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International journal of endocrinology 7 (71) 2015

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Insulin Toujeo® — a Novel Basal Long-Acting Insulin Formulation Part 1. Pharmacokinetic and Pharmacodynamic Aspects

Authors: Poltorak V.V., Kravchun N.A. - State Institution «Institute of Problems of Endocrine Pathology named after V.Ya. Danylevskyi of National Academy of Medical Sciences of Ukraine», Kharkiv; Gorshunska M.Yu. - Kharkiv Medical Academy of Postgraduate Education, Kharkiv, Ukraine

Categories: Endocrinology

Sections: Specialist manual

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Summary

В данном обзоре, состоящем из двух частей, рассматривается новая формула инсулина гларгин (рДНК происхождения) в форме инъекций 300 ЕД/мл (Gla-300, Тожео). Gla-300 представляет следующую генерацию базального инсулина с новой формулой инсулина гларгин, поставляющего то же количество инсулина, что и гларгин-100 (Gla-100, Лантус®) в 1/3 объема. После подкожной инъекции фармакокинетический и фармакодинамический профили Gla-300 являются более постоянными и продолжительными (более 24 часов) по сравнению с Gla-100, что обусловлено более постепенным и длительным выделением гларгина из подкожного депо (Gla-300 образует более компактное подкожное депо с уменьшенной поверхностью по сравнению с Gla-100). С акцентом на недавних результатах клинических исследований EDITION (3а-фаза) обсуждается клиническая эффективность и безопасность Gla-300 у больных сахарным диабетом 1-го и 2-го типа. Gla-300 демонстрировал сопоставимый гликемическиий контроль и подобный профиль безопасности при условиях более низкой частоты гипогликемических событий по сравнению с Gla-100. Gla-300 обеспечивал гибкий режим введения инсулина (24 ± 3 часа или утром vs вечером) и был ассоциирован с меньшим увеличением массы тела.

В цьому огляді, що складається з двох частин, розглядається нова формула інсуліну гларгін (рДНК походження) у формі ін’єкцій 300 ОД/мл (Gla-300, Тожео). Gla-300 являє собою наступну генерацію базального інсуліну з новою формулою інсуліну гларгін, що поставляє ту ж кількість інсуліну, як і гларгін-100 (Gla-100, Лантус®) в 1/3 об’єму. Після підшкірної ін’єкції фармакокінетичний та фармакодинамічний профілі Gla-300 є більш постійними та тривалими (більше ніж 24 години) порівняно з Gla-100, що пов’язано з більш поступовим та тривалим виділенням гларгіну із підшкірного депо (Gla-300 утворює більш компактне підшкірне депо зі зменшеною поверхнею порівняно з Gla-100). З акцентом на недавніх результатах клінічних досліджень EDITION (3а-фаза) обговорюється клінічна ефективність та безпечність Gla-300 у хворих на цукровий діабет 1-го та 2-го типу. Gla-300 демонстрував порівнянний глікемічний контроль та подібний профіль безпечності за умов більш низької частоти гіпоглікемічних подій порівняно з Gla-100. Gla-300 забезпечував гнучкий режим введення інсуліну (24 ± 3 години або ранком vs вечером) та був асоційований iз меншим збільшенням ваги.

This review, consisting of two parts, considers a new formulation of insulin glargine (rDNA origin) in the form of injections 300 U/ml (Gla-300, Toujeo®). Gla-300 is a next generation basal insulin with a novel formulation of insulin glargin delivering the same amount of insulin, as glargine-100 (Gla-100, Lantus®) in 1/3 volume. Following the subcutaneous injection, pharmacokinetic and pharmacodynamic profiles of Gla-300 are more constant and prolonged (beyond 24 hours) compared with Gla-100 due to a more gradual and extended release of glargine from subcutaneous depot (Gla-300 forms a more compact subcutaneous depot with reduced surface area compared to Gla-100). The clinical efficacy and safety of Gla-300 in patients with type 1 and type 2 diabetes mellitus are discussed with an emphasis on recently released data from EDITION (the phase 3a) clinical trials. Gla-300 showed comparable glycaemic control and similar safety profile with lower incidence of hypoglycaemia events compared with Gla-100. Gla-300 provided flexible dosing of insulin (24 ± 3 h or morning vs evening) and was associated with less body weight gain.


Keywords

сахарный диабет, гликированный гемоглобин, гипогликемия, гларгин, инсулин, ­Gla-100 (Лантус®), Gla-300 (Тожео).

цукровий діабет, глікований гемоглобін, гіпоглікемія, гларгін, інсулін, Gla-100 (Лантус®), Gla-300 (Тожео).

diabetes mellitus, glycated hemoglobin, hypoglycaemia, glargine, insulin, Gla-100 (Lantus®), Gla-300 (Toujeo®).

Summary.  Тhe focus of this review is insulin glargine [rDNA origin] injection 300 U/ml (Gla-300, Toujeo®).  Gla-300 is a next generation basal insulin with a novel formulation of insulin glargin delivering the same amount [as glargine-100, Gla-100, Lantus®] in 1/3 volume. Following the SC injection pharmacokinetic and pharmacodynamic profiles of Gla-300 are more constant and prolonged (beyond 24 hours) compared with Gla-100 due to a more gradual and extended release of glargine from SC depot (Gla-300 forms a more compact subcutaneous depot with a reduce surface area compare with Gla-100). The clinical efficacy and safety of Gla-300 in people with type 1 and type 2 diabetes mellitus are discussed with an emphasis on recently released data from the phase 3a EDITION clinical trials. Gla-300 exhibits  comparable glycaemic control and similar safety profile with lower incidence of hypoglycaemia events [compared with Gla-100]. Gla-300 provides flexible dosing (24 h±3 h or morning vs evening) and associated with less body weight gain.

