respectively. Icodec duration of action was at least 1 week in all participants. Once-weekly icodec was overall safe and well tolerated in the current trial. The pharmacokinetic and pharmacodynamic characteristics of icodec in individuals with T2D support its potential as a once-weekly basal insulin.

One-year safety and efficacy results of insulin treatment simplification with IDegLira in type 2 diabetes.

This study aimed to investigate the sustained safety and efficacy of insulin treatment simplification with IDegLira in patients with type 2 diabetes and an HbA1c ≤ 7.5% (58 mmol/mol) during a 12-month follow-up. Seventy-two adults with type 2 diabetes and an HbA1c ≤ 7.5% (58 mmol/mol) treated with multiple daily insulin injections (MDI) participated in the trial (age 63.8 ± 9.5 years, HbA1c 6.4 ± 0.7%, [46 ± 8 mmol/mol] body weight 92.95 ± 18.83 kg, total daily insulin dose: 43.21 ± 10.80 units; mean ± SD). Previous insulins were stopped, and once daily IDegLira was started. IDegLira was titrated by the patients to achieve a self-measured prebreakfast plasma glucose concentration of ≥5 mmol/L to ≤6 mmol/L. After 12 months, good glycaemic control was maintained, while body weight decreased significantly. Mean HbA1c changed to 6.2 ± 0.8% (44 ± 9 mmol/mol) (p=.109) and body weight changed by -3.89 kg to 89.06 ± 18.61 kg (p < .0001). The simplified treatment was safe and well-tolerated. Percentage of patients experiencing at least one episode of hypoglycaemia was 49% during the month before simplification and 17% during the last 3months of the follow-up. Insulin treatment simplification with IDegLira in selected patients with type 2 diabetes is safe, maintains adequate glycaemic control and is associated with weight loss over 12 months.

A Difference Between Bedtime and Pre-Breakfast Plasma Glucose Levels Indicates the Need for Prandial Insulin in Basal Insulin-Treated Type 2 Diabetic Patients with Normal Fasting Glucose.

AimIn the present analysis, we characterised the efficacy and safety of adding a single daily injection of insulin glulisine to optimised basal-supported oral therapy (BOT) in patients with a high BeAM value, defined as a more than 50 mg/dl difference between bedtime and pre-breakfast blood glucose.MethodsThe BeAM value was retrospectively calculated for patients pooled from two clinical trials that supplemented BOT with glulisine. Data regarding changes in HbA1c, fasting plasma glucose (FPG), and postprandial glucose (PPG) levels from observation periods of 3 to 6 months were assessed.ResultsOut of 358 patients that received BOT/glulisine, 182 had a high BeAM value. Patients with a high BeAM value were older and had a longer diabetes duration than patients with a medium BeAM value. Significant reductions in HbA1c (7.5% to 7.2% [59 to 55 mmol/mol], p<0.0001) and PPG (202 to 143 mg/dl, p<0.0001) levels were documented. The proportion of patients with a high BeAM value achieving an HbA1c <7% [53 mmol/mol], alone or in combination with no hypoglycaemia, was lower than that of patients with a medium BeAM value.ConclusionThe analysis indicates that the supplementation of BOT with a single daily injection of prandial insulin is safe and effective for reducing HbA1c and PPG levels in patients with a high BeAM value (more than 50 mg/dl). However, patients with a medium BeAM value also responded well, which suggests that they should also be considered candidates for this change in therapy.

Efficacy and safety of MK‐1293 insulin glargine compared with originator insulin glargine (Lantus) in type 1 diabetes: A randomized, open‐label clinical trial

To compare the efficacy and safety of MK-1293 insulin glargine (Mk-Gla; 100 U/mL) with originator insulin glargine, Lantus (Sa-Gla), in people with type 1 diabetes mellitus (T1DM). This phase 3, randomized, active-controlled, open-label, 52-week study (ClinicalTrials.gov NCT02059161) enrolled 508 people with T1DM (HbA1c ≤11.0%; 97 mmol/mol) taking basal and prandial insulin. Participants were randomized 1:1 to once-daily Mk-Gla (n = 245) or Sa-Gla (n = 263). Dose titration of basal insulin was by a pre-breakfast plasma glucose dosing algorithm. The primary efficacy objective was assessment of the non-inferiority of HbA1c change from baseline (margin of 0.40% [4.4 mmol/mol]) for Mk-Gla compared with Sa-Gla over 24 weeks. The primary safety objective was assessment of anti-insulin antibody development over 24 weeks. The least squares (LS) mean HbA1c change from baseline at week 24 was -0.62 (95% CI -0.79, -0.45)% (-6.8 [-8.7, -4.9] mmol/mol) and -0.66 (-0.82, -0.50)% (-7.2 [-9.0, -5.4] mmol/mol) for Mk-Gla and Sa-Gla. The LS mean HbA1c difference was 0.04 (-0.11, 0.19)% (0.4 [-1.2, 2.0] mmol/mol) for Mk-Gla minus Sa-Gla, meeting the primary and secondary objective criteria for non-inferiority and equivalence. Week 24 mean insulin glargine dose for Mk-Gla and Sa-Gla was 0.46 and 0.48 U/kg, respectively. Similarity of HbA1c response and basal insulin dose trajectory persisted over the 52 weeks. Safety and tolerability, including anti-insulin antibody responses, hypoglycaemia, adverse events and body weight, were similar between insulins over the 52-week study duration. Mk-Gla and Sa-Gla exhibited similar efficacy and safety over 52 weeks in people with T1DM. ClinicalTrials.gov: NCT02059161.

