In patients with heart failure and diabetes, sotagliflozin can lower glucose quite well, even when patients are facing suboptimal glomerular filtration rates, noted Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital and Harvard Medical School.
In patients with heart failure and diabetes, sotagliflozin, an SGLT1/2 inhibitor, can lower glucose quite well, even when patients are facing suboptimal glomerular filtration rates, whereas with SGLT2 inhibitors, that capability is markedly diminished, explained Deepak L. Bhatt, MD, MPH, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center and professor of medicine at Harvard Medical School.
Bhatt's presentation "Benefits of SGLT2-1/2 Inhibition on Heart Failure, Ischemic, and Kidney Endpoints" will be available on-demand during ESC Congress 2021, this year's virtual meeting of the European Society of Cardiology.
Can you recap the findings for the SOLOIST and SCORED trials for sotagliflozin, a combined SGLT1/2 inhibitor?
It's an SGLT2 [sodium glucose co-porter 2] inhibitor. Sometimes it's a lumped in with that class. And of course, there are several SGLT2 inhibitors that have great data: empagliflozin, dapagliflozin, for example; canagliflozin; ertugliflozin, as well. So, there's a lot of great data for the SGLT2 inhibitors as a class, and sotagliflozin is indeed an SGLT2 inhibitor. But additionally to that property, which it shares with those other drugs, it's also an SGLT1 inhibitor.
First of all, SGLT2, probably everyone in your audience knows this, already is expressed in the kidney and inhibition of SGLT2 leads to enhanced excretion of glucose. That's why SGLT2 inhibitors are still good diabetes drugs, although now they're also turning into heart failure and kidney drugs. There's also SGLT1 expressed in the kidney, and by inhibiting SGLT1, there’s some additional glucose-lowering, glucose excretion that can occur from the urine. But the bigger place that SGLT1 is expressed more so than the kidneys, in the gut and thereby by inhibiting SGLT1, there are decreases in postprandial glucose excursion.
So typically after a meal, the glucose gets higher. SGLT1 has a beneficial effect in terms of blunting that rise that would otherwise occur. So, it's a fact that’s somewhat distinct from the kidney effects, and potentially then in patients that have various degrees of kidney dysfunction, diminished GFR [glomerular filtration rate], the SGLT1 can kick in for helping stabilize glucose levels—even if the SGLT1 doesn't have as much effect—because the GFR is low.
We know from other trials of other SGLT2 inhibitors that the glucose-lowering ability of SGLT2 inhibitors is diminished—say as the estimated GFR gets under 30—but there may still be benefit for heart failure or kidney end points. But in terms of the glucose-lowering capability, it's markedly diminished. But with sotagliflozin, there's still the ability to lower glucose quite well. In fact, in one of the two trials, I mentioned, the SCORED trial, we see that there was a significant reduction in hemoglobin A1C and similar magnitude in those with GFR above or below 30. So the SGLT1 definitely has that benefit, in patients with low GFR, of attaining better glucose control.
Does it have additional benefits beyond that? Well, that's something that I'm sure you and I will discuss here in the next few minutes, and something that will be best sorted out with future studies, but nonetheless, that's what sotagliflozin is.
We studied it in 2 large randomised clinical trials. The first was called SOLOIST, and the second was called SCORED. Both were published in New England Journal of Medicine simultaneously with the AHA [American Heart Association] late-breaking clinical trial presentations in November of 2020. Each was listed among the top advances in heart disease and stroke by the AHA for 2020.
SOLOIST consisted of about 1200 patients with diabetes and heart failure who were randomised to receive either a placebo or sotagliflozin. And they were randomised either in the hospital or within 3 days after discharge. Now when I say heart failure, here I'm referring to heart failure that is acute. So this is acute decompensated heart failure plus diabetes, ending up in the hospital, being initially stabilized, coming off the ventilator, off intravenous inotropes, and that sort of thing—so stabilised transitioning from intravenous oral diuretics. And then they are randomised to placebo or sotagliflozin.
