28th October 2018, Dr Chee L Khoo
There are now 7 glucagon like peptide 1 (GLP 1) injectable analogues used to control hyperglycaemia in patients with type 2 diabetes (T2D). An eighth GLP1 analogue is now available as an oral form. Only four of them are available in Australia of which three are on the PBS under authority prescription (Byetta, Bydureon, Trulicity). Their safety and efficacy in lowering glucose have previously been demonstrated in numerous clinical trials. The GLP1 agonists differ in chemical structures, duration of action and their clinical effects.
Safety and efficacy in lowering glucose is one thing but effect on cardiovascular events is a separate issue. So far, two of the GLP1 agonists have demonstrated significant cardiovascular benefits. The other two have demonstrated cardiovascular safety but not quite statistically significant benefit.
The latest agonist to have demonstrated benefits is albiglutide in the HARMONY trial. The results were released at the recent EASD meeting in Berlin. In 9463 participants who had diabetes AND established CVD, albiglutide demonstrated beneficial effects on cardiovascular outcomes when given to people with type 2 diabetes and atherosclerotic cardiovascular disease. Addition of once-weekly albiglutide to standard care, reduced the risk of the primary composite outcome—death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke by 22%, compared with the addition of placebo.
The mechanisms by which albiglutide and other GLP-1 receptor agonists reduce the risk of atherosclerotic cardiovascular events is not clear. The modest reductions in HbA1c of 0·3–0·8% over 1–3 years are unlikely to account for the reduction in risk and the effect on blood pressure is modest. The three agonists that have shown benefits happens to be based on human GLP1 while the other two that didn’t is based on the exendin-4 molecule. Whether these structural differences translate into clinically relevant differences in treatment effects, however, is not clear.
Is the difference in results across the trials due to the difference in trial design? The subjects in the LEADER, HARMONY and SUSTAIN trials had either established cardiovascular disease or at high cardiac risks. 70% of the subjects in the EXSCEL trial had previous CV events while 30% did not. This could explained why the trial did not show benefits. However, the ELIXA trial only had subjects with acute coronary syndrome.
The latest Harmony trial further strengthen the case for using a GLP1 agent early in the algorithm for management of hyperglycaemia in T2D. Not surprisingly, GLP1 agonist feature very prominently in the most recent recommendations from the joint ADA/EASD consensus statement for the management of hyperglycaemia in patients with T2D.
Interestingly, GlaxoSmithKline (GSK) announced its intention in 2017 to withdrawal Albiglutide for commercial reasons. This was prior to the release of the HARMONY outcome results. Naturally, it must be selling the molecule off to another company to take it to market.
How well do you know your GLP1 agonists? The place and role of GLP1 agonists in the management of T2D will be one of the main feature of the GP Diabetes Injectable Workshop on Saturday November 24, 2018 at Mercure Hotel Liverpool.
Access the abstract here
Hernandez A, Green J, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. The Lancet VOLUME 392, ISSUE 10157, P1519-1529, OCTOBER 27, 2018.