Chronic kidney disease (CKD) is a global health crisis of considerable magnitude. It affects approximately 850 million people worldwide, contributes heavily to cardiovascular morbidity and mortality, and places an enormous burden on healthcare systems across all income levels. For decades, the therapeutic options available to slow the progression of CKD were limited: blood pressure control, renin-angiotensin system blockade, and lifestyle modification. Effective as these tools were, they left a substantial unmet need — particularly for patients with diabetic kidney disease, the leading cause of CKD and end-stage renal disease (ESRD) globally.
That landscape has changed dramatically. The emergence of sodium-glucose cotransporter-2 (SGLT2) inhibitors — a class of medications originally developed for blood sugar control in type 2 diabetes — has introduced a genuinely new dimension in nephroprotection. A growing body of landmark clinical trial evidence has positioned these agents as transformative tools in the management of CKD, extending well beyond their glucose-lowering origins. The International Society of Nephrology has been at the forefront of translating this evidence into international clinical guidance and advocating for equitable global access to these therapies.
What Are SGLT2 Inhibitors and How Do They Work?
To understand why SGLT2 inhibitors are so significant for kidney health, it helps to understand their mechanism of action at a basic level. The kidneys filter blood continuously — around 180 liters per day — and the proximal tubules, a segment of the nephron (the kidney’s functional unit), are responsible for reabsorbing most of the glucose that passes through. This reabsorption is carried out largely by a protein called sodium-glucose cotransporter-2, or SGLT2.
SGLT2 inhibitors — including canagliflozin, dapagliflozin, and empagliflozin — block this transporter. The result is that more glucose is excreted in the urine rather than being reabsorbed into the bloodstream. In patients with type 2 diabetes, this lowers blood sugar levels. But the story does not end there.
The blockade of SGLT2 also reduces the reabsorption of sodium in the proximal tubule. This has downstream effects on a physiological control mechanism known as tubuloglomerular feedback — a system by which the kidneys regulate blood flow through their own filtering units. When sodium delivery to a specialized structure called the macula densa is increased (as happens with SGLT2 inhibition), the afferent arteriole — the vessel feeding the glomerulus — constricts slightly. This reduces pressure within the glomerulus itself, an effect called intraglomerular pressure reduction. Lower intraglomerular pressure translates into less mechanical stress on the delicate filtration membrane, which over time helps preserve kidney function.
Beyond hemodynamics, preclinical research reviewed by Packer in the European Heart Journal (2020) has characterized additional protective mechanisms, including suppression of the NLRP3 inflammasome, a molecular complex involved in triggering inflammation in kidney tissue. SGLT2 inhibitors also appear to reduce oxidative stress and fibrosis — two processes that drive the progressive scarring of kidney tissue in CKD. Together, these mechanisms explain why SGLT2 inhibitors protect the kidneys through pathways far broader than glycemic control alone.
Landmark Clinical Trials: Building the Evidence Base
The nephroprotective promise of SGLT2 inhibitors moved decisively from hypothesis to clinical reality through a series of large, rigorously conducted randomized controlled trials. Each successive study expanded the population who stands to benefit from these therapies.
CREDENCE: The Trial That Changed the Conversation
The CREDENCE trial, published in the New England Journal of Medicine in 2019 by Perkovic and colleagues, was the first dedicated renal outcomes trial for an SGLT2 inhibitor. It enrolled 4,401 patients with type 2 diabetes and CKD who were already receiving maximally tolerated doses of renin-angiotensin system blockers — the then-standard of care. Participants were randomized to receive canagliflozin or placebo.
The results were striking enough that the trial was stopped early for efficacy. Canagliflozin reduced the composite primary endpoint — which included doubling of serum creatinine, end-stage renal disease, or renal or cardiovascular death — by 30 percent in relative terms. The reductions in kidney failure and cardiovascular events were clinically meaningful and consistent across subgroups.
CREDENCE established for the first time that an SGLT2 inhibitor could slow the progression of kidney disease in a dedicated nephrology trial — a result that reverberated through the field.
DAPA-CKD: Beyond Diabetes
A pivotal question remained after CREDENCE: did the renal benefits of SGLT2 inhibitors depend on the presence of diabetes, or were they intrinsic to the drug class regardless of glycemic status? The DAPA-CKD trial, published by Heerspink and colleagues in the New England Journal of Medicine in 2020, answered this question compellingly.
DAPA-CKD enrolled patients with CKD across a spectrum of causes — including those without diabetes — and randomized them to dapagliflozin or placebo. The trial demonstrated significant reductions in CKD progression and cardiovascular mortality in dapagliflozin-treated patients, and this benefit was consistent regardless of whether participants had type 2 diabetes. The non-diabetic subgroup showed similarly robust protection, making clear that SGLT2 inhibitors exert kidney-specific effects that are not dependent on blood sugar reduction.
