See How SGLT2i Promotes Changes in The Treatment Pattern Of CKD Patients

Chronic kidney disease (CKD) has become a major disease threatening public health worldwide. Studies have shown that the incidence of CKD is increasing year by year, and due to factors such as the hidden onset of CKD, low rate of early consultation and treatment, and many complications[1], it has brought a heavy burden to individuals, families, and society.

Click to "genghis khan cistanche" and Chronic kidney disease 

In recent years, with the gradual deepening of the understanding of CKD, various treatment methods and innovative drugs have come out one after another, and various related types of research have been gradually carried out, which has promoted CKD treatment to continuously make new progress and breakthroughs, and also brought CKD patients. More hope and opportunity.

In this context, the medical community is particularly honored to invite academician Liu Zhihong of the Chinese Academy of Engineering to conduct in-depth interviews on CKD treatment ideas and management and other related topics and share unique insights and valuable clinical experience.

Academician Liu Zhihong

Academician of the Chinese Academy of Engineering, professor, doctoral supervisor

Member of the Chinese Academy of Medical Sciences

Director of the National Kidney Disease Clinical Research Center of the Eastern Theater General Hospital

Dean of Zhejiang University School of Medicine

Executive Director of the Council of the Chinese Medical Association

Chairman of the Ninth Session of the Nephrology Branch of the Chinese Medical Association

Chief Scientist of the National "973" Program

Chief Scientist of the National "Precision Medicine" Key R&D Program

Executive Director of the International Society of Nephrology (ISN)

Q1 As we all know, CKD has the characteristics of high morbidity, low awareness rate, and intractability, which brings a heavy burden to global social health and the economy. At the same time, CKD progresses slowly and is a disease caused by multiple factors and multiple causes. Based on your many years of clinical experience, what do you think are the main challenges in the management of CKD?

As a global health problem, CKD remains poorly understood despite its high prevalence and high clinical and economic burden of associated complications. The reason is that the early clinical manifestations of CKD are mostly asymptomatic [2]. Therefore, improving patients' awareness of the occurrence and development of CKD is crucial for early intervention and improved prognosis.

CKD presents enormous challenges in its management. First of all, in the early stage of CKD, factors such as hypertension and diabetes can cause damage to renal function, resulting in glomerular/interstitial damage, impaired glomerular filtration, and reduced glomerular filtration rate (GFR) and increased proteinuria [3]. Even in the absence of clinical symptoms at this stage, multiple risk factors, as well as immune-related diseases, can accelerate the progression of CKD and lead to the development of end-stage kidney disease (ESKD). In addition, as the disease progresses, patients may also develop related complications such as renal anemia[4] and hypertension[5], which greatly increases the clinical burden of CKD. Not only that, but the management of CKD requires a lot of medical resources, which highlights the importance of optimizing CKD management.

Finally, the 2022 KDIGO clinical practice guidelines pointed out that for CKD patients, it is extremely important to slow down the progression of kidney disease, avoid the development of ESKD, and reduce the risk of cardiovascular death [6]. From the current point of view, clinical diagnosis and treatment methods in this area are still relatively limited, so breakthroughs in innovative drugs are urgently needed.

Q2 In recent years, as more pathways that play a key role in the progression of CKD have been discovered, new promising therapeutic approaches have emerged. How do you feel about these drugs?

The pathogenesis of CKD is complex and requires multiple treatments. In addition to diet and lifestyle adjustments, the birth of new drugs has also provided the latest evidence for CKD treatment and long-term cardiorenal protection and has also brought more options for CKD patients.

First of all, renin-angiotensin-aldosterone system inhibitors (RAASi) have been widely used in CKD patients in recent years, including angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor antagonists ( ARB). RAASi may cause hyperkalemia during treatment, and due to the limitation of renal function, patients often have difficulty reaching the target dose or even stopping treatment [7]. In addition, non-steroidal mineralocorticoid receptor antagonists (MRA) can protect the heart and kidney through anti-inflammatory or anti-fibrotic mechanisms, which is an effective supplement to RAAS inhibitors, but the current application is only limited to CKD patients with diabetes mellitus [8].

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) is a rising "star" in the field of kidney disease in recent years. As a new type of hypoglycemic drug, it has multiple functions such as hypoglycemic, weight loss, antihypertensive, and kidney protection [9]. Not only that, the clinical research of SGLT2i has been extended to the non-diabetic population and has achieved success one after another. In the recently published Empagliflozin EMPA-KIDNEY study [10], the non-diabetic kidney disease population accounted for more than half, and China played a leading role in the recruitment and data collection of the research population, which also shows that my country has a high incidence of kidney disease. Significant status and contributions in the field of research.

Q3 From November 3 to 6, 2022, the ASN 2022 high-impact clinical trial section announced the results of the EMPA-KIDNEY study, which were simultaneously published in the New England Journal of Medicine. What do you think of this research?

