Diabetes in 2025: SGLT2 in preventive medicine
McMaster Perspective Extended

Hertzel C. Gerstein, MD, endocrinologist and professor at McMaster University and Hamilton Health Sciences in Hamilton, Canada, joins Roman Jaeschke, MD, to review advancements in diabetes management, particularly focusing on the role of SGLT2 inhibitors and GLP-1 receptor agonists in preventive medicine.

This is part 1 of the interview. Watch part 2.

This video offers playback speed control and subtitles.

Outline

1. Introduction.
2. The revolution of SGLT2 inhibitors and GLP-1 receptor agonists in diabetes care.
3. SGLT2 inhibitors and kidney function: benefits and limitations.
4. Adverse effects of SGLT2 inhibitors: genital infections and amputations.
5. Adverse effects of SGLT2 inhibitors: ketoacidosis and off-label use.

Transcript

Roman Jaeschke, MD, MSc, DPharm: Good morning. Welcome to another edition of McMaster Perspective. It’s my pleasure to introduce a person who has been shaping the management of diabetes mellitus around the world for the last 2 or 3 decades, Professor Hertzel Gerstein. I just did PubMed on you. I put “Gerstein” and “diabetes” and I got over 400 publications. I’m not sure whether you are on all of them, but you are presumably on most of them. Thank you very much for agreeing to be with us.

Hertzel C. Gerstein MD, MSc: It’s a pleasure to be here.

Roman Jaeschke: Hertzel, 30 seconds. If you could describe what you do these days.

Hertzel C. Gerstein: So I’m an endocrinologist and a diabetes researcher at McMaster University and Hamilton Health Sciences. I’m also the current director of the Population Health Research Institute.

Roman Jaeschke: Thank you. And obviously author of numerous primary and secondary publications on diabetes over the last few decades. I would like to start by sharing my screen and putting a background for a second behind our discussion. So we go to share screen and I would like to go here.

So there were 2 articles which caught my attention. One was about using sodium-glucose cotransporter 2 inhibitors, SGLT2 inhibitors, in people with renal failure. And then another one... This is an article which came from McMaster. And the other article, which was a meta-analysis, network meta-analysis of benefits and harms of different drugs used in type 2 diabetes. I am a practicing clinician and I see a lot of people with renal dysfunction and diabetes. I noted that even though those papers are coming from us, they are fairly—they provide high-quality evidence, we do not necessarily follow on this evidence.

So I laid out 3 people to talk to. One of them was a methodologist, author of these papers, Professor Gordon Guyatt, and the other is Professor Hertzel Gerstein, who is probably the most eminent diabetologist, at least that I know. And there will also be an interview with a nephrologist. My questions for them would be to start with management of people with renal dysfunction, and then diabetes, and then management of people with diabetes in terms of choosing all the other medications.

I would like to start, Professor Gerstein, with SGLT2 inhibitors. I actually remember our first interviews, probably 15 years ago or so, where they seemed to be the first drug giving hope of preventing long-term complications. So where are we today in terms of, to start with, SGLT2?

Hertzel C. Gerstein: I’ll just start off by saying that diabetes care is really all about preventive medicine. And this is going back to the very beginning of modern diabetes care, which is the beginning of the last century. When we manage diabetes, we’re trying to keep glucose levels normal and we know that that prevents many problems: eye disease, kidney disease, and depending on how we think about it, cardiovascular disease as well as other problems. We know that all the other therapies that we do with people with diabetes—regular eye exams, foot care—all those things prevent many serious problems in the future. We’ve always been looking for drugs that can do more. And we’ve been really blessed in the diabetes world that in the last 12 years there have been 2 brand new classes of drugs—now they’re not new anymore—that not only lower glucose levels but clearly have additional preventive effects on cardiovascular events, total mortality, heart failure, renal disease, etc.

And the 2 classes you’re referring to are the glucagon-like peptide-1 (GLP-1) receptor agonists and the SGLT2 inhibitors. So these are fantastic. They both came out of randomized controlled trials that were large outcomes trials that were actually designed to show that they were safe and lowered glucose levels. And because they were well designed, they also showed that not only did they lower glucose levels safely, they dramatically reduced serious long-term outcomes, such as the ones I mentioned. And that has spawned a revolution, not just in diabetes care. It started off in diabetes, but as you know, the SGLT2 inhibitors now are routine therapy, routinely recommended for heart failure and kidney disease. And GLP-1 receptor agonists are also now getting involved in cardiovascular prevention in nondiabetes patients, kidney prevention in people with diabetes, and other indications. So this has been fantastic. There are 2 great classes of drugs and they seem to be overall fairly safe and not that difficult to use.

Roman Jaeschke: Okay. If I hear you correctly, they could be, in terms of renal effects probably mostly SGLT2 inhibitors, they should be part of routine care of people with a degree of renal dysfunction. One question which is not clear to me, and maybe I will ask my nephrology colleagues, does it apply to people who are already on dialysis or renal replacement therapy?

