SGLT2 Inhibitors and Chronic Kidney Disease: How a Diabetes Drug Became a Kidney Protector

Research-informed explainer — last updated April 12, 2026

A class of drugs originally developed for type 2 diabetes has become one of the most important advances in kidney medicine in decades. SGLT2 inhibitors — particularly dapagliflozin and empagliflozin — have been shown in large randomized trials to significantly slow the progression of chronic kidney disease, regardless of whether a patient has diabetes.

This article draws on research from four nephrologists whose published work defines both the stakes and the science of this development. Glenn Chertow, MD, Chief of Nephrology at Stanford University School of Medicine, was an investigator on the pivotal DAPA-CKD trial and co-authored the landmark 2004 study in the New England Journal of Medicine that quantified how even modest declines in kidney function dramatically increase the risk of death, cardiovascular events, and hospitalization. Steven Coca, D.O., M.S., Director of Clinical Research in Nephrology at The Mount Sinai Hospital, has published extensively on how acute kidney injury accelerates long-term CKD progression — research that illuminates why preventing any further kidney damage is so important. Eugene Rhee, MD, at Massachusetts General Hospital, has investigated the metabolic mechanisms by which the kidney protects or injures itself at the cellular level, including the role of NAD biosynthesis and FGF-23 signaling. Sevag Demirjian, MD, Director of Critical Care Nephrology at Cleveland Clinic, has studied how CKD from surgical causes — not just diabetes — still carries real mortality risk, reinforcing the broad relevance of kidney protection.

What is CKD and why does it matter so much?

Chronic kidney disease is defined as reduced kidney function — measured by estimated glomerular filtration rate (eGFR) — or markers of kidney damage, such as protein in the urine, persisting for more than three months. Roughly 37 million Americans have CKD, and most are unaware of it.

The 2004 NEJM study by Chertow and colleagues analyzed 1.1 million adults in a community-based population and found a powerful, graded relationship between declining eGFR and the risk of death and cardiovascular events — even at levels of kidney impairment that most doctors would not have called "severe." For example, patients with an eGFR of 45–59 ml/min/1.73 m² (Stage 3a CKD, considered moderate) had a significantly elevated risk of death and hospitalization compared to those with normal kidney function. The message was stark: CKD is not a silent background condition — it is an active cardiovascular and mortality risk factor.

How SGLT2 inhibitors were discovered to protect the kidneys

SGLT2 inhibitors work by blocking a protein in the kidney tubules that reabsorbs glucose from the urine back into the bloodstream. When this transporter is inhibited, excess glucose is excreted in the urine, lowering blood sugar in diabetes patients. That was the original purpose.

But the kidney benefits turned out to be at least as important as the glucose effect — and independent of it. The DAPA-CKD trial, published in the NEJM in 2020, enrolled 4,304 patients with CKD across a wide range of eGFR values and randomized them to dapagliflozin or placebo on top of standard care. The trial was stopped early because the benefit was so clear. Among patients treated with dapagliflozin, the risk of a composite outcome — sustained 50% decline in eGFR, end-stage kidney disease, or death from renal or cardiovascular causes — was reduced by 39% compared to placebo. Critically, this benefit was seen in patients both with and without type 2 diabetes.

How does the drug actually protect the kidney?

The kidney-protective mechanism goes well beyond glucose lowering. Research by Rhee and colleagues has helped illuminate two intersecting pathways.

First, SGLT2 inhibitors reduce oxygen demand in the kidney's proximal tubule. Normally, the proximal tubule is one of the most metabolically active tissues in the body — it has to transport enormous amounts of glucose, sodium, and other solutes. By blocking the SGLT2 transporter, the drug reduces the workload of these cells, lowering their oxygen consumption and protecting them from ischemic injury. This is particularly important because tubular cells are highly vulnerable to hypoxic damage.

