A REVOLUTION IN THE MANAGEMENT OF CHRONIC KIDNEY DISEASE

On 24 February 2024, Boehringer Ingelheim invited experts in the fields of diabetes, cardiology and nephrology to a scientific event at the Grand Hyatt BGC to celebrate new breakthroughs in the use of sodium-glucose transporter 2 inhibitors (SGLT2is) in the management of chronic kidney disease (CKD).

ADDRESSING THE UNMET NEEDS IN CHRONIC KIDNEY DISEASE

CKD affects approximately 850 million people globally, while around 530 million people have diabetes and 60 million people are afflicted by heart failure.^1-3 Notably, 1 in 3 individuals with diabetes also have cardiovascular disease (CVD), and a large percentage of individuals with type 2 diabetes (T2D) also have CKD.^2,4

CKD itself is also associated with a wealth of other conditions. More than 60% of CKD patients have cardiovascular disease while up to 40% of people with heart failure suffer from CKD.^5,6 This suggests a shared underlying etiology among these conditions and emphasizes the need for comprehensive management strategies.

The link between T2D and CKD is particularly important. T2D is the foremost risk factor for CKD and an estimated 50% of T2D patients also suffer from CKD.⁷

CKD is associated with multiple risk factors, with diabetes emerging as the foremost contributor. Notably, approximately 50% of individuals diagnosed with T2D also suffer from CKD.⁷

CKD: Early detection and unmet needs

A lack of early detection is a significant unmet need in CKD treatment. The condition is usually diagnosed by looking at albuminuria and renal function decline (eGFR <60) for over 3 months.⁸

However, diagnosis based on these criteria often occurs when irreversible kidney damage is already present. Most patients with mild albuminuria with an eGFR <60ml/min/ 1.73m² are not recognized. This is one of the unmet needs in CKD care, where kidney injury is undetectable, leading to missed opportunities for intervention before renal and cardiovascular damage occurs.⁹

In fact, an observational study looking at 9,307 patients with T2D in primary care found that while 5,036 (54.1%) met the eGFR and albuminuria criteria for CKD, the condition was only diagnosed by clinicians in 12.1% of these patients.¹⁰

For the last 20 years, RAAS inhibitors have been the standard of care for CKD patients to slow disease progression. However, the residual risk of disease progression remains. In the recent years, SGLT2i therapy – initially indicated for T2DM – has emerged as a promising strategy for CKD management independent of glycemic control thanks to results from some landmark clinical trials.^11,12

HOPE FOR CKD: A REVOLUTION IN CKD CARE WITH EMPAGLIFLOZIN

 

Empagliflozin is an SGLT2i that has shown significant promise in the management of CKD and cardiovascular outcomes.¹¹

A post-hoc analysis of a the landmark EMPA-REG trial which looked at T2D patients with atherosclerotic cardiovascular disease and eGFR≥30 ml/min/1.73 m² treated with empagliflozin. This analysis found that empagliflozin resulted in a consistent risk reduction across KDIGO categories for kidney outcomes (See Figure 1). Notably, patients classified in the very high-risk group had a 71% risk reduction, while those with low to high risk showed no decline in eGFR.¹²

 

To further strengthen the evidence, the EMPA-KIDNEY trial investigated the efficacy of empagliflozin in reducing the risk of kidney disease progression or CVD death in CKD patients. In this study, empagliflozin demonstrated a 28% reduction in cardiorenal outcomes (HR: 0.72; 95% CI 0.64-0.82; p<0.0001) among a diverse population of over 6,000 CKD patients, with more than half of them being non-diabetic.¹¹

This study broadened the scope of CKD patients who could potentially benefit from SGLT2 inhibition to include individuals with a urinary albumin to creatinine ratio <30 mg/g and an eGFR >20 mL/min/1.73 m².¹¹

SGLT2is beyond T2D treatment

In addition to its CKD risk reduction, a systematic review and meta-analysis of randomized controlled trials of SGLT2is demonstrated its benefits in reducing the risk of cardiovascular death, and hospitalization for heart failure in individuals with chronic kidney disease or heart failure, regardless of their diabetes status. The proportional advantages were consistent among patients with and without diabetes and likewise apparent across the diverse spectrum of kidney functions.¹³

There is also data showing that SGLT2is could also have a range of other benefits including reducing serious hyperkalemia and anemia regardless of T2D status, lowering the risk of acute kidney injury in T2D patients, and potentially reducing atrial fibrillation events.^13-16

The benefits of SGLT2 inhibitors outweighs main safety outcomes of diabetic ketoacidosis and lower limb amputation more so in non-diabetic patients.¹³ One commonly cited safety concern with SGLT2is is a dip in eGFR upon their initiation. Professor Thomas described this as a “safe dip,” as it is not indicative of a functional decline. Unlike RAAS blockers, there is no requirement to test for this dip, since it is reversible and not associated with adverse outcomes.¹⁷

The wealth of evidence backing the use of SGLT2is in CKD have led to the 2023 KDIGO guidelines including them as a central pillar in the management of chronic disease (See Figure 2).²¹

TRANSFORMING GUIDELINES IN CKD MANAGEMENT 

Guideline Directed Management: SGLT2 inhibitors in the management of T2D, HF and CKD

SGLT2is are currently recommended for cardiorenal protection in T2D patients by guidelines from the American Diabetes Association (ADA) and the American Association of Clinical Endocrinology. They are also a central part of the KDIGO – ADA consensus report as a first-line therapy in managing T2D with CKD.^17,19

Outside of CKD, SGLTis are also included in several other international guidelines for different cardiovascular conditions. The European Society of Cardiology for example, recommends them for heart failure, while the European Society of Hypertension recommends them for cases involving nephropathies with low eGFR.

In the European Society of Cardiology guidelines for heart failure, SGLT2 inhibitors such as empagliflozin are indicated as a first line drug in the multiple drug regimen for heart failure with reduced ejection fraction (HFrEF). In addition, ESC also recommends Empagliflozin for patients with heart failure with moderately reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF) to reduce the risk of hospitalization and CV death.²⁰

Hypertension is the most common modifiable factor for CKD progression. In the 2023 European Society of Hypertension guidelines for the management of arterial hypertension, SGLT2 inhibitors are also recommended in patients with diabetic and non-diabetic nephropathies if eGFR is at least 20 ml/min/1.73m².²¹ The multitude of benefits of SGLT2 inhibitors promote better collaboration between specialists involved in cardiorenal and diabetes management.

SUMMARY

In summary, the symposium shed light on the urgent need for improved strategies to manage chronic kidney disease CKD, especially among high-risk groups such as individuals with diabetes and hypertension. The discussion emphasized the emerging role of SGLT2is like empagliflozin in transforming CKD treatment algorithms.

Empagliflozin has demonstrated significant efficacy in slowing kidney disease progression, reducing hospitalization and cardiovascular risks across diverse patient populations in multiple studies.^11,12 The integration of these medications into guideline-directed management protocols is crucial in improving patient care and outcomes.

Furthermore, addressing the accessibility and affordability barriers to early CKD screening is paramount in alleviating the burden of this disease in Filipino communities. Initiatives aimed at enhancing access to screening tests, coupled with efforts to reduce costs and increase awareness, can significantly impact the prevention and management of CKD. By advocating for policy changes patients can strive towards a future where all individuals at risk of CKD receive timely diagnosis, effective treatment, and improved quality of life.