Chinese expert consensus on the clinical application of... : Chinese Medical Journal (2024)

Introduction

The prevalence of chronic kidney disease (CKD) in China was 8.2% in 2018–2019.^[^¹^] CKD may progress to end-stage kidney disease (ESKD), necessitating kidney replacement treatment such as dialysis or kidney transplantation,^[^²^] which imposes a substantial burden on both family and society. Moreover, patients with CKD have a high risk of comorbidities including cardiovascular diseases.^[^³^] The risk of death rises as the estimated glomerular filtration rate (eGFR) declines.^[^³^] A substantial portion of CKD patients die, primarily from cardiovascular events, before reaching the stage requiring dialysis.^[^³^] As such, delaying the progression of CKD and reducing cardiovascular events are key elements in patient care. In recent years, important progress has been made in the cardiorenal protection of patients with CKD. Specifically, the advent of sodium-glucose cotransporter 2 (SGLT2) inhibitors has provided a new and important approach for the treatment of CKD.

Initially marketed as an antihyperglycemic medicine, SGLT2 inhibitors have a unique mechanism for lowering blood glucose. These agents reduce glucose reabsorption by inhibiting SGLT2 in the proximal tubules.^[^⁴^] In recent years, a series of clinical studies showed that SGLT2 inhibitors had a cardiorenal protective effect independent of their antihyperglycemic effect.^[^⁵^] The Kidney Disease: Improving Global Outcomes (KDIGO) 2022 Clinical Practice Guidelines for Diabetes Management in CKD have upgraded SGLT2 inhibitors from antihyperglycemic therapy to first-line comprehensive treatment for patients with type 2 diabetes (T2D) and CKD.^[^⁶^]

SGLT2 inhibitors currently available in China include canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and henagliflozin. To promote better implementation of the evidence and more effective utilization of SGLT2 inhibitors in clinical practice, a Consensus Working Group comprising experts in nephrology, endocrinology, and cardiovascular disease from China collaboratively developed this consensus based on available evidence and clinical experiences.

Consensus development methodology

The Consensus Secretarial Group initially proposed 20 clinical questions through literature review and sent them via email to members of the Consensus Expert Group. Through scoring, clinical questions were selected and added. Based on expert voting and suggestions, the Secretarial Group selected 16 clinical issues that required consensus.

The evidence evaluation team formed an evidence summary and preliminary recommendations based on existing clinical evidence and comprehensive consideration of patient preferences, costs, pros and cons of interventions, and other factors. Preliminary recommendations were revised based on expert discussion and voting via email and a Consensus Working Group meeting.

Target audience

The aim of this consensus statement is to provide clinicians with a comprehensive reference and guidance in the management of patients with CKD. The target population for the application of consensus recommendations is the adult patients with CKD.

Consensus recommendations and clinical practice highlights

Part 1. Recommended patient population for SGLT2 inhibitors

1. We recommend initiating an SGLT2 inhibitor in patients with CKD with an eGFR ≥20mL·min^–1·1.73m^–2, with or without T2D.
2. We preferentially recommend using an SGLT2 inhibitor for treating the following patients with CKD:

(1) At moderate or higher risk for CKD progression (referring to 2012 KDIGO risk stratification for CKD);
(2) With high-risk factors for cardiovascular events, including obesity/overweight, hypertension, dyslipidemia, smoking, a family history of premature atherosclerotic cardiovascular disease (ASCVD), duration of diabetes, and the presence of albuminuria;
(3) With heart failure (regardless of ejection fraction).

3. We recommend selecting SGLT2 inhibitors with documented evidence of cardiorenal benefit.
4. The consensus 1 recommendation may not apply to some patients with CKD due to a current lack of evidence-based support. The potential risks and benefits of SGLT2 inhibitors should be evaluated carefully before considering their use in the following circ*mstances:

(1) Patients with type 1 diabetes;
(2) Patients with kidney transplantation;
(3) Patients who are taking high doses of corticosteroids or immunosuppressants;
(4) Patients with massive albuminuria (urine albumin creatinine ratio [UACR] ≥5000mg/g);
(5) Patients with polycystic kidney disease (PKD).

Part 2. Assessing the risk of potential adverse reactions before starting SGLT2 inhibitor therapy

5. We suggest evaluating the blood volume and blood pressure before starting SGLT2 inhibitor therapy. In patients with, or at risk of, volume deficit, it is advisable to correct the deficit and/or discontinue or reduce diuretics before initiating SGLT2 inhibitors.
6. We suggest evaluating the risk of hypoglycemia and ketoacidosis before initiating SGLT2 inhibitors in patients with T2D and CKD:

(1) We suggest evaluating the risk of hypoglycemia before initiating SGLT2 inhibitors in patients with T2D and CKD who are receiving other hypoglycemic agents, particularly insulin, sulfonylureas, and glinides;
(2) We suggest that patients with T2D be evaluated for risk of ketoacidosis before starting SGLT2 inhibitor therapy. SGLT2 inhibitors should be used cautiously in patients at high risk for ketoacidosis.

7. We suggest evaluating risk factors for urinary tract and genital infection before initiating treatment with SGLT2 inhibitors.

