Introduction

Chronic Kidney Disease (CKD) is a progressive condition affecting over 850 million people worldwide, making it one of the most pressing global health challenges. Often silent in its early stages, CKD not only leads to kidney failure and the need for dialysis or transplantation but also significantly increases the risk of cardiovascular disease (CVD)—the leading cause of death in this population.

Patients with CKD are more likely to die from heart attacks, strokes, or heart failure than to reach end-stage kidney disease. This dual burden of renal and cardiovascular complications has long demanded therapies that can protect both organs simultaneously.

The EMPA-Kidney trial was launched in response to this unmet need. While earlier studies had shown promise with SGLT2 inhibitors in people with diabetes, it remained unclear whether these benefits extended to the broader CKD population, especially those without diabetes. EMPA-Kidney sought to answer that question—ushering in a potential shift in the standard of care for millions of patients.

Background

What Are SGLT2 Inhibitors?

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a class of medications initially developed to lower blood sugar in people with type 2 diabetes. They work by preventing the reabsorption of glucose in the kidneys, leading to glucose excretion through urine. However, beyond their glucose-lowering effect, researchers observed unexpected benefits: improvements in kidney function, reduced blood pressure, and lower rates of heart failure hospitalization.

From Diabetes to Kidney Protection: Paving the Way

Several landmark trials brought SGLT2 inhibitors to the forefront of cardio-renal medicine:

• EMPA-REG OUTCOME (2015): Empagliflozin was shown to reduce cardiovascular death and heart failure hospitalization in patients with type 2 diabetes and established cardiovascular disease.

• CANVAS and DECLARE-TIMI 58: Reinforced the cardiovascular and renal benefits of SGLT2 inhibitors.

• CREDENCE (2019): Demonstrated that canagliflozin significantly reduced the risk of kidney failure in people with diabetic kidney disease.

• DAPA-CKD (2020): The first major trial to show that dapagliflozin could benefit non-diabetic CKD patients, sparking new hope.

These trials shifted the perception of SGLT2 inhibitors from diabetes medications to organ-protective therapies. Yet, questions remained: Could these benefits be extended to a wider CKD population, including those with lower levels of kidney function and without diabetes?

Unmet Needs in Non-Diabetic CKD

Historically, most treatments for CKD were focused on controlling blood pressure, glucose, and using RAAS inhibitors (e.g., ACE inhibitors). However, these strategies offered limited protection and did not address the accelerated cardiovascular risk.

Many CKD patients—especially those without diabetes—had few options for slowing disease progression or preventing cardiovascular events. There was an urgent need for therapies that could bridge the gap between kidney and heart protection in this broader patient group.

This is where EMPA-Kidney stepped in—designed specifically to evaluate whether empagliflozin could offer meaningful benefits in both diabetic and non-diabetic CKD populations.

About the EMPA-Kidney Trial

The EMPA-Kidney trial was one of the most ambitious and inclusive studies ever conducted in the field of chronic kidney disease. Designed as a large-scale, randomized, double-blind, placebo-controlled trial, it sought to determine whether empagliflozin, an SGLT2 inhibitor, could improve renal and cardiovascular outcomes in a broad spectrum of CKD patients, regardless of the presence of diabetes.

Design and Scope

• The trial enrolled over 6,600 participants from more than 260 centers across multiple countries.
• Crucially, it included individuals with:
• Diabetic and non-diabetic CKD.
• A broad range of kidney function, with estimated glomerular filtration rates (eGFR) ranging from 20 to 45 mL/min/1.73m², and even some up to 90, if they had elevated albuminuria.
• Participants were randomly assigned to receive empagliflozin 10 mg daily or placebo, in addition to standard care.
• The median follow-up period was approximately 2 years.

Primary Endpoint

The primary composite endpoint was the time to the first occurrence of:

• Progression of kidney disease, defined as:
• End-stage kidney disease (requiring dialysis or transplant),
• A sustained decline in eGFR to below 10 mL/min/1.73m²,
• A sustained reduction of at least 40% in eGFR from baseline, or
• Cardiovascular death.

Secondary Outcomes

Secondary outcomes included:

• Hospitalization for heart failure.
• Death from any cause.
• Assessment of adverse effects, including volume depletion, ketoacidosis, and urinary tract infections.

Key Findings

The EMPA-Kidney trial results, published in 2022, delivered compelling evidence in favor of empagliflozin’s protective role in both kidney and cardiovascular health.

Risk Reduction in Kidney Disease and Cardiovascular Death

• Empagliflozin reduced the risk of the primary composite endpoint by 28% compared to placebo.
• This effect was consistent across all subgroups, including those without diabetes, a groundbreaking finding that broadened the therapeutic scope of SGLT2 inhibitors.

Significance for Non-Diabetic Patients

• One of the most notable breakthroughs of the trial was its inclusion of a significant proportion (around 50%) of non-diabetic CKD patients.
• For the first time, a therapy originally designed for diabetes showed robust kidney and cardiovascular protection in non-diabetics, signaling a paradigm shift in nephrology and cardiology.

Reduction in Heart Failure Hospitalizations

• There was a significant reduction in hospitalizations for heart failure, reinforcing the heart-protective properties of empagliflozin already seen in previous cardiovascular trials.
• This finding is particularly relevant given the high overlap of CKD and heart failure, often referred to as the cardio-renal syndrome.

