Pharmacokinetics and Pharmacodynamics of the Long-Acting Insulin Analog Glargine After 1 Week of Use Compared With Its First Administration in Subjects With Type 1 Diabetes

Porcellati, Francesca; Rossetti, Paolo; Ricci, N; Pampanelli, S.; Torlone, Elisabetta; Campos, Susana Hernandez; Andreoli, Anna Marinelli; Bolli, Geremia B.; Fanelli, Carmine G.

doi:10.2337/dc06-2208

Cited by 56 publications

(46 citation statements)

References 14 publications

(17 reference statements)

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“…Few clinical trials (1,8,9) have used 24-h euglycemic clamp techniques to determine PK and PD parameters of insulin glargine in subjects with T1DM; there are no comparable clinical trials for ILPS in this population. Although the s.c. injected doses of glargine varied from 0.3 to 0.6 U/kg in previous clamp studies (1,8,9) and pre-clamp/clamp techniques and subject populations varied somewhat from the present study, the results for the PD and PK parameters determined were similar to those determined in this study, confirming the procedure and results presented here.…”

Section: Discussionmentioning

confidence: 99%

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

Ocheltree¹,

Hompesch²,

Wondmagegnehu³

et al. 2010

European Journal of Endocrinology

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Objective: The objective of the study was to evaluate pharmacodynamic (PD) intrasubject variability of a single, s.c. dose of insulin lispro protamine suspension (ILPS) compared with insulin glargine in subjects with type 1 diabetes mellitus and additionally, to compare the intrasubject variability of pharmacokinetic parameters of both insulins. Design: This was a single-center, investigator-blinded and subject-blinded, two-arm, parallel, randomized, four-period study. During the replicate visits, subjects received a single s.c. 0.6 U/kg dose of either ILPS or glargine, and underwent 24-h euglycemic glucose clamps. Results: The intrasubject variabilities of the primary PD parameters, total amount of glucose infused (G tot ) and maximum glucose infusion rate (GIR; R max ), were statistically significantly lower for ILPS when compared with glargine (P!0.0001). Least-square (LS) mean estimates for G tot and R max were 2512.7 mg/kg and 3.740 mg/min per kg respectively for ILPS, and 1291.9 mg/kg and 1.793 mg/min per kg respectively for glargine. The LS mean estimates for G tot and R max were statistically greater (PZ0.0010 and P!0.0001 respectively) for ILPS compared with glargine, suggesting that ILPS had greater 24-h glucose-lowering activity. Glargine demonstrated a flatter GIR-time curve, and ILPS demonstrated a significantly shorter time of maximum GIR (tR max ) and earlier time to half-maximal GIR before tR max and time to half-maximal GIR after tR max . ILPS administration resulted in significantly greater exposure compared with glargine (area under the baseline-corrected serum concentration versus time curve from time 0 to 24 h (AUC 0-24 ): 77 150 vs 53 111 pmol min/l; maximum serum insulin concentration (C max ): 119 vs 68 pmol/l; ILPS versus glargine respectively), but the intrasubject variabilities for AUC and C max were comparable. Conclusion: Although glargine demonstrated a flatter GIR-time profile, the lower PD intrasubject variability of ILPS may provide a more predictable response.

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Section: Discussionmentioning

confidence: 99%

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

Ocheltree¹,

Hompesch²,

Wondmagegnehu³

et al. 2010

European Journal of Endocrinology

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“…[34][35][36][37][38] Duration of action is most reliably measured through euglycemic clamp studies in patients with type 1 diabetes, rather than in healthy subjects or those with type 2 diabetes, because of the confounding influence of endogenous insulin secretion. 39 Studies of this nature with insulin glargine have reported a duration of action of 20 to 24 hours after single dose administration 35,36,40 and 24 to 25.6 hours at steady-state. 40 The slight increase in duration of action at steady state may suggest an accumulation of insulin glargine after multiple doses, although a previous multiple-dose study reported no evidence of accumulation after 12 days of dosing.…”

Section: Rapid-acting Analogsmentioning

confidence: 99%

“…39 Studies of this nature with insulin glargine have reported a duration of action of 20 to 24 hours after single dose administration 35,36,40 and 24 to 25.6 hours at steady-state. 40 The slight increase in duration of action at steady state may suggest an accumulation of insulin glargine after multiple doses, although a previous multiple-dose study reported no evidence of accumulation after 12 days of dosing. 41 Compared with NPH insulin, insulin glargine is characterized by a smoother, relatively flat, GIR curve ( figure 2).…”

