Pharmacokinetic and glucodynamic variability: assessment of insulin glargine, NPH insulin and insulin ultralente in healthy volunteers using a euglycaemic clamp technique

Abstract

Aims/hypothesis: This single-dose, doubleblind, randomised, parallel-group study evaluated the reproducibility in systemic exposure and glucodynamic effect of insulin glargine, NPH insulin (NPH) and insulin ultralente (ultralente) using the manually adjusted euglycaemic clamp technique. Methods: In total, 36 healthy volunteers received two consecutive s.c. injections (0.4 IU/kg) of glargine, NPH or ultralente with a wash-out period of 7 days between treatments. Results: In healthy volunteers, glargine presented well-reproduced flat concentration profiles and no pronounced peaks in activity. NPH, by contrast, showed well-defined peaks in concentration and glucose disposal, while ultralente had highly variable profiles. Within-subject variability (ANOVA) for insulin exposure over 24 h was 15% for glargine and 19% for NPH, compared with 67% for ultralente (p<0.05, glargine and NPH vs ultralente). The 49% within-subject variability in total glucose disposal (glucose infusion rate [GIR]-AUC 0-24 h ) with ultralente was about twice as large as the 22% with NPH (p<0.05), but was intermediate with glargine at 31% (p=NS). By contrast, variability in the diurnal time-action profile (SD of diurnal day-to-day differences in GIR) for glargine was 30% (p<0.05) and 50% (p<0.05) less than with NPH and ultralente, respectively. No serious adverse events were reported. Conclusions/ interpretation: Although representing insulins of different profiles, glargine and NPH showed a high and similar reproducibility of total absorption and glucodynamic effect, whereas ultralente proved to have poor reproducibility. However, while NPH yields peaks in concentration and activity, glargine shows flat and non-fluctuating profiles resulting in less variation in day-to-day 24-h activity.

Comparison of pharmacodynamic intrasubject variability of insulin lispro protamine suspension and insulin glargine in subjects with type 1 diabetes

“…Few studies have determined the PD intrasubject variability of glargine (1,11,12), and only one study has made this determination using subjects with T1DM (1). Similar to the results seen in this study, Heise et al (1) found high G tot and R max intrasubject variabilities for glargine.…”

To: Scholtz HE, Pretorius SG, Wessels DH, Becker RHA (2005) Pharmacokinetic and glucodynamic variability: assessment of insulin glargine, NPH insulin and insulin ultralente in healthy volunteers using a euglycaemic clamp technique. Diabetologia 48:1988–1995

“…1 Pharmacodynamic profile of insulin glargine, reproduced from Scholtz et al (Fig. 1a) [1]. The two lines denote the median GIR after subcutaneous injection of insulin glargine in twelve healthy volunteers, clamped at two different occasions J. H. DeVries (*)…”

“…To the Editor: Scholz et al present a comprehensive clamp study on pharmacokinetics, pharmacodynamics and variability of insulins NPH, ultralente and glargine [1]. Figure 1a from their article ( Fig.…”

The interpretation of glucose clamp studies of long-acting insulin analogues: from physiology to marketing and back

“…This may again lead to overestimation of the duration of action of the study insulin (D. K. W. Soon, Exploratory and Program Medicine, Lilly-NUS Centre for Clinical Pharmacology, Singapore, personal communication). Moreover, suppression of endogenous insulin secretion is incomplete, with reported reductions in C-peptide levels to about 45% of the baseline values [16] or '>50%' [8]. However, clamp studies in healthy volunteers may serve regulatory requirements (i.e.…”

“…For example, insulin glargine's time-action profile has been characterised as being flat [7,8] and as waxing and waning with a maximum effect approximately 10 h after injection [9][10][11]. Also, in one head-to-head study in type 2 diabetic patients the two long-acting insulin analogues were found to be comparable [10], whereas another comparison in individuals with type 1 diabetes showed lower total activity and a shorter duration of action for insulin detemir [12].…”