EMPA-KIDNEY: Could the benefits outlast the drug?

In the original EMPA-KIDNEY trial, 6,609 patients with CKD at risk of progression were randomised to an SGLT2 inhibitor or placebo and followed for a median of two years. The trial showed a 28% reduction in kidney disease progression or cardiovascular death.² So, what happens next?

In the post-trial phase, 4,891 patients (74% of the original cohort) were observed for a further two years. No trial drug was provided. Blinding was maintained. Local practitioners could prescribe open-label SGLT2 inhibitors if they chose to, and roughly equal proportions in both groups did (43% in the original treatment group, 40% in the placebo group).

Over the combined four years (two years on treatment and two years off), 26.2% of the treatment group had a primary outcome event. In contrast, 30.3% of the placebo group experienced the same event. The hazard ratio was 0.79, with a 95% confidence interval of 0.72 to 0.87. Kidney disease progression was lower (23.5% vs 27.1%), end-stage kidney disease was lower (9.0% vs 11.3%), and cardiovascular death was lower (3.8% vs 4.9%).

The American College of Cardiology described this as a “legacy effect.” Most of the residual benefit is seen in the first 12 months after stopping the trial drug. After that, the curves begin to converge. This aligns with the idea that the structural kidney benefits of SGLT2 inhibition last for a time but do not persist indefinitely once the drug is removed.

A few important caveats. The trial included patients with advanced CKD. Their average eGFR was 37 mL/min/1.73m². They also had significant albuminuria, with a median uACR of 317 mg/g.

These are patients under nephrology care, not the broader primary care CKD population. The post-trial follow-up was observational. It did not control for open-label SGLT2 inhibitor use. However, usage was similar in both groups. The findings show what occurs after a set treatment time in a specific group. They don't say if shorter or longer treatment times would have the same carry-over. They also don’t mention if the same results would appear in earlier-stage CKD.

What could this mean for primary care?

This is a secondary care trial, but the principle it demonstrates is relevant to any clinician managing CKD. For patients with advanced CKD and high albumin levels, SGLT2 inhibitors helped cardiorenal health. These benefits lasted even after stopping the medication. Whether this translates to earlier-stage disease managed in primary care remains an open question. The data does not answer it, but it adds to the growing evidence base around these agents in kidney disease.

References

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