Part 3. Recommendations for combination treatment of SGLT2 inhibitors with other organ protective medicines

8. We recommend the combination treatment of an SGLT2 inhibitor and angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB).
9. We suggest using an SGLT2 inhibitor for patients who are intolerant to ACEI/ARB.
10. SGLT2 inhibitors can be used in combination with ACEI/ARB and non-steroidal mineralocorticoid receptor antagonists (nsMRA) in CKD patients with T2D.

Part 4. Monitoring and managing adverse reactions during use of SGLT2 inhibitors

11. We suggest testing kidney function and monitoring blood pressure and blood volume within 2–4 weeks after starting SGLT2 inhibitors:

(1) We suggest not discontinuing SGLT2 inhibitors if the eGFR decreases by less than 30% of the baseline value within 2–4 weeks after treatment initiation;
(2) If the decrease in eGFR reaches 30% or more of the baseline within 2–4 weeks after starting SGLT2 inhibitors, we suggest discontinuing the treatment and investigating potential causes.

12. We suggest being vigilant about the risk of ketoacidosis during SGLT2 inhibitor treatment in CKD patients with T2D:

(1) We suggest discontinuing SGLT2 inhibitors if ketoacidosis occurs;
(2) We suggest discontinuing SGLT2 inhibitors when patients exhibit symptoms such as fatigue, excessive thirst, unexplained vomiting, abdominal pain, dehydration, or altered consciousness. Timely measurement of blood or urine ketones is advised;
(3) We suggest educating patients about the clinical symptoms and risk factors of ketoacidosis, including acute disease, starvation, trauma, surgery, vomiting, and dehydration.

13. For patients with T2D experiencing recurrent hypoglycemic events, the antihyperglycemic regimen should be adjusted, and the dosage of insulin, sulfonylurea, or glinides should be reduced.
14. We suggest discontinuing SGLT2 inhibitors when severe urinary tract infection or genital fungal infection occurs during the treatment:

(1) SGLT2 inhibitors should either not be used or used cautiously in patients with a history of recurrent urinary tract and genital infections;
(2) Patients should be advised about the importance of consuming an appropriate amount of water and maintaining proper perineal hygiene.

15. We suggest discontinuing SGLT2 inhibitors in patients who experience acute kidney injury (AKI) from various causes.
16. For patients who are already on SGLT2 inhibitor treatment, it is reasonable to continue the SGLT2 inhibitor even if the eGFR slowly falls below 20mL·min^–1·1.73m^–2, unless it is not tolerated or until the initiation of dialysis or kidney transplantation. Close follow-up is required in these patients.

The full text and the rationales for these recommendations are detailed in the Supplementary Material, https://links.lww.com/CM9/C11.

Summary and perspective

Strong evidence indicates that SGLT2 inhibitors, which were initially marketed as antihyperglycemic drugs, have cardiorenal protective effects independent on their glucose-lowering effect. Clinical studies suggest that SGLT2 inhibitors improve cardiac and renal outcomes in CKD patients with or without T2D, demonstrating good overall safety and a low incidence of adverse events. SGLT2 inhibitor has become an important organ protective therapy in patients with CKD.

Writing Committee

Min Zhang (Division of Nephrology, Huashan Hospital, Fudan University), Chuanming Hao (Division of Nephrology, Huashan Hospital, Fudan University).

Working Group Membership (Experts are listed in alphabetical order of their last name)

Jianghua Chen (First Affiliated Hospital of Zhejiang University School of Medicine), Nan Chen (Ruijin Hospital, Shanghai Jiao Tong University School of Medicine), Wei Chen (First Affiliated Hospital of Sun Yat-sen University), Leyi Gu (Renji Hospital, Shanghai Jiao Tong University School of Medicine), Chuanming Hao (Huashan Hospital, Fudan University), Fan Fan Hou (Nanfang Hospital, Southern Medical University), Yong Huo (Peking University First Hospital), Guisen Li (Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital), Xiaoying Li (Zhongshan Hospital, Fudan University), Yong Li (Huashan Hospital, Fudan University), Min Liang (Nanfang Hospital, Southern Medical University), Bicheng Liu (Zhongda Hospital, Southeast University), Huijuan Mao (First Affiliated Hospital of Nanjing Medical University), Gang Xu (Tongji Hospital, Huazhong University of Science and Technology), Li Yao (First Hospital of China Medical University), Minghui Zhao (Peking University First Hospital), and Li Zuo (Peking University People’s Hospital).

Acknowledgements

Thanks to Guangdong Precision Medicine Application Society for organizing and coordinating.

Conflicts of interest

None.

References

1.Wang L, Xu X, Zhang M, Hu C, Zhang X, Li C, et al. Prevalence of chronic kidney disease in China: Results from the Sixth China Chronic Disease and Risk Factor Surveillance. JAMA Intern Med 2023;183:298–310. doi: 10.1001/jamainternmed.2022.6817.

Supplemental Digital Content

CM9_2024_04_08_ZHANG_cmj-2023-3723r1_SDC2.docx; [Word] (67 KB)