Haahr H.,Novo Nordisk AS |
Clinical Pharmacokinetics | Year: 2014
Insulin degludec (IDeg) is a new-generation basal insulin with an ultra-long duration of action. To date, a large number of studies have been conducted to investigate the pharmacokinetic and pharmacodynamic properties of IDeg. Standardised methods for collection and analysis of blood samples (for pharmacokinetic endpoints) and euglycaemic clamp procedures (for pharmacodynamic endpoints) were applied across studies to enable cross-study evaluation of important pharmacokinetic and pharmacodynamic parameters. Data show that IDeg has a half-life of >25 h [compared with ~12 h for insulin glargine (IGlar)] and reaches steady state within 3 days of administration in all patient populations investigated. The pharmacokinetic profile of IDeg demonstrates an even distribution of exposure across one dosing interval. The pharmacodynamic profile of IDeg is flat and stable, demonstrated by an even distribution of glucose-lowering effect across all four 6-h intervals in a 24-h period (one dosing day). These properties were consistently demonstrated across different type 1 and type 2 diabetes mellitus patient populations, including those from different ethnic origins (both males and females with type 2 diabetes), the elderly, and patients with hepatic or renal impairment. IDeg has an ultra-long duration of action exceeding 42 h and demonstrates four times lower day-to-day within-subject variability in glucose-lowering effect than IGlar. This review discusses the pharmacokinetic and pharmacodynamic data accumulated thus far, and the relevance of these results from a clinical perspective. © 2014 The Author(s).
Frier B.M.,Queens Medical Research Institute |
Russell-Jones D.,University of Surrey |
Diabetes, Obesity and Metabolism | Year: 2013
The aim of this review is to summarize the clinical efficacy, tolerability and safety data of insulin detemir, and compare its use with that of neutral protamine Hagedorn (NPH) insulin in randomized controlled trials in people with type 1 or type 2 diabetes. A literature search was conducted with PubMed using predefined search terms. Studies were included if they met the following criteria: randomized, controlled trial, comparison of insulin detemir with NPH insulin, non-hospitalized adults aged ≥18years with either type 1 or type 2 diabetes, and study duration of ≥12weeks. The following types of studies were excluded: non-randomized controlled trials, studies of mixed cohorts of patients with type 1 or type 2 diabetes that did not report results separately, pharmacokinetic/pharmacodynamic studies, reviews, pooled or meta-analyses or health-economic analyses. Fourteen publications met the inclusion criteria. Nine studies in people with type 1 diabetes and three studies in people with type 2 diabetes, using insulin detemir in a basal-bolus regimen were included. Two studies were in people with type 2 diabetes using insulin detemir with oral antidiabetes medicines. In 14 studies of people with type 1 or type 2 diabetes, insulin detemir treatment provided similar or better glycaemic control, lower within-subject variability, similar or lower frequency of hypoglycaemia and less weight gain when compared with NPH insulin. © 2013 John Wiley & Sons Ltd.
Becker R.H.A.,Sanofi S.A. |
Stechl J.,Sanofi S.A. |
Msihid J.,Sanofi S.A. |
Diabetes, Obesity and Metabolism | Year: 2014
Aims: Glucagon-like peptide-1 (GLP-1) receptor agonists improve blood glucose control by enhancing glucose-sensitive insulin release, delaying gastric emptying and reducing postprandial glucagon secretion. The studies reported here investigated the insulin response to an intravenous (iv) glucose challenge after injection of lixisenatide (LIXI) 20μg or placebo. Methods: Two single-centre, double-blind, randomized, placebo-controlled, single-dose, crossover studies were performed in healthy subjects (HS) and people with type 2 diabetes mellitus (T2DM). Participants received subcutaneous LIXI or placebo 2h before an iv glucose challenge. Study endpoints included first- and second-phase insulin response, insulin concentration (INS), glucagon response and glucose disposal rate (Kglucose). LIXI exposure was measured over 12h. Results: LIXI 20μg reached maximum concentration after 2h and resensitized first-phase insulin secretion by 2.8-fold in T2DM to rates comparable with those in HS on placebo, and raised second-phase insulin secretion by 1.6-fold in T2DM. INS rose correspondingly and glucose disposal was accelerated by 1.8-fold in T2DM. First-phase insulin secretion and glucose disposal were also augmented by LIXI in HS, whereas second-phase insulin secretion reduced blood glucose concentrations to below fasting levels and then ceased, accompanied by a rapid, short-lasting rise in glucagon. Otherwise, suppression of glucagon release subsequent to augmentation of insulin release was unaffected in T2DM and in HS. Conclusions: LIXI resensitized the insulin response to an iv glucose challenge in people with T2DM, thereby accelerating glucose disposal to nearly physiological intensity, and did not impair counter-regulation to low glucose levels by glucagon. © 2014 John Wiley and Sons Ltd.
Sinha V.P.,Eli Lilly and Company |
Howey D.C.,Eli Lilly and Company |
Choi S.L.,Eli Lilly and Company |
Mace K.F.,Eli Lilly and Company |
Diabetes, Obesity and Metabolism | Year: 2014
Aims: To assess the pharmacokinetics (PK) and glucodynamics (GD) of LY2605541 in patients with type 2 diabetes mellitus. Methods: 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 (0.33-1.00U/kg) were given once-daily (QD) for 14days to insulin-treated patients with type 2 diabetes. A 24-h euglycaemic glucose clamp was conducted on days 1 and 14. Results: PK steady state was achieved within 7-10days 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 24h. Across dose levels t1/2 ranged from 44.7 to 75.5h (̃2-3days). As steady state was achieved, there were dose-dependent reductions in the prandial insulin dose and in fasting blood glucose, which decreased to 60-100mg/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 09:00hours was relatively unchanged. Mild hypoglycaemia was the most common adverse event. Conclusions: 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. © 2013 John Wiley & Sons Ltd.
Heise T.,Profil |
Meneghini L.,University of Miami
Endocrine Practice | Year: 2014
Objective: The build-up in insulin levels following repeated injection of prandial insulin at close intervals - referred to as insulin stacking - can increase the risk of hypoglycemia. With the development of basal insulins with a half-life >24 hours and a duration of action >40 hours, clinicians may be concerned about stacking when these long-Acting formulations are administered once daily. The objective of this review is to clarify the difference between inappropriate insulin stacking when shorter-Acting insulin formulations are repeatedly used to correct hyperglycemia and the appropriate accumulation of long-Acting insulin formulations dosed to steady-state pharmacokinetic (PK) profiles.Methods: Relevant literature on insulin stacking, glucose-clamp studies, and clinical studies of insulin, in conjunction with the clinical experience of the authors, were used to present an overview of insulin PK properties and the effects of appropriate and inappropriate dosing intervals on steady-state conditions and likely clinical outcomes.Results: Clinical studies confirm theoretical PK principles showing that unwanted insulin stacking (excessive concentrations) for basal insulin can be avoided by following recommended dosing and titration algorithms. Long-Acting basal insulins need more time to reach steady state than shorter-Acting basal insulins but then show reduced peak-trough fluctuations, translating into more consistent biologic action over a 24-hour period.Conclusion: The unwanted stacking and consequent hypoglycemia that can occur when correctional doses of rapid-Acting insulin are administered at close intervals does not occur when long-Acting basal insulins are dosed in appropriate amounts and adjusted at appropriate time intervals (e.g., insulin stacking, insulin administration, diabetes, ultralong duration of action, hypoglycemia every three or more days), allowing for pharmacologic steady-state accumulation © 2014 AACE.