Benefits, Mechanisms of SGLT2 Inhibitors in Diabetic Kidney Disease, Other Communities

In an interview with Pharmacy Times, William Herrington, MD, MA, MBBS, clinical research fellow, Honorary Consultant Nephrologist at Oxford Kidney Unit, clinician scientist at the Nuffield Department of Population Health, University of Oxford, discusses the mechanisms and benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors in managing diabetic kidney disease by slowing progression and reducing the risk of declining kidney function, or the need for dialysis or kidney transplant. Herrington will be presenting at the panel “Are SGLT2 Inhibitors New Again?” during ASN Kidney Week in Philadelphia, Pennsylvania (November 2, 2023, to November 5, 2023).

Pharmacy Times: SGLT2 inhibitors have garnered significant attention for their potential benefits in managing diabetic kidney disease. Can you discuss the key mechanisms of action of SGLT2 inhibitors, and how they contribute to improving kidney health in individuals with diabetes?

William Herrington: Okay, so, SGLT2 inhibitors, they're remarkably effective and the trials, which had demonstrated that they slow kidney disease progression had been described as landmark, partly because we had no positive trials for 20 years after discovery of the effectiveness of renin-angiotensin-system (RAS) blockers, like irbesartan and losartan. But partly also because of the size of the effects, which we were observing and people with diabetic kidney disease, were so large that it was almost too good to be true when we first saw the results.

First trial was EMPA-REG OUTCOME, and it raised a very strong hypothesis. We've had 12 other trials published since, 3 of which are dedicated trials which included thousands of people with diabetic kidney disease. And when you meta-analyze those trials together, what we see is about a 40% reduction in the risk of kidney function falling by 50%, or needing to start dialysis or have a kidney transplant.

What's amazing about [SGLT2 inhibitors] is that, to be honest, we thought they were going to be good for treating diabetes and they're actually only modestly effective at treating diabetes. And when you've got low kidney function, you actually don't excrete large amounts of glucose in the urine, which is the main mechanism by which the drug has its action in the body, but what they do is remarkably reduce risk. And unusually for a drug, we are now scratching our heads to try and work out exactly how they work. And so, they're very effective and they must work by at least 1 major mechanism, and the most cited mechanism is reduce intraglomerular pressure—so the drug causes sodium and glucose to pass into the urine—which can restore some pathways within the kidney…and restore something which is called hyperfiltration back to normal. So, kidneys are thought when you have diabetes or obesity to over filter, and these drugs are thought to correct the feedback mechanism which is distorted by the presence of diabetes and glycosuria.

So, we think that's the main method…there are several signs with the trials that there's something else happening, and because a marker of over filtration of the kidneys is hyperfiltration—the leaking of protein or alcohol into the urine—and we observe in these SGLT2 inhibitor trials that the reduction is now when albuminuria is about 20%, well, we start to see effects which are as large as 40%. So, there's a mismatch suggesting there are other mechanisms there.

I have a personal hypothesis…and I'm investigating at the moment, which is that there are benefits on the tubules—the parts of the kidneys which are beyond the glomerulus, beyond the filtration structure—[are] where these drugs have their main action, and that might explain why we also see these drugs reducing the risk of acute kidney injury (AKI) if they are affecting the tubules. It might also explain why we see benefits of these drugs in people who've got heart failure, who don't generally have such raised intraglomerular pressure. So, the jury's out on exactly how these drugs work, but I bet it's more than 1 way.

Pharmacy Times: What are some of the key challenges or gaps in the current treatment options for individuals with diabetic kidney disease? How do the novel therapies—particularly SGLT2 inhibitors—address these unmet needs?

Herrington: Well, for years, we only had 1 treatment which was shown to be effective at reducing levels of protein, albuminuria, and now this means we've got we've got 2. There is another class of medication called non-steroidal mineralocorticoid receptor antagonist finerenone, and together these are looking like they might be the 3 pillars of treatment—or the 3 arrows in the quiver—which we can use to shoot this disease. Despite the fact that we use these treatments, we are still seeing people with diabetic kidney disease having progression. So, we're reducing the risk, but it's not a cure yet.

And the heart failure community is a very interesting community to observe because they've been doing large trials like the nephrology community have started to do for many years, and they've got many tools in which they can treat people with heart failure, to try and reduce risk. They still haven't cured heart failure, so what we need is in our, essentially, in our doctor's bags is more than 1 tool. Now we've got 3 tools, but they're not enough necessarily to cure the disease.

