Response to [Challenging the Restrictive Approach: Reconsidering SGLT-2 Inhibitor Use in CKD]

Dear editors, we would like to counter the questions raised by Helvaci et al.1Challenging the Restrictive Approach: Reconsidering SGLT-2 Inhibitor Use in CKD. Helvaci O, Yasar E. Helvaci B. Kidney Int Rep.Google Scholar regarding the beneficial effects of SGLT2i in absence of RAASi and in absence of albuminuria when eGFR is >45. Use of SGLT2i in these 2 clinical settings remain debatable based on all data available. For the first clinical setting, although subgroup analyses of the EMPA-KIDNEY trial showed beneficial effects of SGLT2i regardless of RAASi use,2Herrington W.G. Staplin N. Wanner C. et al.The EMPA-KIDNEY Collaborative GroupEmpagliflozin in Patients with Chronic Kidney Disease.N Engl J Med. 2023 Jan 12; 388: 117-127https://doi.org/10.1056/NEJMoa2204233Crossref PubMed Scopus (558) Google Scholar,3EMPA-KIDNEY Collaborative GroupEffects of empagliflozin on progression of chronic kidney disease: a prespecified secondary analysis from the empa-kidney trial.Lancet Diabetes Endocrinol. 2024 Jan; 12: 39-50https://doi.org/10.1016/S2213-8587(23)00321-2Abstract Full Text Full Text PDF Scopus (5) Google Scholar there were fewer patients recruited (18%) who were not on RAASi. This small sample size resulted in a wide confidence interval of the effect size for subgroup without RAASi in the randomized controlled trial (RCT); absolute difference in mean slope for eGFR 0.81, 95% confidence interval: 0.21, 1.40. One could argue that other analyses have also shown consistent benefit of SGLT2i in CKD patients not on RAASi.4Neuen B.L. Young T. Heerspink H.J.L. et al.SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis [published correction appears in Lancet Diabetes Endocrinol. 2019 Dec;7(12):e23].Lancet Diabetes Endocrinol. 2019; 7: 845-854https://doi.org/10.1016/S2213-8587(19)30256-6Abstract Full Text Full Text PDF PubMed Scopus (587) Google Scholar However, we would like to highlight that most of the RCTs of SGLT2i summarized in our article5Tarun T. Ghanta S.N. Ong V. et al.Updates on New Therapies for Patients with CKD.Kidney Int Rep. 2023 Oct 12; 9: 16-28https://doi.org/10.1016/j.ekir.2023.10.006Abstract Full Text Full Text PDF Scopus (0) Google Scholar recruited fewer "high risk" patients with CKD who were at more than 20% 5-year risk of kidney failure. This CKD subgroup is particularly difficult to treat given higher rates of adverse events from renoprotective treatments. For example, in the EMPA-KIDNEY trial, RAASi use was 91% in participants with eGFR >45 and 82% in participants with eGFR <30.2Herrington W.G. Staplin N. Wanner C. et al.The EMPA-KIDNEY Collaborative GroupEmpagliflozin in Patients with Chronic Kidney Disease.N Engl J Med. 2023 Jan 12; 388: 117-127https://doi.org/10.1056/NEJMoa2204233Crossref PubMed Scopus (558) Google Scholar,3EMPA-KIDNEY Collaborative GroupEffects of empagliflozin on progression of chronic kidney disease: a prespecified secondary analysis from the empa-kidney trial.Lancet Diabetes Endocrinol. 2024 Jan; 12: 39-50https://doi.org/10.1016/S2213-8587(23)00321-2Abstract Full Text Full Text PDF Scopus (5) Google Scholar Although the RCTs did not report significant differences in adverse events from SGLT2i use in the high-risk CKD subgroup,5Tarun T. Ghanta S.N. Ong V. et al.Updates on New Therapies for Patients with CKD.Kidney Int Rep. 2023 Oct 12; 9: 16-28https://doi.org/10.1016/j.ekir.2023.10.006Abstract Full Text Full Text PDF Scopus (0) Google Scholar the protocol implemented in RCTs is hard to implement in real-world patients. On one hand, in CREDENCE and many other RCTs, SGLT2i was not stopped even after eGFR decline met the eligibility criteria, and often continued until dialysis-dependence; this strict protocol adherence resulted in >70% of participants using SGLT2i at 2 years.5Tarun T. Ghanta S.N. Ong V. et al.Updates on New Therapies for Patients with CKD.Kidney Int Rep. 2023 Oct 12; 9: 16-28https://doi.org/10.1016/j.ekir.2023.10.006Abstract Full Text Full Text PDF Scopus (0) Google Scholar On the other hand, recent publications from real-world patients show high discontinuation rates for SGLT2i prescriptions-25% at 1-year and up to 50% at 5-years.S1, S2 Furthermore, one of the risk factors for high discontinuation rates of SGLT2i prescriptions was comorbid CKDS3-a clinical setting where SGLT2i is likely to benefit these patients. Taken together, there are paradoxical risks associated with beneficial treatments in patients with CKD, i.e., people who are more likely to benefit from a treatment might also be the ones who don't tolerate them. For the second clinical setting-non-albuminuric CKD patients with eGFR >45-there is not enough data regarding efficacy of SGLT2i. The EMPA-KIDNEY trial included non-albuminuric CKD patients with eGFR <45 where efficacy of SGLT2i is clear even in absence of albuminuria.S4 In our review article,5Tarun T. Ghanta S.N. Ong V. et al.Updates on New Therapies for Patients with CKD.Kidney Int Rep. 2023 Oct 12; 9: 16-28https://doi.org/10.1016/j.ekir.2023.10.006Abstract Full Text Full Text PDF Scopus (0) Google Scholar we have highlighted this eGFR cut-off from CKD subgroups where there is lack of clear evidence, i.e., patients with eGFR >45 and albuminuria <200 mg per gm of creatinine. Therefore, we recommend SGLT2i only for those receiving RAASi and for CKD subgroups with no albuminuria if eGFR is <45 until more data becomes available. Download .pdf (.1 MB) Help with pdf files Challenging the Restrictive Approach: Reconsidering SGLT-2 Inhibitor Use in CKDKidney International ReportsPreviewWe have read with interest the review by Tarun et al. titled "Updates on New Therapies for Patients with CKD," which provides a comprehensive discussion of new treatment options for chronic kidney disease (CKD).1 While we appreciate the thoroughness of the authors' work, we wish to raise some concerns regarding their proposed treatment algorithms. Full-Text PDF Open Access