About half the patients got randomised in the hospital, about half in the 3 days after discharge. The primary end point is the total number of cardiovascular deaths, hospitalizations for heart failure, and urgent heart failure visits, and the randomization is to placebo vs sotagliflozin 200 mg/day with restart protocol intended to get all the patients up to 400 mg/day of sotagliflozin or matching placebo, unless there were side effects. Things like hypotension or kidney failure, something that prevented that type of uptitration.
And we got to make sure to come back to that, because those data for what happens with the uptight tration is what I just presented at the European Society of Cardiology. But, you know, first, let me just stick with the overall trial design and results for soloist. And as I mentioned, patients with decompensated heart failure are admitted to the hospital, we check BNP [brain natriuretic peptide] levels to make sure it was really heart failure.
The overall primary end point that I mentioned, was very significantly reduced. There was a large reduction both in relative and absolute terms. In relative terms, it was a 33% reduction, so a hazard ratio of 0.67 and a P value 0.0009. In that primary end point of total cardiovascular deaths, hospitalizations for heart failure, urgent heart failure visits, the absolute risk reduction was large as well: about 25 events per 100 patient-years that were averted. Flipping that around in terms of numbers needed to treat, you'd have to treat 4 patients for a year to avoid 1 event. So that's a really low number needed to treat. So very large benefit, a very early benefit in that end point. It was statistically significant by a month.
So you might say, “Well, you know, SGLT2 inhibitors, I like them, but you know, I'm not going to start them in the hospital. Let's wait and see. When a patient comes back in 2 weeks or a month or 6 months or a year, you know, think about it then.” Well, better to do it then than ever. But the problem with that approach, is there are a lot of events that occurred just in that first month. See, really, if otherwise appropriate, no contraindications, I think these data support early initiation of SGLT2 inhibitors as a class. We studied specifically sotagliflozin, but I think ultimately future trials will show this to be a class effect.
Can you discuss the importance of the finding of the 400-mg dose presented at ESC?
I presented the overall SOLOIST and SCORED results, as published New England Journal of Medicine, but we've also pooled the data. Some of it was presented as a late breaker at the American College of Cardiology, where we looked at the benefit across the full range of ejection fraction and found significant benefit for sotagliflozin vs placebo. That is, pooling SOLOIST and SCORED, there was a benefit across the full range of ejection fraction, whether it was HFrEF [heart failure with reduced ejection fraction], heart failure with midrange injection fraction, heart failure with preserved ejection fraction [HFpEF]. So across that full range, even just totally normal ejection fraction, there was a consistent significant benefit of sotagliflozin vs placebo.
So the benefit of that analysis is it showed us that the HFpEF finding that we found in SOLOIST, in a subgroup with HFpEF, we also saw on SCORED. In fact, those data are published in the supplement the New England Journal of Medicine [did for] SCORED. I don't know that everyone necessarily looked at the supplement, but if you look at the HFpEF subgroup as we defined it there, there's also a significant benefit in SCORED. So we trial individually did show benefit. But when we pooled the data for HFpEF there, it's quite clear there's a robust benefit across the entire range of ejection fraction, confirming that this really is the first data set to show a significant benefit in heart failure with preserved ejection fraction. Those data were formally presented as a late-breaker at ACC [American College of Cardiology].
Now, at ESC, as a late breaker, what was presented specifically is the dosing. It turned out that about three-quarters of patients were titrated to the 400-mg dose, and the other 27% or so stayed at their 200 mg initial dose. Now that could have been because of side effects. Of course, clearly the physician and/ or patient thought side effects were occurring and therefore the uptitration didn't occur. But what's interesting, though, is that these rates were identical, essentially, in the placebo and drug arm. Yes, about a quarter of the patients weren't uptitrated because of perceived side effects, but those rates were the same in placebo and drug. So the drug overall was tolerated as well as the placebo. So the lack of uptitration, yes, the patient might have been hypertensive, but it wasn't because of the drug. And so the lack of uptitration, it’s just because that often happens in real life. There are perceived side effects that are attributed to a drug or a placebo. So overall, this drug was as safe as and tolerated as well as the placebo.
