Publication of Studies During 2016 – Type 2 Diabetes

2016 has seen the publication of two large type 2 diabetes (T2DM) cardiovascular safety outcome trials (CVOTs) which showed benefit of glucagon-like receptor-1 agonists (GLP-1RAs). The LEADER study compared once-daily liraglutide with placebo in over 9,000 patients treated for a median of 3.8 years and showed statistically significant superiority in the primary end-point of a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. The SUSTAIN 6 study was a smaller (3,297 patients), shorter (104 weeks) pre-license analysis of once-weekly semaglutide versus placebo. Using the same primary end-point, it demonstrated superiority, albeit in an analysis which was not pre-specified; for this reason, a further much larger CVOT of injected semaglutide is anticipated.

GLP-1RAs are currently administered by subcutaneous injection and, although this is a very simple procedure, it does act as a barrier to their early inclusion in therapy algorithms. Indeed, in the NICE T2DM guideline, published in December 2015, this class of anti-diabetes therapy is restricted to the pre-insulin segment and only after failure of triple oral therapy. However, there is rapid progress being reported in this field. In December 2016, vTv Therapeutics Inc. announced positive data from a phase 2 study evaluating TTP273, an oral small molecule GLP-1RA. TTP273 demonstrated a statistically significant reduction in HbA1c with negligible incidence of nausea and vomiting, the most common side-effects of GLP-1RA administration. A trend towards weight loss was also observed.

The development of an oral version of semaglutide is even more advanced. This once-daily GLP-1RA is currently going through an extensive phase 3 programme, having demonstrated impressive reductions of both HbA1c (of almost 2.0%) and weight (up to 6.5Kg) in the phase 2 trials. The pre-license CVOT of oral semaglutide, known as PIONEER 6 is due to recruit its first patients in January 2017.

So, there is the prospect of oral GLP-1RAs, with superior CV profiles to established anti-diabetes therapies. And these follow-on from the results of the EMPA-REG OUTCOME study which showed CV superiority of oral empagliflozin over placebo, once again using the primary end-point used in LEADER and SUSTAIN 6. Moreover, this sodium-glucose 2 transporter (SGLT2) inhibitor also dramatically reduced heart failure admissions, something not seen with GLP-1RAs. A caveat for all three studies is that only patients at extremely high-risk of CV disease were included and so their generalisablity to all patients with T2DM has yet to be demonstrated. More studies, currently on-going, will help address this question (e.g. the CANVAS study of canagliflozin, due to publish in 2017).

The EMPA-REG OUTCOME data has, however, led the FDA to approve a new indication for empagliflozin ‘to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and cardiovascular disease’. The 2017 American Diabetes Association Guidelines will include a new recommendation ‘to consider the use of empagliflozin in people with type 2 diabetes and established cardiovascular disease to reduce the risk of cardiovascular death’. And other national guidelines, such as those of the Canadian Diabetes Association, have already made changes based on these data.

The question remains as to how these developments will be integrated into guidance in the UK. The 2015 NICE update came over six years after its previous iteration and it almost didn’t include any reference to the SGLT inhibitors, despite the first of them being licensed for use in the EU in 2012. The full guideline assessment by NICE is clearly too slow, something acknowledged by the agency when Clinical Guideline 28 was launched, however, the process for early updating has not been disclosed. The therapy landscape is rapidly changing and this issue needs to be addressed.

Professor Steve Bain