The benefits of SGLT-2 inhibitors for people with type 2 diabetes and chronic kidney disease (CKD) have been amply demonstrated in recent years. So is it time to prescribe them to all those who have both conditions or should certain groups be treated with caution? This key clinical question was under debate at the 59th EASD Annual Meeting. Dr Susan Aldridge reports.
The title of the debate was ‘All people with diabetes and CKD should be on SGLT-2 inhibitors by default’ and a vote taken at the start showed 66% of delegates in favour of the motion. Hoping to shore up his majority by the end of the session, Dr Andrew Frankel, Consultant Nephrologist at Imperial College Kidney & Transplant Institute, opened with: “We have a huge problem. For the last 15 to 20 years, the number of people requiring end-stage kidney treatment has increased year on year, but the message I want to give you is that we also have a huge issue ahead of us. If you travel outside Europe, if you go to the Middle East and the Far East, they are already facing a deluge of diabetic kidney disease (DKD).”
This is because the people with diabetes and CKD, including end-stage kidney disease, currently being cared for started their journey 15 years ago when the number of people with diabetes was significantly fewer than it is now. So the numbers are going up all the time. “The second factor – and this is a good thing – is that with modern diabetes and cardiovascular interventions, individuals with diabetes are living longer,” he continued. “But longer duration is associated with decreased estimated glomerular filtration rate (eGFR) and a greater likelihood of developing CKD and cardiorenal complications.”
Today, people with diabetes and CKD are more likely to die of cardiovascular disease, but in 10 years’ time that will no longer be true. “End-stage renal disease is growing by 50 to 300% and that will truly bankrupt the system,” said Dr Frankel. “The fantastic news for me as a kidney doctor interested in diabetic kidney disease is that we now have excellent treatment.”
As in with heart failure, there are now ‘pillars’ of treatment for DKD, with angiotensin receptor blockers (ARBs), ACE inhibitors, SGLT-2 inhibitors, finerenone and blood pressure medications, as well as glycaemic and lipid control and lifestyle management to reduce cardiovascular risk.
“SGLT-2 inhibitors have been a key treatment for CKD and we have had this data now for nine years,” he said. “But in the UK, the number of people who should be on them that actually are is exceedingly small. We must do better.”
There are the various cardiovascular trials, the heart failure trials and the three renal trials – CREDENCE, DAPA-CKD, EMPA-KIDNEY. These involved different populations, with and without diabetes, but have all shown the same results with respect to hospitalisation for heart failure and hard endpoints of CKD progression. SGLT-2 inhibitors also reduce the decline in eGFR, need for dialysis and renal death. “The earlier you intervene and lift up that progression pathway, the better the outcome for the individual in terms of the need for dialysis or transplant,” he said. In a post-hoc analysis of the CREDENCE trial, among people who start out with an eGFR in the 40s, canagliflozin delays the need for dialysis by 13 years, so there are real benefits to the individual, population health and the population health economy.
Dr Frankel went on to highlight some points about the EMPA-KIDNEY trial, which involved a broad range of participants, with and without diabetes, and had an endpoint of cardiovascular death or kidney disease progression. A significant number did not have albuminuria. The outcome was strongly positive, with a 30% reduction in kidney disease progression, irrespective of starting eGFR. “There is no loss of efficacy with declining kidney function, which is a really important point to remember because I want to convince you about the extremes in CKD – the well preserved and the poorer kidney function.”
In EMPA-KIDNEY, there was a predetermined analysis using the slope of eGFR decline, where a 0.5 to 1.0 reduction in decline per month is considered meaningful and an accepted surrogate outcome for disease progression. “If you focus on those with no albuminuria, empagliflozin is abrogating age-related decline in eGFR,” he said, “so it is effective both at the end of the spectrum where you’ve got advanced kidney disease and at the other end with no albuminuria.”
Also, a post-hoc analysis of DECLARE showed that dapagliflozin was able to reduce the appearance of microalbuminuria. “So maybe we should put all people with diabetes on SGLT-2 inhibitors because we know that ACE inhibitors and ARBs do not work for primary prevention, but SGLT-2 inhibitors may do,” said Dr Frankel.
Dr Frankel has talked to many diabetes specialist nurses and clinicians about their worries over SGLT-2 inhibitors to reassure them. “The Oxford Trials Unit has carried out a meta-analysis that looked at absolute risk and absolute benefit of SGLT-2 inhibitors and found the balance to be way, way in favour for the person taking them in terms of kidney disease progression, acute kidney injury, cardiovascular death or hospitalisation for heart failure,” he said. “We have to keep that in mind, but it doesn’t mean that we don’t do things safely – educating so that people with diabetes know how to use sick-day guidance, for instance.”
What about SGLT-2 inhibitors in type 1 diabetes where there have so far been no large trials. “I’m putting this as a challenge because I think you need to do this,” he said. “We know that the trials that have been undertaken did demonstrate reductions in albuminuria.” The UK Kidney Association does recommend considering SGLT-2 inhibitors for people with type 1 diabetes if their eGFR is 20 or more – that is, relatively preserved – and if they have a urinary albumin-to-creatinine ratio of 25 or more, despite maximum ARB/ACE inhibitor medication. “But you need to be sure to do ketone monitoring and be under the strict direction of the diabetes team, which is one reason I’m here to talk to you,” said Dr Frankel. “We’ve started doing this and many other units have for those who are at high risk of progression.”
