COMMENTARY

2020: The Year of the SGLT2 Inhibitor

Prof Kamlesh Khunti 

Disclosures

December 22, 2020

Professor Kamlesh Khunti reflects on the 'exciting times' for SGLT2 inhibitors in patients with and without diabetes. He's recently rounded up the year's developments in an article in Nature and here he explains the main developments.

This transcript has been edited for clarity.

My name is Kamlesh Khunti, I'm professor of primary care diabetes and vascular medicine at the University of Leicester.

Thank you for joining me for this short recap on some of the exciting findings from recent trials that have been published over the last 12 months. We've seen over the last few years some incredible results from cardiovascular outcome trials with glucose lowering therapies that have changed guidelines for management of people with type 2 diabetes. These include the ADA/EASD consensus report and many, many other international guidelines. However, now we've seen that some of these therapies are also going to be useful in people without diabetes.

We know in people with type 2 diabetes, heart failure and chronic kidney disease are frequent causes of morbidity and mortality. Cardiovascular outcome trials have confirmed benefits of sodium glucose cotransporter 2 inhibitors in cardiovascular events, cardiovascular deaths, hospitalisation for heart failure, and renal outcomes. These benefits will now extend to people with and without type 2 diabetes.

Recent Trials

As you all know, type 2 diabetes is a chronic cardiometabolic condition that is associated with high prevalence of chronic kidney diseases, cardiovascular disease and heart failure. All of these are intricately interlinked, and are associated with morbidity, mortality, poor quality of life, and increased healthcare costs.

Recent cardiovascular outcome trials have therefore generated huge excitement in those managing people with type 2 diabetes, not only in primary care, but also diabetologists, endocrinologists, cardiologists, and indeed nephrologists.

The key reason is the novel therapies, the sodium glucose cotransporter 2 inhibitors and GLP-1 receptor agonists which have demonstrated beneficial effects on not only cardiovascular outcomes, but also renal benefits, and with just SGLT2 inhibitors, hospitalisation for heart failure. The EMPEROR-Reduced outcome trial was the first cardiovascular outcome trial to demonstrate beneficial effects of SGLT2 inhibitors on cardiovascular death, major adverse cardiovascular outcomes, MACE events, heart failure, and progression of kidney disease in people with type 2 diabetes.

Since then, we've had some similar benefits with the CANVAS trial programme, and the DECLARE–TIMI 58 trials. These included patients with a broader population with and without established cardiovascular disease.

The CREDENCE trial was the first pre-specified renal and cardiovascular outcome trial in people with type 2 diabetes and chronic kidney disease, and again demonstrated renal and cardiovascular benefits of SGLT2 inhibitors in people with these two comorbidities. The latest SGLT2 inhibitor trial is the VERTIS CV, which surprisingly did not show beneficial effects on MACE outcomes or renal outcomes, but did show that the therapy was safe.

However, it also showed, similar to other SGLT2 inhibitor cardiovascular outcome trials, a significant reduction in hospitalisation for heart failure.

These studies have therefore paved the way for trials in the broader population without type 2 diabetes due to their mechanism of action.

In recent months, we've seen the results of the DAPA-HF heart failure trial evaluating the efficacy and safety of SGLT2 inhibitor dapagliflozin in patients with New York Heart Association Class 2, 3, or 4 heart failure and an ejection fraction of 40% or less.

DAPA-HF showed the beneficial effect in favour of dapagliflozin for the primary outcome of composite of worsening of heart failure, which is hospitalisation or an urgent visit resulting in intravenous therapy for heart failure, or cardiovascular death. This showed a 26% relative reduction, which was significant in favour of dapagliflozin.

These benefits were also recently replicated in the EMPEROR-Reduced trial with empagliflozin.

'Exciting Times'

What's exciting about these studies is that they included people with and without diabetes, and the trials showed similar benefits in these populations.

In the Dapa-CKD trial, participants with an EGFR of 25 to 75 mL/min, were randomised to receive dapagliflozin 10mg or placebo.

This shift study showed beneficial effects on the primary endpoint, which is a composite of the sustained decline in the estimated EGFR of at least 50%, end stage kidney disease, or death from renal or cardiovascular causes, with consistent benefits, as shown in those with and without type 2 diabetes.

The study also confirmed benefits in terms of reduction of all cause mortality, reduction in hospitalisation for heart failure, and cardiovascular death. And there was a 44% reduction in the incidence of worsening renal function and death from kidney failure.

These are exciting times, not only for the management of people with diabetes, but also people without diabetes who have CKD or heart failure. We now wait for regulatory authorities to change guideline recommendations. Now only time will tell if these novel therapies will be adopted in clinical practice, and if we will realise the benefits that have been seen in these randomised control trials. Thank you for joining me.

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