SGLT2 Inhibitors, Muscle Loss, and Creatinine-Based Estimated GFR: An Integrative Conceptual Review of Renoprotection

Diabetes mellitus profoundly affects the kidneys, driving many individuals to kidney failure. With the rising global incidence of diabetic kidney disease straining health care systems, effective interventions are imperative. Landmark trials have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors attenuate the decline in estimated glomerular filtration rate (GFR), even without diabetes. However, these trials largely relied on creatinine-based GFR estimates, which are only valid if an intervention does not alter muscle-derived creatinine generation. Because SGLT2 inhibitors reduce muscle mass, the observed attenuation in estimated GFR decline may partly reflect reduced creatinine generation rather than true preservation of GFR. This methodological bias could also skew hard endpoints such as dialysis initiation, transplantation, and mortality. Using representative data from a landmark SGLT2 inhibitor trial, we show that a physiologically plausible reduction in muscle mass could account for the observed preservation of estimated GFR, underscoring the need for careful reinterpretation. The hypothesis that therapy-induced muscle loss contributed to the observed kidney benefits can be tested using directly measured GFR or, alternatively, cystatin C-based GFR estimates. Future modeling studies integrating dual GFR assessments with objective measures of muscle mass and strength are essential to disentangle genuine renoprotection from artifacts arising from creatinine-based GFR estimation.