The place of Glucagon-like 1 peptide receptor agonists (GLP-1RAs) in the new NICE guidelines – what is going on?

The article by Miles Fisher in this edition of the British Journal of Diabetes discusses cardiovascular outcome trials (CVOTs) which have examined the impact of GLP-1RAs in type 2 diabetes (T2DM). He queries ‘why updated guidance from NICE...fails to acknowledge the evidence-based cardiovascular benefits’. Indeed, clinicians in the UK will be puzzled as to why this class of glucose-lowering therapy is now a first-line option in European and North American guidelines for people with T2DM at high cardiovascular risk, but remains well down the pecking order in NICE guideline (NG) 28.1-3 This editorial will provide a short précis of the history of GLP-1RAs and NICE and try to explain the current impasse. The National Institute of Clinical Excellence (NICE) was established in 1999 to ‘diffuse the postcode lottery’ of healthcare (for example, varying access to medicines according to where people lived) and serves the National Health Services (NHS) in England, Northern Ireland and Wales. Since its set-up, there have been two changes in name, the National Institute for Health and Clinical Excellence (2005) and the National Institute for Health and Care Excellence (2013) but the abbreviation of NICE has stood the test of time and is a globally recognised brand. Well over fifty countries world-wide access guidelines produced by NICE rather than doing their own in-depth assessment of new medicines.4 When it was launched, NICE inherited various guidelines for the management of T2DM, which were rebadged. It produced its first clinical guideline for T2DM (CG66) in 2008.5 This was rapidly followed by the release of CG87 in May 2009, which was a short update on the ‘newer agents’ for blood glucose lowering.6 This guideline included exenatide, given twice daily, which was the first GLP-1RA to be licensed in the UK (in 2007). Exenatide was positioned as a third-line ‘alternative’ add-on therapy to be considered after insulin, a thiazolidinedione or a dipeptidyl peptase-4 inhibitor and it was only sanctioned for use with metformin and a sulfonylurea. CG87 introduced the body mass index (BMI) cut-off of 35 Kg/m2 for GLP-1RAs, which was not based on data from clinical trials but was the BMI at which the average cost of a long-acting insulin analogue was the same as BD exenatide. NICE also introduced ‘stopping rules’ where exenatide should be withheld when a reduction of at least 1% (11mmol/mol) in HbA1c and weight loss of at least 3% initial body weight was not achieved after six months. Stopping rules have not been recommended for any other glucose-lowering class. The next NICE guidance for the management of T2DM (NG28) was published in 2015 and is best remembered for the furore created by the recommendation of repaglinide as firstline treatment for people intolerant of metformin.7,8 In the preceding six years, GLP-1RAs had been added to the glucoselowering algorithm by means of single technology appraisals (TAs). These individual assessments by NICE had a more binding legal status than their guidelines, in that a positive TA recommendation mandated that funding should be made available by clinical commissioning groups. Thus, liraglutide (TA203, 2010), exenatide extended-release (TA248, 2012) and lixisenatide (2013) were all sanctioned for use, although NICE limited the dose of liraglutide to a maximum of 1.2mg OD on the basis that this dose had the same acquisition cost as BD exenatide.9-11 The overall position of GLP-1RAs in the glucose-lowering algorithm was unchanged, however. They remained a third-line option for consideration after various triple oral combinations or insulin and were not even mentioned for people who could not tolerate metformin or for whom it was contra-indicated. The first CVOT of a glucose-lowering therapy to demonstrate superiority was the EMPA-REG OUTCOME study of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and this trial was published three months before NG28 was launched in December 2015.12 NG28 did not take into account these positive data, but this was not thought to be important since NICE had committed to regular updates every two years and more CVOT data were in the pipeline. Indeed, in 2016 there were positive CVOTs for both liraglutide (LEADER) and onceweekly semaglutide (SUSTAIN 6).13,14 The positive superiority CVOT for dulaglutide (REWIND) was published in 2019 and there 1 Swansea University Medical School, Swansea, UK