Editor's note: Chronic kidney disease (CKD) is one of the most important microvascular complications of diabetes mellitus, which can affect the whole kidney (including glomeruli, tubules, and renal interstitium), and is currently the main cause of end-stage renal disease (ESKD) [1]. Mineralocorticoid receptor (MR) overactivation is a key driver of renal disease progression and cardiovascular impairment in diabetic patients. Finerenone is a new non-steroidal mineralocorticoid receptor antagonist (NS-MRA), which has shown good application prospects in diabetes mellitus complicated with CKD.
With the increasing clinical experience of finerenone in the past two years since its launch in China, its excellent efficacy has been recognized by more and more doctors and patients. In order to guide or help more doctors standardize the treatment of patients with type 2 diabetes mellitus (T2DM)-related CKD, and to achieve the goal of "Kidney Health for All: Promoting Medical Equity and Optimizing Medication Practices" proposed by the 19th World Kidney Day (WKD), Dr. Lin Zhen from Peking University People's Hospital shared the diagnosis and treatment experience of a case of finerenone in the treatment of patients with T2DM-related CKD, and invited Professor Cai Xiaoling, chief physician of the Department of Endocrinology, Peking University People's Hospital, to comment. The core content of this journal is compiled for readers' reference.
Case authors
Dr. Lin Zhen
Review experts
Professor Cai Xiaoling
Case information
A 67-year-old female was admitted to the hospital with "elevated blood sugar for 5 years and increased foam in the urine for 3 months".
History of present illness
5 years ago, the fasting blood glucose was found to be 9.8 mmol/L, no polydipsia, polyphagia, polyuria, and weight loss. Three years ago, the patient was admitted to the hospital due to poor blood glucose control, and the fasting blood glucose was 8.9 mmol/L, the postprandial blood glucose was 14.4 mmol/L, and the glycosylated hemoglobin (HbA1c) was 9.8%, and empagliflozin 10 mg qd and sitagliptin 100 mg qd were added to the original metformin treatment, and the blood glucose gradually improved. 3 months ago, the patient found that there was an increase in foam in the urine, no urinary frequency, urgency, dysuria, urine protein+, urine ketone negative, and urine albumin-creatinine ratio (UACR) of 226.3 mg/g. HbA1c 7.6%。 During the course of the disease, there was no blurred vision, no numbness of limbs, no changes in gloves and socks, urine as mentioned above, no abnormalities in stool, spirit, appetite, sleep, and no obvious changes in weight.
Anamnesis, family history
History of hypertension for 5 years, blood pressure up to 180/100 mmHg, treatment with irbesartan 150 mg qd, blood pressure control at 110~120/70~80 mmHg; History of hyperlipidemia for 4 years, treated with Pingsu Xuezhikang; Hyperuricemia, treated with benzbromarone 50 mg once a day to lower uric acid; No history of smoking and drinking; Family history is unremarkable.
physical examination
Blood pressure was 125/80 mmHg, heart rate was 82 beats/min, body mass index (BMI) was 25.5 kg/m2, there was no abnormality in cardiopulmonary and abdominal examination, and there was no edema in both lower limbs.
INVESTIGATIONS
HbA1c 7.4%，血肌酐91 μmol/L，估算的肾小球滤过率（eGFR）56.82 ml/（min·1.73m2），UACR 314.89 mg/g，尿糖4+，尿蛋白+，血钾4.45 mmol/L，尿酮体阴性。 超声心动图提示二尖瓣、三尖瓣轻度反流；左室舒张功能减低；左室射血分数（LVEF）为62%。 无糖尿病视网膜病变（DR）。
Initial diagnosis
Type 2 Diabetes
糖尿病肾病（G3aA3期）
Hypertension grade 3 (very high risk)
Hyperlipidemia
Hyperuricemia
Clinical diagnosis and treatment ideas and medication adjustment
The patient has been treated with the renin-angiotensin system inhibitor (RASi) irbesartan and has substantial proteinuria despite stable blood pressure control; Glycemic control improved with sodium-glucose cotransporter 2 inhibitors (SGLT2i) empagliflozin and sitagliptin hypoglycemic therapy; Hyperlipidemia and hyperuricemia can be controlled. According to domestic and international guidelines, patients with diabetes-related CKD should take comprehensive management measures and use drugs with renal and cardiovascular benefits. Considering that finerenone is another major breakthrough in the treatment of diabetes-related CKD, the 2023 American Diabetes Association (ADA) guidelines [2] and the 2022 edition of the Global Organization for the Improvement of Kidney Disease Prognosis (KDIGO) guidelines for the management of diabetes in patients with CKD [3] recommend ns-MRA therapy with renal-cardiac benefits for patients with T2DM-associated CKD.
