SGLT2 Inhibitors vs GLP-1 Agonists: Go It Alone or Join Forces?

This transcript has been edited for clarity.

Yehuda Handelsman, MD, FACP, FNLA, FASPC, MACE: Welcome and thank you for joining our discussion. My name is Yehuda Handelsman. I'm an endocrinologist in solo private practice in Los Angeles. I am also involved in clinical research and education. With me is Dr Matt Budoff.

Matthew J. Budoff, MD: I'm Matt Budoff. I'm a preventive cardiologist and I've been involved in many of the diabetes trials throughout the past 5-10 years. I also work with Dr Handelsman on some of the educational programs.

Handelsman: I thought we would discuss today the whole issue of the new medications for diabetes. We call them new but they're not that new. We're talking about the GLP-1 receptor agonists that have actually been on the market for 17 years. The long-acting ones have been on the market for 15 years.

We are also discussing the new SGLT2 inhibitors that came to the market in 2013, so that's 9 years. These drugs are not new anymore. The reason we keep saying "new" is because of the outcomes of recent trials which show that these drugs, which were initially for glucose control, actually have cardiovascular and kidney benefits. We say "new" even though the results are not so new, with outcomes starting to be reported in 2015. If we count, it's already 7 years. Nothing is new in medicine nowadays when we receive double the information every 3 months or so.

Matt, when did you become interested in these drugs?

Eye-Opening Outcomes: Clinical Trial Results and Practice Recommendations

Budoff: When the EMPA-REG OUTCOME trial came out, I think that really changed [cardiologists'] perception of these agents and their ability to reduce cardiovascular events. This has been followed by so many trials that have just shown more and more cardiovascular benefits of both of these classes of agents.

Handelsman: I heard you in a discussion with other cardiologists, and I keep hearing it all the time, that we, the endocrinologists and diabetologists, have this glycemic-centric view of managing patients with diabetes. That's absolutely not correct. As you know, I've always looked at the comprehensive approach — the lipids, the blood pressure, and cardiovascular disease. I'm glad that cardiologists now finally recognize the fact that patients with diabetes have a high cardiovascular risk that we need to manage to prevent cardiovascular disease.

Are you able to use these drugs in your practice?

Budoff: Yes. We have a wide access to both in our system here. We can use SGLT2 inhibitors and GLP-1 receptor agonists for the appropriate patient.

Handelsman: It's kind of interesting. I said we're not glucose-centric, and in fact I do believe that controlling glucose is very important long term. In the short term, the data surrounding these drugs show that, independent of glycemia, we can actually prevent cardiovascular disease.

How do you use it? How do you choose?

Areas of Expertise

Budoff: From a cardiovascular standpoint, these agents, although they have a lot of overlap and benefits with their weight reduction and A1c benefits, I see the SGLT2 inhibitors as being a little stronger in the heart failure and the renal side of things, and the GLP-1 receptor agonists being a little stronger in the ASCVD (atherosclerotic cardiovascular disease), coronary artery, and ischemic stroke realm. I think of vascular disease vs pump disease and choose the right one first, although both are probably better, of course.

Handelsman: I've been involved in guidelines — and full disclosure, specifically the American Association of Clinical Endocrinology — and various recommendations. In the last recommendation we had in 2020, we still said to choose either one. We really did not differentiate.

Recently, you and others joined me and we created this DCRM (diabetes, cardiorenal, metabolic) Multispecialty Practice Recommendations. We were trying to approach managing these very complicated patients with diabetes from each direction — from the cardiologist, from the nephrologist, from the primary care physician, and from the diabetologist.

What did you take out of this approach?

Budoff: I think it was incredible to be working with so many people from different specialties to try to come up with a uniform practice recommendation. To your credit as our chair, it was really a big success and I hope it gets widely used.

I think it's very helpful. I think you can talk about what disease predominates in that person. If it's obesity, then you might want to go with a GLP-1 receptor agonist because they're a little better for weight reduction. If it's A1c control, probably a GLP-1 receptor agonist may be the better first-line therapy. I think our guidelines were to try to use both these great agents, if possible, together, and we can't always do that because of cost. I think, largely, that's where we should be going with diabetes control these days.

Handelsman: I think in the recommendation, we did try to differentiate better when to choose one, so kind of improving what we've done in the past with other medical societies and trying to say when to use which.

Best Practices in Optimizing Medication Usage for Renal and Heart Failure Considerations

Handelsman: I think you're right. I think it's clear that if somebody has chronic kidney disease today, we have to choose an SGLT2 inhibitor because of the great data that we received, actually from all the SGLT2 inhibitors, and particularly we have seen it with empagliflozin and dapagliflozin. We also see that impact in patients without diabetes, which was important for our recommendation because we looked at patients not just with diabetes but also with cardiorenal metabolic complications.

When we are looking at strokes, clearly long-acting GLP-1 receptor agonists — specifically semaglutide and dulaglutide — are very specific in preventing stroke. These two extremes are very clear. Another extreme is HFrEF (heart failure with reduced ejection fraction or systolic heart failure). A patient with HFrEF with diabetes or without diabetes should use an SGLT2 inhibitor.

Is that what you're doing in your practice, now that we're separating it this way?

Budoff: Yes, for sure. For coronary disease, I believe the data will bear out and the GLP-1 receptor agonists will also be better — although the biggest benefit was ischemic stroke — but I agree. In my practice, if they lean toward coronary disease and diabetes, I'm thinking GLP-1. If they're leaning toward heart failure, certainly, SGLT2 inhibitors. I think we have to remember that the SGLT2 inhibitors, as you mentioned, now extend beyond diabetes for both the renal benefit and the heart failure benefit. We don't have that type of data with the GLP-1s; they're still relegated to persons with diabetes.

