Preserving Renal Function with SGLT-2 Inhibitors

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The MD Magazine Peer Exchange "Improving Management of Type 2 Diabetes Mellitus" features a panel of physician experts discussing current best practices to treating and managing patients with T2DM that generally includes lifestyle modifications as well as medication. The mechanisms of action, patient selection criteria, and side effects for various oral medication classes are included in the discussion.

This Peer Exchange is moderated by Peter Salgo, MD, professor of medicine and anesthesiology at Columbia University College of Physicians and Surgeons, and an associate director of Surgical Intensive Care at New York-Presbyterian Hospital.

The panelists are:

• Robert Busch, MD, director of clinical research in the Community Endocrine Group at Albany Medical Faculty Practice in Albany, NY
• Ralph DeFronzo, MD, professor of medicine and chief of the diabetes division at the University of Texas Health Science Center in San Antonio, TX
• Pamela Kushner, MD, clinical professor at UC Irvine Medical Center and director of Kushner Wellness at UC Irvine Medical Center in Los Alamitos, CA
• Jeffrey Miller, MD, professor of medicine and clinical director of the Division of Endocrinology and Diabetes at Jefferson Medical School in Philadelphia, PA

Robert Busch, MD: Dr. DeFronzo, one question. The stroke reduction, despite the blood pressure lowering in SGLT2s, was not there. Not only with that, but this recent meta-analysis was in Lancet; the stroke was not reduced in any of them. Why do you think that is?

Ralph DeFronzo, MD: I have to say I was very surprised. I usually make my predictions well in advance, unlike most other people. So, I thought that EMPA-REG would be positive, but I thought it would be positive primarily because of the reduction in stroke. To me, that was very surprising. What people have said is that within this group of high-risk people, you probably have people with high-grade stenosis, and there may be a little bit of a drop in the blood pressure. It may be in that particular prone person that you see an increase in the incidence of stroke. Is that proving? The answer is no, but at least it’s one explanation, which I think is positive.

Peter L. Salgo, MD: Let me go off the reservation and ask. Did they parse out if you had ischemic stroke versus hemorrhagic stroke?

Ralph DeFronzo, MD: Yes, they were basically all ischemic strokes.

Peter L. Salgo, MD: They were all ischemic, as you’d expect.

Ralph DeFronzo, MD: As you’d expect, yes.

Robert Busch, MD: So, if someone is on thiazide and their pressure is fine, I routinely get rid of it when I start an SGLT2.

Pamela Kushner, MD: If it’s a low-dose thiazide, 100%.

Robert Busch, MD: I keep the ACE or ARB naturally for the other things.

Ralph DeFronzo, MD: And I think that’s reasonable, but, even more important than the thiazide is a loop diuretic. That, I think you really need to be very careful about. But, remember, in the big trials they didn’t stop a thiazide diuretic. They even allowed loop diuretics not to be stopped and let the clinician decide with time. But I think if you are on a loop diuretic, you should probably stop the loop diuretic…

Pamela Kushner, MD: Or decrease it.

Ralph DeFronzo, MD: Or at least decrease it. And in elderly people, I think it’s very important. They’ll tell you they get up at night to go to the bathroom, they get a little dizzy. Watch the SGLT2 there, and always check for orthostatic hypotension before you start an SGLT2 inhibitor. I think these are warning signs, groups that you need to be a little bit careful about even though we tend to be very positive about SGLT2 inhibitors.

Pamela Kushner, MD: Peter, I do have one more question. Then, we’ll let you move on. But I know our audience is interested in hearing about the effect of SGLT2s on EGFR. What do we tell our audience about kidney function, and when we’re so concerned about that in our diabetic patients?

Ralph DeFronzo, MD: So, because you go into a little bit negative salt and water balance, there is a decrease in the EGFR of about 4 to 5 mL per minute. It either stabilizes or gradually returns, but this is because of the hemodynamic. You decrease the intravascular volume. I think the data now is starting to mount that in a long-term basis, that these drugs will actually protect you against renal disease.

Pamela Kushner, MD: Very important.

Ralph DeFronzo, MD: Yes. If you look at the American Society of Nephrology where the presentation was given from EMPA-REG, the composite endpoint, which was renal death—meaning transplantation, dialysis, doubling of the serum creatinine or new onset proteinuria—there’s a dramatic decrease in the composite endpoint of about 41%.

Peter L. Salgo, MD: Forty-one? That’s a real big number.

Ralph DeFronzo, MD: Huge. These data haven’t been published, the paper is under review right now. But there’s reason to believe—even in people with advanced disease with GFRs less than 45—that because the remaining nephrons are hyperfiltering, that the SGLT2 inhibitors will decrease the intraglomerular pressure, decrease the hyperfiltration, and preserve renal function. And we have a large study called the CREDENCE study, which is designed to specifically get and look at people with advanced renal disease and see, in fact, if you can prevent end-stage renal disease. And I believe if the study turns out to be positive, that they will get an indication.

Peter L. Salgo, MD: That’s absolutely huge. I’m really glad you asked that. Because the number of patients I see with diabetic-induced renal failure come to transplant and have all kinds of post-operative problems because they’re diabetic. If you can drop that, I mean 40% is just astronomical.

Jeffrey Miller, MD: But Ralph, I think you have to follow up on that, that there’s published data that SGLT2 inhibitors significantly decrease albuminuria and proteinuria.

Ralph DeFronzo, MD: Absolutely correct. All three of the currently approved SGLT2 inhibitors have been shown to decrease microalbuminuria and macroalbuminuria. There are also experimental animal models of diabetes where the SGLT2 inhibitors have been shown to prevent the development of diabetic nephropathy. So, there’s a large body of evidence that I think supports the use of these drugs. And then there’s the study from David Cherney looking at hyperfiltering type 1s that, in fact, you decrease the hyperfiltration primarily due to a decrease in intraglomerular pressure. And hyperfiltration is a big risk factor for the future development of nephropathy.

Robert Busch, MD: And since our audience is primary care, we must mention to them don’t use NSAIDs and COX2s in your patients with diabetes, which is used all the time, unfortunately. And that’s probably a bigger cause of renal disease than anything else.