Advice

Key points from the evidence

Key points from the evidence

The content of this evidence summary was up-to-date in December 2015. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

High-strength insulin products such as insulin glargine 300 units/ml (Toujeo) have been developed for people with type 1 or type 2 diabetes who have large daily insulin requirements to reduce the number and volume of injections. In 3 randomised controlled trials (RCTs) in 2496 adults with type 2 diabetes, Toujeo had similar efficacy to insulin glargine 100 units/ml (Lantus) in terms of HbA1c reduction. There was a statistically significant reduction in confirmed or severe nocturnal hypoglycaemia with Toujeo in 2 of the RCTs, but not in the third trial. Severe hypoglycaemic events were rare and not statistically significantly different between Toujeo and Lantus. The safety profile of Toujeo is largely similar to that of Lantus. Toujeo is not bioequivalent to Lantus and they are not interchangeable without dose adjustment. An evidence summary on Toujeo in type 1 diabetes has also been published.

Regulatory status: insulin glargine 300 units/ml (Toujeo) received a European marketing authorisation in April 2015. It was launched in the UK in August 2015.

Effectiveness

  • Once-daily Toujeo was non‑inferior to once‑daily Lantus in HbA1c reduction from baseline to month 6 (difference between groups 0.00% [0.00 mmol/mol], 95% confidence interval [CI] –0.08 to 0.07% [−0.9 to 0.8 mmol/mol]) in adults with type 2 diabetes (meta-analysis of 3 RCTs, n=2496).

  • The percentage of adults with confirmed or severe nocturnal hypoglycaemia was lower with Toujeo than with Lantus in 2 of the 3 RCTs (36% versus 46%, p=0.0045 and 22% versus 28%, p=0.038) but not in the third trial (16% versus 17%, not statistically significant).

  • At 6 months the basal insulin dose was approximately 12% higher with Toujeo than with Lantus (meta‑analysis of 3 RCTs, n=2496).

Safety

  • The safety profile of Toujeo is largely similar to that of Lantus. The most frequent adverse events are nasopharyngitis and upper respiratory tract infection; the most frequent severe adverse event is hypoglycaemia (European public assessment report [EPAR] for Toujeo).

  • In 3 RCTs (n=2496), similar numbers of participants reported injection site reactions with Toujeo (2.4%) and Lantus (3.1%), and similar numbers withdrew because of adverse events (1.4% with Toujeo and 1.3% with Lantus).

Patient factors

  • Toujeo is a high‑strength insulin. It is not simply interchangeable with other long‑acting insulins and there is a potential risk of medication error. However, the dose window of the Toujeo pen shows the number of Toujeo units to be injected. Patients should read and understand the patient leaflet and education material and should have training on the correct use of Toujeo.

  • Toujeo is given once daily, preferably at the same time each day but can be up to 3 hours before or after usual time.

  • There was a reduction of approximately 1 confirmed or severe nocturnal event per person per year with Toujeo compared with Lantus. Severe hypoglycaemic events were rare and not statistically significantly different between Toujeo and Lantus (meta-analysis of 3 RCTs, n=2496)

  • Body weight increased less with Toujeo than with Lantus (mean increase at 6 months 0.51 kg compared with 0.79 kg; p=0.039; meta‑analysis of 3 RCTs, n=2496).

  • The higher concentration of insulin in Toujeo means the volume to be injected is smaller, which may be less painful for people injecting large volumes.

Resource implications

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

  • The manufacturer has stated that Toujeo has been priced at a level to match the daily cost of Lantus on the basis of average insulin glargine usage in the EDITION trials. The cost of Toujeo is £33.13 for 3×1.5 ml pre‑filled pens (excluding VAT; MIMS, November 2015).

Introduction and current guidance

Type 2 diabetes is a chronic metabolic condition characterised by insulin resistance and insufficient pancreatic insulin production, resulting in high blood glucose levels. Type 2 diabetes is commonly associated with obesity, physical inactivity, raised blood pressure and disturbed blood lipid levels, and therefore is recognised to have an increased cardiovascular risk. It is associated with long‑term microvascular and macrovascular complications, together with reduced quality of life and life expectancy. The updated NICE guideline on type 2 diabetes in adults: management recommends adopting an individualised approach to diabetes care.

Full text of introduction and current guidance.

Product overview

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 (type 1 and type 2) in adults. In people with type 2 diabetes, it can be given together with other anti‑hyperglycaemic medicinal products.

Toujeo is not bioequivalent to insulin glargine 100 units/ml (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). 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 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. The cost of a pack of 3 pens is £33.13 (excluding VAT; MIMS, November 2015).

