Lindsay Clegg, PhD: Effects of SGLT2i with Exenatide on CV, Renal Outcomes

While results of the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial were presented in Aug. 2018, investigators are still using the results and data to learn more about cardiovascular health.

At the American Diabetes Association (ADA) 2019 Scientific Sessions in San Francisco, CA, investigators presented a study that examined the effect of open-label SGLT2 inhibitor treatment combined with exenatide on cardiovascular and renal outcomes.

The original EXSCEL trial was a randomized, blinded, placebo-controlled study that included 14,752 participants who were randomized to receive either subcutaneous exenatide 2 mg once weekly or subcutaneous placebo once weekly.

Using the data from the original trial, investigators examined a cohort that initiated treatment with an SGLT2 inhibitor, which made up roughly 10% of participants, to determine the impact of the treatment on cardiovascular and renal outcomes when combined with exenatide.

After analyses, investigators found that SGLT2 inhibitors plus exenatide use decreased the major adverse cardiovascular event rate and significantly reduced all-cause mortality among participants.

Between sessions at ADA 2019, lead investigator Lindsay Clegg, PhD, postdoctoral fellow with AstraZeneca, sat down with MD Magazine® to discuss the findings of the study and the impact they could have on clinical practice.

MD Mag: What did you find when analyzing the results of the EXSCEL trial?

Clegg: EXSCEL was the cardiovascular outcomes trial for the once weekly formulation of exenatide, a GLP-1 receptor agonist. So, the trial readout now coming up on a couple years ago showing a trend but not a statistically significant improvement in major cardiovascular events. So, the poster we're presenting here at this meeting is looking at the subsets of subjects in EXSCEL that picked up an SGLT2 inhibitor during the course of the trial. So, patients still saw the regular doctor and were allowed to add additional medicines to control their diabetes. So, the question we had here was we know some of the GLP-1 receptor agonists have a benefit on cardiovascular outcomes, we know SGLT2 inhibitors have cardio renal benefits so what happens when patients take both classes? Do they get additional benefit or do you kind of max out with one or the other? So, there are reasons to hope there'd be additional benefit because the mechanisms of action are quite different and the exact endpoints you see improvement on are different. So, we took that subset of subjects in EXSCEL that took both a GLP-1 receptor agonist exenatide and an SGLT2 inhibitor and compared those to subjects that took just exenatide but not an SGLT2 inhibitor or people that took placebo and no SGLT2 inhibitors.

So, to do this we used propensity matching, which is a method that you use for observational research. So, we took an observational technique and applied that to clinical trial data — since we had open labeled nonrandomized SGLT2 inhibitors and when we did this and looked at those subjects taking the combination the results suggest a trend for benefit on MACE and a potentially really interesting decrease particularly in cardiovascular death and all-cause mortality in these patients that took both. So, it's important to keep in mind with the sort of analysis that it's very much hypothesis generating it's not confirmatory.

So, we hope that this will be some motivation for additional studies and more populations with different methods in the future to really dig in and see if this the these results we see replicate and maybe you know a real benefit for patients, but our cohorts here we want to keep in mind they're moderately sized and it's a mixture of patients that took the two drugs at the same time and patience that took exenatide and stopped and then picked up a SGLT2 inhibitor. So, either in parallel or in sequence and there's always the possibility — we do our best to match the subject so we can do a fair comparison — but there's always the possibility for other differences in the group. So, it's really important to keep in mind that the results are you know directional. So, these trends we see for benefit on particularly mortality are really exciting hypothesis-generating data but you know we'll need more work in the future to dig into those and really flesh out the potential benefit better.