Miyata K, Zhang S, Chan J: The Rationale and Evidence for SGLT2 Inhibitors as a Treatment for Nondiabetic Glomerular Disease. Glomerular Diseases DOI 10.1159/000513659
The report of the benefits of dapagliflozin on the progression of CKD in patients with non-diabetic kidney disease by Heerspink et al.  in late 2020 was a “blockbuster”. It will likely have an enormous practice-changing impact on clinical nephrology just as earlier reports of the benefits of SGLT2 inhibitors on heart failure in non-diabetic subjects had on the practice of clinical cardiology. The biologic effects of SGLT2 inhibitors are pleiotropic and the process is underway to elucidate the fine details of the mechanism(s) for these clinical effects.
Miyata and colleagues provide a masterful overview of current knowledge concerning the biology of SGLT2 inhibition in non-diabetic kidney disease. The main target of SGLT2 inhibitors is SGLT2 expressed in proximal tubules of the nephron. The expression is upregulated in diabetes, but not consistently in many proteinuric non-diabetic kidney diseases, such as IgA nephropathy. Nevertheless, SGLT2 inhibitors, as a class, seem to be effective in reducing the rate of progression of these diseases. SGLT2 inhibitors decrease intra-glomerular capillary pressure likely due to afferent arteriolar constriction. The lower intra-glomerular pressure initially reduces GFR modestly and has a long-term reno-protective action, similar to renin-angiotensin system (RAS) inhibitors that also reduce intra-glomerular capillary pressure mainly by efferent arteriolar relaxation. Thus, the effects of SGLT2 inhibitors are additive to RAS inhibition. This effect of SGLT2 inhibitors may be linked to the inhibition of proximal nephron sodium reabsorption and activation of tubule-glomerular feedback mediated by local adenosine release, but other factors may be in play, such as reduced cardiac elaboration of atrial natriuretic factors, secondary to diuresis and reduction of expanded circulatory volume.
SGLT2 inhibitors have a weak and inconsistent effect on lowering blood pressure (about a –2 to –3 mm Hg systolic), which is unlikely to explain the reno-protective actions. Improved control of blood glucose levels in diabetics is modest at best, and would not explain the reno-protective action in non-diabetic subjects. SGLT2 inhibitors also have anti-inflammatory, hypouricemic, and anti-fibrotic effects. Evidence is also accruing that SGLTR2 inhibitors may have direct modifying effects on endothelial, mesangial, and visceral epithelial cell components of glomeruli. So far, studies of SGLT2 inhibitors in non-diabetic kidney disease have excluded patients with lupus nephritis, autosomal dominant polycystic kidney disease, and vasculitis, and have enrolled too few patients with primary glomerular disease and nephrotic syndrome (such as membranous nephropathy) to be sure of the reno-protective actions in these patients. The reno-protective actions of SGLKT2 inhibitors do extend to patients with IgA nephropathy. So far, most studies have used SGLT2 inhibitors in combination with RAS inhibition, so we know very little about SGLT2 inhibitor monotherapy. Side effects are generally tolerable, with genital mycotic infection the main issue.
Clearly SGLT2 inhibitors have launched a new era of therapy in CKD. The comprehensive review by Miyata et al. is a good place to start for learning more about this very important class of reno- (and cardio-)protective agents. Bon voyage!!
1. Heerspink HJ, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383:1436–46.