Medicine Matters diabetes

I'm Chris Cannon, a cardiologist from Brigham and Women's Hospital in Boston. In the VERTIS-CV trial, we set out and found the cardiovascular safety of ertugliflozin, one of the SGLT2 inhibitors. We did a study in about 8,000 patients with known atherosclerotic cardiovascular disease and did show non-inferiority as the primary endpoint of the study.

With the many benefits that have been seen in the other trials as well, we also tested for superiority but didn't meet significance. So just saw trends in the same directions for the endpoint of cardiovascular death or hospitalization for heart failure. So then, observing the other endpoints, we again saw just numerically lower cardiovascular death, but a lower, about 30% lower rate of hospitalization for heart failure, and then also a tendency towards lower renal endpoint and an improvement in the slope of the EGFR over time. So a pattern very similar to what we're seeing in all the other trials, although not reaching significance for superiority on the various endpoints.

It's a good question as to why we saw just trends versus others. And part of the discussion we presented was to actually look at the other trials. And interestingly, the first trial showed significant reductions in all of the endpoints listed. But then of the subsequent trials, some endpoints were significant. Others were not. And so we actually did a meta analysis, and we find that there is very literal heterogeneity. Just one endpoint has heterogeneity across all the different trials.

And so we fit in, although statistically we didn't quite make it on some of the endpoints we specified. Some of that, I think, has to simply do with confidence intervals, that there is a range of endpoints and percent benefit that you can see. And we tended to be on the range that wasn't quite significant. But the pattern is very similar to what's been seen in all the other trials. And indeed doing this meta analysis, it really reaffirms the role of the class of drugs of SGLT2 inhibitors with reductions in MACE, the Major Adverse Cardiovascular Events, overall.

Cardiovascular death was seen, although again significantly just in the first of the four or five trials, really. Hospitalization for heart failure is a consistent finding in every single trial. And improvements in renal outcome also seen across the trials. And so this really adds further evidence and more patients to the meta analysis to support the guidelines that made a major shift a year or two ago to recommend this class of drugs across various types of patients, notably those with atherosclerotic cardiovascular disease, heart failure, and also chronic kidney disease. So hopefully an additional piece of information that adds to the support for our guidelines to try and use these in more patients.

The improvements in cardiovascular outcomes with this class are really exciting and a wonderful part of a new era in diabetes, really, that we're aiming now for clinical outcome benefits as opposed to tinkering with hemoglobin A1C. And then the benefits are broad. There's atherosclerotic patients, and they benefit largely in the cardiovascular death. Then there's heart failure, with a huge reduction that's seen uniformly. And then there's benefits on progression of kidney disease.

So an array of different areas of benefit of this class of drugs. Compared to GLP-1 receptor agonists, benefits largely parallel that, although with SGLT2s, the improvement in progression of renal disease is a stronger finding, whereas both this class and others will reduce albuminuria as a marker of progression of disease. So I think a better effect there on kidney disease.

And then there is an effect versus not much of an effect of GLP-1s on heart failure. So that aspect of kidney and heart failure is really somewhat unique to the SGLT2 inhibitor class. And so again, so exciting for us as we see patients with diabetes to profile them for atherosclerotic disease, heart failure disease, kidney disease, and then start choosing amongst the different new classes to offer benefits to patients.

I think for research, the findings are exciting, and there are other trials across all the different agents in more dedicated renal populations and heart failure. Many of those trials include patients without diabetes, where this class of drugs has effects on the intraglomerular pressure that probably drives some of the benefits. And that can pertain to those with or without diabetes, as beautifully seen in DAPA-HF. And so these classes may pertain to other disease areas beyond diabetes itself.

So when a drug class works, then it's incumbent on us to make sure we're finding all the patient populations who can benefit on the research side. And then on a day-to-day thing, it's incumbent on us as we see each patient or as we look at our system to try and make sure we're offering these helpful new therapies to all the patients who could benefit from them. And so improving our day-to-day sort of quality of care by making sure we're offering this to patients is a big focus for all of us, I think, and a take-home message from the meeting that we have yet more evidence supporting a beneficial class of drugs, and shouldn't we be sure to offer them to all the patients across these different domains of risk.