Therefore, on the basis of maintaining the original antihypertensive, hypoglycemic, lipid-regulating and uric acid-lowering treatments, Dr. Lin added finerenone, a drug that reduces proteinuria and protects the kidney and heart. Because the patient had a normal serum potassium level and an eGFR of 56.82 mL/min/1.73 m2, finerenone 10 mg once a day was given as initiation. Serum potassium and eGFR should be monitored.
The first follow-up: after 1 month of treatment with finerenone 10 mg qd, the eGFR was 50.70 ml/(min·1.73m2), which was about 11% lower than that before treatment, and the UACR was reduced to 227.05 mg/g, a decrease of about 28%, and the urine routine showed that urine protein was negative, and serum potassium was 4.36 mmol/L. According to the guidelines and finerenone product instructions, serum potassium and eGFR were monitored in time within 4 weeks of initial treatment, and the results showed that serum potassium ≤ 4.8 mmol/L, and eGFR decreased by less than 30% compared with 1 month ago, so the standard dose of 20 mg once a day was increased to continue treatment.
The second follow-up: after 1 month of treatment with finerenone 20 mg qd, compared with the first follow-up, the eGFR was 50.90 ml/(min·1.73 m2), almost unchanged, while the UACR was significantly reduced to a near-normal level (32.44 mg/g), a decrease of up to 86%, and urine routine showed negative urine protein and serum potassium 4.68 mmol/L. During the treatment period, the UACR was significantly reduced, the efficacy was certain, the eGFR was not significantly changed, and the serum potassium was always within the normal range, so the current standard dose of therapy was continued to obtain long-term renal and cardiac benefits.
Expert commentary
It is estimated that CKD affects more than 850 million people worldwide and caused more than 3.1 million deaths in 2019. Kidney disease is currently the eighth leading cause of human death and, if left unaddressed, is expected to become the fifth leading cause of death by 2040. Over the past three decades, CKD treatment efforts have focused on preparing and delivering renal replacement therapy, and recent breakthroughs in treatment have provided unprecedented opportunities to prevent or delay disease progression, mitigate complications such as cardiovascular disease, and kidney failure, ultimately improving the quality of life and prolonging life of patients with CKD [4].
With the change of disease spectrum, diabetes has replaced glomerular disease as the leading cause of CKD, and the number of patients with T2DM complicated with CKD in mainland China has exceeded 31 million [5]. Proteinuria is an early marker of CKD and a marker of cardiovascular disease [6], especially since UACR is more closely associated with the progression of CKD and related complications. T2DM-associated CKD progresses rapidly, and with elevated UACR, patients are at significantly increased risk of progression to ESKD and cardiovascular events. Once massive proteinuria is reached, progression to ESKD is approximately 14 times faster than other renal lesions [7]. Therefore, the 2023 ADA guidelines recommend that all patients with T2DM be tested for urine albumin (such as UACR) or eGFR at least once a year, while for patients with diabetes-related CKD, urine albumin (such as UACR) and eGFR should be monitored 1~4 times a year according to the stage of the disease, so as to detect early and intervene in time to reduce the occurrence of renal failure and cardiovascular events [2].
The patient was found to have foamy urine for 3 months, UACR reached 314.89 mg/g, was in the stage of massive albuminuria, and the eGFR was moderately reduced, which means that CKD progresses rapidly and the risk of further development is extremely high, and proteinuria treatment is required as soon as possible. Finerenone 10 mg once a day was associated with a reduction of approximately 28% in UACR after 4 weeks of initiation and a further significant 86% reduction in UACR after 4 weeks of treatment at a standard dose of 20 mg once a day, and was close to normal. During treatment, serum potassium was consistently monitored within the normal range, and eGFR decreased only slightly. This suggests that finerenone can further significantly reduce UACR in a dose-dependent manner on the basis of RASi and SGLT2i treatment, which is beneficial to reduce the risk of CKD progression and cardiovascular events, and is safe and well tolerated. Therefore, in clinical practice, standardizing the use of finerenone and choosing a reasonable therapeutic dose is the basis for patients to obtain the best efficacy.
