The Role of SGLT2 Inhibitors in Slowing Progression of Chronic Kidney Disease in Diabetic Patients

Fotios Kaltsas^*
*Correspondence: Fotios Kaltsas, Department of Nephrology, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR 999077, China, Email:

Keywords

SGLT2 inhibitors • Chronic kidney disease • Diabetic nephropathy • Renal protection

Introduction

Chronic Kidney Disease (CKD) is a prevalent and severe complication in patients with diabetes mellitus, particularly Type 2 Diabetes (T2D). The progression of CKD in diabetic patients is associated with significant morbidity, mortality, and healthcare costs. Traditional therapies focus on glycemic control and blood pressure management to mitigate the progression of CKD, but these approaches have shown limited effectiveness in halting the decline in kidney function. The emergence of Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors has introduced a new paradigm in the management of diabetic nephropathy. Originally developed as antihyperglycemic agents, SGLT2 inhibitors have demonstrated unexpected but profound benefits on renal outcomes. This article aims to explore the role of SGLT2 inhibitors in slowing the progression of CKD in diabetic patients, discussing the underlying mechanisms, clinical evidence, and future directions [1].

Literature Review

SGLT2 inhibitors reduce glucose reabsorption in the renal proximal tubules, leading to glycosuria and improved glycemic control. Beyond their glucose-lowering effects, SGLT2 inhibitors also exert hemodynamic changes, reducing intraglomerular pressure, which is a key factor in CKD progression. They also promote natriuresis, leading to reductions in blood pressure, and exhibit anti-inflammatory and antifibrotic effects on the kidney [2]. Numerous randomized controlled trials, including the EMPA-REG OUTCOME, CANVAS, and CREDENCE trials, have demonstrated the renoprotective effects of SGLT2 inhibitors in diabetic patients. These trials showed significant reductions in the risk of CKD progression, ESRD, and major adverse renal events in patients treated with SGLT2 inhibitors compared to those on placebo or standard care. Compared to other antidiabetic agents, SGLT2 inhibitors have shown superior renal outcomes. This section compares the efficacy of SGLT2 inhibitors with other classes of glucose-lowering drugs, highlighting their unique benefits in preventing CKD progression [3].

Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors, such as empagliflozin, dapagliflozin, and canagliflozin, have emerged as a novel class of antihyperglycemic agents with significant renoprotective properties. Their primary mechanism involves the inhibition of SGLT2 in the proximal renal tubules, which is responsible for reabsorbing the majority of filtered glucose back into the bloodstream. By blocking this transporter, SGLT2 inhibitors promote glycosuria, leading to reduced plasma glucose levels. Unlike other antidiabetic drugs, SGLT2 inhibitors' glucose-lowering effect is independent of insulin, making them particularly beneficial for patients with insulin resistance or those with declining beta-cell function. Beyond their glucoselowering capabilities, SGLT2 inhibitors offer multiple renal benefits [4]. They induce natriuresis by inhibiting sodium reabsorption alongside glucose, which decreases intravascular volume and subsequently lowers blood pressure. This reduction in blood pressure, particularly within the glomeruli, helps to alleviate the intraglomerular hypertension that often contributes to the progression of diabetic nephropathy. Furthermore, these inhibitors have been shown to reduce albuminuria—a key indicator of kidney damage—by improving the glomerular filtration barrier and reducing hyperfiltration. Additionally, SGLT2 inhibitors exhibit anti-inflammatory and antifibrotic effects, likely through mechanisms that involve decreased oxidative stress and better mitochondrial function in renal cells. These combined effects make SGLT2 inhibitors a powerful tool in slowing the progression of chronic kidney disease (CKD) in diabetic patients [5].

Discussion

The renoprotective effects of SGLT2 inhibitors appear to be multifactorial, involving hemodynamic, metabolic, and anti-inflammatory mechanisms. The reduction in intraglomerular pressure and albuminuria, along with improved glycemic control and blood pressure, contribute to slowing CKD progression. The discussion will delve into these mechanisms in detail, emphasizing the importance of early intervention with SGLT2 inhibitors in diabetic patients with CKD. However, the use of SGLT2 inhibitors is not without challenges. Adverse effects such as genital infections, euglycemic diabetic ketoacidosis, and concerns about volume depletion must be considered. Additionally, their role in non-diabetic CKD patients remains to be fully elucidated. Future research directions should focus on long-term outcomes, combination therapies, and broader applications in various CKD populations [6].

Conclusion

SGLT2 inhibitors represent a significant advancement in the management of CKD in diabetic patients. By addressing multiple pathophysiological pathways involved in CKD progression, these agents offer a promising strategy to delay renal decline and reduce the burden of kidney disease. As evidence continues to accumulate, the integration of SGLT2 inhibitors into standard diabetic nephropathy care protocols could transform treatment outcomes, improving the quality of life and prognosis for millions of patients worldwide.

Acknowledgement

None.

Conflict of Interest

None.

References

1. Kovesdy, Csaba P. "Epidemiology of chronic kidney disease: An update 2022." Kidney Int Suppl 12 (2022): 7-11.

   Google Scholar, Crossref, Indexed at

2. Go, Alan S., Glenn M. Chertow, Dongjie Fan and Charles E. McCulloch, et al. "Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization." N Engl J Med 351 (2004): 1296-1305.

   Google Scholar, Crossref, Indexed at

3. Keith, Douglas S., Gregory A. Nichols, Christina M. Gullion and Jonathan Betz Brown, et al. "Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization." Arch Intern Med 164 (2004): 659-663.

   Google Scholar, Crossref, Indexed at

4. Otobe, Yuhei, Koji Hiraki, Chiharu Hotta and Hajime Nishizawa, et al. "Mild cognitive impairment in older adults with pre‐dialysis patients with chronic kidney disease: Prevalence and association with physical function." Nephrol 24 (2019): 50-55.

   Google Scholar, Crossref, Indexed at

5. Burns, Christine M., David S. Knopman, David E. Tupper and Cynthia S. Davey, et al. "Prevalence and risk of severe cognitive impairment in advanced chronic kidney disease." J Gerontol: Series A 73 (2018): 393-399.

   Google Scholar, Crossref, Indexed at

6. Baaten, Constance CFMJ, Sonja Vondenhoff and Heidi Noels. "Endothelial cell dysfunction and increased cardiovascular risk in patients with chronic kidney disease." Circ Res 132 (2023): 970-992.

   Google Scholar, Crossref, Indexed at