According to current treatment guidelines, for non-diabetic CKD patients with proteinuria, ACEI/ARB and/or SGLT2i can be used alone or in combination to improve the prognosis of patients [11]. For CKD patients without proteinuria, previous studies have not been involved. Therefore, in the current treatment, ACEI/ARB or SGLT2i are usually only used in CKD patients with proteinuria [12,13].

The EMPA-KIDNEY study is a large-scale randomized, double-blind, placebo-controlled trial, which for the first time included CKD patients without proteinuria, accounting for 20% of the overall study population, and nearly half of the study population included normal to microalbuminuria patients. In addition, this study for the first time lowered the inclusion criteria to CKD patients with eGFR>20mL/min/1.73㎡, and the primary endpoint was renal disease progression (end-stage renal disease, eGFR continued to decline to <10mL/min/1.73㎡, renal death or a continuous decline in eGFR ≥ 40% after randomization) or a composite endpoint of cardiovascular death.

The results showed that compared with the placebo group, the risk of renal disease progression or cardiovascular death in the empagliflozin group was significantly reduced by 28% (HR 0.72, 95% CI 0.64-0.82, P<0.001), and the rate of all-cause hospitalization was higher than that of the placebo group. The dose group significantly decreased by 14% (HR 0.86, 95%CI 0.78-0.95, P=0.003). In addition, for patients with normal or microalbuminuria, empagliflozin can delay the decline rate of eGFR, confirming the renal protective effect in such patients. In terms of safety, the results of this study showed that the overall safety of empagliflozin in the treatment of CKD patients was good, consistent with the safety characteristics shown in previous clinical studies, and no new safety signals were found [10].

Compared with previous clinical studies, EMPA-KIDNEY has three major breakthroughs in the patients selected: First, nearly half of the patients with normal or microalbuminuria (UACR<300 mg/g) are included. Such patients usually progress slowly in CKD, so it is difficult to Differences in renal events were observed during the follow-up period, but the study found that Empagliflozin could significantly delay the rate of eGFR decline; second, a higher proportion and larger number of non-diabetic CKD patients were included; third, lower eGFR was included level (lower limit of eGFR 20 mL/min·1.73 ㎡]), more patients with stage 4 CKD.

In my opinion, EMPA-KIDNEY, the largest clinical trial evaluating SGLT2i's cardiorenal protection in CKD patients with the largest scale and broadest inclusion criteria, is a very important milestone. It improves the treatment prospects of more CKD patients for SGLT2i and avoids Progression to dialysis providing stronger evidence support.

Q4 With the release of this study, could you please talk about the value of the preset endpoint of the eGFR slope?

Selecting an appropriate renal replacement endpoint is of great significance for optimizing the design of clinical trials of renal disease. Traditional renal endpoints usually include ESKD and albuminuria, which is widely recognized and used. However, ESKD usually requires decades of follow-up, or the selection of patients with rapid disease progression/advanced CKD to achieve research purposes, which is greatly limited in application. The generation of albuminuria is affected by many factors. The progress of CKD and proteinuria are not completely in parallel, and the increase of urinary albumin does not necessarily lead to renal failure. Therefore, the value of albuminuria as a renal endpoint in clinical trials there is controversial.

At the same time, renal function decline is also considered a major endpoint event, such as eGFR decline of 30%, 40%, 57%, etc., but this indicator has limited application value in people with high baseline GFR.

In view of the shortcomings of the above research endpoints, in 2018, the National Kidney Foundation (NKF), the US Food and Drug Administration (FDA), and the European Medicines Agency (EMA) co-sponsored a study aimed at reducing urinary albumin Changes in creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) were used as endpoints in early CKD clinical trials.

The findings suggest that urinary albumin-to-creatinine ratio (UACR) can also be used as a reliable surrogate endpoint in CKD-related clinical trials, but only in diseases characterized by elevated proteinuria, or to evaluate interventions whose primary mechanism of action is to reduce proteinuria measures, so the practical use is limited. For eGFR, when treatment measures have no acute effect on GFR, eGFR slope can be used as an effective surrogate endpoint to evaluate the treatment effect of CKD, which can reduce the need for study follow-up time and sample size. However, in the initial stage of treatment, acute effects may affect the eGFR slope, so it is necessary to comprehensively consider the acute eGFR slope, chronic eGFR slope, and total eGFR slope, as well as the reversibility of the acute eGFR effect before and after treatment [14].

Summary

CKD is a common disease that poses great harm to human health. With the in-depth study of the pathogenesis of CKD, more and more key pathways have been discovered, providing new ideas and methods for the treatment of CKD. Among them, SGLT2i, represented by Empagliflozin, has promoted the transformation of CKD treatment concepts by virtue of EMPA-KIDNEY research and other heavy evidence. At the same time, eGFR slope as a surrogate endpoint also fills the gap in assessing the impact of early intervention in CKD and promotes the development of clinical practice, research, and public health in kidney disease. I believe that with the acceleration of new drug development and research for CKD in the future, we can better treat and manage CKD so that more patients can be helped.

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