Andrew Kowalski, MD, FASN
Chronic Kidney Disease (CKD) is a silent, progressive condition that affects millions of people worldwide. It involves the gradual loss of kidney function over time, potentially leading to end-stage renal disease (ESRD) requiring dialysis or a kidney transplant. For decades, managing CKD has revolved around controlling risk factors like hypertension, diabetes, and cardiovascular disease, as well as mitigating further damage to the kidneys. However, the therapeutic landscape for CKD has been rapidly evolving, with the emergence of Sodium-Glucose Co-Transporter 2 (SGLT2) inhibitors, notably Farxiga (Dapagliflozin) and Jardiance (Empagliflozin) showing unprecedented promise in slowing the progression of the disease.
What is Chronic Kidney Disease (CKD)?
CKD is characterized by a decline in kidney function over time, often without noticeable symptoms in the early stages. It is classified into five stages, ranging from mild kidney damage (Stage 1) to complete kidney failure (Stage 5). Common causes of CKD include diabetes, high blood pressure, and glomerulonephritis, all of which can cause irreversible damage to the kidneys.
People with CKD often suffer from complications like fluid retention, electrolyte imbalances, anemia, and cardiovascular issues. Managing CKD requires a multi-faceted approach, which includes lifestyle modifications, medications to control blood pressure and glucose levels, and in some cases, dialysis or transplantation. Despite these treatments, CKD has historically been difficult to manage, with a significant risk of progression to ESRD.
The Role of SGLT2 Inhibitors in CKD
Sodium-glucose co-transporter 2 (SGLT2) inhibitors, a relatively new class of drugs, were initially developed to treat type 2 diabetes. Their primary mechanism is to block the reabsorption of glucose in the kidneys, allowing excess glucose to be excreted in the urine, thereby lowering blood sugar levels. However, in recent years, their role has expanded significantly, particularly in the context of CKD and heart failure.
How SGLT2 Inhibitors Work
SGLT2 inhibitors work by targeting proteins in the kidneys that are responsible for reabsorbing glucose from the urine back into the blood. By inhibiting these proteins, SGLT2 inhibitors not only help to reduce blood glucose levels in diabetic patients but also offer several renal and cardiovascular benefits. The key mechanisms that make SGLT2 inhibitors beneficial for kidney health include:
• Reduction in Intraglomerular Pressure: SGLT2 inhibitors reduce the pressure inside the glomeruli (the filtering units of the kidney) by decreasing sodium reabsorption. This helps to preserve kidney function over time.
• Improvement in Glycemic Control: By lowering blood sugar levels, SGLT2 inhibitors prevent the damage that high glucose levels can cause to the delicate blood vessels in the kidneys.
• Reduction in Proteinuria: Excess protein in the urine is a hallmark of kidney damage. SGLT2 inhibitors have been shown to reduce proteinuria, which is a significant marker of improved kidney health.
• Cardiovascular Protection: Many CKD patients are at high risk of cardiovascular events. SGLT2 inhibitors have been shown to reduce the risk of heart failure, which indirectly benefits kidney health by reducing the strain on the cardiovascular system.
Blocking this receptor results in an increased delivery of sodium and glucose to the far parts of the kidney, triggering a feedback mechanism that ultimately reduces filtration by constricting and dilating various arteries, leading to a significant decrease in glomerular pressure. Essentially, this medication helps bring the kidney out of the high-stress zone, similar to the effects of the more popular blood pressure medications, ACE inhibitors and ARBs.
In diabetic patients, increased reabsorption at the SGLT-2 receptors causes less sodium to be recognized in the latter part of the kidney. This prompts various hormomnes to be secreted as a protective response, but over time, it can lead to a dysregulated system resulting in hyperfiltration and the characteristic changes often observed in diabetic kidney disease, accelerating the progression of chronic kidney disease. Addressing hyperfiltration in the kidney and reducing these hormones has also been linked to lowering pressures coming to and out of the heart, demonstrating cardioprotective effects.
