PracticeUpdate: There were two trials that studied sotagliflozin presented at this year's ACC. What issues did these trials study?
Dr. Scirica: There are two trials that evaluated the SGLT1 and 2 inhibitor sotagliflozin. And they are the SOLOIST, which was focused on patients with heart failure, and the SCORED study, which was focused on patients with cardiovascular disease and renal disease. The primary results of both of those studies were presented last year and came out and showed that sotagliflozin was effective at reducing hospitalization for heart failure; it was effective at reducing cardiovascular death, MI, and stroke, across both of those studies. So, in general, they were, I'd say, a very much a home run for this drug. That's a little bit different than the SGLT2 inhibitors that are on the market right now that we've learned a lot about over the past couple of years.
PracticeUpdate: How does SGLT1 inhibition clinically differ from SGLT2 inhibition?
Dr. Scirica: SGLT2 inhibitors really predominantly have their mechanisms of action, as far as we know, on the kidney where the sodium-glucose transport is inhibited and that increased glucose excretion helps with volume overload, it helps reduce blood pressure, it has favorable effects on renal hemodynamics to improve kidney function, and it also likely reduces the sympathetic nervous system and some of the hormonal effects of the kidney. The SGLT1 is actually a transporter for absorption of glucose and galactose in the GI tract. And by inhibiting that, sotagliflozin reduces the relation that the absorption of glucose absorption which may, and that's independent of insulin and some other activities, and sotagliflozin has a significant effect on the SGLT1 transporter as well as the SGLT2. So, there's still questions of whether that SGLT1 adds more in terms of glucose-lowering, but also how much does it add in terms of other non-glucose effects on the heart and the kidneys.
PracticeUpdate: What data were reported at the meeting?
Dr. Scirica: In this report, they pooled the data from SOLOIST and SCORED and looked at the overall outcomes of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in almost 12,000 patients from the two studies. And overall, and not surprisingly, they saw a significant reduction, about 28% in this endpoint between the two groups, between sotagliflozin and placebo, which is not surprising because that's what basically was seen in both trials.
But then what was important is that they then looked at this outcome based on baseline ejection fraction, and they found a very consistent result in those patients with heart failure, with reduced ejection fraction, meaning less than 40%, those patients in the so-called heart failure with mid-grade ejection fractions, or an EF of 40 to 50%, and in those patients with heart failure with preserved ejection fraction, so EF greater than 50%, where there was an almost 40% reduction in the risk of cardiovascular death, heart failure, or urgent heart failure visits.
And that's pretty important because we just haven't seen that quite so clearly from the other studies. When they looked at a couple of different ways of evaluating the outcome by ejection fraction, they showed that there really was a very consistent reduction across the spectrums of ejection fractions. So this does not seem to be a benefit that's limited to just low EF or reduced EF.
PracticeUpdate: How would you assess the clinical relevance of both SGLT2 and SGLT1/2 inhibitors?
Dr. Scirica: Yeah. I think this is important for clinicians in several ways. First, I think we all learned how powerful the SGLT2 and now SGLT1/2 inhibitor class is in heart failure. And for the SGLT1 and 2, we now have pretty robust data that it seems to have a benefit across the spectrum of ejection fractions. What is missing in the SOLOIST and the SCORED study is patients without diabetes. It is a totally type 2 diabetes population. In contrast, for the SGLT2 inhibitors, so for dapagliflozin and empagliflozin and canagliflozin, we have a lot of data in patients with diabetes, but they have with dapagliflozin now shown the benefit of SGLT2 inhibitor in patients without diabetes and heart failure with reduced ejection fraction. So they've taken that leap and demonstrated that in patients without diabetes.
PracticeUpdate: What data are you looking forward to on these drugs that can help you in your practice?
Dr. Scirica: We're waiting over the next year or two, hopefully, to hear the results of several of the ongoing studies of non-diabetic patients with heart failure with preserved ejection fraction with dapagliflozin and empagliflozin. But I think what will be very interesting, and what we don't know, is what is the effect of an SGLT1 and 2 inhibitor, like sotagliflozin, in non-diabetic patients. And whether the SGLT1 inhibition, which is predominantly affecting the gut glucose absorption, has any importance in the non-diabetic patient and whether that would translate into improved heart failure outcomes.
So, again, very exciting data. Overall, I think this is one more block of evidence showing that this class of drugs is a cornerstone in the treatment of heart failure overall, and I think now we're just waiting for data to try to fill in some of the smaller areas, with particular heart failure and whether they have diabetes or not, to really identify if it's a class-wide effect across all of them, or whether there is some benefit of one particular agent, SGLT2 inhibitor versus SGLT1/2 inhibitor, based on diabetes or ejection fraction.
PracticeUpdate: Are there clinically relevant differences in the adverse effect profiles of these two classes of drugs?
Dr. Scirica: For sure. So the side effect differences for SGLT2 inhibitor versus SGLT1 and 2 inhibitors is subtle, but it is there. All of the drugs that affect the kidney, so the SGLT2 effect, can be associated with some volume depletion, with hypotension, and it will increase the creatinine though it does preserve renal function, and those are things that have to be known. And it has been described that some patients, because they do not develop elevated glucose because of the SGLT2 inhibitor effect, couldn't get a hyperosmolar nonketotic acidosis. The SGLT1 inhibition, it seems to be, in some people it can cause some more GI discomfort and diarrhea, just because you are having a greater glucose load move through the gut, and that will bring liquid with it. And so, there tends to be more GI symptoms with the SGLT1 and 2 inhibitors versus what's reported in the SGLT2 inhibitors.