Harms and benefits of SGLT2 inhibitors

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I'm Dhineli Perera, your host for this episode. And it's a pleasure to be speaking to Dr Tilenka Thynne. Tilenka is a clinical pharmacologist and endocrinologist at Flinders Medical Centre. Tilenka writes about the harms and benefits of the SGLT2 inhibitors in managing type 2 diabetes. Tilenka, welcome to the program.

Thank you.

So Tilenka, after a relatively quiet period in the world of diabetes medications, there was a flurry of new agents that appeared on the market around the same time as each other a few years ago. The SGLT2 inhibitors, also known as the sodium-glucose co-transporter-2 inhibitors, was one of them. How did these agents fit in? And when should prescribers be considering them as an alternative to other oral hypoglycaemics?

I think you're right. I think it was an exciting time when all these sort of newer drugs came onto the market. And initially, it was a bit unclear exactly where they fit into management and algorithms. But I think increasingly, that's becoming a lot clearer and it's even going to keep changing now. I think the SGLT2 inhibitors certainly sit after metformin as the first line, but certainly as a second-line agent. And I think where initially we were just comparing them to all the other second-line agents, we've now started to think of them as second-line agents with extra benefits to them as well.

So a few years ago, the treatment algorithms kind of went metformin first line and then second line would just have a whole list of every other diabetes drug, almost, without too much comparison between them as to which one you should pick. But as the evidence around the cardiovascular benefits and the renal benefits of SGLT2 inhibitors has become more apparent, it's clear that our second question after first line with metformin should really be, "Is a patient at high risk of cardiovascular disease or do they have chronic kidney disease?" And if the answer's yes, then that's sort of where we'd certainly be considering an SGLT2 inhibitor as that second-line agent.

Right, so there’s been sort of additional benefits that have emerged over time that really is pushing the SGLT2s up the ladder, if you like.

That's right. I think in the past, we've very much just focused on glycaemic control and all our algorithms and also our funding as well through the PBS has very much been focused on trying to get adequate glycaemic control and trying to get that HbA1c down. But now we're actually seeing positive effects that are independent of glucose control when it comes to particularly the SGLT2 inhibitors and some of the other diabetes agents as well.

Right. And just for the listeners out there, the SGLT2s are sometimes known as the flozins. Would you agree that's kind of another name for them?

That's a bit of an Australian name for them, I think, as well. We like to abbreviate everything and ...

We do. We do. So how exactly do they work, Tilenka? My understanding is that they have a glucose-lowering effect as well as a diuretic effect.

Yeah, that's right. So traditionally, our agents for type 2 diabetes have always focused on either trying to increase insulin production from the pancreas or focusing on the insulin resistance. And so really, it was quite exciting when the SGLT2 inhibitors came along because they act independently of insulin secretion and the insulin concentration or insulin resistance. So they work by enhancing urinary glucose excretion. They inhibit SGLT2 in the proximal convoluted tubule and that's where glucose is absorbed. And so by doing that, these drugs reduce the renal threshold of glucose.

Normally, we don't see glucosuria until your blood glucose is above about 10­–11 mmol/L. But these drugs reduce that to about 2–7 mmol/L. So you really have urinary excretion of glucose and that's how they actually lower blood glucose.

Right. And then the diuretic effect?

Well, certainly there's an osmotic effect where excreting glucose also sort of pulls along water with it.

Right. Okay. So given that they do lower glucose, and as you said, independently of insulin, do we need to be concerned about hypoglycaemia with SGLT2s?

No. Alone, they don't cause hypoglycaemia because as you said, they're acting independently of insulin secretion. So when you're combining them with other drugs that can cause hypoglycaemia, like insulin or sulfonylureas, then sometimes we do have to be careful about the risk of hypoglycaemia, but certainly alone they should not cause hypoglycaemia.

Right. Okay. So when you were talking about those benefits, those extra benefits before, and we were saying that we have focused so much on the HbA1c, what kind of benefits would we expect to see in both the HbA1c and the other cardiovascular disease factors, like your weight and blood pressure?

Well, in terms of glycaemic control, they're sort of comparable to many of our other agents where we tend to see a HbA1c reduction of about 0.5 to 1% compared to placebo. It can depend on what you're starting HbA1c is as well. And so that's relatively consistent with other second-line agents.

What we're seeing in terms of cardiovascular benefits, the EMPA-REG trial was the first that actually showed in those that were a high risk of cardiovascular disease or had established cardiovascular disease as well, there was a 14% reduction in the composite end point of cardiovascular disease outcomes in patients who were treated with empagliflozin as compared to placebo.

Okay. So both factors? Weight as well as blood pressure?