Handelsman: What's interesting with the SGLT2 inhibitors, and we already incorporated this in our DCRM recommendations, is that they have data not only on HFrEF but also on HFpEF (heart failure with preserved ejection fraction). I hope they're not going to change the name to normal ejection fraction, but that's a different discussion altogether.

Now, the recommendation for SGLT2 inhibitors is for any heart failure. Is that what you see in practice?

Budoff: Yes, absolutely. Now that we have trials, one with empagliflozin and one with dapagliflozin, I think it's going to be a class I recommendation for any type of heart failure to be on an SGLT2 inhibitor.

Exciting Developments on the Horizon

Handelsman: Yes, it's interesting. We already have another drug, but we don't have it yet on the market — sotagliflozin — which also showed very strong data on both HFrEF and HFpEF. It's supposed to be an SGLT1 and SGLT2 inhibitor. Some people like to target one part of that, maybe for cardiovascular considerations. It's not on the market, so I don't want to spend too much time on it in this discussion, but it does look like an SGLT2 inhibitor will help heart failure, whether it's HFpEF or HFrEF.

HFpEF seems to track the obesity epidemic. Is that what you're seeing in practice?

Budoff: Absolutely. I think that's why I'm optimistic that we might get some good data out of a GLP-1 receptor agonist, especially for HFpEF, where weight reduction is pronounced, and it looks like it has a nice benefit in that regard. We're obviously waiting for those trials to finish before we can start using it in that capacity.

Handelsman: In the studies that we have seen, and that's how our recommendations developed, SGLT2 inhibitors were for the kidney first, but because we've seen some benefit in trial outcomes of GLP-1 receptor agonists on the kidney as well, we said that if we cannot go with an SGLT2 inhibitor, we will go with a GLP-1 receptor agonist. For HFrEF it's a bit more complicated. Using it for HFpEF, there may be emerging data, as you're saying, and there are some trials going on in that area. [Editor's note: Ongoing clinical trials include SOUL, STEP-HFpEF, STEP HFpEF DM, and FLOW.]

You mentioned that you're looking at vascular disease as a cardiovascular disease, and that's actually your profession and your forte. There are some data to show that the SGLT2 inhibitors do have some impact in the vascular area, even in EMPA-REG OUTCOME that we mentioned, in which we saw there was a differentiation within 2-3 months. The differentiation primarily, as you said, has to do with fluid imbalance and volume. After 1 year or so, it was like a new start of the pump and it looked like it could have been more of an atherosclerosis type of condition.

The Advantages of Joining Forces

Handelsman: With the SGLT2/SGLT1 sotagliflozin, clearly a vascular component is there. We allowed that if a person cannot have a GLP-1, we would opt for an SGLT2 inhibitor instead, except for strokes, where SGLT2 inhibitors clearly do not have a benefit on strokes. Just like with HFrEF, where so far, we don't see a benefit with GLP-1 receptor agonists. What about using both?

Budoff: I think that they're so complementary. Again, most of our patients with diabetes suffer from obesity. These therapies both help with weight reduction through different mechanisms. They both help with A1c control through different mechanisms for patients with diabetes. I think there's going to be a large amount of overlap. The GLP-1s have benefit for the kidney also — maybe not as pronounced as the SGLT2 inhibitors, but I think there are going to be some complementary benefits there as well. I try to get them on both, but of course, we have to be careful with prescription therapies, expensive treatments, and how many therapies a patient can afford.

Handelsman: I definitely agree. More and more data are emerging showing that a combination is actually giving more benefit than each one of them alone. There is an issue with price. We have moved to a whole new paradigm in managing patients with diabetes.

We have to look to prevent the next event in the short term. I don't know of any drugs that we have to show for stroke and prevention of a stroke in less than 2 years as we've seen with the GLP-1 receptor agonists. It's clear that every patient that has a stroke or a very high risk for stroke needs to be on a GLP-1 receptor agonist. Many of those patients may have a kidney problem or heart failure. Using them together would help for weight loss. The two of them together are very good, and we didn't even mention some off-target aspects like liver, for example, where they have some great effect.

Taking price into account, I agree. For the short term, it will prevent the next event, each one as we describe it. For the long term, we still need to control glucose and the other CV risk factors, like lipids and so on. It's an exciting time.

The Way Forward

Budoff: I'm very enthusiastic and I'm so glad that we have some of these new therapies that can really benefit our high-risk patients. Patients with diabetes, especially those with established ASCVD, if they have cardiovascular disease already, their risk is really high of having an event and dying prematurely. The same can be said of patients with heart failure and kidney failure or kidney disease. I think we really are taking the highest-risk patients and affording them a great benefit.

Handelsman: I hope that many other cardiologists will follow suit because we [endocrinologists and diabetologists] are a very small group. We cannot care for all these patients. Not only that, you've got the patients with heart failure who need a specialist, those with a kidney problem who need a specialist, and those requiring cardiovascular risk prevention and management who need a specialist; yet, many places do not have these specialists.

I think we will all need to know how to manage these patients and how to use these drugs. Maybe that's the strength of the DCRM Practice Recommendations that we developed, because they allow the nonexperts to follow simple directions and to do what you're now doing with all the knowledge that you have, to manage these patients.

Budoff: Absolutely. I strongly encourage people to look at those DCRM guidelines and take from that multispecialty group some great advice on how we can co-manage these patients.

Handelsman: With this, Matt, it's always great sharing some opinions, discussions, and practice pearls. I would like to thank you all for joining us. We had a wonderful time.

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