EMPA-KIDNEY: Expanding the Eligible Population
The most recent and largest dedicated renal outcomes trial to date is the EMPA-KIDNEY study, conducted by the EMPA-KIDNEY Collaborative Group and published in the New England Journal of Medicine in 2023. With 6,609 participants, it is the largest trial of an SGLT2 inhibitor in CKD and was specifically designed to include patients at the lower end of kidney function and those with lower levels of protein in the urine (albuminuria).
The trial enrolled patients with estimated glomerular filtration rates (eGFR) as low as 20 mL/min/1.73 m² — a threshold closer to advanced kidney disease — and included patients with low albuminuria who would not have met eligibility criteria in earlier trials. Empagliflozin significantly reduced the composite of kidney disease progression or cardiovascular death, and this benefit was observed irrespective of albuminuria level or diabetes status.
EMPA-KIDNEY substantially expanded the population of patients who may benefit from SGLT2 inhibitor therapy and confirmed that these agents retain protective effects even in more advanced stages of CKD.
From Evidence to Guidance: The Role of ISN and KDIGO
Translating clinical trial evidence into actionable recommendations for clinicians worldwide is a core responsibility of nephrology’s leading professional organizations. The International Society of Nephrology (ISN) has played a central role in this process, supporting the development and dissemination of international clinical practice guidelines that incorporate the accumulated evidence on SGLT2 inhibitors.
The 2022 KDIGO Clinical Practice Guideline for Diabetes Management in CKD — developed with the support of ISN — represents the most comprehensive and authoritative clinical framework in this space. KDIGO, or Kidney Disease: Improving Global Outcomes, is the leading international guideline-setting body for nephrology. The 2022 guideline recommends SGLT2 inhibitors for patients with type 2 diabetes and CKD who have an eGFR of 20 mL/min/1.73 m² or above. This threshold reflects the evidence base from the major trials, while recognizing that patients with more severely reduced kidney function were not adequately represented in those studies.
The recommendation represents a significant shift in the standard of care. Whereas renin-angiotensin system blockade with agents such as ACE inhibitors or angiotensin receptor blockers was previously considered the cornerstone of renoprotective therapy in diabetic CKD, SGLT2 inhibitors are now positioned as complementary and — in many settings — essential additions to treatment.
Key Trial Findings at a Glance
| Trial | Drug | N (Patients) | Population | Key Outcome | Published |
|---|---|---|---|---|---|
| CREDENCE | Canagliflozin | 4,401 | Type 2 diabetes + CKD | 30% reduction in composite renal/CV endpoint | NEJM, 2019 |
| DAPA-CKD | Dapagliflozin | 4,304 | CKD with or without diabetes | Reduced CKD progression and CV mortality | NEJM, 2020 |
| EMPA-KIDNEY | Empagliflozin | 6,609 | CKD (eGFR ≥20), any albuminuria, ± diabetes | Reduced disease progression and CV death | NEJM, 2023 |
Who Benefits? Understanding the Eligible Patient Population
Based on current evidence, the following patient groups are recognized as candidates for SGLT2 inhibitor therapy in the context of CKD:
- Patients with type 2 diabetes and CKD: The original and best-characterized group, with robust evidence from CREDENCE and multiple other trials.
- Patients with CKD without diabetes: Supported by DAPA-CKD and EMPA-KIDNEY, which demonstrated consistent benefit regardless of glycemic status.
- Patients with lower eGFR (as low as 20 mL/min/1.73 m²): EMPA-KIDNEY extended the evidence base to patients with more advanced CKD.
- Patients with lower albuminuria: Previously, high levels of urinary protein (albuminuria) were considered a prerequisite for likely benefit; EMPA-KIDNEY demonstrated protective effects across a broader albuminuria spectrum.
- Patients with heart failure and CKD: Overlapping cardiovascular trial data supports the use of SGLT2 inhibitors in this population, often with concurrent renal benefit.
It is important to note that SGLT2 inhibitors are generally not recommended for patients with type 1 diabetes or those with eGFR below 20 mL/min/1.73 m², given limited evidence and potential risks in these groups. Clinical judgment, individual patient characteristics, and local prescribing guidelines should always guide treatment decisions.
Safety Profile and Practical Considerations
No therapeutic advance is without considerations of safety and tolerability. SGLT2 inhibitors have a well-characterized safety profile that clinicians must weigh appropriately.
