The Rest is Kidneys

Sweet Urine; good times never seemed so good!

• Season 1 • Episode 6

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The Rest is Kidneys podcast series is brought to you by Imperial College Healthcare NHS Trust and North West London Integrated Care Board (NWL NHS)

In this episode, Jeremy Levy and Andrew Frankel discuss the game-changing role of SGLT2 inhibitors in treating chronic kidney disease (CKD). These drugs, initially developed for diabetes, have shown remarkable benefits in slowing CKD progression, reducing cardiovascular risks, and delaying dialysis. They cover the key patient groups, prescribing tips, and how to use these medications safely and effectively.

Top Three Takeaways:
1. Broad Benefits Beyond Diabetes:
SGLT2 inhibitors significantly slow CKD progression, reduce cardiovascular risks, and delay the need for dialysis, benefiting patients with or without diabetes.

2. Who Should Get Them:

  • Heart failure patients.
  • CKD patients with or without diabetes and/or albuminuria.
  • Patients with GFR between 20-45, regardless of urine albumin levels.


3. Safety and Usage Tips:

  • Avoid type 1 diabetes or "type 1-like" patients.
  • Manage minor side effects (e.g., fungal infections) and provide "Sick Day Guidance" to minimise risks like ketoacidosis.

This episode provides practical insights and actionable advice for clinicians managing CKD patients.

Resource Links:
NICE GUIDELINES [NG203] chronic kidney disease: assessment and management Overview | Chronic kidney disease: assessment and management | Guidance | NICE

Northwest London CKD guidelines for primary care Chronic kidney disease (nwlondonicb.nhs.uk)

The purpose of this podcast is to inform and educate health care professionals working in the primary care and community setting. The content is evidence based and consistent with NICE guidelines and North West Guidelines available at the time of publication.

The content of this podcast does not constitute medical advice and it is not intended to function as a substitute for a healthcare practitioner’s judgement.

Produced by award-winning media and marketing specialist Heather Pownall of Heather's Media Hub

The Rest is Kidneys makes kidney disease management easy.  The Rest is Kidneys is for primary care clinicians.  The Rest is Kidneys is NICE consistent, short and sweet. Welcome to the Restless Kidneys brought to you by the Northwest London NHS Kidney Care Team.

Jeremy Levy

Hello. I'm Professor Jeremy Levy, a Consultant Kidney Doctor & Nephrologist at Imperial College Healthcare NHS Trust, and I'm joined by a good friend of mine.


Andrew Frankel

Hello, Jeremy. It's Andrew Frankel here, also a Consultant Kidney Doctor at Imperial Healthcare NHS Trust. Delighted to be here with you again.


Jeremy Levy

We're talking all things kidney, and today we're going to be talking particularly about pharmacological, or drug therapy, of chronic kidney disease, and particularly focusing on this relatively new group of drugs, the SGLT2 inhibitors, the flozins, of which there are several, and you can't not have heard of by now.


And we're going to focus on why these have become, very rapidly, very important medicines in kidney disease. Previous episodes, which I hope you've listened to, covered diet, lifestyle advice, and general advice about managing people with kidney disease, chronic kidney disease. The second episode we talked about renin angiotensin system blockers, and how to use those effectively - still very important medicines in people with chronic kidney disease.


So now we're going to move to these SGLT2 inhibitors. Why use them? How to use them? How to use them safely and effectively? So Andrew, tell us, these drugs were originally designed only for diabetes. So tell us a bit about their effects in terms of cardiac and renal disease, because of course, we're not really using them for diabetes, even though that's what they were designed for.


Andrew Frankel

So Jeremy, you're absolutely right, the SGLT2 inhibitors were developed because of their effect on blocking the reabsorption of glucose within the kidney tubules. That led to excretion of glucose in the urine, and provided glycaemic benefit. But that benefit was really only seen in people with well preserved kidney function, and as the GFR dropped, that glycaemic effectiveness also dropped, and that informed the original licensing, because by the time the GFR hits 45, the glycaemic effectiveness of these drugs is very low, and by the time it hits 30, there's virtually no glycaemic benefit.


However, the extraordinary thing was that in numerous, and indeed in every single SGLT2 studies across a range of different patient groups, we've now also discovered that these drugs have an additional, and quite separate beneficial effect, in relation to cardiorenal safety. They protect against heart failure deterioration. They provide very significant protection against progression of chronic kidney disease, and indeed, in some trials, have reduced death rates in people who start on these drugs, over only very short periods of time.


Now, whilst it is probable, in my view, and I suspect yours as well, that all these drugs in class have absolutely similar properties, there are variations in the studies that have been undertaken, and the populations included within these studies, and that has informed the recommendations made by NICE for each of these drugs. But broadly, the key message is that these agents will prevent, very effectively decline in GFR, and thereby significantly prolong the time interval before an individual needs to consider dialysis or transplantation. And the earlier we use these drugs in people with CKD, the greater the benefit for those individuals.