New Medications for the Treatment of Diabetes

New Medications for the Treatment of Diabetes

Insulin degludec improves long-term glycaemic control similarly to insulin glargine but with fewer hypoglycaemic episodes in patients with advanced type 2 diabetes on basal-bolus insulin therapy.

The aim of the present study was to compare the long-term safety and efficacy of insulin degludec with those of insulin glargine in patients with advanced type 2 diabetes (T2D) over 78 weeks (the 52-week main trial and a 26-week extension). Patients were randomized to once-daily insulin degludec or insulin glargine, with mealtime insulin aspart ± metformin ± pioglitazone, and titrated to pre-breakfast plasma glucose values of 3.9-4.9 mmol/l (70-88 mg/dl). After 78 weeks, the overall rate of hypoglycaemia was 24% lower (p = 0.011) and the rate of nocturnal hypoglycaemia was 31% lower (p = 0.016) with insulin degludec in the extension trial set, while both groups of patients achieved similar glycaemic control. Rates of adverse events and total insulin doses were similar for both groups in the safety analysis set. During 18 months of treatment, insulin degludec + mealtime insulin aspart ± oral antidiabetic drugs in patients with T2D improves glycaemic control similarly, but confers lower risks of overall and nocturnal hypoglycaemia than with insulin glargine treatment.

Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetes

A fixed-ratio combination of the basal insulin analogue insulin degludec and the glucagon-like peptide-1 (GLP-1) analogue liraglutide has been developed as a once-daily injection for the treatment of type 2 diabetes. We aimed to compare combined insulin degludec-liraglutide (IDegLira) with its components given alone in insulin-naive patients. In this phase 3, 26-week, open-label, randomised trial, adults with type 2 diabetes, HbA1c of 7-10% (inclusive), a BMI of 40 kg/m(2) or less, and treated with metformin with or without pioglitazone were randomly assigned (2:1:1) to daily injections of IDegLira, insulin degludec, or liraglutide (1·8 mg per day). IDegLira and insulin degludec were titrated to achieve a self-measured prebreakfast plasma glucose concentration of 4-5 mmol/L. The primary endpoint was change in HbA1c after 26 weeks of treatment, and the main objective was to assess the non-inferiority of IDegLira to insulin degludec (with an upper 95% CI margin of 0·3%), and the superiority of IDegLira to liraglutide (with a lower 95% CI margin of 0%). This study is registered with ClinicalTrials.gov, number NCT01336023. 1663 adults (mean age 55 years [SD 10], HbA1c 8·3% [0·9], and BMI 31·2 kg/m(2) [4·8]) were randomly assigned, 834 to IDegLira, 414 to insulin degludec, and 415 to liraglutide. After 26 weeks, mean HbA1c had decreased by 1·9% (SD 1·1) to 6·4% (1·0) with IDegLira, by 1·4% (1·0) to 6·9% (1·1) with insulin degludec, and by 1·3% (1·1) to 7·0% (1·2) with liraglutide. IDegLira was non-inferior to insulin degludec (estimated treatment difference -0·47%, 95% CI -0·58 to -0·36, p<0·0001) and superior to liraglutide (-0·64%, -0·75 to -0·53, p<0·0001). IDegLira was generally well tolerated; fewer participants in the IDegLira group than in the liraglutide group reported gastrointestinal adverse events (nausea 8·8 vs 19·7%), although the insulin degludec group had the fewest participants with gastrointestinal adverse events (nausea 3·6%). We noted no clinically relevant differences between treatments with respect to standard safety assessments, and the safety profile of IDegLira reflected those of its component parts. The number of confirmed hypoglycaemic events per patient year was 1·8 for IDegLira, 0·2 for liraglutide, and 2·6 for insulin degludec. Serious adverse events occurred in 19 (2%) of 825 patients in the IDegLira group, eight (2%) of 412 in the insulin degludec group, and 14 (3%) of 412 in the liraglutide group. IDegLira combines the clinical advantages of basal insulin and GLP-1 receptor agonist treatment, resulting in improved glycaemic control compared with its components given alone. Novo Nordisk.

