Type 2 diabetes mellitus in adults: high-strength insulin glargine 300 units/ml (Toujeo)

Drug action

Insulin glargine is a human insulin analogue. Toujeo is a high‑strength insulin glargine product containing 300 units/ml solution for injection in a pre‑filled pen (Toujeo summary of product characteristics). It is a basal insulin for once‑daily use.

Insulin glargine has the same metabolism after subcutaneous injection regardless of its source. The difference between insulin glargine 300 units/ml (Toujeo) and insulin glargine 100 units/ml comes only from the pharmacokinetic and pharmacodynamic profiles of the 2 formulations. Toujeo has a flatter and more prolonged (up to 36 hours) profile of insulin concentration and glucose lowering activity compared with Lantus at the same doses (European public assessment report [EPAR] for Toujeo).

Toujeo is not bioequivalent to Lantus and dose adjustment is needed when patients are switched from Lantus or other basal insulins to Toujeo or vice versa (MHRA Drug Safety Update April 2015).

Licensed therapeutic indication

Insulin glargine 300 units/ml (Toujeo) is licensed for the treatment of diabetes mellitus in adults. In type 1 diabetes mellitus, it must be combined with short or rapid‑acting insulin to cover mealtime insulin requirements. In people with type 2 diabetes mellitus, it can also be given together with other anti‑hyperglycaemic medicinal products. This evidence summary covers the use of insulin glargine 300 units/ml in adults with type 2 diabetes. Another evidence summary covers its use in adults with type 1 diabetes.

Course and cost

Insulin glargine 300 units/ml (Toujeo) is a basal insulin for once‑daily administration at any time of the day, preferably at the same time every day. When needed, people can administer Toujeo up to 3 hours before or after their usual time of administration. It is administered subcutaneously by injection (Toujeo summary of product characteristics).

In adults with type 1 diabetes, Toujeo is used once‑daily with meal‑time insulin and requires individual dose adjustments. In adults with type 2 diabetes, the recommended daily starting dose is 0.2 units/kg followed by individual dose adjustments.

The potency of Toujeo is stated in units. These units are exclusive to Toujeo and are not the same as IU or the units used to express the potency of other insulin analogues (Toujeo summary of product characteristics). Toujeo is not bioequivalent to Lantus and dose adjustment is needed when patients are switched from Lantus or other basal insulins to Toujeo or vice versa (MHRA Drug Safety Update April 2015). Dose conversion instructions are given in the Toujeo guidance for healthcare professionals, and are summarised below.

Switch from insulin glargine 100 units/ml to Toujeo

Switch from other basal insulins to Toujeo

When switching from a treatment regimen with an intermediate or long‑acting insulin product to a regimen with Toujeo, a change of the dose of the basal insulin may be required and the concomitant anti‑hyperglycaemic treatment may need to be adjusted.

Switch from Toujeo to insulin glargine 100 units/ml or other basal insulin products

Close metabolic monitoring is required during any switch and in the initial weeks thereafter.

Toujeo is available in a pack containing 3 pens. Each pen contains 1.5 ml of insulin glargine 300 units/ml solution for injection, equivalent to 450 units. A dose of 1 to 80 units per injection, in steps of 1 unit, can be injected. The dose window shows the number of Toujeo units to be injected. The cost of a pack of 3 pens is £33.13 (excluding VAT; MIMS November 2015).

EDITION 1 (Riddle et al. 2014)

EDITION 2 (Yki-Jarvinen et al. 2014)

EDITION 3 (Bolli et al. 2015)

Clinical effectiveness

In EDITION 1 (n=807), EDITION 2 (n=811) and EDITION 3 (n=878), once‑daily insulin glargine 300 units/ml (Toujeo) was non‑inferior to once‑daily insulin glargine 100 units/ml (Lantus) in adults with type 2 diabetes. A similar reduction in HbA1c from baseline to month 6 was seen in both treatment groups in each study. In EDITION 1 the difference between groups was 0.00% [0.00 mmol/mol], 95% confidence interval [CI] −0.11 to 0.11% [−1.2 to 1.2 mmol/mol] in people who were already using basal and mealtime insulin at baseline. In EDITION 2 the difference was −0.01% [0.1 mmol/mol], 95% CI −0.14 to 0.12% [−1.5 to 1.3 mmol/mol] in people who were using oral blood glucose lowering drugs and basal insulin at baseline. In EDITION 3, in people who were insulin‑naive at baseline, the difference was 0.04% [0.4 mmol/mol], 95% CI −0.09 to 0.17% [−1.0 to 1.9 mmol/mol]. In a post‑hoc patient‑level meta‑analysis of EDITION 1, EDITION 2 and EDITION 3 (n=2496; Ritzel et al 2015) the reduction in HbA1c from baseline to month 6 was 1.02% [11.1 mmol/mol] in both groups (difference 0.00%, 95% CI −0.08 to 0.07% [0.00 mmol/mol, 95% CI −0.9 to 0.8 mmol/mol]). These differences were all below the pre‑specified non‑inferiority margin of 0.4%. A similar proportion of participants in both treatment groups in each trial also achieved HbA1c below 7.0% (53 mmol/mol) at month 6 (see tables 1, 2 and 3 for details).