Jeremy Levy

But it's not just a progression, is it, Andrew? It also reduces cardiovascular risk broadly with the outcome from all of those studies you mentioned (and we're not going to talk about any individual studies), was to reduce not only progression, but cardiovascular death as well, over short periods of time. So these are amazing, and this was an unexpected set of results from these drugs. Of course, the drug companies have absolutely loved it, but it's been fantastically beneficial for people living with chronic kidney disease.

So which patients do you think would benefit most from the addition of SGLT2 inhibitors when they've got chronic kidney disease?

Andrew Frankel
Well, we're not putting it in the water yet, but that might be the situation in another 10 to 20 years, because we're discovering all these benefits. But basically, these are the patients that you should definitively think about an SGLT2 inhibitor.

Firstly, any person with heart failure with reduced or preserved ejection fraction, and particularly if they have some degree of CKD - that trumps all other indications. And the particular SGLT2 inhibitors for that are currently dapagliflozin and empagliflozin.

However, for people with diabetes, this class of drugs is considered a drug that you should rapidly get the patient onto once you have started Metformin and, of course, lifestyle intervention.

So heart failure, diabetes, and then once the person has developed any sign of kidney disease in the context of diabetes, they absolutely should get their SGLT2 inhibitor. And even for people without diabetes, you should be thinking about an SGLT2 inhibitor if they've got any form of albuminuria, irrespective of the GFR, and the cut-off that we use is an ACR of 22.6, but we also now know, that for people with more advanced CKD, GFR is between 20 and 45, these drugs will provide benefit even in the absence of albuminuria. So it's heart failure, diabetes, any form of CKD and diabetes, people without diabetes and CKD, and any form of albuminuria, and people with GFRs between 20 and 45, irrespective of the albuminuria.


Jeremy Levy

And that's been an evolution, hasn't it, over a very rapid time course in the last two years. It was initially just diabetes, then it was Chronic Kidney Disease with Proteinuria, and now it's basically almost all Chronic Kidney Disease, and that's really important. And also telling people, we haven't made a mistake, the label might talk about diabetes, but these are medicines for people without diabetes, but chronic kidney disease.

We'll touch on the specifics, but again, you mentioned these starting GFRs, but the other important thing is we don't stop these medicines either for getting sick day rules, but they seem to work right the way down to very low kidney function. So those starting GFRs are not ranges at which we stop them. Once we start these medicines, they offer benefits right the way down to essentially end stage kidney disease, which you can touch on a bit in a moment. So have you any advice about the most effective way of starting these drugs?


Andrew Frankel
So these drugs, let's be very clear, they are safe, with limited side effects. And the frequency of side effects is influenced a little bit by whether the patient has diabetes, or whether they don't have diabetes, because in people without diabetes, the side effect profile is extremely good. In people with diabetes, there are just a couple of things to watch out for. And the key messages about how to initiate and use these drugs safely are the following.

First of all, get that individual correct, the key is about choosing the right patient, and the most important thing is to exclude anyone who has type one diabetes, but also those who have type two diabetes that may have a type one phenotype. And you can recognise these individuals by the fact they may have type two diabetes, but they are slim (BMIs of 22/23), have had to go on to insulin within the first year of their diagnosis, are on only very small doses of insulin to achieve control, may have suffered an episode of diabetic ketoacidosis in their past, or have had diabetes caused by pancreatic destruction. Now these individuals, those are the type two with type one phenotype, may still benefit from SGLT2 inhibitors, but the key message for that group is you don't commence them unless you are doing it in conjunction with advice from the diabetes team. And the reason you want to get this right, is that there is an increased risk of diabetic ketoacidosis. 

So let me explain to the clinicians listening, the reason for this. SGLT2 inhibitors make the body think that it's starving, and you increase the amount of ketone bodies in the blood. All you need is a second impetus to go from ketosis to ketoacidosis. And that could be infection, it could be starvation, or it could be if they're on insulin, exogenous insulin, withdrawal of insulin. So therefore, you choose the right patient, you make sure they are not particularly already prone to ketosis, and you give them good Sick Day guidance if they become unwell, and you advise them to avoid all forms of low carb ketotic diets, such as the Atkins diet, and if you do all of that, you will never see a case of diabetic ketoacidosis.

Jeremy Levy

So then we should point out, shouldn't we, Andrew, those are a small group of patients. Of all the people with diabetes out there, that's actually a pretty small group.


Andrew Frankel

Absolutely. It was a concern, particularly in the early days, as we extended the use. I'm very keen that clinicians prescribing these drugs never get a letter from the diabetologist saying, you started an SGLT2 inhibitor and your patient presents with DKA. So if you choose the right patient, Sick Day guidance, give them advice on their diet, never stop their insulin, you will never see that complication.

