There was consistent, and significant, benefit across all categories of ejection fraction—preserved, reduced, and midrange—but especially among those with preserved ejection fraction, noted Deepak L. Bhatt, MD, MPH, Brigham and Women’s Hospital Heart & Vascular Center.
There was consistent, and significant, benefit across all categories of ejection fraction—preserved, reduced, and midrange—but especially among those with preserved ejection fraction. And this shows a possible benefit to using sodium-glucose cotransporter inhibitors in these patients, said Deepak L. Bhatt, MD, MPH, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center, professor of medicine at Harvard Medical School, and principal investigator for the study.
Bhatt, who presented “Benefits of Sodium Glucose Co-transporter-1/2 Inhibition With Sotagliflozin Across the Full Spectrum of Ejection Fraction, Including Heart Failure With Preserved Ejection Fraction,” on the final day of ACC.21, the American College of Cardiology’s 70th Scientific Session, was principal investigator of the study that pooled data from the SOLOIST and SCORED trials.
Can you discuss the importance of your findings in light of the connection between diabetes and heart failure?
So what we did first of all, just to recap, was a patient-level analysis of SOLOIST and SCORED, 2 trials of an SGLT1/2 [sodium-glucose cotransporter 1/2] inhibitor in patients with diabetes and heart failure; in fact, admitted with acute heart failure in the case of SOLOIST, and in SCORED, patients with diabetes plus chronic kidney disease outpatients.
Now in SOLOIST, everyone had heart failure; could have been heart failure with reduced ejection fraction, heart failure with preserved ejection fraction. And in SCORED, which was an outpatient population, some of the patients had heart failure, some didn't. And the type of heart failure again, could have been heart failure with preserved ejection fraction, so-called HFpEF; heart failure with reduced ejection fraction [HFrEF]; or heart failure with midrange ejection fraction.
We did capture ejection fraction at baseline, and in the vast majority of patients—and therefore in the overall pooled population—we analyzed the effects of the drug as a function of the ejection fraction and there was a significant reduction in the primary endpoint of cardiovascular death, total hospitalizations for heart failure, and urgent heart failure visits, irrespective of the EF [ejection fraction] in that total pooled population. But then specifically in the 4500 or so patients with a history of heart failure—again, examining outcomes is a function of baseline ejection fraction—we saw consistent and significant benefit across all those categories of ejection fraction I mentioned. Importantly, including a significant benefit in patients with heart failure with preserved ejection fraction, which to date there has not been any randomized clinical trial data, prospectively collected data, in a prespecified analysis that has shown a significant benefit.
So that really is a novel contribution to the field and one that I think is likely generalizable to the SGLT2 inhibitor class, although as I mentioned, the drug we studied is an SGLT2 inhibitor, but it also has some SGLT1 inhibition as well.
What is the dual mechanism of sotagliflozin, and how does it offer an advantage over SGLT2 inhibitors?
With respect to the mechanism of action, it's an SGLT2 inhibitor, similar to several drugs that are available right now for clinical use. And SGLT2 inhibitors lead to enhanced glucose excretion in the urine. in fact, that's the diabetes mechanism. They've got lots of other benefits that they appear to provide in terms of weight reduction and blood pressure reduction of a modest degree. But still, I think all of those different things contribute to the large clinical benefits that have been observed in prior trials with the entire class of medications known as SGLT2 inhibitors.
SGLT1 also has an effect in the kidney, where it does lead to a slight increase in glucose elimination. In that part of the proximal renal tubule where glucose has escaped the SGLT2, SGLT1 is there to do the job SGLT2 was supposed to do. So SGLT1 inhibition does have some slight incremental effects in the kidney, but perhaps more relevant, there is SGLT1 expressed in the gut, the digestive tract, the intestines, and there SGLT1 inhibition leads to decreases in postprandial glucose. That is, if someone, or anybody, eats something, afterwards the blood sugar glucose goes up; if they have diabetes, it can go up a lot. That's believed to be deleterious to health even beyond just having high glucose. That sort of spike in glucose is also believed to be bad for health, and sotagliflozin via its SGLT1 inhibition, blunts that type of postprandial glucose excursion that would otherwise occur.
