Metabolism of Insulin Glargine After Repeated Daily Subcutaneous Injections in Subjects With Type 2 Diabetes

Lucidi, Paola; Porcellati, Francesca; Rossetti, Paolo; Candeloro, Paola; Andreoli, Anna Marinelli; Cioli, Patrizia; Hahn, Annke D.; Schmidt, Ronald; Bolli, Geremia B.; Fanelli, Carmine G.

doi:10.2337/dc12-0271

Cited by 44 publications

(59 citation statements)

References 10 publications

(17 reference statements)

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“…The results are consistent with previous observations at lower glargine doses (#0.8 units/kg) in which sampling at 12 h could still, in some cases, detect glargine (M0) in plasma (1,2). A previous study in T2D on high glargine doses failed to detect M0, but samples were determined only .6 years after storage of blood samples drawn and processed under unspecified conditions, likely not suitable to preserve M0 (5).…”

supporting

confidence: 81%

“…Epidemiological studies indicate that the risk of cancer is especially elevated in obese individuals with insulin-resistant diabetes requiring high insulin doses (4). Unmodified insulin glargine has been suggested to confer a higher risk of cancer (3), but prior studies have shown that, at usual doses, an active metabolite (M1) with actions similar to human insulin is the main circulating molecule after glargine injection (1,2).…”

mentioning

confidence: 99%

“…Glargine metabolism has been studied in insulin-treated people with type 2 diabetes (T2D) at usual glargine doses of 0.4-0.8 units/kg/day (1,2). In some obese subjects with insulin-resistant T2D, higher basal insulin doses are needed, and the question of safety of glargine (3) is therefore still relevant.…”

mentioning

confidence: 99%

“…The aim of the current study was to establish the plasma levels of insulin glargine (M0) and its metabolites M1 and M2 (1,2) in subjects with T2D treated long-term with glargine dose $1.2 units/kg/day.…”

mentioning

confidence: 99%

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Low Levels of Unmodified Insulin Glargine in Plasma of People With Type 2 Diabetes Requiring High Doses of Basal Insulin

Lucidi¹,

Porcellati²,

Yki‐Järvinen³

et al. 2015

Diabetes Care

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supporting

confidence: 81%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Low Levels of Unmodified Insulin Glargine in Plasma of People With Type 2 Diabetes Requiring High Doses of Basal Insulin

Lucidi¹,

Porcellati²,

Yki‐Järvinen³

et al. 2015

Diabetes Care

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“…2). Lucidi et al (11) have reported that after injection, insulin glargine is rapidly and almost completely metabolized to M1 (21A-Gly-insulin) and that serum insulin concentrations measured by RIA closely correspond to circulating M1 concentrations. In all profiles, maximum concentrations of serum insulin were reached at 12 h (median), with serum insulin concentrations falling approximately twofold by 24 h postinjection.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Comparison of the Pharmacokinetics and Pharmacodynamics of LY2963016 Insulin Glargine and EU- and US-Approved Versions of Lantus Insulin Glargine in Healthy Subjects: Three Randomized Euglycemic Clamp Studies

et al. 2015

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OBJECTIVELY2963016 (LY IGlar) and Lantus (IGlar) are insulin glargine products manufactured by distinct processes but with identical amino acid sequences. Three studies evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) similarity of LY IGlar and the European Union-and US-approved versions of IGlar. RESEARCH DESIGN AND METHODSThese were three single-site, randomized, double-blind, two-treatment, fourperiod, crossover, euglycemic clamp studies. In each study, fasted healthy subjects received 0.5 units/kg s.c. doses of two different insulin glargine products on two occasions each, following a randomized sequence. A ‡7-day washout period separated the doses. Blood samples were collected predose and up to 24 h postdose to assess PK; PD was assessed by a euglycemic clamp lasting up to 24 h. RESULTSA total of 211 subjects participated in the three studies. The PK (area under the curve [AUC]; maximum observed concentration [C max ]) and PD (maximum glucose infusion rate [R max ]; total glucose infusion during the clamp [G tot ]) were similar between LY IGlar and IGlar, with the ratios of geometric means ranging from 0.90 to 0.95 for PK parameters and from 0.91 to 0.99 for PD parameters across studies. In all cases, the 90% CIs for the ratios of geometric means were completely contained in the prespecified acceptance limits of 0.80-1.25. Adverse events were similar between treatments. CONCLUSIONSThese studies demonstrated that the PK and PD properties of LY IGlar and IGlar were similar after single 0.5 units/kg s.c. doses in healthy subjects, contributing to the totality of evidence supporting similarity of these products.

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A Euglycemic Glucose Clamp Study to Evaluate the Bioavailability of LY2963016 Relative to Insulin Glargine in Healthy Chinese Subjects

Liu

Wang

et al. 2021

Clinical Pharm in Drug Dev

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Insulin glargine (IGlar) and LY2963016 (LY IGlar) are long-acting insulin analogs with identical primary amino acid sequences. We conducted a randomized, open-label, 2-treatment, 2-period, crossover study in healthy Chinese subjects to evaluate the relative bioavailability of LY IGlar to IGlar and pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of LY IGlar. Subjects (n = 58) were randomized to receive single subcutaneous doses (0.5 U/kg) of LY IGlar and IGlar with a ≥7-day washout period between study treatments. Serum was collected before and up to 24 hours after dosing to assess PK characteristics. PD characteristics were assessed by euglycemic clamp up to 24 hours after dosing. Linear mixed-effects models were used to fit the log-transformed primary PK (maximum observed concentration and area under the concentration-time curve from time 0 to 24 hours) and PD parameters (maximum glucose infusion rate and total amount of glucose infused during clamp period). The geometric least squares means ratios (90% confidence interval) of LY IGlar to IGlar for maximum observed concentration and area under the concentration-time curve from time 0 to 24 hours were 0.961 (0.887-1.04) and 0.941 (0.872-1.01), respectively. The geometric least squares means ratios (90% confidence interval) of LY IGlar to IGlar were 0.91 (0.85-0.98) for maximum glucose infusion rate and 0.89 (0.82-0.97) for total amount of glucose infused during clamp period. LY IGlar demonstrated similarity to IGlar in PK and PD characteristics following single-dose (0.5 U/kg) administration in healthy Chinese subjects.

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Metabolism of Insulin Glargine After Repeated Daily Subcutaneous Injections in Subjects With Type 2 Diabetes

Cited by 44 publications

References 10 publications

Low Levels of Unmodified Insulin Glargine in Plasma of People With Type 2 Diabetes Requiring High Doses of Basal Insulin

Low Levels of Unmodified Insulin Glargine in Plasma of People With Type 2 Diabetes Requiring High Doses of Basal Insulin

Comparison of the Pharmacokinetics and Pharmacodynamics of LY2963016 Insulin Glargine and EU- and US-Approved Versions of Lantus Insulin Glargine in Healthy Subjects: Three Randomized Euglycemic Clamp Studies

A Euglycemic Glucose Clamp Study to Evaluate the Bioavailability of LY2963016 Relative to Insulin Glargine in Healthy Chinese Subjects

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