The main secondary end point in all 3 RCTs was the percentage of participants experiencing at least 1 confirmed or severe nocturnal hypoglycaemic event between week 9 and month 6. This was statistically significantly lower with Toujeo compared with Lantus in EDITION 1 and EDITION 2, but not in EDITION 3. In EDITION 1 the percentages were 36% with Toujeo and 46% with Lantus (relative risk [RR] 0.79; 95% CI 0.67 to 0.93, p=0.0045); in EDITION 2 they were 22% with Toujeo and 28% with Lantus (RR 0.77; 95% CI 0.61 to 0.99, p=0.038); and in EDITION 3 they were 16% with Toujeo and 17% with Lantus (RR 0.89; 95% CI 0.66 to 1.20, p=0.4536). Severe nocturnal hypoglycaemic events were rare in all 3 RCTs and too few for meaningful analysis.

In the post‑hoc meta‑analysis of EDITION 1, EDITION 2 and EDITION 3 (Ritzel et al 2015), the annualised rates of confirmed or severe nocturnal events over the 6‑month study period were 31% lower with Toujeo compared with Lantus (2.10 events per participant‑year with Toujeo and 3.06 events per participant‑year with Lantus; RR 0.69, 95% CI 0.57 to 0.84, p=0.0002). This is a reduction of approximately 1 confirmed or severe nocturnal event per person per year, which is of debatable clinical significance. Severe hypoglycaemia was rare in both groups in all 3 RCTs. In the post‑hoc meta‑analysis, the percentage of participants with at least 1 severe event at any time of day was 2.3% with Toujeo and 2.6% with Lantus; not statistically significantly different (RR 0.85, 95% CI 0.52 to 1.39). There were 0.11 severe events per participant‑year in both groups (Ritzel et al 2015).

In all 3 RCTs, more hypoglycaemic events occurred during the day rather than at night. For hypoglycaemia at any time of day or night, the relative risk of at least 1 confirmed or severe hypoglycaemic event per participant from week 9 to month 6 was not statistically significantly different with Toujeo compared with Lantus in any of the trials (EDITION 1: RR 0.96, 95% CI 0.89 to 1.04; EDITION 2: RR 0.91, 95% CI 0.82 to 1.02; EDITION 3: RR 0.86, 95% CI 0.74 to 1.00). However, in the post‑hoc patient‑level meta‑analysis of EDITION 1, 2 and 3 (Ritzel et al 2015), the annualised rates of confirmed or severe hypoglycaemia at any time of day or night over the 6‑month study period were 14% lower with Toujeo compared with Lantus (15.22 events per participant‑year with Toujeo and 17.73 events per participant‑year with Lantus; RR 0.86, 95% CI 0.77 to 0.97, p=0.0116). When analysed by study period, the meta‑analysis also showed that reductions in hypoglycaemic events with Toujeo compared with Lantus were apparent during the first 8 weeks of treatment as well as during the maintenance period of week 9 to month 6.At 6 months the basal insulin dose was higher with Toujeo than with Lantus in all 3 RCTs. In EDITION 1, the Toujeo dose at 6 months was 0.97 units/kg/day and the Lantus dose was 0.88 units/kg/day; 10% higher with Toujeo. In EDITION 2, the Toujeo dose at 6 months was 0.92 units/kg/day and the Lantus dose was 0.84 units/kg/day; 10% higher with Toujeo. In EDITION 3, the Toujeo dose was 0.62 units/kg/day and the Lantus dose was 0.53 units/kg/day; 17% higher with Toujeo. In the meta‑analysis (Ritzel et al 2015), the mean basal insulin dose at month 6 was 0.85 units/kg/day with Toujeo and 0.76 units/kg/day with Lantus, a 12% higher dose with Toujeo.

