Advice

Key points from the evidence

Key points from the evidence

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

Summary

In people who are insulin-naïve, insulin degludec/liraglutide (Xultophy) was non‑inferior to insulin degludec alone and superior to liraglutide alone for reductions in HbA1c (with a difference of 0.64% compared with liraglutide). In people previously treated with basal insulin, insulin degludec/liraglutide was superior to insulin degludec alone for reducing HbA1c with a difference of 1.1%. The safety profile and long‑term safety concerns of insulin degludec/liraglutide are broadly in line with those of the 2 included components.

Regulatory status: Insulin degludec/liraglutide (Xultophy) was launched in the UK in November 2014. It is the first fixed‑ratio combination basal insulin and glucagon‑like peptide‑1 [GLP‑1] receptor agonist preparation to be licensed in the UK. Insulin degludec (Tresiba: 100 units per ml and 200 units per ml) and liraglutide (Victoza) are available in the UK as the individual component preparations.

Effectiveness

  • Insulin degludec/liraglutide was non‑inferior to insulin degludec alone (treatment difference −0.47% points) and superior to liraglutide alone (treatment difference −0.64% points) for change in HbA1c from baseline (1 RCT; n=1663; 26 weeks).

  • Insulin degludec/liraglutide was superior to insulin degludec alone (treatment difference −1.1% points) for change in HbA1c from baseline (1 RCT; n=413; 26 weeks).

Safety

  • The European public assessment (EPAR) report concluded that the safety profile is in general similar to that of the 2 included components. Long‑term safety concerns are the same as for the other GLP‑1 receptor agonists and long‑acting insulin analogues.

  • The most commonly reported adverse reactions listed in the summary of product characteristics (SPC) are hypoglycaemia, decreased appetite, nausea, diarrhoea, vomiting constipation, dyspepsia, gastritis, abdominal pain, flatulence, gastroesphageal reflux disease, abdominal distension and injection site reactions.

  • Cases of confirmed hypoglycaemia were 32% with insulin degludec/liraglutide, 39% with insulin degludec and 7% with liraglutide (1 RCT; n=1663; 26 weeks).

Patient factors

  • Insulin degludec/liraglutide is given by once‑daily subcutaneous injection which for some people may be preferable to giving basal insulin and GLP‑1 receptor agonist injections separately.

  • The dose is administered in 'dose‑steps'. One dose‑step contains 1 unit of insulin degludec and 0.036 mg of liraglutide. People will be unable to titrate the dose of basal insulin and GLP‑1 receptor agonist separately because insulin degludec/liraglutide is a fixed‑ratio combination product.

  • Average weight loss was 2.22 kg to 2.5 kg with insulin degludec/liraglutide compared with insulin degludec alone. However there was 2.44 kg less weight loss from baseline with insulin degludec/liraglutide compared with liraglutide alone.

Resource implications

  • Annual cost ranges from £387 for a daily dose of 10 dose‑steps (10 units insulin degludec and 0.36 mg liraglutide) to £1987 for a daily dose of 50 dose‑steps (50 units insulin degludec and 1.8 mg liraglutide).

  • The cost of a GLP‑1 receptor agonist and basal insulin given separately will depend on the preparations chosen and insulin dosage. With an insulin dose of 20 units daily, the annual cost for a combination of a GLP‑1 receptor agonist and basal insulin would range from £802 to £1533. With an insulin dose of 50 units daily it would range from £947 to £2058.

Introduction and current guidance

The NICE guideline on type 2 diabetes, which is being updated (publication date to be confirmed) states that managing people with type 2 diabetes is complex. It involves individualising a multifactorial approach, addressing blood pressure, blood lipids and lifestyle issues, as well as blood glucose. Controlling blood glucose needs a careful balance between the intensity of the treatment regimen and avoiding hypoglycaemia. The current NICE guideline on type 2 diabetes recommends that people should be involved in setting their individualised HbA1c target level, which may be above the general target of 48 mmol/mol (6.5%), and that pursuing highly intensive management to HbA1c levels below 48 mmol/mol (6.5%) should be avoided.

Full text of introduction and current guidance.

