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

Abstract

High protein intake may increase intraglomerular pressure through dilation of the afferent arteriole. Sodium-glucose cotransporter-2 (SGLT2) inhibitors may reduce intraglomerular pressure through activation of tubuloglomerular feedback. Given these opposing effects, we assessed whether the effect of dapagliflozin on glomerular filtration rate (GFR) and urinary albumin-to-creatinine ratio (UACR) was modified by estimated dietary protein intake using data from three separate randomized controlled trials (DELIGHT, IMPROVE and DIAMOND). The median protein intake was 58.4, 63.6 and 90.0 g/d, respectively. In the DELIGHT trial (n = 233), dapagliflozin compared to placebo caused an acute and reversible dip in GFR of 2.1 and 2.2 mL/min/1.73 m 2 , and reduced UACR by 20.5% and 28.4% in participants with high and low protein intake, respectively. Similarly, in IMPROVE (n = 30) and DIAMOND (n = 53), the effect of dapagliflozin on GFR and UACR was comparable in participants with high and low protein intake (all P for interaction > 0.40). This post hoc, exploratory analysis of three clinical trials suggests that dietary protein intake does not modify the individual response of clinical kidney variables to dapagliflozin.

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

“…This is a letter to editors Kamyar Kalantar-Zadeh MD 1,2 Srinivasan Beddhu MD 3,4 Csaba P. Kovesdy MD 5,6…”

“…We read the paper by van der Aart-van der Beek et al 1 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.…”

“…3,4 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 5 ; 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 F I G U R E 1 Biologically plausible trends suggesting that a low-protein diet enhances the effect of sodium-glucose cotransporter-2 inhibition on albuminuria (interaction P values are nonsignificant). 1 Adaption of panel A, from the figure in the study by van der Aart-van der Beek et al 1 highlighting the effect of dapagliflozin on urinary albumin-to-creatinine ratio (UACR) according to baseline dietary protein intake (from baseline to week 24 in the DELIGHT trial, and from baseline to week 6 in IMPROVE trial. DIAMOND study not shown here given nonsignificant UACR data) pressure under SGLT2 inhibition.…”

“…What remains even less known is whether plant-based or plantdominant low-protein diets, including the DASH and PLADO diets, would have an even stronger additive effect on renal outcomes under the SGLT2 inhibitory effects of dapagliflozin. 9,10 Given the important data and trends presented in their article, 1 an alternative title for the study by van der Aart-van der Beek et al 1 could have been: "Biologically plausible trends suggesting that a low-protein diet may enhance the effect of flozination on albuminuria". We advocate well-designed, randomized controlled trials examining the potentially synergistic effect of low-protein and plant-dominant diets on improving renal outcomes including under SGLT2 inhibition therapy.…”

Effects of Dietary Sodium and Protein Intake on Glomerular Filtration Rate in Subjects with Type 2 Diabetes Treated with Sodium-Glucose Cotransporter 2 Inhibitors

“…A high dietary intake of proteins leads to a deterioration of renal function, causing a reduction in eGFR and an increase in UACR [7], even in non-nephropathic subjects, independently of the presence of diabetes [8]. However there are limited evidence [9] regarding the correlation between protein intake and renal function in diabetic patients receiving SGLT2i.…”