Section: Rapid-acting Analogsmentioning

confidence: 99%

Insulin Analogs: Impact on Treatment Success, Satisfaction, Quality of Life, and Adherence

Hartman

2008

Clinical Medicine & Research

115

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Despi te 85 years of research since Banting and Best's isolation of insulin-containing extracts, 1 diabetes still remains one of the most significant causes of morbidity and mortality in the world, and its global impact is likely to accelerate over the coming decades. 2,3 Much of the medical and economic consequences of diabetes are attributable to its associated microvascular and macrovascular complications. [4][5][6] Two classic large-scale clinical studies, the Diabetes Control and Complications Trial (DCCT) 6 and the UK Prospective Diabetes Study (UKPDS), 7 demonstrated that intensive blood-glucose control policies can decrease the frequency of complications, arguing that physicians and patients should strive to mimic, as closely as possible, the serum levels of insulin produced by a healthy person. Secretion of insulin by the pancreas, however, is under complex regulation that depends on the intake of nutrients, other gastrointestinal peptides (e.g., incretins), and overall metabolic levels (i.e., exercise versus rest). 8 These physiological variables, which pose real challenges to the accurate metabolic replacement of insulin, are further complicated by the fact that diabetes requires self-management and therefore depends on the psychology, motivation, and understanding of the patient. A growing body of medical research has demonstrated that intensive control of serum glucose levels can minimize the development of diabetes-related complications. Success with insulin management ultimately depends on how closely a given regimen can mimic normal physiologic insulin release patterns.The new insulin analogs, including the rapid-acting analogs (aspart, lispro, glulisine), the long-acting basal analogs (glargine, detemir), and the premixed insulin analog formulations (75% neutral protamine lispro, 25% lispro; 50% neutral protamine lispro, 50% lispro; 70% protamine aspart, 30% aspart) have been formulated to allow for a closer replication of a normal insulin profile.The rapid-acting analogs can be administered at mealtimes and produce a rapid and short-lived insulin spike to address postprandial glucose elevations, while the long-acting analogs come close to the ideal of a smooth, relatively flat, 24-hour basal insulin supply, with less variability in action compared to NPH insulin. Despite these clear pharmacologic advantages, measurable clinical benefits in a complex disease such as diabetes can be hard to measure.To date, reviews of insulin analog studies have not found a dramatic overall improvement in glycosylated hemoglobin (HbA1c) outcomes compared to traditional human insulins, although all-analog basal-bolus regimens were associated with significantly lower HbA1c than all-human-insulin basal bolus regimens in some studies. Beyond HbA1c comparisons, however, insulin analogs have been shown in many instances to be associated with lower risks of hypoglycemia, lower levels of postprandial glucose excursions, better patient adherence, greater quality of life, and higher satisfaction with treatment.The long-act...

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“…after several days of s.c. administration of study insulin [12,18]. Obviously, for long-acting insulin preparations with a duration of action over 24 h, it is especially important to study steady-state time-action profiles as well.…”

Section: Which Insulin Dose?mentioning

confidence: 99%

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

2008

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Glucose clamp studies assessing the time-action profile of long-acting insulin analogues have reported conflicting results. In an attempt to reconcile the data, we organised an expert meeting of four leading European clamp groups, during which consensus was reached on some but not all points discussed. In this paper, which reflects our personal views only, we aim to provide guidance for readers and reviewers on the interpretation of this type of clamp study and to clarify its inherent limitations.Glucose clamp studies are either performed manually or using an automated procedure, but differences in clamp methodology hardly seem a satisfactory explanation for the conflicting results. (Un)conscious investigator-related bias, especially during manual studies, cannot be ruled out, despite attempts at blinding the study insulin during the clamp.The duration of action of study insulins is influenced by many factors, such as glucose and insulin levels prior to injection, endogenous insulin secretion, insulin dose, definitions used for onset and end of action, and insulin sensitivity (which is influenced by the necessity of fasting during the clamp). These factors limit the translation of clamp study results into daily practice.Because of the inherent limitations of the glucose clamp technique and the lack of reproducibility of the outcomes, its results should be regarded as no more than an indication of the clinical action profile of long-acting insulin preparations.

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Pharmacokinetics and Pharmacodynamics of the Long-Acting Insulin Analog Glargine After 1 Week of Use Compared With Its First Administration in Subjects With Type 1 Diabetes

Cited by 56 publications

References 14 publications

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

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

Insulin Analogs: Impact on Treatment Success, Satisfaction, Quality of Life, and Adherence

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

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