Comparison of insulin degludec with insulin glargine in insulin‐naive subjects with Type 2 diabetes: a 2‐year randomized, treat‐to‐target trial

AimsThe aim of this study was to compare long-term safety and efficacy of the basal insulin analogue degludec with glargine in insulin-naive subjects with Type 2 diabetes.MethodsThis open-label trial included a 52-week core period followed by a 52-week extension. Participants were randomized 3:1 to once-daily degludec or glargine, administered with metformin ± dipeptidyl peptidase-4 inhibitors. Basal insulin was titrated to target pre-breakfast plasma glucose 3.9–4.9 mmol/l.ResultsAt end of treatment (104 weeks), mean HbA1c reductions were similar for degludec and glargine; estimated treatment difference between degludec and glargine was 1 mmol/mol (95% CI −1 to 3) [0.07% (95% CI −0.07 to 0.22)], P = 0.339 in the extension trial set (degludec 551, glargine 174), comprising subjects who completed core trial and continued into the extension trial. Overall confirmed hypoglycaemia rates (1.72 vs. 2.05 episodes/patient-year), rates of adverse events possibly or probably related to trial product (0.19 events/patient-year), weight gain (2.7 vs. 2.4 kg) and mean daily insulin doses (0.63 U/kg) were similar between treatments in the safety analysis set (degludec 766, glargine 257) comprising all treated subjects. Rates of nocturnal confirmed hypoglycaemia (0.27 vs. 0.46 episodes/patient-year; P = 0.002) and severe hypoglycaemia (0.006 vs. 0.021 episodes/patient-year, P = 0.023) were significantly lower with degludec for the safety analysis set (analysis based on intention-to-treat full analysis set comprising all randomized subjects).ConclusionsIn Type 2 diabetes, insulin degludec in combination with oral anti-diabetic drugs, safely and effectively improves long-term glycaemic control, with a significantly lower risk of nocturnal hypoglycaemia as compared with glargine.

Insulin degludec improves glycaemic control with lower nocturnal hypoglycaemia risk than insulin glargine in basal–bolus treatment with mealtime insulin aspart in Type 1 diabetes (BEGIN® Basal–Bolus Type 1): 2‐year results of a randomized clinical trial

AimsThe goal of this study was to compare the long-term safety and efficacy of the basal insulin analogue, insulin degludec with insulin glargine (both with insulin aspart) in Type 1 diabetes, over a 2-year time period.MethodsThis open-label trial comprised a 1-year main trial and a 1-year extension. Patients were randomized to once-daily insulin degludec or insulin glargine and titrated to pre-breakfast plasma glucose values of 3.9–4.9 mmol/l.ResultsThe rate of nocturnal confirmed hypoglycaemia was 25% lower with insulin degludec than with insulin glargine (P = 0.02). Rates of confirmed hypoglycaemia, severe hypoglycaemia and adverse events, and reductions in glycated haemoglobin and fasting plasma glucose were similar between groups. Despite achieving similar glycaemic control, insulin degludec-treated patients used 12% less basal and 9% less total daily insulin than did insulin glargine-treated patients (P < 0.01).ConclusionsLong-term basal therapy using insulin degludec in Type 1 diabetes required lower doses and was associated with a 25% lower risk for nocturnal hypoglycaemia than insulin glargine.

Insulin Degludec Versus Insulin Glargine in Insulin-Naive Patients With Type 2 Diabetes

