Chronic Kidney Disease and SGLT2 Inhibitors: From Glucose Drugs to Renal Protection Pillars

An updated version from the last post

Andrew Kowalski, MD, FASN

CKD remains one of the most underdiagnosed and undertreated conditions in modern medicine, affecting more than one in ten adults worldwide and dramatically increasing the risk of cardiovascular disease, kidney failure, and premature death. For decades, our therapeutic approach rested on a familiar foundation, The Big 4:

1. Blood pressure control

2. Renin-angiotensin system blockade

3. Glycemic management in those with diabetes

4. Lifestyle modification

That paradigm has now fundamentally shifted.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors (empagliflozin, dapagliflozin) are no longer simply diabetes medications. They have emerged as foundational kidney-protective agents across a broad spectrum of CKD (with or without diabetes), and understanding why requires a closer look at the renal physiology driving their benefit.

Why These Drugs Work: The Mechanistic Story

The familiar mechanism of SGLT2 inhibitors, blocking glucose and sodium reabsorption in the proximal tubule, is only the beginning of the story. The deeper explanation lies in a process called tubuloglomerular feedback. In diabetic kidney disease, excessive sodium reabsorption in the proximal tubule reduces sodium delivery to the macula densa (main sensor of the kidney), causing the kidney to misinterpret this as low perfusion (or in other words not enough blood entering the kidney). In response, the afferent arteriole dilates, intraglomerular pressure rises, and hyperfiltration ensues, a state that accelerates kidney injury over time.

It is difficult to simplify this explanation, but the way I approach it is that as the kidney "thinks" there is not enough blood flow, it leads to changes in the glomerulus (filter) to squeeze as much filtrate (blood contents to be cleaned) as it can into the tubules to be processed into urine. However, if this stress keeps up the kidney will burn out and that will lead to injury.

"You can only push yourself so far before you get hurt."

So...by blocking sodium reabsorption, SGLT2 inhibitors restore distal sodium delivery, triggering afferent vasoconstriction and normalizing intraglomerular pressure. In other words by blocking the receptor and allowing the sensor to accurately assess kidney blood flow the "switch of badness" gets turned off.

This hemodynamic reset is the mechanistic parallel to what ACE inhibitors and ARBs accomplish through the renin-angiotensin system, but through a completely different pathway. Patient will typically see a modest eGFR dip of 3 to 5 mL/min/1.73m² seen in the first weeks of therapy, and that reflects this hemodynamic recalibration, not kidney injury, and long-term slope data consistently show slower eGFR decline thereafter.

Another reminder that not all changes to the kidney numbers (creatinine, BUN, and eGFR) is because of injury!

Beyond hemodynamics, emerging evidence points to additional mechanisms including:

1. Reduced renal cortical hypoxia (kidney ends up receiving more oxygen)

2. Improved mitochondrial efficiency

3. Decreased inflammation and fibrosis signaling

4. A reduction in overall tubular workload

While causality in humans remains under active investigation, the clinical outcome data are entirely consistent with structural kidney protection.

The Landmark Trials That Changed Practice

The evidence base for SGLT2 inhibitors in CKD has been built through a series of rigorous, well-powered randomized controlled trials. The CREDENCE trial, published in 2019, evaluated canagliflozin (Invokana) in patients with type 2 diabetes and albuminuric CKD and demonstrated a 30% relative risk reduction in the composite kidney outcome, with significant reductions in kidney failure and cardiovascular events.

A year later, DAPA-CKD established that dapagliflozin's benefits extended well beyond diabetes. The trial enrolled patients both with and without diabetes, achieving a 39% relative risk reduction in the primary kidney composite and a 31% reduction in all-cause mortality, with consistent benefit in the non-diabetic subgroup. The absolute risk reduction of approximately 5.3% over 2.4 years translates to a number needed to treat of roughly 19, a remarkably favorable figure for a chronic disease intervention.

The EMPA-KIDNEY trial, published in 2022, broadened the eligible population further still. By enrolling patients with eGFR as low as 20 and including those with lower albuminuria levels, it demonstrated a 28% reduction in kidney disease progression or cardiovascular death. Extending the treatment benefit to populations previously excluded from study. Taken together, these trials represent one of the most compelling evidence bases accumulated for any kidney-protective therapy in the modern era.

Where Guidelines Now Stand

The alignment across major guideline bodies is historically unusual and clinically significant:

1. The 2024 KDIGO CKD guidelines recommend SGLT2 inhibitors for patients with an eGFR of at least 20 mL/min/1.73m² and CKD with albuminuria, regardless of diabetes status, with a Level 1A evidence rating in albuminuric CKD

2. The American Diabetes Association's 2024 Standards of Care recommend SGLT2 inhibitors in patients with type 2 diabetes and CKD independent of A1c control

3. The AHA/ACC heart failure guidelines carry a Class I recommendation for both reduced and preserved ejection fraction heart failure, again independent of diabetes status.

For the record, a Class 1A recommendation is the highest level of advice in medicine. It means that experts strongly agree that a treatment, test, or procedure is beneficial, useful, and effective because there is high-quality evidence supporting it.

-National Institutes of Health (NIH)

Nephrology, cardiology, and endocrinology are pointing in the same direction, a rare convergence that should command attention in clinical practice.