No, sorry. The combined outcomes. They had a composite cardiovascular outcome that looked at cardiovascular death for non-fatal MI and non-fatal stroke. And they saw a reduction in that outcome. That was in patients who had already had established cardiovascular disease or a very high risk.

Right. Okay. So does the evidence out there then suggest that all of the SGLT2s are equally effective? Can prescribers sort of reach for any one of them?

Yeah, so certainly, a lot of it seems to be a class effect and they seem to be quite equally efficacious when it comes to glycaemic benefits and that small degree of weight loss we see of around about 2.5 kg at the one year mark. And up until recently, the data was suggesting that they're all quite equal in terms of their cardiovascular benefit as well. The cardiovascular outcome studies for the dapagliflozin, for the empagliflozin and for canagliflozin, which we don't use in Australia.

But just recently, cardiovascular outcome study of the VERTIS CV trial was published in the New England Journal of Medicine. And that was looking at ertugliflozin and that actually didn't show superiority when it came to cardiovascular outcomes. So when they compared to placebo, it didn't increase the risk of cardiovascular poor outcome, but it was no better than placebo when it came to preventing it.

Right. Oh, that's interesting. So you might want to avoid that particular option, perhaps, if you do have someone with significant cardiovascular risk factors.

Well, I think we have the option of empagliflozin or dapagliflozin, which have that established benefit. So I think we're going to learn a bit more now sort of probably in the coming months about this trial and probably it's starting to question whether it's a whole class of effect. So I imagine we'll start to look at what are the differences between these individual drugs and why some seem to have as a class the cardiovascular benefits, but this one doesn't.

Right. Okay. So then, Tilenka, moving on, I did actually find in your article, there was a comparison between the SGLT2s and ACE inhibitors that was really interesting. Can you tell us a bit more about the use of SGLT2s in patients with renal disease? In particular, the renoprotective effects, as well as that blip in eGFR that we might expect to see?

Yeah. So what we're seeing, again, quite independent of the glucose-lowering effect that we're actually seeing a renal protective effect and the ACE inhibitors have typically been our standard approach to trying to reduce the progression of renal disease in patients with type 2 diabetes. But when the trials have added SGLT2 inhibitors on top of that, we've seen still a further benefit in terms of that renal outcome, where a reduction in development of end stage kidney disease, a reduction in worsening creatinine, and a reduction in death from renal or cardiovascular disease.

And so we're increasingly, I think, going to be using these drugs in patients with chronic kidney disease and in addition to ACE inhibitors. When we first start these agents in patients who do have a reduced creatinine clearance, we do often see a slight reduction, similar to what we see when we start ACE inhibitors, but then, in the long-term they are renoprotective. So that then tends to plateau and then stabilise.

Great. So it's not a long-term effect.

No.

Same sort of thing that we'd expect with ACE inhibitors?

Very much so, that we see that initial glip and then, in the long-term, they're very renoprotective.

So there are some specific genitourinary infections that have been associated with SGLT2s. And I guess this is probably from my experience or something that I've had always linked in with it. Okay. So the flozins and you get your UTIs, but can you tell us a bit more about which types of genitourinary infections might be expected?

Yeah, I suppose from their mechanism of action, it's not too surprising that-

No, not at all.

... you've got glucosuria that you're going to increase the risk of often fungal genital infections, such as candida. So studies have shown that probably a three- to fivefold increased risk of fungal infections, but often they weren't complex infections. They were still treatable with our standard antifungal medication. And it was relatively rare in the studies that patients had to stop SGLT2 inhibitors because of this.

Yeah. Right. So they weren't progressing to a pyelonephritis level of urinary tract-

Well, the fungal infections were usually mild and quite easily treated. There have been, in some studies, certainly, at increased risk of urinary tract infections, more commonly in women because they are at higher risk anyway of urinary tract infections. But this was still relatively rare and it's rare for patients to need to actually stop their SGLT2 inhibitor.

Okay. Oh, that's good. So it's possibly been an overstated side effect, would you say, in your experience?

Well, potentially. I think patients with poorly controlled diabetes are at high risk of genitourinary infections anyway.

Anyway. Okay.

And so I think adding an SGLT2 inhibitor does increase that risk, but often, as you get better glycaemic control, that risk can come down. There are also case reports of quite a severe infection known as Fournier's gangrene.

Oh, right. Yes.

And that's quite a nasty necrotising fasciitis of the perineum. And often, these are the sort of rare complications that aren't necessarily seen in initial trials. And it's only really when they're being used in the wider population and potentially in patients who would never have made it into those tight trial settings, we're actually starting to see an increased risk of this infection. Again, rare, but can be quite severe.