Тhe focus of this review, consisting of two parts, is insulin glargine [rDNA origin] injection 300 U/ml (Gla-300, Toujeo®).  Gla-300 is a next generation basal insulin with a novel formulation of insulin glargin delivering the same amount [as glargine-100, Gla-100, Lantus®] in 1/3 volume.

Toujeo® (Gla-300) is an investigational basal insulin, which has the potential to provide as effective blood sugar control as Lantus® with better tolerated titration-to-target by reducing low blood sugar events (hypoglycaemia), particularly during the first 8-week initiation phase (post hoc analysis)  and possible 3-hour flexibility in dosing regimen. Pharmacokinetic and pharmacodynamic studies have demonstrated a smoother and more prolonged profile for Gla-300 compared with Lantus®, which is expected to lead to effective blood sugar control that lasts beyond 24 hours, with a favorable safety profile and low within-individual, within-day blood sugar variability. Toujeo® demonstrated lower glucose variability compared with Lantus® in people with type 1 diabetes. By comparing morning and evening injections using 24-hour continuous glucose monitoring, Toujeo® demonstrated comparable overall blood sugar control compared with Lantus®, but with a more constant 24-hour blood sugar profile.

The EDITION program is a worldwide and extensive series of six Phase 3a studies demonstrating the efficacy and safety of Gla-300 in broad and diverse populations of people with diabetes. The EDITION program included over 3,500 people with diabetes who were uncontrolled on their current therapy; all studies met their primary endpoints by demonstrating Gla-300 can provide comparable glycemic control (measured by HbA1C reduction) compared with Lantus® in various type 1 and type 2 diabetes populations: people with type 2 diabetes who were uncontrolled on basal plus mealtime insulin or basal insulin plus oral glucose-lowering agents – clinically challenging population (EDITION 1 - basal plus mealtime insulin, n=807; EDITION 2 - basal insulin plus oral glucose-lowering agents, n=811); people with type 2 diabetes who were uncontrolled on anti-diabetic therapies other than insulin (basal insulin initiation) (EDITION 3, n=878); type 1 diabetes patients (EDITION 4, n=549); Japanese diabetes population (EDITION JP 1, type 1 diabetes, n=243; EDITION JP 2, type 2 diabetes, n=240).

In people with type 2 diabetes, EDITION 1 and 2 demonstrated significantly fewer patients experienced severe or confirmed night-time low blood sugar hypoglycaemia from week 9 to month 6 (EDITION 1: 21% fewer patients, p=0.0045; EDITION 2: 23% fewer patients, p=0.038). EDITION 3 included people with less severely progressed type 2 diabetes and showed significantly fewer people who were new to insulin therapy experienced low blood sugar events during the night over the study period (post-hoc analysis), when treated with Gla-300, compared with Lantus® (relative risk reduction of 24%).

In a pooled analysis of EDITION 1, 2, 3 Gla-300 consistently showed significantly fewer hypoglycaemic events at any time of day, including night-time events, compared with Lantus® across studies and differing type 2 patient populations (rate ratio [per participant-year] reduced by 14%; p=0.0116), particularly during the first 8-week titration phase (when comparing -23% at any time of the day and -42% during the night). Documented symptomatic low blood sugar events were also reduced at any time of day (-12%) and during the night (-25%). In Japanese people with type 2 diabetes uncontrolled on basal insulin and oral anti-diabetics (EDITION JP 2), incidence of hypoglycaemia at night-time was also reduced, with 38% fewer patients experiencing ≥1 event over the 6-month study period.

EDITION 4, an international study of people with type 1 diabetes, showed that those randomized to Gla-300 showed similar night-time and any-time of the day low blood sugar event rates compared with Lantus®. But EDITION 4 indicated a 31% relative risk reduction (significant; per participant-year) in confirmed or severe night-time low blood sugar events in the first 8 weeks (post-hoc analysis) for Gla-300 vs. Lantus®. EDITION 4 also demonstrated neither glycemic control nor hypoglycaemia events differed between morning and evening Gla-300 injection groups, as well as at least comparable efficacy and safety. In a study including only Japanese people with type 1 diabetes (EDITION JP 1-basal plus mealtime insulin), night-time low blood sugar event rates were 15% lower with Gla-300 as compared to Lantus® over the 6-month study period. In EDITION JP 1, 29% fewer patients experienced night-time low blood sugar with Gla-300 compared with Lantus® during the first 8 weeks of treatment (post-hoc analysis).

In all EDITION studies, Gla-300 demonstrated weight neutrality (less than 1 kg gain). Furthermore, in EDITION 2, 4 and JP 1, weight gain was significantly less with Gla-300 treatment compared with Lantus® treatment. In EDITION JP 2, the patients treated with Gla-300 lost weight, compared with a slight increase in the Lantus® group (-0.6 kg vs. 0.4 kg respectively).


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