And then the other thing I have to say is the SGLT2 inhibitors…although they're incredibly effective in type 2 diabetes, and we've got some analysis…which shows they're effective in people with type 1 diabetes, at least as effective as in type 2 diabetes. The problem with the drugs is they can induce a condition called ketoacidosis, particularly in people who've got type 1 diabetes that are dependent on insulin, and we do ask people to stop taking the drug if they're not eating because it's a risk for becoming ketotic and developing ketoacidosis. And unfortunately, we haven't got big enough trials to show us yet whether or not widespread use of these drugs and type 1 diabetes is safe. We did this in our trial EMPA-KIDNEY by giving all the participants a ketone meter to monitor their ketones if they became unwell, and we did have 1 episode of ketoacidosis in the 68 patients who were in the trial who had type 1 diabetes. We also saw very, very impressive effects on the overall result with the effects we observed in people with type 1 diabetes. So, the key unmet need is, really, more trials in patients with type 1 diabetes.

Pharmacy Times: How do SGLT2 inhibitors complement existing treatment strategies for diabetic kidney disease? Are there other patient populations that may benefit most from these therapies?

Herrington: Okay, so the SGLT2 inhibitors, they're almost like a gift that keep on giving. They do something, which is really helpful, they reduced the risk of AKI and they modestly reduce potassium. In fact, if you look at the all the trials put together, they reduce the chances of being hospitalized for a high potassium. Now, high potassium is 1 of the common things which happens as kidney disease develops and progresses, but it also it's a common side effect of both RAS inhibitors—which are shown to be beneficial, 20 years ago—but also this new nonsteroidal mineralocorticoid receptor antagonists finerenone. And it's possible that the combination of using an SGLT2 inhibitor with 1 of these other drugs may actually be quite a nice marriage.

So, in the heart failure trials, it was suggested that—this was in the EMPEROR-Reduced trial—use of empagliflozin reduce the chance of needed to stop the mineralocorticoid receptor antagonist. And in a recent analysis—which is about 2 weeks old—looking at the credence and depth of chronic kidney disease (CKD) studies, we've seen a similar result in the CKD population…shows about a 15% reduction in the chances of needing to stop your RAS inhibitor. So, it looks like the combination of an SGLT2 inhibitor with a RAS inhibitor—or an MRA—may be effective. And we've saw results of a phase 2 trial of a drug called BI 690517, and they announced the 11,000-patient trial called Easy Kidney…where 1 of the SGLT2 inhibitors, empagliflozin, in combination with [BI 690517], which targets the aldosterone pathway and will increase potassium, because [researchers] think the 2 might work together very nicely. So, that trial will begin recruiting next year.

Pharmacy Times: What are the important considerations and best practices for prescribing and monitoring patients on SGLT2 inhibitors and GLP1 receptor agonists to ensure their safe and effective use? Is there anything specific that pharmacists need to know?

Herrington: You know, this is excellent question. So, part of my work in the last 2 years has been working with the UK Kidney Association developing guidelines for use of these SGLT2 inhibitors, but we actually focus a lot on guidelines for their implementation…it has a whole section dedicated to how to use these drugs.

One of the things I would say is that when I start the drugs, I do explain to the patients how safe and effective they are. In the meta-analyses we have done, we've shown in the study populations, the net benefit clearly outweigh the risks and this is particularly the case for people with CKD. Particularly, [SGLT2 inhibitors are] actually for people with CKD without diabetes, because the main side effect of ketoacidosis really is incredibly rare in people without diabetes. There are a few things which people are worried about, which I do mention to the patients. So, there has been some discussion about amputation, so if they've got active foot disease, I cancel them very carefully and I often don't start [treatment] until that disease is under control.

And the other thing I mention to them if that is possible, they might get thrush, so men don’t always experience thrush—people diabetes, maybe they've experienced it—but I explain that [clotrimazole] cream might be helpful. And [patients] they develop groin pain, they should stop treatment. So, 1 of the things that I think is really important to say, if these drugs when we trialed them, although they have a decrease in kidney function within a few days of starting the treatment, that is actually potentially a marker of the effect of the drugs and it's not necessarily a reason to stop the treatment. The UK Kidney Association guidelines encourage people not to do tests routinely after starting these drugs. We routinely check for potassium and creatinine after starting a RAS inhibitor or finerenone, because we don't see the risk associated with them and it doesn't affect the frequency of monitoring their CKD and that should continue in the frequency which would have continued irrespective of starting the SGLT2 inhibitor.

So, incredibly easy drugs to start, and they should be started by primary care physicians, nephrologists, cardiologists, diabetologies, you don't need to ask permission from any of the other specialties. I think they're so simple to use and so safe, that if you think there's an indication you should start it.