Dr. Deepak Bhatt on EMPACT-MI: Empagliflozin Cuts Heart Failure, Protects Kidneys

In a recent discussion, Deepak Bhatt, MD, director of the Mount Sinai Fuster Heart Hospital, highlighted key findings from the EMPACT-MI trial, which evaluated the safety and efficacy of the SGLT2 inhibitor empagliflozin in patients with recent acute coronary syndrome (ACS). The trial showed a significant reduction in heart failure-related events and confirmed the renal safety of empagliflozin in this high-risk population. A follow-up analysis, recently published in Nature Cardiovascular Medicine, demonstrated that empagliflozin not only preserves kidney function but also slows its decline compared with placebo—even in patients with pre-existing kidney dysfunction. Dr. Bhatt emphasized that although an initial drop in estimated glomerular filtration rate (eGFR) may occur, this stabilizes over time, reflecting a class-wide renal protective effect. He underscored the importance of not withholding SGLT2 inhibitors from patients with ACS who meet standard indications such as diabetes, chronic kidney disease, or heart failure, while noting that further research is needed to justify their use solely for ACS without these comorbidities.

Transcript:

Cardio Care Today: Let’s begin with the motivation—why was it important to look at kidney outcomes in patients with a recent MI, and how does this analysis expand the clinical relevance of the EMPACT-MI trial?

Dr. Deepak Bhatt:

The EMPACT-MI trial compared the SGLT2 [sodium-glucose cotransporter-2] inhibitor empagliflozin versus placebo in patients with a recent acute coronary syndrome. The overall trial found safety of an SGLT2 inhibitor in this setting. In terms of efficacy, while the primary end point wasn’t met, the total [number] of heart failure adverse events was actually significantly reduced with the SGLT2 inhibitor empagliflozin versus placebo.

These data add to the wealth of data at this point, showing the benefit of SGLT2 inhibitors in reducing heart failure outcomes in at-risk populations—whether they’re patients with diabetes, patients with heart failure, patients with chronic kidney disease, and, in this case, patients with acute coronary syndromes.

What was not entirely examined in that initial report in The New England Journal of Medicine was the effect on kidney outcomes, and that’s what we’ve examined now. This work was recently published in Nature Cardiovascular Medicine.

What we did in this analysis was examine the effects on kidney function, on adverse events related to kidney function, to see if, first of all, it was safe to start an SGLT2 inhibitor in this setting of a recent acute coronary syndrome and whether there was any benefit beyond what we initially showed with respect to heart failure adverse events.

The study shows an early decline in kidney function with empagliflozin at two weeks, but then recovery by week 4. Can you explain what causes this early drop, and why it’s not necessarily harmful?

It’s important to realize that in patients started on an SGLT2 inhibitor, there might be a decline in the eGFR, the estimated glomerular filtration rate, in the first couple of weeks after initiation. But, in general, there is recovery by about week four.

This is true in general with SGLT2 inhibitors. It’s particularly notable in acute coronary syndrome (ACS) patients where we might be worried that a patient that had an ACS is at risk for kidney dysfunction. A patient with acute coronary syndrome who gets a cardiac catheterization and intravenous, or in the case of a catheterization, intercoronary divide, that might alter kidney function.

In this milieu, would it be safe to introduce an SGLT2 inhibitor? There were legitimate concerns about this. But what we found was, in fact, it is safe to start an SGLT2 inhibitor in this setting.

Now having said that, one does need to be careful and need to be mindful of the overall kidney function, changes in kidney function, concomitant medications that might affect kidney function. But as a general statement, it’s fair to say that in the EMPACT-MI trial, in patients with ACS, it was indeed safe to start an SGLT2 inhibitor.

Now what causes that early drop is really multifactorial. The SGLT2 inhibitors have multiple effects on the kidney, [and] for that matter, on the heart as well. One of the effects they have is as a bit of a diuretic. So one tip in starting an SGLT2 inhibitor is if the patient is already on a diuretic, especially if the kidney function seems somewhat tenuous, it might be a good idea to back off on the dose of the diuretic. Again, that depends on not just their kidney function, but their overall volume status, whether they do or don’t have symptomatic heart failure.

But the bottom line is that as physicians, we shouldn’t necessarily be scared by an early decline in the eGFR on initiating an SGLT2 inhibitor, and for that reason alone, stop it. In fact, this is something that’s also noted with things like ACE [angiotensin-converting enzyme] inhibitors or angiotensin receptor blockers, though with longer follow-up. SGLT2 inhibitors and those other drugs I mentioned do have kidney-protective effects. So, yes, there can be a dip in measurements of kidney function initially, but [we] mustn’t overreact to that.