That's not to say there aren't some side effects with the drug. Obviously—as we previously presented, as published in New England Journal—compared with placebo, there's a slight but significant increase in diarrhea, probably from the SGLT1. And otherwise, it has the same side effects that other SGLT2 inhibitors have: small but potential risk of things like DKA [diabetic ketoacidosis], and so forth, but overall, really well tolerated.
And if we look then at the patients who achieved that 400-mg dose of drug or placebo, and see how the drug fared, the results look even better than what I presented. So that was really the gist of the ESC presentation: Where the uptitration successfully occurred, the reductions in heart failure were even larger than what was seen in the overall trial. So as is typically the case, when there's a target dose, if you attain it, it appears there's even greater benefit.
Given the stroke benefit seen with sotagliflozin, how does that relate to the GLP-1 receptor agonists, which are more commonly associated with a stroke benefit?
In terms of SGLT2 or SGLT1/2 inhibitors vs GLP-1 receptor agonists, again, I don't see it as an either/or. I think these are both great classes of medicine, and putting cost issues aside, which are not trivial issues—it's quite substantial if you're using both classes of medicines—I think there are many patients with diabetes that would benefit from being on an SGLT1/2 inhibitor. Potentially in the future, an SGLT1/2 inhibitor, plus a GLP-1 receptor agonist. I've no reason to think that the two are competitive. I think they're complimentary. I don't know if I’d go so far as to say they're synergistic.We don't have a ton of data about combining these classes of medicines. But we do have from the AMPLITUDE trial, for example, as published in New England Journal of Medicine, some data for that particular GLP-1 receptor agonist—and it's not commercially available, what was studied there—plus SGLT2 inhibitors, that subgroup looked pretty good to me and pretty convincing that there wasn't any diminution of benefit.
So my own feeling is, both of these are great classes of medicine. Now, the SGLT1 perhaps is having some benefit on atherosclerotic events, as GLP-1 receptor agonists do, but once more, I think that they're likely complimentary and not competitive in their mechanisms of action. And even other SGLT2 numbers, beyond sotagliflozin, in some of the trials do show benefits on myocardial infarction as well. Perhaps more modest than what we saw, but still there appears to be something there. So sometimes hard to tease out what are the differences between trials, whether it's a drug or there's a specific population study—usually it's a bit of all of the above—but I think with respect to your question, I would say that GLP-1 receptor agonists are here to stay.
The amount of data for them is certainly growing by leaps and bounds, as is also true for SGLT2 inhibitors. To date, SGLT2 inhibitors have had more effect on sort of heart failure–related outcomes, GLP-1 receptor agonists more so on ischemic outcomes. Those are some signals of benefit on heart failure as well. Both appear to have benefits with respect to kidney-related outcomes. Both presumably would have effects on microvascular outcomes. Overall, both really good, underutilized classes of medicines and both reasonably well tolerated with good side effect profiles.
As you mentioned, the majority of GLP-1 receptor agonists are injectable, but now there is also an oral version as well. I think both classes of medicines will grow. Perhaps the SGLT2 inhibitor growth curve will be a little bit quicker, because there are a bunch of oral medications that are available and doctors are more familiar with, but I suspect over time, both classes will really grow.
And as far as sotagliflozin and it's fate, that first depends on its regulatory status. We're hoping in the meanwhile to get out a lot of data from the SOLOIST and SCORED programme that will help the field in general understand SGLT2 inhibitors and, if the drug is approved, hopefully help doctors understand exactly where it might provide benefits and perhaps specific benefits beyond other SGLT2 inhibitors.