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Biologically plausible trends suggesting that a low‐protein diet may enhance the effect of flozination caused by the sodium‐glucose cotransporter‐2 inhibitor dapagliflozin on albuminuria

We read the paper by van der Aart-van der Beek et al with great interest and understand that a core message of this secondary analysis of three relatively small-sized randomized controlled trials is that high dietary protein intake does not offset the benefits of sodium-glucose cotransporter-2 (SGLT2) inhibition, also known as “flozination”. However, it may also be true that low protein intake could offer additional synergistic benefits to patients undergoing flozination. We feel that the presented data could have been interpreted differently given that there appear to be clinically relevant and biologically plausible trends in support of combining a low-protein diet with SGLT2 inhibition to improve the salutary effects of this pharmacotherapy approach to reducing albuminuria and protecting kidney health and longevity. In the DELIGHT trial (n = 233), dapagliflozin versus placebo reduced urinary albumin to creatinine ratio (UACR) by 21% in the high-proteindiet group versus 28% in the low-protein-diet group, suggesting 39% more effect of the SGLT2 inhibitor if combined with low protein intake. The interaction P value was not significant, probably because of the limited sample size. Interestingly, the IMPROVE trial (n = 30) showed a very similar trend in that there was 38% more effect of restricted protein intake added to the effect of dapagliflozin as compared to the pharmacotherapy alone or in combination with high dietary protein intake (Figure 1), although the P value for interaction was not significant. The third study, the DIAMOND trial (n = 53), significant showed a marginal effect of SGLT2 inhibition on UACR (P = 0.072). Dichotomization of dietary protein intake decreases statistical power. Treating dietary protein intake as a continuous variable could be more useful in this context, as methodologically implemented in other studies. We feel that these consistent trends from two separate trials of dapagliflozin, even though statistically nonsignificant, are consistent with the well-established data in the past, showing that a low-protein diet enhanced the effect of angiotensin-converting-enzyme inhibition or angiotensin receptor blockade on renal protection. Indeed, a lowprotein diet leads to contraction of the afferent arteriole of the glomeruli, resulting in reduced intraglomerular pressure, hence, opposing the renal hyperfiltration that is invariably harmful to kidneys in the long term; this mechanism is similar to what flozination with such SGLT2 inhibitors as dapagliflozin appears to engender, given the modulation of the tubuloglomerular feedback that abrogates intraglomerular