SGLT2 inhibitors and kidney dysfunction
McMaster Perspective Extended

Gordon Guyatt, MD, MSc, distinguished professor in the Departments of Medicine and Health Research Methods, Evidence, and Impact at McMaster University, joins Roman Jaeschke, MD, MSc, to discuss the latest evidence on diabetes mellitus (DM) management. In part 1 they focus on SGLT2 inhibitors and their efficacy in patients with kidney dysfunction, with or without DM.

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Outline

1. Introduction, background on kidney failure in diabetes.
2. SGLT2 inhibitors in preventing the progression of kidney disease in patients with or without diabetes.
3. Clinically relevant outcomes: mortality, admissions for heart failure, progression of kidney failure, myocardial infarction.
4. Effect of patient risk factors on the effectiveness of SGLT2 inhibitors.
5. Methods for assessing patient risk: risk calculators; consideration of factors like age, diabetes status, and creatinine levels.
6. Relative risks consistent across risk groups, absolute benefits greater for higher-risk patients.
7. Importance of considering SGLT2 inhibitors.

Transcript

Roman Jaeschke, MD, MSc, DPharm: Good morning. Welcome to another edition of McMaster Perspective Extended. We have the privilege to host Professor Gordon Guyatt from the Department of Medicine and Department of Health Research Methods, Evidence, and Impact at McMaster University. As most of you know, he is also really the ideological father of evidence-based medicine. I’m really privileged to have him.

The goal of this extended McMaster Perspective is to explore the changing landscape of diabetes mellitus treatment. I plan 3 separate interviews: with Dr Guyatt, who is a methodologist and internist treating these patients but here will speak mostly as an author of numerous meta-analyses and practice guidelines in this area; I hope to interview an endocrinologist and opinion leader as well; and a nephrologist who could provide some more information.

The impetus for those interviews comes from two recent publications in which Gordon was the lead person: one dealing with sodium-glucose cotransporter-2 (SGLT2) inhibitors in people with renal dysfunction [doi:10.1136/bmjmed-2024-001009], and the other was the choice of diabetic drugs in a general diabetic population [doi:10.1136/bmj-2022-074068]. Gordon, any questions on your part at this stage or any comments you would like to make?

Gordon Guyatt, MD, MSc: Only comment is thank you for still thinking I’m worth talking to.

Roman Jaeschke: Okay. I will share the screen and I will go to the first paper I would like to talk about. Could you tell us a little bit about what led to it, who did it, and to some degree what was done before we go to the results?

Gordon Guyatt: Clearly, as you have said, there is an evolving perspective. If you were a nephrologist, you were very unhappy for many years because there was nothing you could do that could prevent—except perhaps angiotensin-converting enzyme (ACE) inhibitors—in diabetes, nothing you could do to prevent progression of renal disease to renal failure.

Now the situation has changed. The nephrologists in general are delighted that they now have other medication that can prevent progression, and the SGLT inhibitors are perhaps the best of those.

So clearly we wanted to get the message out to people. We wanted to summarize, and we believe of course that we need systematic reviews of the highest quality evidence available to give the best summaries and our clinicians and patients deserve such summaries.

Roman Jaeschke: The starting point of these particular medications was diabetic treatment. Did you look at the diabetic population or expand it to different populations?

Gordon Guyatt: All populations in which it’s been used. One of the things with the SGLT inhibitors has been that it doesn’t matter whether you have diabetes or not. For instance, people with heart failure. [SGLT inhibitors are] going to reduce your admissions for heart failure irrespective of whether you have diabetes or not, and it’s going to prevent the progression of your renal failure whether you have diabetes or not. So where it started with diabetes, now it turns out for the those other two important outcomes—admission for heart failure or renal failure; it doesn’t matter whether you have diabetes or not.

Roman Jaeschke: In this paper which we are referring to there were patients with diabetes and renal dysfunction and people with renal dysfunction without diabetes.

Gordon Guyatt: Correct.

Roman Jaeschke: Which outcomes have you looked at? What were the outcomes of interest?

Gordon Guyatt: You’re going to interview me about another paper, and I might get confused between the two in terms of exactly what we looked at. But the outcomes that are relevant from a clinical point of view are mortality. The SGLT2s reduce mortality. They reduce admissions for heart failure. They reduce progression of renal failure. They reduce myocardial infarction. So for all the major vascular events, and renal failure, and all-cause mortality, SGLT2 inhibitors are effective.

Roman Jaeschke: Does the effect depend on risks of patients?

Gordon Guyatt: Of course. To put it at the extreme, if you’re a 30-year-old with diet-controlled diabetes and no other morbidity, your risks of dying in the next decade are very, very low, and nothing can make major decreases in risk because you have almost no risk, to take an extreme example.

Of course, nowadays that goes true for treatment of hypertension or prevention in people at risk. The low-risk people are only going to get small benefits because they are at low risk and thus it becomes discretionary, use of these agents becomes discretionary in low-risk [groups]; perhaps they shouldn’t do it in the very low risk. Anyway, as the risk goes up, the arguments, or the compelling reasons, to use these agents goes up.

Roman Jaeschke: How can clinicians establish the risks or judge the risk?

Gordon Guyatt: There are various risk calculators around for cardiovascular risk. There are methods for renal risk [assessment], and the papers that we are talking about, including the papers here, describe ways of getting at the risks. When we were doing these papers, we looked at all the various ways of establishing risk. None of them are perfect, but in general you can say if you’re older, you have diabetes, and your creatinine is higher, these are the major factors that are going to determine people’s risk.

Roman Jaeschke: So unfortunately if you are young and healthy you have low risks. And if you are older and ill, your risk goes up.

Gordon Guyatt: That’s right. And if you’re young and healthy, you may not want to be taking these drugs. Even if you’re older and healthy, you may not want to be. Like me, for instance—I don’t. Although I’m old, I’m still healthy, so my risk is sufficiently low and I’m not interested in taking medication.

Roman Jaeschke: Okay. The conclusion from that would be that we are talking about risks. Are we talking about relative or absolute risk?

Gordon Guyatt: We are talking about absolute risk. So if tomorrow I have a myocardial infarction, or develop diabetes, or develop some degree of renal dysfunction, my situation now, when I have none of those things, and my situation if tomorrow these terrible things happen to me, the relative effect of these medications is identical.

In other words, for mortality, for the SGLT2 inhibitors there is—I don’t remember the exact numbers—between 15% and 20% relative risk reduction. And that’s the same for me while I’m healthy and the same once I get sick. So the relative effects are the same across risk groups.

That, by the way, is a general phenomenon across just about everything we use in medicine. Relative risks are similar across risk groups.

On the other hand, the absolute benefits are much greater. The sicker I get, the more I’m going to benefit, ironically enough perhaps. The high-risk groups get the benefits. So the absolute risk depends on your baseline risk a lot.

Roman Jaeschke: To summarize this part: we both work in hospital, we both see patients who have diabetes or not but have significant renal dysfunction, and who are older, who may have heart failure, who may have albuminuria and so forth. It sounds to me that on each of those occasions we should at least ask ourselves the question and maybe talk to patients about the use of SGLT2 inhibitors, like in the not-remote past we were asking the same question about using ACE inhibitors. Are we at the similar level of potential benefits here?

Gordon Guyatt: Yes, we are. Certainly the relative risk reductions are a little bit less than they were with ACE inhibitors, but still enough that for the high-risk patients they’re going to get appreciable absolute risk reductions.

Roman Jaeschke: Okay. That answers and maybe even finishes the first part of our discussion.