LAUSR

To the Editor: The eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes (VERTIS CV) trial reported that ertugliflozin reduced the risk of the composite exploratory endpoint of sustained 40% decline in baseline creatininebased eGFR (eGFRCr), chronic renal replacement therapy and death from renal causes [1]. Moreover, treatment with ertugliflozin was associated with a decreased urinary albumin/creatinine ratio and attenuation of deterioration in eGFRCr. Use of eGFRCr-based endpoints is endorsed by the National Kidney Foundation and the US Food and Drug Administration, provided that interventions do not affect creatinine generation from muscle [2]. These authorities recommend that potential effects of interventions on determinants of serum creatinine other than GFR (including muscle mass) are excluded, when eGFRCr is used to approximate renal function. However, this condition is not satisfied by studies investigating the effect of sodium–glucose cotransporter 2 (SGLT2) inhibitors on renal outcomes, since these studies do not account for the fact that the pharmacological mechanism of action of SGLT2 inhibitors likely promotes loss of muscle mass [3, 4]. This mechanism involves induction of glucosuria through inhibition of SGLT2 in the renal proximal tubule. Loss of glucose molecules with urine can stimulate hepatic gluconeogenesis, which uses amino acids from skeletal muscle as primary substrates to endogenously produce new glucose molecules [3]. In this respect, excess loss of glucose is replenished at the expense of muscle tissue. Indeed, numerous studies investigating the effect of SGLT2 inhibitors on body composition have demonstrated that SGLT2 inhibition is associated with a substantial loss of muscle mass (an overview of these studies has been published previously [4]). Although no such study has been conducted for ertugliflozin to date, it is highly plausible that the observed weight reduction following treatment with ertugliflozin [5] is, at least in part, attributable to loss of muscle mass, given that ertugliflozin has the same pharmacological mechanism of action as the other SGLT2 inhibitors. Clearly, the effect of SGLT2 inhibitors on muscle mass involves a slow process that affects outcomes in the long term, which must be discriminated from the acute effects of SGLT2 inhibitors [4, 6]. The acute effects of SGLT2 inhibitors include enhancement of renal tubuloglomerular feedback through increased sodium concentrations at the macula densa, which induces afferent vasoconstriction and explains the characteristic acute drop in eGFR that occurs upon initiation of treatment with SGLT2 inhibitors [7]. In the VERTIS CV trial, this acute drop in eGFR was accompanied by a simultaneous drop in urinary albumin/creatinine ratio [1], a combination generally considered reflective of a change in glomerular haemodynamics [8]. Importantly, reduced muscle mass unequivocally leads to reduced serum creatinine, independently of underlying renal function [9]. Since serum creatinine is reciprocally related to the GFR [10], a reduced muscle mass implies overestimation of GFR (operating through reduced serum creatinine) when such estimates are based on creatinine measures. This line of thought fuels the belief that the surmised renoprotective * Dion Groothof [email protected]