There were no differences in any participant‑reported outcomes between the Toujeo and Lantus groups.

Twelve‑month results from EDITION 1 (Riddle et al 2015) in adults with type 2 diabetes using basal and mealtime insulin and EDITION 2 (Yki-Järvinen H et al. 2015) in adults with type 2 diabetes using oral blood glucose lowering drugs and basal insulin have now been published. In both trials, glycaemic control was sustained with Toujeo, as were the benefits of Toujeo over Lantus in the percentage of people experiencing nocturnal hypoglycaemia.

Safety and tolerability

In a post‑hoc patient‑level meta‑analysis of EDITION 1, EDITION 2 and EDITION 3 (n=2496; Ritzel et al 2015), no differences in the safety profile of Toujeo and Lantus were seen. Treatment‑emergent adverse events were reported by 712 (57.3%) people in the Toujeo group and 669 (53.7%) people in the Lantus group, with 65 (5.2%) and 62 (5.0%) people reporting serious events respectively. Similar numbers of participants reported injection site reactions (2.4% with Toujeo and 3.1% with Lantus), and similar numbers withdrew because of adverse events (1.4% with Toujeo and 1.3% with Lantus). Deaths occurred in 4 people in the Toujeo group and 3 people in the Lantus group, but none of these were considered to be related to study treatment. Body weight increased with both Toujeo and Lantus, but at month 6 the mean increase was smaller with Toujeo (0.51 kg) than with Lantus (0.79 kg; p=0.039). In EDITION 1, body weight increased by 0.9 kg in both groups at month 6. In EDITION 2, the weight gain at 6 months was 0.08 kg with Toujeo and 0.66 kg with Lantus (p=0.015), and in EDITION 3 it was 0.49 kg with Toujeo and 0.71 kg with Lantus (no statistically significant difference). Further safety data from the individual RCTs are given in tables 1, 2 and 3.

In the European public assessment report (EPAR) for Toujeo, all people from phase 1, 2 or 3 studies who were randomised and received at least 1 dose of Toujeo were evaluated for safety. This includes people with type 1 and type 2 diabetes, and some people who were treated for at least 1 year. Across all studies (n=1546 for Toujeo and n=1550 for Lantus) the number and overall pattern of adverse events were comparable between treatment groups. The most frequent adverse events were nasopharyngitis (8.2% with Toujeo, 6.8% with Lantus) and upper respiratory tract infection (6.5% with Toujeo, 5.8% with Lantus). Most of the adverse events were mild to moderate in intensity. Events of severe intensity were reported in 5.1% of the Toujeo group and 4.1% of the Lantus group, with the most frequent in both groups being hypoglycaemia (0.5% with Toujeo and 0.8% with Lantus).

The EPAR reports that the safety profile of Toujeo is largely similar to that of Lantus and no additional safety signals were detected for Toujeo with regard to injection site reactions, hypersensitivity reactions, malignancy, hepatic safety or cardiovascular safety. However, the Toujeo clinical development programme was not designed specifically to address cardiovascular risk because this has been established for Lantus. The percentage of people with any major cardiovascular event was low and comparable with Toujeo and Lantus.

An important risk with high‑strength insulin glargine 300 units/ml (Toujeo) is possible medication errors with other insulins of lower strengths. The European Medicines Agency has recently consulted on guidance to minimise the potential risk of medication errors associated with the availability of high‑strength insulins and fixed combinations of insulin with another non‑insulin injectable blood glucose lowering agent (MHRA Drug Safety Update April 2015).

The MHRA advice in Drug Safety Update April 2015 is that before starting treatment with a high strength, fixed combination or biosimilar insulin product, healthcare professionals should:

Patients should monitor glucose levels closely after starting a new treatment and in the following weeks. They may need to adjust doses and timing of concurrent rapid‑acting or short‑acting insulin products and other antidiabetic treatments.

The Toujeo guidance for healthcare professionals recommends that the trade name and concentration (Toujeo SoloStar 300 units/ml) must be written on each prescription for Toujeo, along with the recommended dose in units. The dose window of the Toujeo SoloStar pen shows the number of units of Toujeo to be injected. The guidance advises patients that Toujeo is not bioequivalent and not interchangeable with any other basal insulin including insulin glargine 100 units/ml, without individualised dose adjustment. Blood glucose monitoring is needed during the switch and the initial weeks thereafter. Toujeo guidance for patients and carers is also available.