Product overview

Insulin degludec/liraglutide (Xultophy) is a solution for subcutaneous injection containing both insulin degludec (a long‑acting insulin analogue) and liraglutide (a GLP‑1 receptor agonist). It is licensed for the treatment of adults with type 2 diabetes mellitus to improve glycaemic control in combination with oral glucose‑lowering treatments when these alone or combined with basal insulin do not provide adequate glycaemic control. The SPC recommends that when it is being used as an add‑on to oral glucose‑lowering drugs the starting dose is 10 dose‑steps once a day (10 units insulin degludec and 0.36 mg liraglutide). When transferring from basal insulin the recommended starting dose is 16 dose‑steps once a day. The maximum dose is 50 dose‑steps once a day (50 units insulin degludec and 1.8 mg liraglutide).

Full text of product overview.

Evidence review

  • The study programme for insulin degludec/liraglutide includes 7 phase III randomised controlled trials (RCTs). This evidence summary is based on the 2 phase III studies that have been published in full: DUAL I and DUAL II. All of the studies in the study program have change from baseline in HbA1c as primary outcomes. As with the other GLP‑1 receptor agonists and long‑acting insulin analogues, there are limited data from RCTs of insulin degludec/liraglutide relating to patient‑oriented outcomes, such as rates of macrovascular or microvascular events.

  • DUAL I compared insulin degludec/liraglutide with insulin degludec alone and liraglutide alone in adults with type 2 diabetes who were insulin‑naïve and taking metformin with or without pioglitazone. DUAL II compared insulin degludec/liraglutide with insulin degludec alone in adults with type 2 diabetes who had previously used basal insulin and were also taking metformin. In the DUAL II study, the insulin degludec alone group could be titrated to a maximum of 50 units.

  • In DUAL I insulin degludec/liraglutide was non‑inferior to insulin degludec alone and superior to liraglutide alone for change in HbA1c from baseline. After 26 weeks' treatment HbA1c was reduced to 6.4% (46 mmol/mol) with insulin degludec/liraglutide, 6.9% (52 mmol/mol) with insulin degludec and 7% (53 mmol/mol) with liraglutide (from a baseline of 8.3% [67mmol/mol] in all 3 groups). Insulin degludec/liraglutide reduced HbA1c by an additional 0.47% points compared with insulin degludec (95% confidence interval [CI] −0.58 to −0.36; p<0.0001) and an additional 0.64% compared with liraglutide (95% CI −0.75 to −0.53; p<0.0001).

  • In DUAL I there was more weight loss from baseline with insulin degludec/liraglutide compared with insulin degludec alone (−0.5 kg compared with +1.6 kg, treatment difference −2.22 kg; 95% CI −2.64 to −1.80; p<0.0001). However there was less weight loss from baseline with insulin degludec/liraglutide compared with liraglutide alone (−0.5 kg compared with −3.0 kg, treatment difference 2.44 kg; 95% CI 2.02 to 2.86; p<0.0001). At week 26, mean insulin dose was 38 units in the insulin degludec/liraglutide group and 53 units in the insulin degludec group. The mean liraglutide dose was 1.4 mg in the insulin degludec/liraglutide group and 1.8 mg in the liraglutide group.

  • In the DUAL I study more participants achieved a HbA1c of less than 7.0% (53 mmol/mol) without weight gain or hypoglycaemia with insulin degludec/liraglutide compared with insulin degludec alone (36% compared with 14%; odds ratio [OR] 3.56; 95% CI 2.59 to 4.90; p<0.0001). However, fewer people achieved this with insulin degludec/liraglutide compared with liraglutide alone (36% compared with 52%; OR 0.49; 95% CI 0.38 to 0.63; p<0.0001).

  • In DUAL II insulin degludec/liraglutide was superior to insulin degludec alone for change in HbA1c from baseline. After 26 weeks' treatment HbA1c was reduced to 6.9% (52 mmol/mol) from a baseline of 8.8% (73 mmol/mol) with insulin degludec/liraglutide and to 8.0% (64 mmol/mol) from a baseline of 8.9% (74 mmol/mol) with insulin degludec. Insulin degludec/liraglutide reduced HbA1c by an additional 1.1% (95% CI −1.3 to −0.8; p<0.0001) compared with insulin degludec. At the end of the study the mean daily dose of insulin degludec was the same in both groups (45 units).