Second, there is evidence involving the NAD biosynthesis pathway. Research published in Nature demonstrated that the transcriptional coactivator PGC-1α drives NAD production in kidney tubular cells, linking oxidative metabolism to cellular protection. Separately, a 2018 Nature Medicine study found that NAD biosynthetic capacity is impaired during acute kidney injury in humans — suggesting that restoring or preserving this pathway could meaningfully reduce kidney damage. SGLT2 inhibitors appear to reduce the metabolic stress that depletes this protective capacity.

There is also a hemodynamic component: SGLT2 inhibitors reduce intraglomerular pressure by affecting the way the kidney regulates blood flow into and out of the glomerulus, the filtering unit. This reduces the mechanical stress on the glomerulus that contributes to scarring over time.

Who qualifies for SGLT2 inhibitors in CKD?

Current FDA-approved labeling for dapagliflozin (Farxiga) and empagliflozin (Jardiance) for CKD protection generally covers patients with eGFR in the range of 25–75 ml/min/1.73 m² and elevated protein in the urine (albuminuria), regardless of diabetes status. Patients with eGFR below 20 are typically not candidates because the drug requires some residual kidney function to work. The 2024 KDIGO clinical guidelines now include SGLT2 inhibitors as a first-line recommendation for CKD patients with albuminuria, alongside ACE inhibitors or ARBs.

Research by Demirjian and colleagues has added an important nuance: CKD due to surgical causes (such as partial nephrectomy or donor nephrectomy) tends to follow a more stable trajectory than CKD from medical causes like diabetes or hypertension. However, patients with medically caused CKD — which is the majority — are at significantly higher risk of progressive decline, making nephroprotective therapies like SGLT2 inhibitors particularly important in this group.

What about patients with prior acute kidney injury?

Work by Coca and colleagues has documented that a single episode of acute kidney injury (AKI) — even a relatively modest one requiring no dialysis — significantly raises long-term risk of developing CKD and progressing to end-stage kidney disease. A 2011 meta-analysis in Kidney International found that survivors of AKI were more than 8 times as likely to develop CKD and more than 3 times as likely to develop end-stage renal disease compared to matched patients without AKI.

This AKI-to-CKD pipeline is one reason SGLT2 inhibitors' ability to reduce acute tubular stress matters beyond just their clinical trial endpoints. Any reduction in recurrent tubular injury may slow the long-term CKD progression that follows repeated AKI episodes.

Side effects and precautions

SGLT2 inhibitors are generally well tolerated but carry some specific risks patients should know about. Genital mycotic infections (yeast infections) are the most common side effect, occurring in roughly 5–10% of patients. A rare but serious condition called diabetic ketoacidosis can occur, particularly in patients with type 1 diabetes or those who are fasting; patients with type 2 diabetes or non-diabetic CKD have a much lower risk. Euglycemic ketoacidosis — where blood sugar remains near normal — is the particular form to watch for. Patients should hold the drug before major surgery or extended fasting.

There is also a well-documented early dip in eGFR after starting these drugs, which reflects the intended hemodynamic effect on the glomerulus. This initial decline — typically 2–4 ml/min — is not a sign of harm; it actually predicts better long-term kidney preservation and should not prompt discontinuation.

Questions to ask your doctor

• Does my eGFR and urine albumin level make me a candidate for an SGLT2 inhibitor regardless of whether I have diabetes?
• If my eGFR drops slightly after starting the drug, how will we decide whether to continue?
• Are there any interactions between an SGLT2 inhibitor and my other kidney or blood pressure medications?
• Should I hold the drug before any upcoming procedure, surgery, or colonoscopy prep?
• How frequently will you monitor my kidney function after starting?

The bottom line

SGLT2 inhibitors have moved from diabetes management into nephrology as one of the most evidence-based kidney-protective strategies available today. The DAPA-CKD trial demonstrated a 39% reduction in kidney failure and death outcomes in a non-diabetic as well as diabetic CKD population. If you have CKD with protein in your urine and your eGFR is above 20, ask your nephrologist whether you are a candidate — the evidence is strong and the benefit extends well beyond blood sugar control.