Quantifying the Benefits

Across the major randomized controlled trials, the benefits of SGLT2 inhibitors are both broad and reproducible.

• Kidney outcomes show a 30 to 40% reduction in progression to kidney failure, a meaningfully slower annual eGFR decline, and approximately a 30% reduction in albuminuria

• Heart failure hospitalization is reduced by roughly 30%, cardiovascular mortality by 15 to 20% depending on the population studied

• Meta-analyses have demonstrated a 20 to 25% reduction in acute kidney injury events

• Modest reductions in systolic blood pressure of 2 to 4 mmHg

• A weight reduction of 2 to 3 kg (about 6lbs)

  
  

This is the opposite of what some clinicians initially feared. They are hard endpoints, consistently reproduced across trials and across populations.

The Emerging Combination Therapy Landscape

SGLT2 inhibitors are increasingly being positioned not as standalone agents but as one layer within a multi-pathway approach to CKD risk modification. Combined use with ACE inhibitors or ARBs is now standard of care in albuminuric CKD. Data from the FIDELIO-DKD and FIGARO-DKD trials established the independent benefit of finerenone (Kerendia), a non-steroidal mineralocorticoid receptor antagonist, in diabetic CKD, and subgroup analyses suggest additive benefit when combined with SGLT2 inhibitors.

Currently there are ongoing studies evaluating this synergy more formally. GLP-1 receptor agonists (Ozempic, Mounjaro)appear to offer complementary cardiovascular and metabolic benefits, with stronger signals for atherosclerotic cardiovascular disease reduction and weight loss, while SGLT2 inhibitors lead on heart failure and kidney outcomes. This layered approach is reshaping how we think about CKD care, from single-drug mitigation to coordinated, multi-pathway risk reduction.

Safety, Practical Considerations, and Expanding Indications

The safety profile of SGLT2 inhibitors is well-characterized:

• Genital mycotic infections (they are fungal infections caused by an overgrowth of Candida yeast, resulting in symptoms like itching, burning, and discharge) occur in 2 to 6% of patients

• Volume depletion (commonly referred to as dehydration) warrants attention in those on diuretics

• Euglycemic diabetic ketoacidosis is a rare but important concern, primarily in insulin-treated type 2 diabetes

• Fournier's gangrene has been reported but remains extremely rare

• Reassuringly, increased rates of acute kidney injury and hypoglycemia in non-diabetic patients have NOT been observed...trials have in fact shown the opposite with respect to AKI.

Clinically, the most important practical point is to expect and accept the initial eGFR dip. Unless the decline exceeds 30%, therapy should be continued. These agents can be initiated down to an eGFR of 20 per current EMPA-KIDNEY data and KDIGO 2024 guidance, and while holding during severe dehydration or serious illness is a must, they should NOT be reflexively discontinued at the first hint of eGFR fluctuation.

Active investigation is underway in other kidney diseases, such as IgA nephropathy, FSGS, polycystic kidney disease, and kidney transplant recipients, with early signals of benefit in some of these conditions. Where data are not yet definitive, clinical enthusiasm should remain evidence-bound.

A Profound Shift in Renal Medicine

SGLT2 inhibitors are no longer adjunctive therapy. They are foundational treatment in diabetic CKD, non-diabetic albuminuric CKD, heart failure with reduced or preserved ejection fraction, and CKD with eGFR of at least 20...PERIOD!

They reduce kidney failure, slow decline, lower hospitalization, and reduce mortality in populations that historically had very few disease-modifying options.

CKD progression once felt inevitable and then you see the kidney doctor to discuss dialysis or transplant. Now, through RAAS blockade, reduction of hyperfiltration, mineralocorticoid modulation, and metabolic reprogramming, we are actively reshaping the kidney's trajectory rather than simply bearing witness to its decline. For clinicians who manage CKD, that is not a small development...it is a fundamental change in what we can offer our patients.

Remember Start your patients EARLY, and start prescribing these medications OFTEN.

References

1. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295–2306.

2. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383:1436–1446.

3. Wheeler DC, Stefánsson BV, Jongs N, et al. Effects of dapagliflozin on kidney outcomes in diabetic and non-diabetic CKD. Lancet Diabetes Endocrinol. 2021;9:22–31.

4. Jongs N, Greene T, Chertow GM, et al. Effect of dapagliflozin on albuminuria in CKD. Lancet Diabetes Endocrinol. 2021;9:755–766.

5. Herrington WG, Staplin N, Wanner C, et al. Empagliflozin in patients with chronic kidney disease. N Engl J Med. 2022;388:117–127.

6. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024.

7. American Diabetes Association. Standards of Care in Diabetes—2024. Diabetes Care. 2024.

8. Pitt B, Filippatos G, Agarwal R, et al. Cardiovascular events with finerenone in CKD and T2DM (FIDELIO-DKD). N Engl J Med. 2020;383:2219–2229.

9. Filippatos G, Agarwal R, Pitt B, et al. FIGARO-DKD trial. N Engl J Med. 2021;385:2252–2263.

10. McGuire DK, Shih WJ, Cosentino F, et al. Association of SGLT2 inhibitors with risk of AKI: meta-analysis of RCTs. Circulation. 2021.