Hertzel C. Gerstein: There have really not been studies in that context. The way that SGLT2 inhibitors work is by, well, we’re not totally sure how they work, but they seem to—a strong part of their mechanism is through the kidney. So when somebody’s got end-stage kidney disease, and I mean they’re on dialysis, like you suggested, to my knowledge there have been no studies that look at what the effect of this drug is on survival, on heart failure, on all the associated things. As you know, end-stage kidney disease is a risk factor for a whole bunch of things, including amputations, peripheral vascular disease, cardiovascular disease, mortality, and arrhythmias. So I don’t think that’s being carefully assessed from an outcomes perspective. And to my knowledge the nephrologists don’t use it routinely in people who are in kidney failure.

Roman Jaeschke: Alright. Again, I will follow it with our nephrologist.

Hertzel C. Gerstein: But let me just jump in. In people who have renal insufficiency, who have GFRs that are above 15 to 20 and are not on dialysis, there is evidence that these drugs do slow the progression of kidney decline, of renal decline. So there is a preventive effect on them. But once they get to kidney failure, that’s where I think the evidence sort of is unknown.

Roman Jaeschke: Right. So the benefits are there. I was with Professor Guyatt and we were talking about major benefits, especially in people with high risk, which would be the sicker and older, so to speak. How about the concerns about harmful effects? When I’m looking at it, I see infections, which is probably lesser of an evil compared to amputations or DKA. Could you comment on those?

Hertzel C. Gerstein: The SGLT2 inhibitors, the most common side effect is genital infections, not urinary tract infections. They have not increased the risk of UTIs in the randomized trials, but of genital infections. Mostly it is Candida-type fungal infections in the perineal area. And these are more of a nuisance side effect, in about 1 in 10 women and about 1 in 20, 1 in 25 men, less common if they’re circumcised, more common if they’re uncircumcised, and it’s easily treated with over-the-counter or prescription antifungal creams, etc. When people get yeast, I warn every one of my patients when I prescribe it that this can happen. Most people get it once and then they don’t get it—if they get it. The 1 in 10 women who get it, they’ll have it one time and won’t get it again. There are some people that get recurrent episodes and it’s unpleasant, and they stop using the drug. But it’s not a reason to not use the drug at all.

As far as amputations, there is much less clear data about that. As I mentioned earlier to you, there is data, old data, that thiazide diuretics can increase the risk of amputations. That was many years ago in a meta-analysis. And one of the randomized trials of an SGLT2 inhibitor did note an increased risk of amputations. That has not been replicated in the other trials. And these have been in people with diabetes. There is possibly a single signal when you meta-analyze them, the actual incidence is low, and it’s most likely if it’s going to be a problem in people that got bad foot disease, bad leg disease, etc. So that would be a reason to be cautious. And if I have people that have evidence of bad neuropathy and vascular disease in their feet, etc, that are at risk for amputations and they’re otherwise appropriate for a drug like this, I have a clear and transparent discussion with them. I say it’s important that you do good foot care, if you see anything, stop, etc. I think it’s a manageable risk, but you need to talk to patients about it if they appear to be at high risk, for sure.

As far as ketoacidosis, it seems to only be a problem in people with diabetes, type 2 diabetes. People who are not on an SGLT2 inhibitor, they have a very low incidence of ketoacidosis, less than 1 in 1000. It may be doubled with an SGLT2 inhibitor, but we’re still talking maybe 2 in 1000 per year or something of that nature. The caution that I tell every one of my patients when I prescribe the drug is that if when you’re taking this drug you have an intercurrent illness that causes dehydration, nausea, vomiting, diarrhea—especially vomiting—diarrhea, stop the drug until you’re better and then restart it.

We know that dehydration in combination with this drug—because the drug does cause some diuresis—together it seems to be the precipitant for ketoacidosis. If people are on insulin it’s much less of a problem, because insulin helps to mitigate or prevent ketoacidosis. If they stop their insulin, that could be a problem.

The last point I’ll say, some doctors use the drug off-label in type 1 diabetes. Type 1 diabetes is a risk factor for ketoacidosis itself. And this drug triples and quadruples the risk in type 1 diabetes. It’s not a trivial number, right? So if you’re using it off-label in type 1 diabetes, you’ve really got to have in my mind a very good reason to use it because you are increasing the risk of ketoacidosis, which can be a terminal event. And so I want to say be very cautious off-label.

Roman Jaeschke: I’m curious, what would be the good reason to use it in type 1 diabetes?

Hertzel C. Gerstein: I’m a physician who rarely if ever uses it in type 1 diabetes because of the ketoacidosis risk. There are some of my colleagues who use it more often. Obviously it can help mitigate kidney decline and there’s no reason it wouldn’t work in type 1. There have been some studies in type 1 diabetes. It does lower glucose level, it does reduce some of the fluctuations in glucose levels, and some people with type 1 diabetes do report better and easier-to-manage diabetes care. But I would say that if it’s going to be used in type 1, it’s explicitly off-label and it needs to be done with a highly informed patient who really is involved in their management and with a highly informed and knowledgeable care team. I don’t think it’s a routine thing at all and it’s clearly off-label.

Roman Jaeschke: Alright. Hertzel, this was very, very informative as far as I’m concerned. I thank you for this part.