OBJECTIVETo compare ultra-long-acting insulin degludec with glargine for efficacy and safety in insulin-naive patients with type 2 diabetes inadequately controlled with oral antidiabetic drugs (OADs).RESEARCH DESIGN AND METHODSIn this 1-year, parallel-group, randomized, open-label, treat-to-target trial, adults with type 2 diabetes with A1C of 7−10% taking OADs were randomized 3:1 to receive once daily degludec or glargine, both with metformin. Insulin was titrated to achieve prebreakfast plasma glucose (PG) of 3.9−4.9 mmol/L. The primary end point was confirmation of noninferiority of degludec to glargine in A1C reduction after 52 weeks in an intent-to-treat analysis.RESULTSIn all, 1,030 participants (mean age 59 years; baseline A1C 8.2%) were randomized (degludec 773, glargine 257). Reduction in A1C with degludec was similar (noninferior) to that with glargine (1.06 vs. 1.19%), with an estimated treatment difference of degludec to glargine of 0.09% (95% CI −0.04 to 0.22). Overall rates of confirmed hypoglycemia (PG <3.1 mmol/L or severe episodes requiring assistance) were similar, with degludec and glargine at 1.52 versus 1.85 episodes/patient-year of exposure (PYE). There were few episodes of nocturnal confirmed hypoglycemia in the overall population, and these occurred at a lower rate with degludec versus glargine (0.25 vs. 0.39 episodes/PYE; P = 0.038). Similar percentages of patients in both groups achieved A1C levels <7% without hypoglycemia. End-of-trial mean daily insulin doses were 0.59 and 0.60 units/kg for degludec and glargine, respectively. Adverse event rates were similar.CONCLUSIONSInsulins degludec and glargine administered once daily in combination with OADs provided similar long-term glycemic control in insulin-naive patients with type 2 diabetes, with lower rates of nocturnal hypoglycemia with degludec.

The Effect of Insulin Degludec on Glycemic Control and Nocturnal Hypoglycemia Compared with Insulin Glargine: a 1-year Randomized Trial in Insulin-naïve People with Type 2 Diabetes

s / Can J Diabetes 36 (2012) S24eS76 S58 The study comprised a 1-yr main period followed by 1-yr extension; subjects maintained prior randomization. Subjects were randomized 3:1 to IDeg or IGlar given subcutaneously once daily with mealtime insulin aspart. Basal insulin was titrated to target pre-breakfast plasma glucose (PG) (>3.9e<5.0mmol/L). Data at end of 2yrs of treatment (EOT) are presented. Of 629 subjects (baseline: mean age 43yrs; diabetes duration 18.9yrs; HbA1c 7.7%; fasting PG 9.3mmol/L), 443 (IDeg: 330; IGlar: 113) completed 2yrs’ treatment. EOT HbA1c reduction was similar: e0.27% (IDeg) vs. e0.24% (IGlar); estimated treatment difference (ETD) IDegeIGlar: 0.04% [95%CI 0.17;0.09], p1⁄4NS. Similar proportions of subjects achieved HbA1c<7% (IDeg: 34%; IGlar: 31%; p1⁄4NS). Rates of overall hypoglycemia (PG<3.1mmol/L or severe) were similar for entire period (37.5[IDeg] vs. 37.4[IGlar] episodes/ pt-yr; estimated rate ratio [ERR] IDeg/IGlar: 1.02 [0.85;1.24]; p1⁄4NS) and maintenance period (16wk to EOT, when mean dose and glycemia stabilized; 34.0 vs. 35.0 episodes/pt-yr; ERR: 0.98 [0.80;1.20]; p1⁄4NS). Nocturnal hypoglycemia was significantly lower with IDeg (3.9 vs. 5.3 episodes/pt-yr; ERR: 0.75 [0.59;0.95]; p1⁄40.02). Therefore, treating one patient for w9 months with IDeg will avoid one nocturnal hypoglycemic episode. In conclusion, IDeg safely and effectively improves glycemic control with a lower risk of nocturnal hypoglycemia than IGlar when part of 2-yr BB therapy in T1DM. This furthermore provides evidence for the long-term safety of IDeg in T1DM.

Interindividual Divergence in the Relationship between the Values of Plasma Glucose and Hemoglobin A1c in Type 2 Diabetes

To verify the relationships between the values of plasma glucose (PG) and hemoglobin A(1c)(HbA(1c)) in type 2 diabetic outpatients. The pre- and postbreakfast PG and HbA(1c) values were monitored every month for 44-90 months. The single regression lines between the values of PG and HbA(1c) were compared for the slopes and intercepts on the designated ordinates of the regression lines. Nine patients of type 2 diabetes not treated with insulin: three males and six females, aged 43-79 years participated. The HbA(1c) level was combined with the pre- and postbreakfast PG values obtained at one month prior to its determination, because the combinations were correlated most strongly. The slopes of the regression line ranged from 0.33-0.50%/mmol/L and the intercepts at PG level equal to 9.6 mmol/L ranged from 6.95-9.77% in the relationship between the values of 1-month earlier prebreakfast PG and HbA(1c). Twenty-eight pairs had significantly different intercepts. Meanwhile, there was no pair that had significantly different slopes. Similar results were obtained in the relationship between the values of 1-month earlier postbreakfast PG and HbA(1c). There was interindividual divergence of the regression lines which was due to the difference in the intercepts but not the slopes.

Less weight gain and hypoglycaemia with once‐daily insulin detemir than NPH insulin in intensification of insulin therapy in overweight Type 2 diabetes patients—The PREDICTIVE™ BMI clinical trial1

To assess weight change when once-daily insulin detemir (detemir) or neutral protamine Hagedorn insulin (NPH) are used in already overweight Type 2 diabetes patients requiring intensified insulin therapy. This 26-week randomized, controlled trial included adults with Type 2 diabetes [glycated haemoglobin (HbA(1c)) 7.5-11.0%, body mass index (BMI) 25-40 kg/m(2)] who had received two daily doses of insulin (at least one a premix) for > or = 3 months. Subjects received either detemir (n = 125) or NPH (n = 146) once daily in the evening and insulin aspart at main meals. Concomitant treatment with metformin was allowed. Basal insulin was titrated to a pre-breakfast plasma glucose target of 6.1 mmol/l without unacceptable hypoglycaemia. Insulin aspart was also titrated (target, postprandial glucose < or = 10.0 mmol/l without unacceptable hypoglycaemia). At 26 weeks, weight had increased significantly less with detemir (0.4 kg) than with NPH (1.9 kg; difference 1.5 kg, P < 0.0001). BMI increase was also less with detemir than with NPH (difference 0.6 kg/m(2), P < 0.0001). HbA(1c) decreased from 8.9 to 7.8% (detemir) and from 8.8 to 7.8% (NPH; not significant for between-treatment difference). Incidence of hypoglycaemia was lower with detemir [relative risks 0.62 (all events) and 0.43 (nocturnal); P < 0.0001 for both]. PREDICTIVE BMI was the first study to examine the effect of once-daily detemir with weight as the primary endpoint in a large population of overweight Type 2 diabetes patients. Use of once-daily detemir for intensification of insulin therapy resulted in less weight gain, less hypoglycaemia and equivalent glycaemic control compared with NPH.

Strongest correlation of HbA 1c with 1-month-earlier glucose levels in type 2 diabetes

We examined the correlations of hemoglobin A 1c (HbA 1c) with each plasma glucose (PG) level obtained at 0 (the same day), 1 and 2 month(s) prior to HbA 1c determination. Data were from glycemic profiles of four patients of type 2 diabetes mellitus treated with tablets whose HbA 1c and pre- and post-breakfast PG levels were monitored each month. There was no significant difference in the correlation coefficients in cases 1 and 2, who presented with linear glycemic time courses. In contrast, HbA 1c correlated with 1-month-earlier pre-breakfast PG level more strongly than 2-month-earlier post-breakfast PG level in cases 3 and 4, and than same-day post-breakfast PG level in case 3 ( P<0.05, ANOVA). The cases 3 and 4 presented with fluctuating glycemic time courses. Samples were separated into upslope’s and downslope’s sections according to HbA 1c fluctuation in the latter two cases. Reflecting around the 1-month lag between HbA 1c and PG, the two sections’ regression lines for PG versus HbA 1c corresponded in the only samples related to 1-month-earlier pre- and post-breakfast PG ( t-test). In conclusion, it appears that pre- and post-breakfast PG levels are the most reliable predictors of 1-month-later HbA 1c in type 2 diabetic outpatients who undergo medical examinations every month.

Ultralente based insulin regimens--clinical applications, advantages and disadvantages.

The prolonged action of daily injections of beef ultralente insulin provides a source for the basal, steady state insulin supply which diabetics need in addition to their meal requirements. The complete distinction between basal and meal insulin requirements, provided by two or three injections of soluble insulin per day, allows simple rules to guide both the physician and patient. Thus, the required ultralente dose needs to be continued daily, irrespective of illness or missing meals, whereas the soluble insulin requirements are given according to meals. When starting ultralente insulin therapy a loading dose is required. The doses of ultralente and soluble insulin needed for different severities of diabetes and degrees of insulin resistance can be predicted. A simple regimen to cover the decreasing insulin requirements of newly presenting, ketotic juvenile-onset diabetics has been developed. During surgical operations the continued basal insulin supply, from ultralente insulin, greatly facilitates diabetes control. Whilst many patients have improved nocturnal blood glucose control after transfer to ultralente insulin, optimal control of diabetes sometimes remains difficult in view of the pre-breakfast plasma glucose rise and the longer action of subcutaneous soluble insulin than the physiological meal insulin response. Purified monocomponent beef ultralente insulin is antigenic, and human ultralente insulin might be advantageous.