CKD The Sequel - The EMPA Strikes Back

You’re running late and trying to whip through the last few path results of the day before heading home. You see Ruth’s results from her annual IHD check including her U&E - eGFR 42, so you quickly check for any progression - no it’s stable over the past few years and her ACR is normal. You hover over the ‘stable, repeat in 6 months’ option, but something is nagging away in the back of your brain - ‘should I be doing more here?’

We all know lots of ‘Ruths’ with stable CKD, and until recently the focus for reducing her progression of kidney disease was good BP control and an ACEI (or ARB). However things have changed substantially over the past 5 years. Kicked off by the DAPA-CKD trial in 2020, which showed cardio-renal benefits for dapagliflozin in people with CKD with or without diabetes, a class effect was then established with the publication of the EMPA-KIDNEY trial in 2023 which showed similar benefits for empagliflozin across a much wider group of people with CKD, including those without albuminuria. 

The EMPA-KIDNEY trial was stopped early at a median of 2 years due to benefits seen at the interim analysis based on the primary outcome (a composite of CKD progression or death from renal or CVD causes). This can be a double-edged sword when trials are stopped early with positive outcomes - good in that benefits have been established early, but the downside is that longer term benefits (or harms) may not have become apparent, particularly for certain clinical outcomes such as end stage renal failure. 

So the authors of EMPA-KIDNEY undertook a post-trial follow up with ~75% of participants from the original trial to assess longer term benefits and risks and assess specific subgroups/secondary endpoints. Patients had CKD with eGFR 20-44 (regardless of ACR levels) or eGFR 45-90 with raised ACR (>200mg/g = NB this equates to 22.6 mg/mmol which are the units we use in the UK), and although patients and investigators remained blinded to their original trial-group assignment (empagliflozin or placebo) local practitioners were free to use an SGLT2i if they thought appropriate during the post-trial follow up. In the post-trial phase use of SGLT2i was similar across the original trial groups (43% in the empagliflozin group and 40% in the placebo group). Importantly most (>85%) were on a renin-angiotensin drug (i.e. ACEI or ARB).

The cardio-renal benefits for those in the original empagliflozin group were maintained in the post-trial analysis irrespective of diabetes status, although it was notable that the benefits were most apparent in the first 6-12 months - the authors concluding that ‘the maximization of cardiorenal clinical benefits of SGLT2 inhibitors in chronic kidney disease requires long-term treatment’. The post-trial analysis also showed important improvements in key secondary outcomes for empagliflozin, notably reductions in end stage kidney disease (i.e. needing dialysis or renal transplant). In absolute terms empagliflozin reduced the numbers progressing to end stage kidney disease by 25 per 1000 patients, giving an NNT of 40. Given the substantial burdens and costs to both individuals and the health care system of dialysis or renal transplant, these are significant findings. 

These results consolidate the importance of SGLT2 inhibitors in the management of CKD. As discussed in the associated editorial ‘Despite the compelling benefit seen for SGLT2 inhibitors, prescription rates remain suboptimal’ and the latest results from the EMPA-KIDNEY follow up trial should encourage us to ‘bridge the implementation gap for SGLT2 inhibitor initiation and continuation in virtually all patients with chronic kidney disease who are at risk for progression’. One important caveat to note is that the trial participants were relatively young (median age ~63 years old), so whether these benefits are applicable to our older, frailer population remains to be seen, especially as they are more at risk of side effects from SGLT2 inhibitors, notably hypovolaemia, hypotension and falls. 

We go back to Ruth. Her eGFR is relatively stable at 42, normal ACR, but with her known IHD she is at high risk for future cardio-renal deterioration. She is already on maximal CVD secondary prevention with 10mg ramipril and 80mg atorvastatin. She is a relatively fit 70 year old and would benefit from empagliflozin, as recommended by NICE. Time to move from ‘screen’ to ‘intervene’ for her CKD.