The other thing, of course, to bear in mind is that these drugs are diabetes drugs, as well as being cardiorenal protective drugs, and you can see hypoglycaemia, but only when you use these drugs with other drugs that cause hypos, such as insulin or sulfonylureas. And you also only see it in preserved GFR, because once that GFR falls to 45, these drugs provide no glycaemic benefit. So the advice that we give is that if you're starting an SGLT2 inhibitor in a person on a sulfonylurea or insulin, you need to make a reduction of those drugs, but only if the GFR is greater than 45, and/or the HbA1C is less than 58, and in that situation, you should reduce the soft, the sulphonylurea by 50%, and the insulin by 20%, but never ever stop the insulin. So if you're using it with sulphonylurea as an insulin, GFR greater than 45, and HbA1C less than 58, make the cut.


Jeremy Levy

Very, very helpful advice. But again, people with poor kidney function, not an issue, only those with preserved kidney function. What about the diuresis? You're peeing out sugar, doesn't that make most people pee more?


Andrew Frankel

So the diuresis is a little bit overstated. We know it causes diuresis, that usually settles back when the patient gets into a sort of more of an equilibrium state, within a week or two. The only patients to be cautious about, are those with really poor glycaemic control, HbA1C above 90, and normal kidney function, (because again, if you've got GFRs of under 45 this is irrelevant), but if you've got normal kidney function, poor HbA1C, you can get a massive diuresis. So what I recommend in that group of patients is you actually do need to put them on sulphonylureas and insulin, get their HbA1C down to 70 or so, then start the SGLT2 inhibitor, and then the key, deprescribe the insulin or sulfonylurea.


Jeremy Levy

Really, really helpful. And there's been this story, which is not a story, but is overstated, isn't there, about both urinary tract infections, or groin fungal infections, penile, vaginal, depending on the person and the risk, because your urine is a bit sugary, tell us a bit about that.


Andrew Frankel

So the urine infection, let me deal with that first, Jeremy, because that's easy, has really been totally overstated. The risk is very marginal indeed, and I would only be cautious in people who've had documented episodes of urinary sepsis, and it's caution doesn't even mean you don't prescribe it. So the risk of urine infections, very low.

Risk of genital fungal infections, vulva vaginitis, balanitis, very common, but what we find is it's easily treated with anti candida treatment, anti fungal treatment, often doesn't come back, and it's very unlikely in the studies, that someone stopped taking the drug because of it. And if you give those individuals good personal hygiene advice, and tell them, if they get that itching and redness, go to their pharmacist, get the treatment, easily resolved.

There is a very, very rare disorder called fourniers gangrene, which is a poly microbial genital infection that's devastating. There is no actual evidence that this is increased in people using SGLT2 inhibitors, but it's a disease that occurs in people with very poor diabetes control, poor personal hygiene, and it presents differently from vulva vaginitis or balanitis. It presents with perineal inflammation, tenderness, and fever. And so I always tell people, if you get perineal (and I tell them what I mean by that) tenderness, you get fever and pain, then you should seek medical attention. But it's a very, very rare complication.


Jeremy Levy

I'm very impressed that you tell people about that last thing Andrew, it's so rare. I mean, there was this minor concern when the SGLT2 inhibitors came out. I talk about urine infections being rare and fungal infections, I don't mention the fourniers gangrene myself at all.


Andrew Frankel

No, you're absolutely right Jeremy, and I would rather not. But the problem that primary care has is that the CQC have said they have to have informed every person who starts on an SGLT2 inhibitor about fourniers gangrene. And my view is you give them the advice sheet that's got all the details on, you tell them about the difference between itching and redness and pain, and jobs done.


Jeremy Levy

There's a balance here, isn't there - the massive benefits from these absolutely tiny risks for some people, but overall.

So SGLT2 inhibitors. In the UK we've been very lucky. They've been approved very rapidly on the basis of fantastic trials. These are really important medicines. They should be prescribed in basically everybody with heart failure, everybody with diabetes and chronic kidney disease, and then those without diabetes but chronic kidney disease, with or without proteinuria, with some minor GFR boundaries. We don't stop them as GFR falls. So we've got a good place to use them. We advise people about the small risks of fungal groin infections and urinary infections, but all of those are treatable, and shouldn't need the drugs being stopped, and we can continue the medicines (unless they're recurrent - clearly, a small number of people do run into problems), but most can be treated and continue the medicines, and these will slow down progression of kidney disease, and protect them from cardiovascular risks, in addition to renin angiotensin blockade and the other things we've talked about in previous episodes.

I hope that's been really helpful to our audience Andrew, it's been great talking to you again!


Andrew Frankel

A pleasure Jeremy!