Full text of product overview.

Evidence review

This evidence summary is based on the 3 main phase 3 studies of Toujeo in adults with type 2 diabetes (EDITION 1, EDITION 2 and EDITION 3). EDITION 1 was in adults with type 2 diabetes who were using basal and mealtime insulin. In EDITION 2, adults with type 2 diabetes were using oral blood glucose lowering drugs and basal insulin; and in EDITION 3, adults with type 2 diabetes were insulin‑naive. The objective of these RCTs was 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. The main phase 3 study of Toujeo in adults with type 1 diabetes (EDITION 4) is reviewed in the evidence summary on type 1 diabetes.

  • 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]. 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.

  • The percentage of participants experiencing at least 1 confirmed or severe nocturnal hypoglycaemic event between week 9 and month 6 was statistically significantly lower with Toujeo compared with Lantus in EDITION 1 and EDITION 2, but not in EDITION 3:

    • 36% with Toujeo and 46% with Lantus in EDITION 1 (relative risk [RR] 0.79; 95% CI 0.67 to 0.93, p=0.0045)

    • 22% with Toujeo and 28% with Lantus in EDITION 2 (RR 0.77; 95% CI 0.61 to 0.99, p=0.038)

    • 16% with Toujeo and 17% with Lantus in EDITION 3 (RR 0.89; 95% CI 0.66 to 1.20)

    • severe nocturnal hypoglycaemic events were rare in all 3 RCTs and too few for meaningful analysis in each trial.

  • In a post-hoc meta‑analysis of the 3 RCTs (Ritzel et al 2015), the annualised rate of confirmed or severe nocturnal events over the 6‑month study period was 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 hypoglycaemic events at any time of day were rare and not statistically significantly different between groups; the percentage of participants experiencing at least 1 severe event at any time of day was 2.3% in the Toujeo group and 2.6% in the Lantus group (RR 0.85, 95% CI 0.52 to 1.39).

  • At 6 months the basal insulin dose was approximately 12% higher with Toujeo than with Lantus in a meta‑analysis of the 3 RCTs in adults with type 2 diabetes (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. The dose of Toujeo was 10% higher in EDITION 1 and EDITION 2, and 17% higher in EDITION 3.

  • In the 3 RCTs in adults with type 2 diabetes, the number of participants with any adverse event or any serious adverse event was similar in the Toujeo and Lantus groups. 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).

  • The EPAR states that the safety profile of Toujeo is largely similar to that of Lantus and no additional safety signals were detected. 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).

  • An important risk with high‑strength insulin glargine 300 units/ml (Toujeo) is possible medication errors with other insulins of lower strengths. Toujeo is not bioequivalent to insulin glargine 100 units/ml (Lantus) and dose adjustment is needed. However, the dose window of the Toujeo pen shows the number of Toujeo units to be injected.

  • The primary end point of the EDITION 1, 2 and 3 (total n=2496) was an HbA1c end point at 6 months. Extension studies to 12 months have been completed, and published for 2 of the RCTs. There are very limited patient‑oriented outcome data for the effects of Toujeo on macrovascular or microvascular outcomes, and very limited long‑term safety data for the 300 units/ml insulin glargine strength specifically.

Full text of evidence review.

Context

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

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 at a 200 units/ml strength.

The cost of Toujeo and other basal insulins will depend on the preparation chosen and the insulin dosage used. The manufacturer has stated that Toujeo has been priced at a level to match the daily cost of Lantus on the basis of average insulin glargine usage in the EDITION trials.

Full text of context.

Estimated impact for the NHS

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. In the phase 3 studies of Toujeo in adults with type 2 diabetes, the mean injection volume at 6 months was calculated to be 0.3 ml (77 units) with Toujeo and 0.8 ml (68 units) with Lantus for a 90 kg adult.

In the phase 3 studies of Toujeo in adults with type 2 diabetes (EDITION 1, EDITION 2 and EDITION 3), Toujeo had similar efficacy to Lantus in terms of HbA1c reduction. In 2 of the 3 studies, Toujeo statistically significantly reduced the risk of confirmed or severe nocturnal hypoglycaemia compared with Lantus (by about 1 event per person per year), but severe hypoglycaemic events 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 (Ritzel et al 2015).

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, such as Toujeo (MHRA Drug Safety Update April 2015).

Toujeo (insulin glargine 300 units/ml) 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 in adults 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).

Full text of estimated impact for the NHS.

About this evidence summary

'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance.