SGLT2 inhibitors: diabetic kidney disease and beyond

Recent clinical trials have shed light on the critical importance of sodium-glucose cotransporter-2 (SGLT2) inhibitors for reducing major adverse kidney and cardiac events as well as mortality (5, 6). These trials, the dissemination of their results, and potential mechanisms of action have arrived at a critical time for nephrology. There is less enthusiasm toward pursuing nephrology training in the United States, and among several explanations for this trend, the lack of novel therapies that target chronic kidney disease (CKD) progression and reduce the burden of dialysis is primary (2). SGLT2 inhibitors present the most significant advance in the field of nephrology in the past 20 yr. Not since the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial and Irbesartan Diabetic Nephropathy Trial (IDNT), which showed a reduction in renal events with blockade of type 1 angiotensin II receptors, has there been a new disease-modifying option for patients with CKD. The success of these trials also provides further motivation to connect clinical and basic scientists toward a common goal.

SGLT2 inhibitors reduce reabsorption of glucose and sodium in the proximal tubule, and, as yet, we know comparatively little about their mechanism of action for their potent clinical benefits. To what degree do the reduction of hyperglycemia, weight loss, and reduction of volume overload account for the clinical benefits (4)? Are the protective effects in the kidney responsible for the reduction in major adverse cardiovascular events? What is the contribution of the reduction in glomerular hyperfiltration via tubuloglomerular feedback, as elegantly shown by Vallon and Rieg (8) and Vallon and Thomson (9)? What are the potential contributions of redox biology, energy utilization, and immunosuppression? Are the benefits of this class of medications due primarily to inhibition of SGLT2 versus off-target effects? Answering these questions will not only inform our understanding of how best to treat patients but also our understanding of proximal tubular physiology and progressive CKD. It is likely that investigations into SGLT2 biology and these life-saving medicines will occupy the minds of basic scientists, clinical scientists, statisticians, and, importantly, trainees for years to come.

In a recent issue of Circulation, on behalf of the American Heart Association (AHA) Council on the Kidney in Cardiovascular Disease in partnership with other AHA Councils, we and colleagues (7) have prepared a scientific statement on the cardiorenal protective effects of SGLT2 inhibitors and glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus and CKD. In this statement, we summarize the current knowledge on the cardiorenal protective effects of these drugs, potential mechanisms, known adverse effects, and practical guidance on a proposed collaborative care model for the management of patients with type 2 diabetes mellitus and CKD. The writing group limited the summary of available evidence to a prespecified time point of March 31, 2020. Since then, results from the Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease (DAPA-CKD) trial, which was stopped early for overwhelming efficacy, were presented at the European Society of Cardiology Congress in August 2020 and published the following month in the New England Journal of Medicine (3). The findings from DAPA-CKD confirm the data on nephroprotection with SGLT2 inhibitors from the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial in 2019 (6) and, importantly, affirmed the role of SGLT2 inhibitors in preventing kidney function decline in patients with CKD without diabetes. Along with the kidney benefits afforded by glucagon-like peptide-1 receptor antagonists as well as soon-to-reported data from nonsteroidal mineralocorticoid blockade [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial (1)], the field of nephrology is poised to enter a new therapeutic era with the potential to change the landscape of CKD and the clinical, social, and financial burdens of end-stage kidney disease.

We recognize the contribution of basic and clinical scientists and of patients to realize these achievements, and we look forward to insights from renal physiologists into the mechanisms of these important drug classes and to the translational research collaborations that will surely arise. To this end, the AHA Council on the Kidney in Cardiovascular Disease, which the authors of this editorial represent, confirms its ongoing commitment to supporting excellence in research and collaboration between physicians and scientists in cardiology and nephrology, to ensure the best outcomes for vulnerable patients with heart and/or kidney disease.

GRANTS

Research in the authors’ laboratories was partially supported by National Institutes of Health Grants R35HL135749 (to A.S.) and R01DK115770 (to V.B.) and Department of Veteran Affairs Grant I01 BX004024 (to A.S.).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author(s).

AUTHOR CONTRIBUTIONS

A.S., V.B. and J.R. drafted manuscript; A.S., V.B. and J.R. edited and revised manuscript; A.S., V.B. and J.R. approved final version of manuscript.