  • In DUAL I cases of confirmed hypoglycaemia were statistically significantly higher with insulin degludec/liraglutide compared with liraglutide (32% compared with 7%; estimated rate ratio [RR] 7.61; 95% CI 5.17 to 11.21; p<0.0001) but lower compared with insulin degludec (32% compared with 39%; estimated RR 0.68; 95% CI 0.53 to 0.87; p=0.0023).

  • In DUAL I the most frequently reported adverse events were headache, nasopharyngitis and gastrointestinal disorders. Headache and nasopharyngitis were similarly reported across the groups but gastrointestinal disorders occurred more frequently with insulin degludec/liraglutide compared with insulin degludec but less frequently compared with liraglutide. For example, nausea occurred in 9%, 4% and 20% of participants, respectively, for insulin degludec/liraglutide, insulin degludec and liraglutide.

  • The European public assessment (EPAR) report for Xultophy concluded that the safety profile for insulin degludec/liraglutide is in general similar to the 2 included components, with no indications of additive toxicity. It further states that the long‑term safety concerns are the same as for the other GLP‑1 receptor agonist and long‑acting insulin analogues; in particular, there is an identified risk of pancreatitis and potential risk of malignancies for example, pancreatic and thyroid tumours.

  • There are no data available on the use of insulin degludec/liraglutide in combination with dipeptidyl peptidase 4 (DPP‑4) inhibitors, glinides (such as nateglinide or repaglinide) or prandial insulin. There are also no published data on initiating insulin degludec/liraglutide in people who are already taking a GLP‑1 receptor agonist. The use of insulin degludec/liraglutide in people taking basal insulin doses greater than 40 units has not been studied.

  • There are now several new insulin products (high strength, fixed combination and biosimilar insulin products) which have recently been launched or are soon to be launched in the UK. In April 2015 the MHRA issued advice on how to minimise the risk of medication errors such as the wrong insulin dose being given.

Full text of evidence review.

Context

Insulin degludec/liraglutide is the first combination basal insulin and GLP‑1 receptor agonist preparation to be licensed in the UK. It is available in packs of 5×3 ml prefilled pens at a cost of £159.22 per pack (MIMS June 2015). Annual costs range from approximately £387 for a daily dose of 10 dose‑steps to £1937 for a daily dose of 50 dose‑steps.

In addition to liraglutide, 3 other GLP‑1 receptor agonists are licensed in the UK: exenatide, lixisenatide and dulaglutide. Liraglutide and lixisenatide are administered once daily, exenatide is administered twice daily or once a week depending on the preparation, and dulaglutide is administered once a week. In addition to insulin degludec, there are 2 other long‑acting insulin analogues currently licensed in the UK: insulin detemir and insulin glargine.

The cost of a GLP‑1 receptor agonist and basal insulin given separately will depend on the preparations chosen and insulin dosage.

Full text of context.

Estimated impact for the NHS

Insulin degludec/liraglutide has been shown to be non‑inferior to insulin degludec alone and superior to liraglutide alone for reducing HbA1c in the DUAL I study (with a difference of 0.64% compared with liraglutide).

Compared with insulin degludec alone, the combination preparation may have other potential advantages such as weight loss, reduced insulin dose and less hypoglycaemia, but these potential advantages were not seen for the combination product compared with liraglutide alone. The DUAL I population had an average HbA1c of 8.3% (67 mmol/mol) at baseline on oral therapy alone, were insulin‑naïve, and had not been treated with GLP‑1 receptor agonists. Although this approach to blood glucose control is within the licensed indication for insulin degludec/liraglutide, other less intensive treatment options are available as options for individuals.

The manufacturer suggests that a potential place in therapy for insulin degludec/liraglutide is for adults with type 2 diabetes who are uncontrolled on basal insulin. For this group of people for whom the use of basal insulin and a GLP‑1 receptor agonist in combination is being considered, the alternative treatment option would be to add a separate GLP‑1 receptor agonist. This treatment option would allow flexible titration of the insulin and GLP‑1 receptor agonist doses, but could increase the complexity of the administration regimen.

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.