Key points from the evidence | Type 2 diabetes: insulin degludec | Advice

Summary

The long-acting insulin analogue, insulin degludec, is available in 2 strengths: 100 units/ml and 200 units/ml. It is non-inferior to insulin glargine in terms of glycaemic control in type 2 diabetes, with statistically significantly lower rates of some, but not all, measures of hypoglycaemia, particularly nocturnal hypoglycaemia. Although there are published studies with one year data, there are none comparing insulin degludec with NPH (isophane) insulin and none that measure patient-oriented efficacy outcomes.

Effectiveness

Insulin degludec is non-inferior to insulin glargine for glycaemic control
- Insulin degludec reduced HbA_1c by about 1.1% points [12 mmol/mol] from baseline (2 RCTs, 52 weeks).
Insulin degludec statistically significantly improved glycaemic control compared with sitagliptin
- estimated treatment difference in HbA_1c 0.43% points [5 mmol/mol] (1 RCT, 26 weeks).

Safety

The MHRA has issued advice to minimise the risk of medication errors associated with the higher strength, 200 units/ml formulation.
The dose-counter window of the pen device shows the number of units, irrespective of strength. Therefore, no dose conversion is needed.

Patient factors

Once daily, with flexibility in timing of administration. SmPC states that a minimum of 8 hours between injections should always be ensured.
Compared with insulin glargine:
- similar tolerability
- statistically significant reductions in hypoglycaemic events (various definitions of between 0.02 and 2.5 episodes per patient per year) (2 RCTs, 52 weeks).
Compared with sitagliptin:
- more withdrawals because of adverse effects: 3.9% compared with 0.9% (1 RCT, 26 weeks)
- statistically significant increase in overall hypoglycaemia of 1.81 episodes per patient per year (1 RCT, 26 weeks).

Resource implications

5×3 ml cartridges (100 units/ml) and 5×3 ml pre-filled pen (100 units/ml), £72.00.
3×3 ml pre-filled pen (200 units/ml), £86.40.
More expensive than NPH (isophane) insulin, insulin glargine and insulin detemir.

Key points

Insulin degludec (Tresiba) is a long-acting insulin analogue that has been marketed in the UK for basal insulin therapy in adults (18 years or over) with type 1 or type 2 diabetes. It is available in 2 strengths: 100 units/ml and 200 units/ml. This evidence summary considers the use of insulin degludec in adults with type 2 diabetes. It supersedes an earlier evidence summary (ESNM4), published in November 2012. Another evidence summary considers its use in adults with type 1 diabetes.

This evidence summary is based on the 3 randomised controlled trials (RCTs) that provide the best (highest quality) available published evidence relating to the efficacy and safety of insulin degludec to treat people with type 2 diabetes. In these trials, insulin degludec was compared with insulin glargine in people who had previously used basal insulin (Garber et al. 2012) and in people who were insulin naive (Zinman et al. 2012). Insulin degludec was also compared with sitagliptin in people who were insulin naive (Philis-Tsimikas et al. 2013). Two other published phase III studies (Meneghini et al. 2013 and Gough et al. 2013) are discussed briefly in the evidence review section.

Evidence from the 2 open-label RCTs comparing insulin degludec with insulin glargine indicates that insulin degludec is non-inferior to insulin glargine in terms of glycaemic control: both basal insulins reduced glycated haemoglobin (HbA_1c) levels to a similar degree (as would be expected with a treat-to-target trial design). With regard to hypoglycaemia, insulin degludec statistically significantly reduced the rate of overall hypoglycaemia, nocturnal hypoglycaemia and (in a post-hoc analysis) daytime hypoglycaemia, compared with insulin glargine in 1 RCT (Garber et al. 2012); and nocturnal hypoglycaemia and severe hypoglycaemia in the other RCT (Zinman et al. 2012). However, the absolute differences in these rates were small and the findings relating to severe hypoglycaemia, in particular, need to be viewed with caution because of very low event rates. Although these studies include data at one year, there are no published studies comparing insulin degludec with NPH (isophane) insulin and none that measure patient-oriented efficacy outcomes.

Compared with sitagliptin, insulin degludec was superior in terms of glycaemic control, but resulted in more episodes of overall confirmed hypoglycaemia (Philis-Tsimikas et al. 2013). However, because insulin was titrated weekly in a treat-to-target approach, and the mean insulin dose increased throughout the trial, these results may be expected.

Insulin degludec is given once daily at any time of the day, preferably at the same time every day. On occasions when this is not possible, there can be some flexibility in the timing of insulin administration. The Summary of product Characteristics states that a minimum of 8 hours between injections should always be ensured.

Insulin degludec is the first insulin approved in Europe at a higher strength than the European Union-wide standard of 100 units/ml. The Medicines and Healthcare products Regulatory Agency (MHRA) has issued advice to minimise the risk of medication errors associated with the 200 units/ml formulation. The dose-counter window of the pen device shows the number of units that will be injected, irrespective of strength. Therefore, no dose conversion is needed when transferring a person from one strength of insulin degludec to another.

Type 2 diabetes: the management of type 2 diabetes (NICE clinical guideline 87; which is currently being updated) recommends that, when insulin therapy is necessary, human NPH (isophane) insulin is the preferred option. Examples of NPH (isophane) insulin include Insulatard, Humulin I or Insuman Basal. The guideline recommends that the long-acting insulin analogues, insulin glargine and insulin detemir, can be considered as an alternative in some people, for example those who need assistance from a carer or healthcare professional to inject their insulin, or whose lifestyle is restricted by recurrent symptomatic hypoglycaemic episodes. Insulin degludec will be included in the update of this guideline, the publication date of which is still to be confirmed.

Local decision makers will need to consider the evidence for insulin degludec in type 2 diabetes alongside that for other basal insulins, taking into account the current NICE guidance which recommends the use of long-acting insulin analogues in some limited circumstances. Individual patient factors and their experience of hypoglycaemia together with the higher cost of insulin degludec will need to be taken into account.

Key evidence

Garber AJ, King AB, Del Prato S et al. (2012) Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. The Lancet 379: 1498–507 doi: 10.1016/S0140-6736(12)60205-0

Zinman B, Philis-Tsimikas A, Cariou B et al. (2012) Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: a 1-year, randomized, treat-to-target trial (BEGIN Once Long). Diabetes Care 35: 2464–71 doi: 10.2337/dc12-1205

Philis-Tsimikas A, Del Prato S, Satman I et al. (2013) Effect of insulin degludec versus sitagliptin in patients with type 2 diabetes uncontrolled on oral antidiabetic agents. Diabetes, Obesity and Metabolism 15: 760–6 doi: 10.1111/dom.12115

Update

The following information has become available since this ESNM was produced.

April 2015: High strength, fixed combination and biosimilar insulin products minimising the risk of medication error

The MHRA has issued advice on how to minimise the risk of medication errors with high strength, fixed combination or biosimilar insulin products. Insulin degludec is available in 2 strengths and as a fixed combination product with liraglutide. See the Drug Safety Update April 2015 for more information.

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.