ly2605541 and Diabetes-Mellitus--Type-2

There is a clinical rationale for a basal insulin with a predictable action and low inter- and intra-individual variability coupled with an improved side effect and metabolic profile. Since insulin therapy is anabolic and its initiation is commonly associated with weight gain, an insulin preparation associated with a beneficial weight profile would represent a particularly valuable therapeutic entity. LY2605541, or PEGylated insulin Lispro, has a large hydrodynamic size while still exerting the metabolic effects of insulin. This may reduce absorption and clearance of the compound following subcutaneous administration. A number of preclinical and clinical studies have been constructed to evaluate the utility of this novel insulin. The currently available data from preclinical, phase I and phase II studies suggests LY2605541 has a non-inferior glucose-lowering efficacy compared to insulin glargine in people with type 1 and type 2 diabetes and may afford a weight-loss advantage. Pre-clinical studies indicate that LY2605541 has low mitogenic potency, exerting a preferential hepatic effect on glucose homeostasis. LY2605541 appears to cause elevated transaminases and derangement of lipid profiles. On the basis of these initial observations, LY2605541 requires further extensive clinical evaluation to fully assess its risk/benefit profile in the management in people with diabetes.

Topics: Body Weight; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Humans; Hypoglycemic Agents; Insulin Lispro; Insulin, Long-Acting; Male; Polyethylene Glycols; Risk Assessment; Treatment Outcome

The basal insulin products currently on market do not optimally mimic endogenous insulin secretion. These unmet clinical needs have fueled the development of new basal insulin analogues for improving their pharmacokinetics/pharmacodynamics profile.. We review the recent literature investigating the efficacy and safety of new basal insulin analogues in type 2 diabetes, as in the USA, insulin utilization accounted for 26% of treatment visits for these patients in 2012. Insulin degludec is a desB30 insulin acylated at the LysB29 residue with a glutamate linker and 16-carbon fatty diacyl side chain. Insulin lispro has been PEGylated at lysine B28, via a urethane bond, which increases the hydrodynamic size of the molecule and reduces its absorption and clearance following subcutaneous administration. Glargine U300 represents a new high-strength glargine formulation (300 U/ml): once injected, U300 forms a compact subcutaneous depot with a smaller surface area to produce a more gradual and prolonged release. Both PEG-lispro and glargine U300 are not yet on the market.. Ultra-long acting and high-strength formulations of new basal analogues have the potential for less glycemic variability, less (nocturnal) hypoglycemia and weight-loss advantage for PEG-lispro. However, these new basal insulin analogues need to be monitored closely for adverse signals.

Topics: Animals; Biomarkers; Blood Glucose; Chemistry, Pharmaceutical; Diabetes Mellitus, Type 2; Drug Design; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin Lispro; Insulin, Long-Acting; Insulins; Polyethylene Glycols; Treatment Outcome

To assess the pharmacokinetics (PK) and glucodynamics (GD) of LY2605541 in patients with type 2 diabetes mellitus.. This parallel-group, open-label, dose-escalation study examined the PK and GD of basal insulin LY2605541 after single and multiple-dose administration. Fixed doses of LY2605541 (0.33-1.00 U/kg) were given once-daily (QD) for 14 days to insulin-treated patients with type 2 diabetes. A 24-h euglycaemic glucose clamp was conducted on days 1 and 14.. PK steady state was achieved within 7-10 days and the peak-to-trough fluctuation was <2, translating to a nearly 'peakless' glucose infusion rate at steady state and with a duration of action of at least 24 h. Across dose levels t1/2 ranged from 44.7 to 75.5 h (~2-3 days). As steady state was achieved, there were dose-dependent reductions in the prandial insulin dose and in fasting blood glucose, which decreased to 60-100 mg/dl across dose levels. Within-patient variability was <14 and <26% for the area under the concentration versus time curve (AUC) of the 8-point blood glucose profile and fasting blood glucose, respectively. The nocturnal glucose control between 03:00 and 09:00 hours was relatively unchanged. Mild hypoglycaemia was the most common adverse event.. In this Phase I study of fixed LY2605541 doses without titration, LY2605541 was well-tolerated and demonstrated a flat PK and GD profile accompanied by glucose normalization, prandial insulin dose reduction and no severe hypoglycaemia.