And how and when should prescribers mitigate the consequences of the volume depletion side of things, so the diuretic effect of the SGLT2s?

Well, I think this is going to be a really interesting area over the coming months and years with these drugs as they're increasingly being used in the setting of heart failure, both in patients with diabetes, but potentially in those with not as well. The initial advice had been that these SGLT2 inhibitors certainly have a diuretic effect and that can be associated therefore with volume depletion. And so we were quite careful if we were starting them in patients already on a thiazide diuretic or a loop diuretic.

More recently, now that these drugs have also been used in a lot of heart failure patients, most of whom will have been on diuretics in those trials, I think we're going to start learning more about when we do actually have to hold or reduce a diuretic when we're adding the SGLT2 inhibitors in. And in a lot of those heart failure trials, they didn't actually adjust the diuretic therapy. So I'm always careful when I have somebody who's on a diuretic that ... I warn them about the risk of that further diuresis, and certainly think about if somebody was to get dehydrated further from gastroenteritis, that it might be worth holding these drugs. But I don't think the diuretic effect is always, or it's not always adverse and may be actually having some benefit as well.

Okay. So could you then refresh us, Tilenka, on what exactly ketones are and how SGLT2s impact their concentration? So I guess I'm interested to know a bit more about this class and their effects on the whole group of ketoacidosis, ketones and testing for those ketones.

Yeah. I think the area around this ketoacidosis risk has been a really interesting one and it's led to a lot of hypothesis generating about why these agents may be effective in terms of cardiovascular outcomes as well. Normally, we don't see ketoacidosis in the setting of type 2 diabetes. It's relatively rare. We see it much more commonly in patients with type 1 diabetes, who have an absolute insulin deficiency. And so if they become unwell and their insulin requirements go up and their blood glucose rises, and they're unable to use glucose as their substrate, then they start making ketones.

So these ketone bodies are an alternative energy source, but as they build up, they can cause an acidosis. So what's been seen quite consistently with the SGLT2 inhibitors is that they are associated with an increased risk of diabetic ketoacidosis. And it's often been where there's been a precipitant.

Some patients, it has clearly been undiagnosed type 1 diabetes, and using an SGLT2 inhibitor may have uncovered that diagnosis. But in other situations, it's probably been associated with infection, prolonged fasting or low carbohydrate diet, or a significant reduction in insulin doses that has actually led to development of a ketoacidosis. And the thought is that, because you have ongoing glucosuria, if you become unwell, normally your blood glucose would rise and that would prompt an increased insulin secretion of your own endogenous insulin. Whereas in this situation, if you've got an SGLT2 inhibitor on board, as you become unwell, your glucose levels may not rise to the same degree because you've still got that ongoing glucosuria. And so you end up with a net insulin deficiency and that's when ketones start to develop.

Okay. So in your opinion, Tilenka, what would be the most promising emerging indication for SGLT2s?

Well, I think certainly the two big areas are heart failure and chronic kidney disease. And I mean, we've been using ACE inhibitors for a long time for their renoprotective effect, but the SGLT2 inhibitors are really the first drug we've had for a while that's actually shown a significant reduction in poor renal outcome. And I think that's a really exciting area to have some options for our patients to try and reduce that risk of progression of their kidney disease.

Yeah. Excellent. So finally, Tilenka, your article mentions a type 2 diabetes treatment algorithm published by the Australian Diabetes Society. And I jumped online and had a look at it and it actually is looking really good, like something that could be quite user friendly. Can you run us through some key points or key take-home messages from that particular algorithm?

Yeah, I think it is really useful and there for a while, the Australian Diabetes Society have had these treatment algorithms and this last one was updated in December last year. I think it's very user-friendly and I think it's really taking us down that path of thinking about that patient in front of you and what extra benefit do you want from that next drug? So still we're thinking about metformin first line, unless there's a contraindication or it's not tolerated. But certainly, this treatment algorithm really highlights those issues of that next step of individualising treatment for a patient. You're thinking not only about glycaemic benefits, but is this a patient who's at high risk of cardiovascular disease or has established cardiovascular disease already, or is this a patient who also has renal impairment? And the new treatment algorithm really focuses on kind of questioning that and highlights which drugs, including the SGLT2 inhibitors, that would be important in those patients.

Excellent. Okay. Well, thank you so much, Tilenka. That's unfortunately all the time we've got for this episode. I really appreciate you joining us today.

Thank you very much.

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The views of the hosts and guests on the podcast are their own, and may not represent Australian Prescriber or NPS MedicineWise. I'm Dhineli Perera and thanks for joining us on the Australian Prescriber Podcast.