Tolerability and Safety Profile

• Empagliflozin was well tolerated, with a low incidence of serious adverse events.
• Rates of urinary tract infections, ketoacidosis, and volume depletion were comparable to placebo, affirming its safety even in those with advanced kidney impairment.

Implications for Kidney and Cardiovascular Care

The findings of the EMPA-Kidney trial mark a significant turning point in the management of chronic kidney disease. No longer confined to the realm of diabetes care, empagliflozin now emerges as a powerful therapeutic option for a much broader CKD population.

A Broader Therapeutic Landscape

EMPA-Kidney expanded the clinical application of empagliflozin to:

• Non-diabetic CKD patients, a group previously underserved in clinical trials.
• Patients with milder forms of albuminuria or lower eGFR, including those not traditionally considered for SGLT2 inhibitor therapy.

This broad applicability makes empagliflozin a compelling option for earlier intervention, potentially delaying disease progression before patients reach more severe stages of CKD.

From Glucose Control to Organ Protection

The trial reinforces a critical shift in how we view SGLT2 inhibitors—from glucose-lowering drugs to multi-organ protective agents. The benefits seen in EMPA-Kidney were independent of blood glucose levels, underscoring their role in:

• Renal protection through reduction of intraglomerular pressure and inflammation.
• Cardiovascular protection by reducing volume overload and improving hemodynamics.

Impact on Clinical Guidelines and Practice

Based on EMPA-Kidney and similar trials, clinical guidelines from major organizations (e.g., KDIGO, ESC, ADA) are being updated to:

• Recommend SGLT2 inhibitors as standard therapy in CKD patients, regardless of diabetes status.
• Encourage early adoption of these agents in patients with eGFR >20 mL/min/1.73m² and albuminuria.

In real-world settings, nephrologists, cardiologists, and primary care providers now have stronger evidence to prescribe empagliflozin confidently to a wider population, potentially altering the natural course of kidney and cardiovascular disease.

Comparison with Other Trials

The EMPA-Kidney trial stands alongside other major SGLT2 inhibitor studies such as DAPA-CKD and CREDENCE, but it introduces unique contributions to the field.

How EMPA-Kidney Complements DAPA-CKD and CREDENCE

While CREDENCE and DAPA-CKD laid the foundation, EMPA-Kidney pushed the boundaries by:

• Including a wider range of CKD etiologies, not limited to diabetes or albuminuria.
• Enrolling patients with lower eGFRs and even normal albumin levels—groups often excluded from previous trials.
• Providing the largest dataset to date on SGLT2 inhibitor use in non-diabetic kidney disease.

Future Directions

While the EMPA-Kidney trial has significantly advanced our understanding of SGLT2 inhibitors in CKD, it also opens the door to new questions and research opportunities.

Advanced CKD: The Untouched Frontier

The trial included patients with eGFR as low as 20 mL/min/1.73m², but those with more advanced kidney failure—especially below this threshold—remain understudied. More data are needed to determine:

• The efficacy and safety of empagliflozin in late-stage CKD or patients approaching dialysis.
• Whether benefits persist in those already receiving renal replacement therapy.

Specific Subpopulations

Future trials should also explore the effects of SGLT2 inhibitors in specific CKD etiologies, such as:

• Glomerulonephritis (e.g., IgA nephropathy).
• Autosomal dominant polycystic kidney disease (ADPKD).
• Transplant recipients, who are at high risk of both CKD progression and cardiovascular events.

These nuanced patient groups may respond differently, and tailored data are critical for personalized treatment strategies.

SGLT2 Inhibitors in Primary Prevention

One of the most exciting prospects is the potential role of SGLT2 inhibitors in primary prevention—delaying or preventing the onset of CKD in high-risk populations such as:

• People with hypertension and metabolic syndrome.
• Those with a family history of kidney disease but without current dysfunction.
  Ongoing and future studies may help establish whether early intervention can modify the long-term trajectory of kidney and cardiovascular health.

Combination Therapies: A Synergistic Future

There is growing interest in combining SGLT2 inhibitors with other agents that offer complementary benefits, such as:

• Mineralocorticoid receptor antagonists (MRAs) like finerenone, which reduce inflammation and fibrosis.
• GLP-1 receptor agonists, which provide additional cardiovascular protection.
  Such multi-targeted strategies may offer enhanced outcomes, especially in patients with complex comorbidities.

Conclusion

The EMPA-Kidney trial represents a paradigm shift in the management of chronic kidney disease and its cardiovascular complications. By proving that empagliflozin can slow kidney disease progression and reduce cardiovascular risk—even in patients without diabetes—it redefines the therapeutic potential of SGLT2 inhibitors.

What was once a class of drugs reserved for glycemic control is now firmly established as a pillar of organ protection—offering hope to millions living with or at risk of CKD and heart disease.

Call to Action

• Early identification of at-risk individuals, especially those with albuminuria or declining eGFR, is critical.
• Multidisciplinary care, involving nephrologists, cardiologists, endocrinologists, and primary care providers, will be key to implementing these advances effectively.
• Health systems and policymakers should ensure access and affordability of these medications to maximize public health impact.

As we enter this new era in kidney and cardiovascular care, EMPA-Kidney reminds us that with the right tools—and timely intervention—we can change the course of chronic disease.