Common and Notable Adverse Effects
- Genital mycotic infections: The most frequently observed side effect, due to increased urinary glucose providing a substrate for fungal growth. These infections are generally mild, manageable, and more common in women.
- Urinary tract infections: A modest increase in risk has been observed in some trials, though not consistently across all studies.
- Volume depletion and hypotension: The natriuretic effect of SGLT2 inhibitors can cause a modest reduction in blood pressure and, in susceptible patients, symptomatic volume depletion. This is generally considered beneficial but warrants monitoring in elderly or frail patients.
- Euglycemic diabetic ketoacidosis (DKA): A rare but serious complication, primarily in patients with type 1 diabetes or those undergoing significant caloric restriction or fasting. It is essential that clinicians recognize this risk and counsel patients appropriately.
- Initial eGFR dip: SGLT2 inhibitors typically cause a small, reversible decline in eGFR shortly after initiation — a hemodynamic effect reflecting the reduction in intraglomerular pressure. This dip is not a sign of kidney injury and does not predict long-term harm; rather, it reflects the drug’s mechanism of action.
The Global Access Challenge: ISN’s Equity Agenda
The scientific evidence for SGLT2 inhibitors is compelling. The clinical guidelines are clear. And yet, for the majority of people living with CKD globally, these medications remain out of reach.
This is one of the most pressing concerns highlighted by the International Society of Nephrology. ISN has consistently emphasized that the translation of scientific advances into real-world benefit depends critically on equitable access — and that access is profoundly unequal. In low- and middle-income countries (LMICs), where the burden of CKD is growing most rapidly due to rising rates of diabetes, hypertension, and limited healthcare infrastructure, SGLT2 inhibitors remain largely unavailable or unaffordable.
ISN’s Global Kidney Health Roadmap, outlined by Levin and colleagues in Kidney International (2023), identifies this gap explicitly. The Roadmap calls for prioritizing generic formulations of SGLT2 inhibitors, strengthening procurement mechanisms, and working with national governments and international agencies to facilitate affordable access. These are not merely aspirational goals — they represent a recognition that the greatest potential gains in kidney health outcomes will come from ensuring that proven therapies reach the patients who need them most.
The ISN (International Society of Nephrology) has framed access and equity as central pillars of its global mission, not secondary concerns. Without deliberate policy action, the benefits documented in clinical trials in well-resourced settings risk remaining invisible to the populations who bear the heaviest burden of kidney disease worldwide.
What This Means for Nephrology Practice Going Forward
The integration of SGLT2 inhibitors into nephrology practice represents one of the most significant paradigm shifts the field has witnessed in a generation. Several implications deserve consideration:
- Earlier identification of CKD: The availability of disease-modifying therapy makes early diagnosis of CKD more consequential than ever. Screening high-risk populations — those with diabetes, hypertension, and family history of kidney disease — takes on greater urgency when intervention can meaningfully alter disease trajectory.
- Multidisciplinary care: SGLT2 inhibitors straddle the boundaries between nephrology, endocrinology, and cardiology. Optimal management of patients with CKD increasingly requires coordinated care across specialties.
- Clinical inertia: Despite strong guideline recommendations, adoption of SGLT2 inhibitors in nephrology practice remains inconsistent globally. Addressing knowledge gaps, prescribing barriers, and patient-level hesitancy will require active effort from professional societies including ISN.
- Ongoing research: While the major trials have established the class effect of SGLT2 inhibitors in CKD, important questions remain — including optimal use in advanced CKD (eGFR below 20), pediatric populations, specific CKD etiologies such as IgA nephropathy, and combination strategies with emerging agents like finerenone.
Conclusion
SGLT2 inhibitors represent a genuine breakthrough in the care of patients with chronic kidney disease. Across three landmark trials — CREDENCE, DAPA-CKD, and EMPA-KIDNEY — these agents have demonstrated consistent, clinically meaningful reductions in kidney disease progression and cardiovascular mortality, in patients with and without diabetes, and across a broad range of CKD severity. Their
mechanisms extend well beyond glucose control, operating through hemodynamic, anti-inflammatory, and metabolic pathways that directly protect kidney tissue.
The International Society of Nephrology has been instrumental in incorporating this evidence into international clinical guidance and in raising awareness of the equity imperative — ensuring that the benefits of these therapies are not confined to patients in high-income settings. ISN’s commitment to global kidney health demands that scientific progress translate into real-world access for all patients, regardless of geography or economic circumstance.
As the evidence base continues to evolve and guideline recommendations become more firmly embedded in clinical practice, SGLT2 inhibitors are poised to become a defining feature of modern nephrology — one of the clearest examples of how rigorous science, thoughtful policy, and determined advocacy can together change the course of a devastating disease for millions of people worldwide.