Evidence strengths and limitations

There are several limitations with EDITION 1, EDITION 2 and EDITION 3, which the authors discuss. The trials were all open‑label because Toujeo and Lantus are different pen injectors. This could lead to technology bias in favour of the new insulin or familiarity bias in favour of the comparator. There is also a concern over possible confounding by adjustment of the prandial insulin dose in EDITION 1

In EDITION 1 and EDITION 2, participants were required to have current basal insulin treatment of 42 units/day or more, and these results may not be generalisable to people with lower basal insulin requirements. Although EDITION 3 was conducted in people who were insulin‑naive at baseline.

More hypoglycaemia events in EDITION 1, 2 and 3 occurred during the day rather than at night. These could have been related to prandial rather than basal insulin in EDITION 1. However, the prolonged action of Toujeo may have caused a relative shift of long‑acting insulin action from night to day. The EPAR states that for Toujeo, nocturnal hypoglycaemia events were somewhat lower and daytime hypoglycaemia events were higher in some categories, especially in combination with mealtime insulin. However, most differences were small and mealtime insulin in combination with basal insulin contributes significantly to the increase in the number of daytime hypoglycaemia events.

The baseline characteristics were largely similar between groups in EDITION 1, 2 and 3. In all 3 RCTs, mean BMI was high (in EDITION 1 it was 36.6 kg/m², in EDITION 2 it was 34.8 kg/m² and in EDITION 3 it was 33.0 kg/m²) and results may not be generalisable to people with a lower BMI. Discontinuation of treatment insulin before 6 months was 7% in the Toujeo group and 8% in the Lantus group in EDITION 1, 9% in both groups in EDITION 2, and 14% in the Toujeo group and 17% in the Lantus group in EDITION 3.

EDITION 1, 2 and 3 were designed to demonstrate non‑inferiority of Toujeo to Lantus using a pre‑specified non‑inferiority margin of 0.4% [4.4 mmol/mol]. The EPAR states that although a margin of 0.4% is considered too wide, the actual upper limits (0.11%, 0.12% and 0.17%) were well below the more desired margin of 0.3%. End points were analysed in the modified intention to treat population using an ANCOVA model or a mixed model for repeated measurements (MMRM) approach. There are no data reported in the published papers or the EPAR for the per‑protocol population, which would be usual for a non‑inferiority study.

The primary end point of EDITION 1, 2 and 3, which were conducted in 2496 adults with type 2 diabetes, was an HbA1c end point at 6 months. Extension studies to 12 months have been completed, and published for EDITION 1 and EDITION 2. There are very limited patient‑oriented outcome data on macrovascular or microvascular outcomes with Toujeo, or on the long‑term safety of this particular formulation. However, the Toujeo summary of product characteristics includes reference to long‑term studies with insulin glargine 100 units/ml (Lantus), such as the Early Treatment Diabetic Retinopathy Study (ETDRS) and the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial.

Alternative treatments

Basal insulin supply for adults with type 2 diabetes can be provided by:

Costs of alternative treatments

Toujeo (insulin glargine 300 units/ml) is the third insulin to be approved in Europe at a higher strength than the European Union‑wide standard of 100 units/ml. Insulin degludec (Tresiba) and insulin lispro (Humalog) are already available as 200 units/ml strength.

The cost of Toujeo and other basal insulins will depend on the preparation chosen and the insulin dosage used.

Likely place in therapy

Toujeo is a high‑strength insulin glargine product containing 300 units/ml solution for injection in a pre‑filled pen (Toujeo Summary of Product Characteristics). It is a basal insulin for once‑daily use for the treatment of diabetes mellitus in adults. In people with type 2 diabetes mellitus, it can be given together with other anti‑hyperglycaemic medicinal products.

High strength insulin products have been developed for people with large daily insulin requirements to reduce the number and volume of injections (MHRA Drug Safety Update April 2015). Specialists involved in the production of this publication have suggested that certain people with type 2 diabetes who are insulin resistant use very high basal insulin doses. Due to the higher concentration of insulin, the volume to be injected is smaller, which may be less painful for people injecting large volumes. However, there was no information on injection site pain with Toujeo compared with Lantus in the Toujeo study programme. In the main phase 3 studies of Toujeo in type 2 diabetes, similar numbers of people reported injection site reactions in both groups (2.4% with Toujeo and 3.1% with Lantus).

