Dr Lindsay E Clegg (Postdoctoral Fellow at AstraZeneca) discusses EXSCEL – Cardiovascular and renal outcomes with combination exenartide and open-label SGLT2 inhibitor treatment in EXSCEL.
You excel was the cardiovascular outcomes trial for the once weekly glp-1 receptor agonist eggs an atty so 14750 two subjects were randomized to receive your once weekly sanitizer placebo and then followed up with visits every six months to evaluate their cardiovascular outcomes the analysis we did here was specifically looking at subjects in excel that picked up
An sglt2 inhibitors as part of usual care during the study so we use the subset of subjects to look at our subjects taking both eggs init id and an sglt2 inhibitors during the course of the trial and studied their outcomes as compared to those of subjects that took eggs an atty but non-national t2 inhibitor or subjects in the placebo arm who did not take an stl t
2 inhibitor so they were exposed to neither a glp-1 agonists or nor an sglt2 inhibitors in our analysis here what we found after propensity matching these sets of cohorts so that we had equivalent subjects that we could compare taking both eggs anyt initial t2 inhibitor to either eggs anna type or to placebo so now their agent was that we saw a numerical trend for
Reduction in major adverse cardiovascular events and that point estimate was a little bit lower compared to placebo than in senate id so this suggested that there may be some additional effects of combining these glp-1 receptor agonist and sglt2 inhibitors now these effects were not statistically significant which is what we would expect because this is a post hoc
Analysis so it wasn’t powered and also the size of the cohorts were fairly moderate about 570 subjects in each arm in the two comparisons so this trend was interesting though because it fits with the idea the hypotheses that because these mechanisms are different maybe putting them together would provide additional benefit and we do know we see additional risk factor
Improvements there when we broke into that maze endpoint which is a composite of cardiovascular death non-fatal mi and non-fatal stroke we saw that that was improvement was specifically in cardiovascular deaths so we saw a nominally significant reduction in cardiovascular death with this combination and also a nominal reduction in all cause mortality on the renal
Side of things what we looked at was egfr slope so in this population we don’t have very many patients progressing on to end-stage renal disease so egfr slope is something we can look at to capture that progressive decline earlier on in a population and when we do that we see that in both comparisons so compared to exenatide alone or compared to placebo subjects
Taking this combination of exenatide nitesh guilty to inhibitor had improvement in egfr slope of about 2 mils per min per year and so we could actually see over time before taking a shield t2 inhibitor this gradual decline in egfr slope that we expect with age and when they add the sglt2 inhibitors we can actually see that slope flattening out so the similarity in
These two comparisons suggests that most of what we’re seeing here in this relatively really healthy population is likely the sglt2 inhibitors fact which looked consistent top of either examine side or placebo so here we have data on subjects taking both a glp-1 receptor agonist eggs an anti d an open-label sglt2 inhibitors and this is the first data to date on
Clinical outcomes and subjects taking both of these classes of drugs so that’s the main new thing here when we look at existing cardiovascular outcomes trials for these two classes of drugs we’ve seen multiple agents that have cardio and renal protective actions though the results vary between the two classes and between trial to trial so in this case we have the
Open label sglt2 inhibitors which is a little bit different than in a cardiovascular outcomes trial but it does give us an opportunity to look in the specific cohort at these outcomes so this analysis was very much hypothesis-generating it wasn’t powered and we do need to keep in mind when we do this propensity matching approach which allows us to account for the
Non-randomized as she’ll do to inhibitor use so making sure we have equivalent subjects we’re looking at they took the combination and making sure we compared them to subjects that are very similar on laboratory values medical history demographics that sort of thing in our comparator groups so that makes gives us an opportunity to look at causation and the effect
Of this combination however it does mean our results really applies specifically to that population in this trial that are choosing to take a message alt to inhibitor and we have to remember that what we’re doing our best to match these cohorts anything we don’t have measure and control for could introduce unmeasured confounding so in this case this is exciting
Interesting new clinical data on these outcomes which we haven’t had before but it’s really a first piece of evidence it supports the hypothesis that this combination may provide additional benefit and motivates the collection of future additional data but we really will need more data to have definitive ideas of what the outcomes are with this combination so this
Analysis will generating really motivates and supports the hypothesis that this combination of glp-1 receptor agonist and sglt2 inhibitors may provide additional benefit particularly a mortality where we may see these different mechanisms coming together but since it’s very much hypothesis generating the main outcome we hope is motivation for additional study an
Additional collection of clinical outcomes in these populations to better understand how these two classes of drugs are working together to affect cardio renal risk
Transcribed from video
EASD 2019: EXSCEL – Dr Lindsay E Clegg By Radcliffe
