The “4 pillars” of guideline-directed medical therapy for patients with type 2 diabetes and chronic kidney disease are clear cut but the best way to deliver them to reduce cardiovascular-kidney-metabolic risk remains debatable.
An article in the journal Circulation [link here] said there were three distinct approaches to the delivery of renin angiotensin system blockade, an SGLT2i, a nonsteroidal mineralocorticoid receptor antagonist (ns-MRA) and GLP-1 receptor antagonist.
The article, coauthored by Australian nephrologist Dr Brendon Neuen, said the traditional approach of sequentially adding in each therapy had the disadvantage of being time-consuming.
It ignored the very high early cardiovascular risk faced by patients with type 2 diabetes and albuminuric CKD, in particular, related to heart failure.
“Current recommendations to reassess and modify treatment every 3 to 6 months, such as those from the American Diabetes Association and European Association for the Study of Diabetes, would mean it could take >18 months until all 4 therapies are fully implemented.”
The authors said the multiple steps also increased the likelihood of therapeutic inertia.
Yet a faster ‘rapid-sequence’ approach of initiating multiple therapies either simultaneously or within a very short time frame also had its downsides.
“The appeal of this approach is that it is likely to reduce therapeutic inertia through rapid uptake of recommended therapies, translating into greater and earlier benefits on clinical outcomes,” they said.
“However, a rapid-sequence paradigm is predicated on the assumption that all patients are at very high risk, which may not be true for CKD, where the rates of progression to kidney failure are more heterogeneous.”
They also said some patients may not tolerate such an intensive approach to treatment.
Instead, they raised the concept of adopting a hybrid “accelerated risk-based” approach which stratifies individuals on the basis of absolute risk and prioritises accelerated uptake of the 4 pillars of therapy in those likely to benefit most.
“The Kidney Disease Improving Global Outcomes heat map has been shown to identify those with type 2 diabetes who benefit most in absolute terms from SGLT2i, with risk-based initiation of SGLT2i also estimated to prevent more kidney failure and heart failure events compared with a strategy based on glycated haemoglobin or albuminuria alone.”
“Such an approach is analogous to the initiation of statins in primary prevention on the basis of absolute cardiovascular risk,” they said.
“An accelerated risk-based approach to combination therapy captures the benefits of rapid-sequence initiation, but also matches the intensity of treatment to risk and ensures that those who might receive the largest absolute risk reductions are prioritised for accelerated, intensified treatment.”
They said the approach was also likely to be more cost effective and acceptable to patients, clinicians, health systems, and payors/insurers.
Equity and access
Dr Neuen, from the Royal North Shore Hospital and George Institute for Global Health, told the limbic he felt the accelerated risk-based approach was probably the best way going forward now there were so many effective therapies.
“How to allocate those in an equitable manner that prioritises absolute risk reductions, maximises cost effectiveness and ensures that we obtain the most in terms of population health benefits is going to be really critical,” he said.
“What I predict is the use of those medications in people who should be receiving them is going to be atrociously low.
“If you look at SGLT2 inhibitors in Australia in primary care, where the cost is less than the cost of a cup of coffee a day, their use is about 10% in people with diabetes and kidney disease. That’s not even looking at non-diabetic kidney disease and when you include that it’s probably less than 5%.” [link here]
“If that is the experience with SGLT2 inhibitors, which are a simple, cheap, one pill a day tablet, with no dose titration and no drug-drug interactions, what is it going to be with GLP-1s and finerenone [nsMRA] in combination?”
He said ideally an implementation trial comparing accelerated risk-based care versus usual care was required.
“The best early return on investment of accelerated risk-based care is probably prevention of cardiovascular disease and testing that in a randomised trial will be important. But in the absence of a randomised trial testing those approaches, I think accelerated risk-based care is still the most practical and relevant way to implement these therapies.”
He said the conversation would be dramatically “supercharged” next month (24 May) by the presentation of the FLOW trial at the European Renal Association Congress in Stockholm.
“FLOW is the only dedicated renal outcome trial of the GLP-1 receptor agonist semaglutide… [and] has been stopped early because of overwhelming efficacy. And we know from the press release that all the secondary endpoints were met including all cause mortality.” [link here]
“So this conversation is going to take on a completely different urgency and light after the 24th because of the dramatic benefits of semaglutide… and then we have SGLT2 inhibitors, finerenone… how we can use all these medications in combination? How do we prioritise individuals? How do we wrap them? How do we get people on to guideline-directed therapy as quickly as possible to reduce their cardiorenal risk?”
How can we prioritise accelerated therapeutic implementation of the "four pillars" of GDMT for diabetes & CKD?
-RASi
-SGLT2i
-ns-MRA
-GLP-1RA@mvaduganathan @KatherineTuttl8 & I outline what an "accelerated, risk-based approach" might look like@CircAHA https://t.co/Vb6z9gAFnL pic.twitter.com/G5O0elQgrT— Brendon Neuen (@brendonneuen) April 15, 2024