The EPAR states that the reduction in injection volume could be of importance especially for people who require large amounts of insulin. However, the limitation to 80 units per injection may mean that some people still need more than 1 injection, to some extent negating the most obvious advantage of Toujeo (European public assessment report [EPAR] for Toujeo). Injection volumes aren't given in EDITION 1, 2 or 3. However, based on the mean insulin dose at 6 months (Ritzel et al 2015), for a 90 kg adult, these are calculated to be 77 units in 0.3 ml for Toujeo and 68 units in 0.8 ml for Lantus. Specialists involved in the production of this evidence summary have suggested that single injections containing up to 60 units of standard strength insulin (0.6 ml for Lantus) are usually well tolerated; above this more than 1 injection is advised.

The phase 3 studies of Toujeo in adults with type 2 diabetes (EDITION 1, EDITION 2 and EDITION 3) were designed to demonstrate that insulin glargine 300 units/ml (Toujeo) is non‑inferior to insulin glargine 100 units/ml (Lantus) in terms of HbA1c reduction and, based on its pharmacodynamic and pharmacokinetic profiles, is associated with a lower risk of hypoglycaemia. All the EDITION studies in people with type 2 diabetes showed that Toujeo had similar efficacy to Lantus, and 2 of the 3 found that there was a statistically significant reduction in confirmed or severe nocturnal hypoglycaemia with Toujeo compared with Lantus. In a post‑hoc meta‑analysis (Ritzel et al 2015), the absolute reduction in these nocturnal hypoglycaemic events was about 1 event per person per year (2.10 events per participant‑year with Toujeo and 3.06 events per participant‑year with Lantus; RR 0.69, 95% CI 0.57 to 0.84, p=0.0002). Severe hypoglycaemic events at any time of day were rare and not statistically significantly different between groups. The EPAR states that the more gradual glucose lowering effect of Toujeo compared with Lantus did not translate into important advantages, and the higher use of basal insulin may be a disadvantage. In order to obtain a similar effect on HbA1c, on average 12% higher doses of Toujeo than Lantus were used in people with type 2 diabetes.

Toujeo (insulin glargine 300 units/ml) is the third insulin to be approved in Europe at a higher strength than the European Union‑wide standard of 100 units/ml. The European Medicines Agency has recently consulted on guidance to minimise the potential risk of medication errors associated with the availability of these high‑strength insulins (MHRA Drug Safety Update April 2015).

Toujeo is not simply interchangeable with other long‑acting insulins, including insulin glargine 100 units/ml. When switching between Toujeo and other basal insulins, different doses may be needed to achieve target ranges for plasma glucose levels, giving rise to a potential risk of medication error. This risk is addressed in advice given in the summary of product characteristics, and educational material for healthcare professionals and patients has been produced as an additional risk minimisation measure.

The updated NICE guideline on type 2 diabetes recommends that when insulin therapy is necessary, it should be started from a choice of a number of insulin types and regimens. NPH insulin injected once or twice daily according to need is the preferred option. Insulin detemir or insulin glargine can be considered as an alternative in certain circumstances (see the guideline for details). There are several insulin glargine products available including Lantus, the biosimilar Abasaglar or high‑strength Toujeo).

Estimated usage

The manufacturer estimates that the uptake of insulin glargine 300 units/ml (Toujeo) over the next 5 years for England will be as follows: 2015 (734 people), 2016 (9994 people), 2017 (27,900 people), 2018 (65,386 people), 2019 (80,948 people) and 2020 (90,581 people)

Expert advisers

Dr Paula Chattington, Consultant Physician, Warrington and Halton Hospitals NHS Foundation Trust

Dr Sutapa Ray, Consultant Diabetologist, Harrogate and District Foundation Trust

Dr Vinod Patel, Hon Consultant in Endocrinology and Diabetes, George Eliot Hospital NHS Trust, Nuneaton

Declarations of interest

Dr Paula Chattington: no relevant interests declared.

Dr Sutapa Ray: spoken at and attended meetings organised or sponsored by pharmaceutical companies.

Dr Vinod Patel: occasional lectures and educational events for all major pharmaceutical companies in the field of diabetes. Conference travel on average once or twice a year and occasional advisory board work.

Copyright

© National Institute for Health and Care Excellence, 2015. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not‑for‑profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.

ISBN: 978-1-4731-1570-5