Topics: Adolescent; Adult; Aged; Area Under Curve; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Lispro; Male; Middle Aged; Polyethylene Glycols; Treatment Outcome

To use continuous glucose monitoring (CGM) to evaluate the impact of the novel, long-acting basal insulin analog LY2605541 on hypoglycemia and glycemic variability in patients with type 2 diabetes.. Hypoglycemia and glucose variability were assessed with CGM of interstitial glucose (IG) in a subset of patients with type 2 diabetes from a phase II, randomized, open-label, parallel study of LY2605541 (n = 51) or insulin glargine (GL) (n = 25). CGM was conducted on 3 consecutive days (72-84 h) during the week before week 0, 6, and 12 study visits.. Measured by CGM for 3 days prior to the 12-week visit, fewer LY2605541-treated patients experienced hypoglycemic events overall (50.0 vs. 78.3%, P = 0.036) and nocturnally (20.5 vs. 47.8%, P = 0.027) and spent less time with IG ≤70 mg/dL than GL-treated patients during the 24-h (25 ± 6 vs. 83 ± 16 min, P = 0.012) and nocturnal periods (11 ± 5 vs. 38 ± 13 min, P = 0.024). These observations were detected without associated differences in the average duration of individual hypoglycemic episodes (LY2605541 compared with GL 57.2 ± 5.4 vs. 69.9 ± 10.2 min per episode, P = NS). Additionally, LY2605541-treated patients had lower within-day glucose SD for both 24-h and nocturnal periods.. By CGM, LY2605541 treatment compared with GL resulted in fewer patients with hypoglycemic events and less time in the hypoglycemic range and was not associated with protracted hypoglycemia.

Topics: Blood Glucose; Blood Glucose Self-Monitoring; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin Lispro; Insulin, Long-Acting; Male; Middle Aged; Polyethylene Glycols; Treatment Outcome

The basal insulin analogue LY2605541, a PEGylated insulin lispro with prolonged duration of action, was previously shown to be associated with modest weight loss in Phase 2, randomized, open-label trials in type 2 (N=288) and type 1 (N=137) diabetes mellitus (T2DM and T1DM), compared with modest weight gain with insulin glargine. Exploratory analyses were conducted to further characterize these findings.. Pearson correlations between change in body weight and other variables were calculated. Continuous variables were analysed using a mixed linear model with repeated measurements. Proportions of subjects with weight loss were analysed using Fisher's exact test for T2DM and Nagelkerke's method for T1DM.. Weight loss was more common in LY2605541-treated patients than in patients treated with insulin glargine (T2DM: 56.9 vs. 40.2%, p=0.011; T1DM: 66.1 vs. 40.3%, p<0.001). More LY2605541-treated patients experienced ≥5% weight loss compared to patients treated with glargine (T2DM: 4.8 vs. 0%, p=0.033; T1DM: 11.9 vs. 0.8%, p<0.001). In both the T1DM and T2DM studies, weight change did not correlate with baseline body mass index (BMI), or change in HDL-cholesterol in either treatment group. No consistent correlations were found across both studies between weight change and any of the variables assessed; however, weight change was significantly correlated with hypoglycaemia rate in glargine-treated T2DM patients.. In two Phase 2 trials, improved glycaemic control with long-acting basal insulin analogue LY2605541 is associated with weight loss in previously insulin-treated patients. This weight change is independent of baseline BMI or hypoglycaemia.