Landmark Trials Supporting SGLT2 Inhibitors in CKD
Several large clinical trials have demonstrated the effectiveness of SGLT2 inhibitors in slowing the progression of CKD, regardless of whether the patient has diabetes. Some of the most significant studies include:
1. The CREDENCE Trial: The CREDENCE trial was the first large-scale study to show that the SGLT2 inhibitor canagliflozin significantly reduced the risk of kidney failure and cardiovascular events in patients with type 2 diabetes and CKD. This trial led to the first approval of an SGLT2 inhibitor specifically for the treatment of CKD.
2. The DAPA-CKD Trial: The DAPA-CKD trial investigated the effects of dapagliflozin on patients with CKD, both with and without diabetes. The results were remarkable, showing that dapagliflozin reduced the risk of worsening kidney function, cardiovascular death, and hospitalization for heart failure. Notably, this trial included patients with and without type 2 diabetes, expanding the potential benefits of SGLT2 inhibitors to a broader population.
Images below taken from https://www.farxiga-hcp.com/chronic-kidney-disease
3. The EMPA-KIDNEY Trial: Ongoing research, such as the EMPA-KIDNEY trial, continues to explore the renal benefits of SGLT2 inhibitors in a broader CKD population, offering hope for even more comprehensive treatment approaches.
Benefits of SGLT2 Inhibitors for CKD Patients
The benefits of SGLT2 inhibitors in CKD extend beyond glycemic control, making them a valuable tool for nephrologists and other healthcare providers. Some key benefits include:
• Slowed Progression of CKD: SGLT2 inhibitors reduce the rate of decline in kidney function, helping to delay or prevent the need for dialysis or transplantation.
• Cardiovascular Protection: Many patients with CKD are also at high risk of cardiovascular disease. SGLT2 inhibitors have been shown to reduce the risk of heart failure and other cardiovascular events, which are common causes of morbidity and mortality in CKD patients.
• Improved Quality of Life: By reducing the burden of symptoms like fluid retention and proteinuria, SGLT2 inhibitors may help improve the overall quality of life for CKD patients.
• Applicability Beyond Diabetes: While initially developed for diabetic patients, SGLT2 inhibitors have proven effective in CKD patients without diabetes, broadening their therapeutic potential.
Studies were completed in non-diabetic CKD patients and patients with cardiovascular disease with amazing results. These studies have shown that the use of these medications can decrease CKD progression and delay the risk for dialysis by 40%. It was also noted that while taking these medications patients had a reduction in the rate of AKI by 25% with no symptomatic hypoglycemia. Studies have also shown that taking these medications have resulted in a 30-40% decrease in CKD progression and a significant decrease in albuminuria. Furthermore, among patients with cardiovascular disease there was a reduction in total and cardiovascular mortality by 15-20% along with a decrease in hospitalizations for heart failure by 30%. Additional benefits include a decrease in systolic blood pressure by approximately 2-4 mmHg (2-4 points) and a decrease in body weight by approximately 2-3 kg (about 2-6lbs).
Safety and Considerations
While SGLT2 inhibitors are generally well-tolerated, they are not without potential side effects. The most common concerns include urinary tract infections, genital mycotic infections, and dehydration. However, these side effects are generally manageable and must be weighed against the substantial benefits of the drug. Patients should be closely monitored by their healthcare provider to ensure the safe use of these medications, particularly in the context of CKD.
Conclusion
SGLT2 inhibitors represent a paradigm shift in the management of CKD, offering not only glucose-lowering effects for diabetic patients but also substantial renal and cardiovascular protection for a broad range of individuals with chronic kidney disease. As research continues to expand our understanding of their benefits, SGLT2 inhibitors are becoming an essential component of CKD management, offering hope for slowing disease progression and improving outcomes in millions of patients worldwide.
For those with CKD or at risk of kidney disease, discussing the potential of SGLT2 inhibitors with a healthcare provider is a crucial step toward better long-term kidney health.
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