Characterization and implications of the initial estimated glomerular filtration rate ‘dip’ upon sodium-glucose cotransporter-2 inhibition with empagliflozin in the EMPA-REG OUTCOME trial

Impact of the initial decline in estimated glomerular filtration rate on the risk of new‐onset atrial fibrillation and adverse cardiovascular and renal events in patients with type 2 diabetes treated with sodium‐glucose co‐transporter‐2 inhibitors

“…Our analysis indicated that the use of any diuretic, the presence of stroke, older age, female sex and a lower BMI were independent factors associated with a significant eGFR decline of more than 30% during SGLT2i treatment. Our data are in line with the findings of the EMPA‐REG OUTCOME and CREDENCE trials, as well as real‐world data, indicating that patients treated with SGLT2is who were receiving diuretic therapy were more probable to experience an initial eGFR decline 8,9,25 . Hypovolaemia substantially reduced the eGFR by reducing the effective plasma volume and renal hypoperfusion.…”

“…In the EMPA‐REG OUTCOME trial, 6668 patients who had their eGFR available at baseline and 4 weeks later were randomized to receive 10 mg of empagliflozin, 25 mg of empagliflozin, or placebo. The post hoc analysis findings revealed that 30.5%, 41.1% and 28.3% of patients with no initial eGFR decline, an eGFR decline of 0%‐10%, and an eGFR decline of more than 10%, respectively, were all treated with empagliflozin 8 . Compared with placebo, the safety and beneficial treatment effects of empagliflozin on kidney and cardiovascular outcomes were consistent among subgroups with different values of eGFR decline.…”

“…In the current study (and also for the post‐hoc analyses of the EMPA‐REG OUTCOME and CREDENCE trials 8,9 ), only single measurements of baseline and follow‐up eGFR were available, and owing to their high biological variability, we may not have been able to correctly classify each patient. Second, in contrast to the post hoc analyses of the CREDENCE and EMPA‐REG OUTCOME trials using eGFR data obtained 3‐4 weeks after SGLT2i treatment for the calculation of eGFR decline, 8,9 we adopted eGFR data obtained nearest to the date of 3 months (12 weeks) after the date of the first prescription of the index drug to calculate the initial eGFR decline after SGLT2i initiation. In most cases, as per routine clinical practice, patients were requested to visit a clinic to refill their medications and recheck vital laboratory items at intervals of less than 12 weeks.…”

“…These findings indicated that the long‐term eGFR trajectory, as well as the overall and renal safety profiles during canagliflozin treatment, were comparable across the subgroups with different values of initial eGFR decline. Of note, these post hoc analyses of randomized controlled trials were markedly confounded by the fact that eGFR decline is a postrandomization subgroup and that the different eGFR decline categories had significant differences in baseline characteristics 8,9 . Therefore, the results should be interpreted cautiously.…”

Renal haemodynamic response to sodium‐glucose cotransporter‐2 inhibition does not depend on protein intake: An analysis of three randomized controlled trials

“…These beneficial effects are attributed to decreased sodium resorption in the proximal tubule and normalization of tubuloglomerular feedback, resulting in reduced intraglomerular pressure. Clinically this is manifested by an acute reversible dip in glomerular filtration rate (GFR) 4,5 . However, although effective at a population level, the albuminuric response to SGLT2 inhibitors varies markedly between individual patients, leaving a proportion of patients at high risk of kidney and cardiovascular outcomes 6–9 .…”