Conclusion – in favour
We face a healthcare emergency in terms of cardiorenal complications of diabetes. “You might think you see a lot of DKD now, but you wait – you will see a tsunami of DKD in the next 10 years,” said Dr Frankel.
We now have therapeutic options that can demonstrably slow down progression of cardiorenal complications and improve cardiorenal outcomes and quality of life. SGLT-2 inhibitors are central to that strategy. “As a healthcare community, we need to manage this problem proactively and effectively,” said Dr Frankel. “Aside from their excellent glycaemic benefits, we know that providing people with diabetes with SGLT-2 inhibitors gives better long-term quality of life, reduces the risk of cardiovascular complications and slows down progression of kidney disease, such that more people will likely avoid the need for dialysis in their lifetime.
“In an era of increasing medical specialisation, we become very ‘siloed’ in the UK, which is why I’m so pleased to be here – I tell all my trainees ‘we are all diabetologists now’. Because if you walk around the general medical wards or renal units, it’s all diabetes. However, diabetologists are the system leaders and we are going to need your help to ensure that all who can benefit from SGLT-2 inhibitors receive them,” he concluded.
The case against universal SGLT-2 inhibitors
Professor Daniel van Raalte from Amsterdam University Medical Centers took to the stage to urge caution when prescribing SGLT-2 inhibitors to people with diabetes and CKD. But first he said: “I agree that CKD is a major health problem and it’s also very clear that the SGLT-2 inhibitors are the strongest kidney protective drugs out there. It’s also very worrying that there are a lot of people worldwide that should receive these drugs that don’t.”
He went on to say that the important words in the motion being debated were ‘all’ and‘default’. “We have to think about which groups are not suited to SGLT-2 inhibitors or where we lack evidence,” he said. “I think, from this point of view, my opponent has been skating on thin ice. For each group, we must have data on safety and efficacy to be sure we ‘first do no harm’.”
First, there are people with type 1 diabetes, although Professor van Raalte agreed that SGLT-2 inhibitors will work for some. “But there is an issue and it is a pretty big one – the occurrence of DKA, which has been a consistent finding in the trials,” he said. “The mortality of DKA requiring hospitalisation is 0.2 to 1.2%, which is low, but is true only in countries with good healthcare.”
There is also the danger of euglycaemic DKA – he cited a case of a young woman in the Amsterdam area who died because of this and, from the mechanism of the drug, it is difficult to prevent it. “Although there are guidelines on mitigating the risk of DKA, I think we have to be careful not to underestimate it,” he continued. “People in trials are motivated with frequent study visits where they learn about DKA mitigation. The risk in the real world is higher.”
The good news is that further trials of SGLT-2 inhibitors in type 1 diabetes are ongoing, including the recently announced Steno 1 study. There are also technical developments in continuous ketone measurement, which might help reduce DKA risk, while a new trial on finerenone may show it to be a better option without the DKA risk. “I hope I’ve convinced you that not all patients with type 1 diabetes should be on SGLT-2 inhibitors,” concluded Professor van Raalte.
Then there is the issue of the type of patient with respect to kidney function. There is no data on those with an eGFR below 20 or for those with kidney failure. “So we don’t know if the drug is safe and has efficacy in these cases,” he said. “And if you’re on dialysis, will the drug give cardiovascular protection? Note that statins do not prevent cardiovascular disease, despite lowering cholesterol, in people on dialysis or with a kidney transplant. So we have to be really careful not to blindly assume that these drugs are going to be efficacious in this group.”
Meanwhile, genital mycotic infection and urinary tract infections (UTIs) are known side-effects of SGLT-2 inhibitors. People with a transplanted kidney are at particularly high risk of these infections because they take immunosuppressants and have abnormal kidney anatomy. UTIs are associated with loss of kidney function and are the main reason why kidney transplant recipients are admitted to hospital with septic shock. “So we really have to be careful,” he warned.
He cited the ongoing RENAL LIFECYCLE trial of dapagliflozin, which includes kidney transplant recipients, those on dialysis and with stage 4 and 5 CKD, with and without type 2 diabetes, among its 1500 participants. “This will shed light on whether these drugs have efficacy and are safe in these populations,” he said. “Putting them on these drugs by default is jumping the gun.”
What about the frail elderly, who are not usually included in studies like EMPA-REG and already have a higher risk for UTIs? One study shows that 25% of elderly people stopped SGLT-2 inhibitors because of UTIs. There is also the increased risk of hypotension, which could lead to a fall among the elderly. And another study shows that elderly people with kidney disease usually die of other things, so maybe there is less need to treat those who are in nursing homes and with an eGFR of less than 40, for instance.
Finally, there are non-responders. “SGLT-2 inhibitors are great drugs, but not everyone benefits from them – maybe finerenone is a better option,” said Professor van Raalte, who concluded his presentation by urging delegates to talk to their patients about the benefits and risks of SGLT-2 inhibitors.
Professor van Raalte’s arguments proved persuasive – when a final vote was taken there was a dramatic switch in opinion, with only 28% being for the motion and 72% against.
To learn more, enrol on the EASD e-Learning course ‘SGLT-2 inhibitors’.
Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.