Returning to the guidelines, the 2024 edition of the KDIGO Guidelines for the Assessment and Management of CKD has been released for the first time in 12 years, and ns-MRA is the best choice for adult patients with T2DM who are at high risk of persistent albuminuria, CKD progression, and cardiovascular events despite other standard therapies [8]. Similarly, since 2022, the ADA guidelines have been included and recommended at the highest level of ns-MRA. Compared with the 2023 ADA guidelines, the 2024 ADA guidelines continue the three A-level recommendations for finerenone as a whole, and add a new A-level recommendation related to the benefits of heart failure to delay the progression of CKD and reduce the risk of cardiovascular events and HF hospitalization [9]. Finerenone is currently the only ns-MRA with conclusive evidence of cardiorenal benefit, and has little effect on serum potassium. Compared with traditional steroidal MRAs, finerenone has higher selectivity and stronger affinity for mineralocorticoid receptor (MR), which can comprehensively and efficiently block MR overactivation caused by aldosterone, directly attack the nature of inflammatory fibrosis, and delay the damage caused by renal structure and function [10].
The high level of affirmation given to up-and-comers by the 2024 KDIGO guidelines and the 2024 ADA guidelines is based on evidence-based evidence provided by two phase III clinical trials (FIDELIO-DKD and FIGARO-DKD). At a median follow-up of 2.6 years in the FIDELIO-DKD study, finerenone significantly reduced the risk of the renal composite endpoint by 18 percent, the risk of cardiovascular events by 14 percent, and the UACR by 31 percent after four months of treatment at the maximum RASi tolerated dose [11].
At a median follow-up of 3.4 years in the FIGARO-DKD study, finerenone significantly reduced the risk of cardiovascular events by 13 percent, the risk of hospitalization for heart failure by 29 percent (only 7.8 percent of the FIGARO-DKD population had a history of heart failure), the risk of a composite renal endpoint of 23 percent, and a significant reduction in UACR by 32 percent after four months of treatment [12]. In addition, both the FIDELITY study (a pooled study of FIDELIO-DKD and FIGARO-DKD) and the FIGARO-DKD study demonstrated that finerenone further reduced UACR in patients who were already on SGLT2i in addition to conventional RASi therapy [13-14] (Figure 1). This suggests that finerenone treatment can still significantly reduce massive proteinuria in patients with complex clinical treatment, and long-term use can significantly reduce the risk of sustained decline in eGFR, renal failure, and cardiovascular events.
Figure 1. In patients who have been treated with SGLT2i at baseline, finerenone can further reduce UACR
It is worth noting that the patient's hypoglycemic regimen was adjusted to metformin, empagliflozin and sitagliptin 3 years ago, and the HbA1c was 7.4% after admission, and the original hypoglycemic regimen was maintained, and the blood glucose was further improved after 2 months of finerenone treatment, and HbA1c decreased to 6.9%, which may require further analysis.
In summary, patients with T2DM-associated CKD should follow comprehensive management measures, control risk factors, and choose ns-MRA finerenone therapy with direct evidence of renal-cardiac benefit to improve the quality of life and prognosis. After 2 months of finerenone treatment, the patient's massive proteinuria was almost reduced to normal levels, and there was no significant fluctuation in serum potassium and eGFR, indicating that finerenone may be another "magic weapon" for the management of such patients. We hope that doctors can optimize clinical practice, standardize medication, and choose the best dose to ensure that patients can maximize their benefits and contribute to the promotion of global kidney health.
Expert Profile
Cai Xiaoling
Graduated from Peking University, Department of Endocrinology, Peking University People's Hospital; Chief physician, associate professor, doctoral supervisor. He is mainly engaged in the drug treatment of newly diagnosed diabetes, type 1 diabetes and obesity. Youth Committee Member of Diabetes Branch of Chinese Medical Association; Member of the Education Group of the Diabetes Branch of the Chinese Medical Association; Member of the Diabetes Branch of Beijing Medical Association; Member of the Diabetes Committee of the Chinese Association of Women Physicians; Vice Chairman of the Diabetes Prevention and Rehabilitation Committee of the Chinese Association of Rehabilitation Medicine; Vice Chairman of the Endocrinology and Metabolism Special Committee of the Smart Health Education Working Committee of the China Intelligent Engineering Research Association; Editorial Board Member of Chinese Journal of Diabetes Mellitus; Member of the Corresponding Editorial Board of the English Edition of the Chinese Medical Journal; Visiting Scholar at the University of Melbourne, Australia.
Lin Zhen
He is an eight-year doctor of clinical medicine at Peking University, an endocrinologist at Peking University People's Hospital, engaged in diabetes therapeutics, inflammation and autoimmunity-related research, and has been published as the first author or co-first author in eClinicalMedicine, Cardiovascular Diabetology, Diabetes Obesity Metabolism, Pharmacological Research, and BMC He has published more than 20 original articles in international medical journals such as Medicine, with a total of more than 200 citations. He presided over 1 Youth Cultivation Fund of Peking University Health Science Center's "Sail Plan" and 1 Special Fund for Basic Cultivation of Peking University People's Hospital.
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