SGLT-2 Inhibitors in Nephrotic-range Proteinuria: Emerging Clinical Evidence Ⅱ

DISCUSSION

The role of SGLT-2 inhibitors in patients with microalbuminuria and macroalbuminuria has been well-established. However, there is limited information on the outcomes of SGLT-2 inhibitors in patients with NRP. The studies included in this review suggest that SGLT-2 inhibitors may successfully reduce proteinuria and prevent CKD progression in patients with NRP, although outcome measures were variable across studies. 

CLICK HERE TO KNOW CISTANCHE FOR CKD TREATMENTS

The impact of SGLT-2 inhibitors on proteinuria was variable. While 12 patients experienced complete resolution of proteinuria [23, 24], other patients continued to have NRP at follow-up [18–20, 22, 24]. Differences in proteinuria reduction may be attributable to heterogeneous underlying disease etiologies, proteinuria severity, variable follow-up duration and method of proteinuria quantification. Despite our findings suggesting a reduction in proteinuria and preservation of kidney function in both diabetic and non-diabetic participants, most participants had underlying diabetic kidney disease. Therefore, future studies evaluating the effectiveness of SGLT-2 inhibitors in other etiologies of NRP are needed. Only 12 participants did not have diabetic kidney disease and these included patients with FSGS, Alport syndrome and Dent disease. Consistent with findings from randomized controlled trials, additional proteinuria reduction with SGLT-2 inhibitors was observed on a background of the renin-angiotensin-aldosterone blockade [6, 19, 21, 22, 24]. The predominant SGLT-2 inhibitor prescribed was empagliflozin, although all agents demonstrated a reduction in proteinuria. However, contradictory findings also exist in the literature [27]. 

When the effect of SGLT-2 inhibitors was explored across varying levels of proteinuria, patients with UACR >3000 mg/g demonstrated the highest absolute but lowest relative reduction in albuminuria [25]. Similarly, differences in terms of proteinuria as an outcome may be attributable to the differences among studies in terms of the baseline eGFR values of the participants as shown by few clinical studies [20, 26]. A study that evaluated pediatric patients [21] provided evidence not available from randomized controlled trials as pediatric patients were excluded.

It should be noted that the DAPA-CKD trial was not included in the present analysis, although it included patients with a wide range of glomerular disease and 1484 of the participants had UACR >3000 mg/g consistent with NRP. In DAPA-CKD no heterogeneity was observed between patients with UACR ≤1000 or >1000 mg/g; however, secondary analyses have not been specifically performed in patients with NRP. However, a pre-specified analysis in 104 biopsy-confirmed FSGS patients, a common cause of NRP, with a median UACR of 997 (interquartile range 736–2290 mg/g) did not observe a significant reduction in the rate of eGFR decline, although albuminuria reduction was observed and albuminuria reduction is associated with chronic eGFR slope.

Limitations to this study include the low total number of patients, varying study quality, variability in proteinuria measurement, different durations of follow-up, and low representation of diverse etiologies of nephrotic syndrome which limits generalizability beyond diabetic kidney disease. Additionally, the differences between the effects of SGLT-2 inhibitors on NRP may partially be attributable to the eGFR of the patients included in individual studies. Nevertheless, this is the first study to comprehensively review the role of SGLT-2 inhibitors in patients with NRP and supports a promising therapeutic role for these agents in this population, although larger dedicated studies for patients with NRP will be required in the future.

In conclusion, SGLT-2 inhibitors significantly decrease albuminuria and proteinuria. Thus, NRP patients might benefit from them in terms of kidney disease protection. However, clinical experience with SGLT-2 inhibitors in patients with NRP is scarce, as patients with NRP or with certain types of glomerulonephritis were excluded from some clinical trials, with kidney outcomes and pre-specified subanalyses not always addressing this population. Despite these limitations, the present analysis supports that the kidney protective effect of SGLT-2 inhibitors extends to patients with NRP, at least for patients with diabetic kidney disease. A prospective study should be planned to evaluate the kidney and heart-protective effect of SGLT-2 inhibitors in patients with NRP due to diabetes or glomerulonephritis.

REFERENCES

1. Huri HZ, Lim LP, Lim SK. Glycemic control and antidiabetic drugs in type 2 diabetes mellitus patients with renal complications. Drug Des Dev Ther 2015;9:4355–71. https://doi.org/ 10.2147/DDDT.S85676 

2. Opie LH. Sodium-glucose co-transporter 2 (SGLT2) inhibitors: new among antidiabetic drugs. Cardiovasc Drugs Ther 2014;28:331–4. https://doi.org/10.1007/s10557-014-6522-0 

3. Brown E, Heerspink HJL, Cuthbertson DJ et al. SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications. Lancet North Am Ed 2021;398:262–76. https://doi.org/10.1016/S0140-6736(21)00536-5

4. Heerspink HJL, Stefansson BV, Correa-Rotter R et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436–46. https://doi.org/10.1056/ NEJMoa2024816

5. Perkovic V, Jardine MJ, Neal B et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295–306. https://doi.org/10.1056/ NEJMoa1811744 

6. Tanaka A, Nakamura T, Sato E et al. Therapeutic potential of tofogliflozin on nephrotic syndrome secondary to diabetic nephropathy. J Cardiol Cases 2017;16:30–3. https://doi.org/10. 1016/j.jccase.2017.04.003 

7. Nagasu H, Yano Y, Kanegae H et al. Kidney outcomes associated with SGLT2 inhibitors versus other glucose-lowering drugs in real-world clinical practice: the Japan Chronic Kidney Disease Database. Diabetes Care 2021;44: 2542–51. https://doi.org/10.2337/dc21-1081 

8. Cherney DZ, Kanbay M, Lovshin JA. Renal physiology of glucose handling and therapeutic implications. Nephrol Dial Transplant 2020;35:i3–12. https://doi.org/10.1093/ndt/gfz230

9. Kanbay M, Demiray A, Afsar B et al. Sodium-glucose cotransporter 2 inhibitors for diabetes mellitus control after kidney transplantation: review of the current evidence. Nephrology 2021;26:1007–17. https://doi.org/10.1111/nep.13941 

10. Kanbay M, Ertuglu LA, Afsar B et al. Renal hyperfiltration defined by high estimated glomerular filtration rate: a risk factor for cardiovascular disease and mortality. Diabetes Obes Metab 2019;21:2368–83. https://doi.org/10.1111/dom.13831

Supportive Service:

Email:wallence.suen@wecistanche.com 

Whatsapp/Tel:+86 15292862950

Shop:

https://www.xjcistanche.com/cistanche-shop