After the initial dip, patients on empagliflozin had more stable kidney function than those on placebo. What do you think drives this longer-term kidney benefit in post-MI patients?

What we saw in EMPACT-MI was that, over time—in those patients where the kidney function was measured—that it was stable in those patients on empagliflozin but declined, that is worsened, in the patients on placebo. Essentially when you compare the two, there is a significant benefit in favor of empagliflozin versus placebo. These data add to the other data for this class of medicines, SGLT2 inhibitors, showing that they have kidney-protective effects.

Now this benefit is magnified in patients with heart failure or patients with diminished kidney function to start. In fact, there’s a lot of overlap between those two populations. The reason that SGLT2 inhibitors, such as empagliflozin, have a benefit on kidney function is really due to multiple different effects that they have, and it’s really been well demonstrated in trials of patients with kidney disease, dedicated trials of patients with CKD [chronic kidney disease], that this protective effect is real and reproducible and appears to be a class effect across SGLT2 and, for that matter, SGLT1 combined SGLT2 inhibitors as well.

So a class effect. But we demonstrated very nicely, in an ACS population, which hadn’t been done before, that SGLT2 inhibitors, in fact, are overall safe, safe from a kidney perspective and also efficacious from a kidney perspective.

Empagliflozin helped preserve kidney function even in patients who started with lower eGFR. Were you surprised that the benefits were so consistent?

It was reassuring to see that the benefits of empagliflozin in the EMPACT-MI trial were so consistent across various subgroups. As we examined the effect on kidney function, it seemed to be a consistent benefit even in patients with diminished kidney function to start, that is on the lower range of the eGFR spectrum. To me, that’s really very encouraging data showing that SGLT2 inhibitors … empagliflozin specifically in this case, but I do think it can be generalized to the class of drugs, that SGLT2 inhibitors help preserve kidney function even in those [patients] that start off with pretty bad kidney function.

This is consistent with the labeling in most parts of the world for the SGLT2 inhibitors, where even down to an eGFR of 20, it seems like a good strategy to start these medicines, and in fact, they help preserve kidney function.

Of course, one does need to be careful when using SGLT2 inhibitors in this range of GFR. These sorts of patients really should also be under the care of a nephrologist because … not due to the SGLT2 inhibitor, but if their eGFR is out low to begin with, well, dialysis is something that’s potentially in their future; and, of course, steps to try to prevent that, such as SGLT2 inhibition, are generally warranted but must be done with care and with caution. But the benefit across the various subgroups of diminished kidney function is really an important finding.

The study also showed empagliflozin reduced the risk of heart failure events and death, no matter the patient’s kidney function. How do you think these heart and kidney effects are connected?

In addition to the kidney benefits, there was also a reduction in heart failure– type events with empagliflozin versus placebo in EMPACT-MI. It is, in fact, the case that heart failure and kidney dysfunction are interconnected in many ways; that is, heart failure can contribute to kidney dysfunction, and likewise, preexisting kidney dysfunction makes the treatment of heart failure more complex because many of the medicines that we use to treat heart failure end up affecting kidney function deleteriously. It’s a bit of a vicious circle, each making the other worse and each coexisting oftentimes.

It’s really tricky when both these conditions are present. But, fortunately, SGLT2 inhibitors—as we saw with empagliflozin in EMPACT-MI—can be particularly useful not only to prevent heart failure events in patients with varying degrees of kidney dysfunction, but likewise in patients with varying degrees of kidney dysfunction, heart failure events are also reduced. So it goes in both directions, that is, reductions in heart failure events across kidney dysfunction and reductions in kidney events across levels of kidney dysfunction. The coexistence of both of these two disease states, which is common, is well addressed by SGLT2 inhibitors.

Some physicians worry about using SGLT2 inhibitors in patients with low blood pressure or poor kidney function. What did this analysis show about empagliflozin’s safety in those groups?

With respect to low blood pressure, one does need to be a bit cautious. SGLT2 inhibitors do lower blood pressure by a little bit, but that is not so much an issue when the blood pressure is normal or low to begin with. But if someone had symptomatic low blood pressure, then you really do need to think twice about starting [an] SGLT2 inhibitor. In that context, you have to figure out why their blood pressure is low and correct it.

Oftentimes in the heart failure patient, that’s because of excessive volume depletion, perhaps from diuretic use. If one backs off on the diuretic and the blood pressure normalizes, then initiation of an SGLT2 inhibitor is typically safe.