Topics: Adult; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin Lispro; Insulin, Long-Acting; Male; Middle Aged; Polyethylene Glycols; Treatment Outcome; Weight Gain; Weight Loss

Because insulin dosing requires optimization of glycemic control, it is important to use a single metric of benefit and risk to determine best insulin dosing practices. We retrospectively applied a multiplicative clinical utility index (CUI) to a study of LY2605541 (Eli Lilly and Company, Indianapolis, IN), a novel, long-acting basal insulin.. A CUI was developed to transform the multidimensional problem of assessing benefit/risk of multiple dosing algorithms into a single decision-making metric to evaluate two LY2605541 dosing algorithms relative to the insulin glargine (GL) dosing algorithm. The CUI was applied to data in a 12-week, open-label, Phase 2 trial in patients with type 2 diabetes mellitus who were randomized to one of two dosing algorithms for LY2605541 (LY1 or LY2) or GL (algorithm similar to LY1). The CUI was created (via expert input) by weighing the relative benefit/risk of four components (glycosylated hemoglobin [HbA1c], percentage of patients with HbA1c ≤ 7%, hypoglycemia rate, and time to steady-state dose); individual utility values were multiplied to compute CUI values for LY1 and LY2 relative to GL, and bootstrap samples were used to determine variability.. The mean CUI was 0.82 for LY1 and 1.35 for LY2. Based on 3,000 bootstrap samples, there was a 48% probability of LY2 performing better than LY1 and a 28% probability of LY1 performing better than LY2.. CUI methodology, and in particular this CUI, is a useful tool for comparing dosing algorithms. Based on this CUI, LY2 is likely to be a better dosing algorithm than LY1.

Topics: Algorithms; Blood Glucose; Clinical Trials, Phase II as Topic; Decision Making; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin Lispro; Insulin, Long-Acting; Male; Middle Aged; Polyethylene Glycols; Retrospective Studies; Risk Assessment; Treatment Outcome

To evaluate whether LY2605541 results in lower fasting blood glucose (FBG) versus insulin glargine (GL).. This 12-week, randomized, open-label, Phase 2 study enrolled patients with type 2 diabetes (hemoglobin A(1c) [A1C] ≤ 10.5%), taking metformin and/or sulfonylurea with GL or NPH insulin once daily. Patients converted to morning insulin administration during lead-in were randomized 2:1 from GL (n = 248) or NPH insulin (n = 39) to LY2605541 (n = 195) or GL (n = 95) once daily in the morning.. At 12 weeks, FBG (mean ± SE) was similar with LY2605541 and GL (118.2 ± 2.0 mg/dL [6.6 ± 0.1 mmol/L] vs. 116.9 ± 2.7 mg/dL [6.5 ± 0.2 mmol/L], P = 0.433) as was A1C (7.0 ± 0.1 vs. 7.2 ± 0.1%, P = 0.279). Intraday blood glucose variability was reduced with LY2605541 (34.4 vs. 39.1 mg/dL [1.9 vs. 2.2 mmol/L], P = 0.031). LY2605541 patients had weight loss (-0.6 ± 0.2 kg, P = 0.007), whereas GL patients gained weight (0.3 ± 0.2 kg, P = 0.662; treatment difference: -0.8 kg, P = 0.001). The incidence and rate of both total hypoglycemia and nocturnal hypoglycemia were comparable between LY2605541 and GL, although, LY2605541 had a 48% reduction in nocturnal hypoglycemia after adjusting for baseline hypoglycemia (P = 0.021). Adverse events were similar across treatments. Alanine aminotransferase and aspartate aminotransferase remained within normal range but were significantly higher with LY2605541 (P ≤ 0.001).. In patients with type 2 diabetes, LY2605541 and GL had comparable glucose control and total hypoglycemia rates, but LY2605541 showed reduced intraday variability, lower nocturnal hypoglycemia, and weight loss relative to GL.

Topics: Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin Lispro; Insulin, Long-Acting; Male; Polyethylene Glycols