Prescribing SGLT2 Inhibitors in Patients With CKD: Expanding Indications and Practical Considerations

To the Editor:

We thank Rico-Fontalvo et al.¹ for raising several important points regarding the use of SGLT2 inhibitors in patients with chronic kidney disease (CKD). We recognize that the evidence for reduction in diuretic dosage with concomitant SGLT2 inhibitor usage is not well established, although some insight may be gleaned from post hoc analyses from SGLT2 inhibitor trials. For example, in DAPA-HF, patients with heart failure and reduced ejection fraction on a background of diuretic therapy experienced more frequent volume depletion events with dapagliflozin compared to placebo (P = 0.004).² In addition, in DAPA-HF, whereas the mean diuretic dosage did not change for the majority of patients during follow-up, decreases in diuretic dosage were more likely in the dapagliflozin arm compared with placebo, although between group differences were small.³ Real world studies in patients with diabetes have also suggested that concurrent SGLT2 inhibitor and loop diuretic use may promote volume depletion.⁴

On the other hand, the CREDENCE, EMPA-REG OUTCOME, and DAPA-CKD trials did not demonstrate differences in volume depletion events with diuretic usage,⁵ although EMPA-REG OUTCOME did report that combination diuretic use with SGLT2 inhibition was associated with a larger initial estimated glomerular filtration rate (eGFR) “dip” compared to those taking SGLT2 inhibition alone.⁶ Interestingly, a post hoc analysis from DAPA-CKD reported a lower risk of kidney injury with dapagliflozin, a benefit that was similar in diuretic users versus nonusers, which serves to re-emphasize the kidney safety of these therapies.⁷

Together, this body of evidence illustrates that SGLT2 inhibitors are safe, and that most patients do not require diuretic dosage reduction with SGLT2 inhibitor initiation. Nevertheless, the risk of volume depletion may be higher in certain populations such as patients with heart failure, and in clinical practice frail patients with a high burden of comorbidities may also be at higher risk. Therefore, the decision to reduce diuretic dosage needs to be determined by clinicians on a case-by-case basis. This is line with the suggestion by the Canadian Cardiovascular Society to consider an optional loop diuretic dose reduction if the patient is euvolemic and to reduce the diuretic dosage by 30% to 50% if clinical evidence of volume depletion occurs.⁸

For the comment regarding heart failure trials, we agree that EMPEROR-Preserved and EMPEROR-Reduced provide complementary data on kidney outcomes in patients with eGFR down to 20 ml/min per 1.73 m². As mentioned, kidney outcomes were secondary and subgroup analyses among those with low eGFR included a limited number of patients. Nevertheless, in both studies, attenuation of eGFR slope was observed in those assigned to empagliflozin with no heterogeneity by CKD status even among those with eGFR 20-30 ml/min per 1.73 m².⁹ In addition, the EMPA-KIDNEY trial was recently stopped early for efficacy and included patients with CKD, with or without diabetes, and with eGFR down to 20 ml/min per 1.73 m². This trial will therefore provide crucial data regarding patients with stage 4 CKD.¹⁰

Finally, we agree that there is a paucity of data regarding the effect of combination therapy with SGLT2 inhibitors and GLP-1-RA in patients with CKD. In SUSTAIN 9, patients with eGFR less than 60 ml/min per 1.73 m² were excluded, while in DURATION-8 only a minority of patients had eGFR 30 to 60 ml/min per 1.73 m². Prospective studies are required to determine the effect of SGLT2 inhibitors and GLP-1 RA on both cardiovascular and kidney outcomes in CKD patients. Hypothetically patients might be expected to derive additional benefit from combination therapy due to differing mechanisms of action. One trial that may provide further evidence regarding this question is the ongoing FLOW trial (NCT03819153), which is evaluating the use of semaglutide on a primary kidney endpoint in patients with type 2 diabetes mellitus and CKD and permits inclusion of patients taking SGLT2 inhibitor therapies.