As far as patients with preexisting kidney dysfunction there as well, SGLT2 inhibitors can be safely initiated. We’ve seen that in prior trials of patients with chronic kidney disease, as well in EMPACT-MI. We see that it’s safe to initiate an SGLT2 inhibitor even in an ACS patient with poor kidney function. So a patient that is somewhat high risk. But nonetheless, it did seem safe to start the SGLT2 inhibitor, safe overall, but safe also with respect to kidney function. But one has to do this with careful monitoring—careful monitoring of the kidney function, the patient’s volume status, and of the patient overall.

The study also showed empagliflozin reduced the risk of heart failure events and death, no matter the patient’s kidney function. How do you think these heart and kidney effects are connected?

Preserved ejection fraction has already been studied. We first showed in the SOLOIST trial as published in New England Journal of Medicine with sotagliflozin, a mixed SGLT1, 2 inhibitor, a significant benefit in the subgroup of patients with heart failure [with] preserved ejection fraction, as we did in the overall trial in patients with acute decompensated heart failure who were then stabilized. Then subsequently, trials of both empagliflozin and dapagliflozin showed benefits specifically in patients with heart failure [with] preserved ejection fraction either with or without diabetes.

So that, I’d say, is already pretty well known; one could still ask questions like, is there a difference between SGLT1, 2 inhibitors versus SGLT2 inhibitors? Those types of trials would be really interesting to see if there are any incremental benefits of SGLT1/2 blockade over SGLT2 blockade alone. But in terms of heart failure [with] preserved ejection fraction, the jury is in: SGLT2 inhibitors are indicated unless there’s some contraindication.

The evidence for SGLT2 inhibitors in both heart failure with reduced and preserved ejection fraction at this point is incontrovertible. As far as EMPACT-MI goes, these were patients with acute coronary syndromes, and I wouldn’t say acute coronary syndromes per se are an indication to use an SGLT2 inhibitor. We’d need more study to really prove that. What EMPACT-MI tells me, at least in terms of conclusions, is that if we have an ACS patient who otherwise should be on an SGLT2 inhibitor, such as a patient with diabetes or with heart failure, with either reduced or preserved ejection fraction, or with chronic kidney disease, we should use an SGLT2 inhibitor for those reasons and not be scared to use it just because the patient had come in with an ACS.

Of course, you’d want the patient to first be stabilized. You wouldn’t want to do this in someone, say, who’s in shock or critically ill. But once they’ve been stabilized towards the end of that ACS hospitalization, then I think it is safe and in fact a good idea to start an SGLT2 inhibitor if they meet those other indications.

But I wouldn’t say that EMPACT-MI, for example, in a patient without heart failure or without chronic kidney disease, without diabetes provides any compelling argument to start an SGLT2 inhibitor. To do that, we would need another larger trial. That would be a good trial to do with an SGLT1, 2 inhibitor where that class of agents also has an effect on ischemic end points, which we didn’t see in EMPACT-MI where empagliflozin didn’t reduce MI [myocardial infarction] or stroke. For that matter, a trial of dapagliflozin in ACS patients also didn’t show a reduction in MI or stroke, whereas sotagliflozin in the SCORED trial of patients with diabetes and chronic kidney disease did show a significant reduction in MI and stroke as recently published in Lancet Diabetes and Endocrinology.

So [there is] definitely room for more research on the topic, but in terms of your question about heart failure with preserved rejection fraction, the bigger challenge is getting the many patients with that condition who aren’t on an SGLT2 inhibitor on one.

What key takeaways would you like to leave our audience with today regarding these data?

Absolutely. So, first of all, the data for SGLT2 inhibitors broadly as a class at this point are extremely large, extremely consistent. The drugs remain underutilized. Some of that has to do with cost, but the drugs will be going generic in the next couple of years worldwide. Hopefully, cost won’t be so much of an issue. But even now, there are certainly patients for whom they should be used despite the potential issues with cost because of the overwhelming amount of evidence from randomized clinical trials, the guideline endorsement of SGLT2 inhibitors.

In particular in patients with heart failure with either reduced or preserved rejection fraction or with chronic kidney disease. And in these patients with or without diabetes, they really should be on an SGLT2 inhibitor unless there’s a contraindication. I’d go one step beyond to say [that] even for patients without heart failure or without chronic kidney disease, if they have diabetes and there’s no contraindication, really SGLT2 inhibitors are something that should be strongly considered, along with GLP-1 [glucagon-like peptide 1] agonists or dual incretins.

These are agents that are much better than the older diabetes drugs. If one puts aside the cost issues, these are drugs and drug classes that have marked benefits on cardiovascular end points and also kidney end points in patients with diabetes. Those are the types of patients for whom I think SGLT2 inhibitors really should be used unless there’s a contraindication.