Key points from the evidence

Key points from the evidence

The content of this evidence summary was up-to-date in September 2013. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

The glucagon-like peptide-1 (GLP-1) mimetic lixisenatide is more effective than placebo in reducing glycated haemoglobin (HbA1c) in people with type 2 diabetes who are receiving oral antidiabetic drugs or basal insulin. Non-inferiority to exenatide has not been shown robustly for this outcome. There are no published data relating to patient-oriented outcomes or long-term safety.

Effectiveness

In people receiving metformin or pioglitazone or both (3 RCTs, 24 weeks):

  • 0.8–0.9% point reduction in HbA1c from baseline; 0.4–0.6% point greater reduction than placebo.

  • Non-inferiority to exenatide not shown robustly.

  • Reduction in body weight from baseline but no difference in weight change compared with placebo; less weight reduction than with exenatide.

In people receiving basal insulin with or without metformin (2 RCTs, 24 weeks):

  • 0.7% point reduction in HbA1c from baseline; 0.3% point greater reduction than placebo.

  • Weight reduction or less weight increase compared with placebo.

Safety

  • GLP-1 mimetics have been associated with a risk of developing acute pancreatitis.

Patient factors

  • Once-daily administration by injection.

  • Nausea, vomiting, diarrhoea and headache are very common (frequency 1 or more in 10), as is hypoglycaemia when lixisenatide is used in combination with a sulfonylurea and/or a basal insulin.

  • When compared with exenatide, fewer people had nausea and symptomatic hypoglycaemia.

Resource implications

  • Annual acquisition cost £705.75; this is 15–26% less than other GLP-1 mimetics.

Key points

Lixisenatide is a GLP-1 mimetic licensed for use in combination with oral antidiabetic drugs and/or basal insulin for treating type 2 diabetes in adults whose blood glucose is not adequately controlled on these treatments alone. It is administered by subcutaneous injection once daily.

NICE published an evidence summary on lixisenatide for type 2 diabetes in January 2013 (ESNM10). However, studies that are more applicable to the UK population and to lixisenatide's licensed indications have been published in full since that summary was prepared. These have been reviewed in this evidence summary, which now updates and replaces the earlier evidence summary on lixisenatide.

Lixisenatide in combination with oral therapies has been investigated in 3 randomised controlled trials (RCTs) that have been published in full:

  • GetGoal-P (Pinget et al. 2013) compared lixisenatide with placebo in people whose diabetes was poorly controlled on pioglitazone, with or without metformin.

  • GetGoal-M (Ahrén et al. 2013) compared lixisenatide with placebo in people whose diabetes was poorly controlled on metformin monotherapy.

  • GetGoal-X (Rosenstock et al. 2013) compared lixisenatide with exenatide in people on metformin monotherapy.

GetGoal-P and GetGoal-M found that lixisenatide was more effective than placebo with regard to their primary outcome of reduction in HbA1c from baseline. However, the 0.8–0.9 percentage point mean reductions from baseline in the lixisenatide groups were slightly less than the 1.0 percentage point (11 mmol/mol) reduction specified in NICE guidance as a criterion for continuing treatment with exenatide or liraglutide in triple or dual therapy beyond 6 months, and the mean difference from placebo was about half of that (see the Introduction for details of NICE guidance).

GetGoal-M and GetGoal-P both found a statistically significant reduction in fasting plasma glucose with lixisenatide compared with placebo, and GetGoal-M found a statistically significant reduction in 2-hour post-prandial plasma glucose (this end point was not reported in GetGoal-P). There was no statistically significant effect from lixisenatide on body weight compared with placebo in either study. However, the European Medicines Agency (EMA) concluded that the effect of lixisenatide on body weight was of clear clinical relevance and advantageous compared with the increase in weight with some other therapeutic options.

GetGoal-X concluded that lixisenatide was non-inferior to exenatide with regard to the primary outcome of reduction in HbA1c from baseline. However, the EMA concluded that non-inferiority to exenatide had not been shown robustly (see the sections on Evidence strengths and limitations and Likely place in therapy for more details). There was no statistically significant difference in fasting plasma glucose between lixisenatide and exenatide. Exenatide produced a statistically significantly greater mean reduction in bodyweight. Statistically significantly fewer people receiving lixisenatide reported nausea or symptomatic hypoglycaemia compared with those receiving exenatide.

Lixisenatide in combination with insulin has been investigated in 2 RCTs relevant to the UK population and that have been published in full:

  • GetGoal-L (Riddle et al. 2013a) compared lixisenatide with placebo in people whose diabetes was poorly controlled on basal insulin, with or without metformin.

  • GetGoal-Duo1 (Riddle et al. 2013b) compared lixisenatide with placebo in people whose diabetes was poorly controlled on recently initiated insulin glargine, plus oral agents.

Lixisenatide was more effective than placebo for the primary outcome of reduction in HbA1c from baseline, producing mean reductions of 0.7 percentage points and mean differences from placebo of 0.3 percentage points in both studies.

Gastrointestinal adverse effects are often reported with GLP-1 mimetics. The summary of product characteristics (SPC) states that the most frequently reported adverse reactions during clinical studies of lixisenatide were nausea, vomiting and diarrhoea (very common: frequency 1 or more in 10). These reactions were mostly mild and transient. In addition, headache was also very common, as was hypoglycaemia when lixisenatide was used in combination with a sulfonylurea and/or a basal insulin. The SPC notes that GLP-1 mimetics have been associated with a risk of developing acute pancreatitis.

Lixisenatide has a lower acquisition cost than the other GLP-1 mimetics currently available.

The place in therapy of exenatide and liraglutide, the other 2 GLP-1 mimetics currently available in the UK, is described in Type 2 diabetes: the management of type 2 diabetes (NICE clinical guideline 87), Liraglutide for the treatment of type 2 diabetes mellitus (NICE technology appraisal guidance 203) and Exenatide prolonged-release suspension for injection in combination with oral antidiabetic therapy for the treatment of type 2 diabetes (NICE technology appraisal guidance 248). Exenatide, liraglutide and lixisenatide will be included in the update of the NICE clinical guideline for the management of type 2 diabetes. The publication date for this guideline is to be confirmed.

Local decision makers will need to consider the evidence for lixisenatide in type 2 diabetes alongside that for other GLP-1 mimetics, taking into account current NICE guidance, differences in individual patient factors and the acquisition costs of the different products.

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.