So that's believed to be its dual mechanism of action and why it might have something more to offer than an SGLT2 inhibitor. Of course, without any head-to-head clinical trials, that's largely speculative. The only thing that I can concretely say whether this particular drug may have a benefit over an SGLT2 inhibitor is in patients with diminished kidney function; that is, a low GFR [glomerular filtration rate]. In those sorts of patients, this particular drug is quite effective in lowering their glucose, their hemoglobin A1C, whereas typical SGLT2 inhibitors lose their ability to effectively lower glucose at the lower ranges of GFR. They still provide cardiovascular benefits, but in terms of glycemic control, they're less potent, so if this drug were to be approved, that’s one potential advantage
Can you discuss your finding on CV death relative to recent findings in dedicated heart failure outcomes trials for SGLT2 inhibitors?
Sure. So first, just to be clear, for the intent-to-treat analysis, we did not see a significant reduction in cardiovascular [CV] death, although directionally it was lower. And an on-treatment analysis—meaning analyzing patients who were actually taking the medication—there was a significant reduction in cardiovascular death in this pooled analysis that I just presented.
The trials, SOLOIST solaced and SCORED, both ended earlier than we had planned because of loss of funding from the sponsor; basically, they didn't have enough money to continue the trials. And at the onset of the COVID pandemic, they were unable to raise any capital to do that. So the trials both ended earlier than we planned, and I think that abbreviated follow-up hurt the statistical power to see things like a significant reduction in cardiovascular death in the intent-to-treat analysis. But by now looking at on treatment, that gives us a bit more of a precise estimate of the drug’s effect, because the patients who stopped that study drug for whatever reason aren'tcounted for that part when they're off the drug. Because, of course, when they're off the drug, it can't possibly provide a benefit. So, the on-treatment analyses, I think, show us what would have happened than if we had just continued the trial longer and have more statistical power, that the drug does lower CV death.
Now, sometimes those on-treatment-type analyses can be quite biased. If, for example, a drug is causing lots of side effects, like, bleeding or something, then the on-treatment analyses may be a little bit biased because it provides us too much of a best-case scenario—because if there are a lot of side effects, and that's why patients are stopping, well, then that's understandable. But in the case of SOLOIST and SCORED, actually the rates of drug discontinuation, overall rates of side effects, tolerability, were virtually identical between the drug and the placebo arm. It was actually very well tolerated.
So the patients coming off the study drug, it was the same percentage with the drug and with the placebo. Those were people that might have been having side effects but were also having them to placebo, so that probably means that it wasn't attributable to the drug per se. And therefore, by looking at those patients who actually were adherent to therapy, we can get the real benefit that would be there from the drug. If it were an isolation, I might be a bit skeptical, but really, as a class, the SGLT2 inhibitors have shown reductions in cardiovascular death. Not in every particular trial, but in the majority of trials, there's either a significant reduction in cardiovascular death, or at least directionally the point estimate is favoring the SGLT2 inhibitor vs a placebo. The exact differences depend on the study durations, the exact populations, but I believe, as meta analyses have shown and confirmed, that as a class, the SGLT2 inhibitors in the right patients, in high-risk patients, do reduce cardiovascular and, for that matter, all-cause mortality.
What is the importance of the findings in HFpEF, especially with the FDA’s recent approval for the indication absent a positive finding?
Well, as it's been publicly disclosed, the company that currently has the rights to sotagliflozin had approached the FDA, and as has been publicly disclosed, that initial communication was quite positive with respect to a potential heart failure indication. The company subsequently publicly announced that they plan to formally file for FDA approval. So our hope is once we get all the analyses together that the FDA will review the data and will hopefully agree that the drug does deserve a heart failure indication. That would hopefully include HFpEF, as well as HFrEF and midrange ejection fraction as well. So that's my hope, but we have to see how that all actually plays out.
But you're right. There are other approvals based on trials that didn't actually meet their primary end point in the strictest sense.
Can you discuss the findings for patients with midrange ejection fraction heart failure?
We had prespecified heart failure with reduced ejection and heart failure with preserved ejection fraction. I guess we didn't really think about prespecifying that middle range. But basically, that's what's left, and that's what's in the middle of those 40% and 50% cut offs. And that's why it wasn't exactly prespecified. But as it turns out, whether one looked at our prespecified or post hoc analyses, everything was really quite consistent, showing significant benefits across the full range of ejection fraction: those with clear heart failure with reduced ejection fraction, that clearly with heart failure with preserved ejection fraction, and those in that middle range.
And the middle range is a bit tricky. Are those people that really have heart failure with mildly reduced ejection fraction? Are they people that had heart failure reduced ejection fraction in the past but they recovered somewhat since then? There's a bit of a heterogeneous bag there in terms of who gets into that. But nonetheless, among heart failure experts that's emerged as another discrete category. So that's why we reported it that way. Unfortunately, there was consistency across all the categories.