A New Era Of Chronic Kidney Disease Treatment
Sep 20, 2022
Chronic kidney disease (CKD) has the characteristics of high prevalence, low awareness, poor prognosis, and high medical costs. It is another disease that seriously endangers human health in addition to cardiovascular and cerebrovascular diseases, diabetes, and malignant tumors. In recent years, the prevalence of CKD has been increasing year by year. A cross-sectional epidemiological survey in China in 2012 showed that the prevalence of CKD in people over 18 years old was 10.8%, and the number of patients was as high as 120 million [1]. With the aging of the Chinese population and the increasing incidence of diabetes, hypertension, and other diseases year by year, the incidence of CKD is also showing a rising trend [1].
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For non-dialysis CKD patients, different treatments are required according to different stages. Including but not limited to control of primary disease; use of renin-angiotensin system inhibitor (RASi) drugs (ACEI or ARB) to reduce proteinuria; treatment of complications, such as correction of acid-base imbalance, correction of renal anemia; Preparation before dialysis, the establishment of long-term vascular access, etc. However, the bottleneck of drug treatment in non-dialysis CKD patients lies in the progress of reducing eGFR, which is always a key problem to be solved urgently in the treatment process [1].
A total of 1715 patients with type 2 diabetic nephropathy and hypertension were included in the US IDNT study [2], randomized to receive renin-angiotensin system inhibitor (RASi) drugs (irbesartan, amlodipine) and placebo A dose-controlled experiment has shown that it can delay the time of entering ESRD in patients with diabetic nephropathy by about 6 months. In addition, a Bayesian network meta-analysis[3] included 564,768 CKD patients treated with RASi in 119 randomized controlled studies, with the primary endpoint being kidney failure; the results showed that RASi reduced renal function compared with placebo risk of exhaustion. However, a Japanese real-world study [4] conducted a secondary analysis of hospitalized patients with CKD stage 1-5 using RASi to assess the incidence of hyperkalemia and showed that the use of RASi drugs increases the risk of hyperkalemia in the CKD population.
The CREDENCE study[5] is a large randomized, controlled, double-blind, event-driven multicenter clinical study with renal composite hard endpoint as the primary endpoint. The study included 4401 patients with type 2 diabetes (T2DM) complicated with chronic kidney disease (CKD) Patients were treated with a daily maximum tolerated dose of a RAS inhibitor at least 4 weeks prior to randomization. The results of the study confirmed that in T2DM with CKD, canagliflozin treatment reduced the risk of renal hard endpoints (end-stage renal disease, serum creatinine doubling, renal or cardiovascular death) by 30%.
On August 30, 2022, China's National Medical Products Administration (NMPA) officially approved the first sodium-glucose cotransporter-2 (SGLT2) inhibitor dapagliflozin for the treatment of adult patients with chronic kidney disease (CKD). This is a major advance in the field of CKD treatment in more than 20 years, and it is the third approved indication for dapagliflozin in addition to the treatment of type 2 diabetes (T2DM) and heart failure (HFrEF).
The approval of dapagliflozin for the treatment of CKD is mainly based on the results of a large phase III randomized double-blind placebo-controlled study DAPA-CKD [1]: Dapagliflozin treatment reduces glomerular filtration Persistent decline in rate (eGFR), progression to end-stage renal disease (ESKD), cardiovascular (CV) death or hospitalization for heart failure (hHF), and all-cause mortality [6]. This study is a renal endpoint study evaluating SGLT2 inhibitors in CKD patients with or without type 2 diabetes.
SGLT2 inhibitors are a new class of drugs with clear evidence of renal protection after renin-angiotensin-converting enzyme inhibitors (RASi) in recent years [7]. Studies have confirmed that SGLT2 inhibitors can improve patients with type 2 diabetes. renal and cardiovascular outcomes [8]. The DAPA-CKD study assessed whether adding dapagliflozin to standard therapy for RASi was superior to placebo in reducing renal and cardiovascular risk in patients with CKD [8].
This global, multicenter, randomized, double-blind, placebo-controlled large phase III clinical study included 4304 patients with CKD (2,906 patients with diabetes-related nephropathy and 1,398 patients with non-diabetic chronic kidney disease) from 386 centers in 21 countries. The patients had an eGFR of 25-75 ml/(min·1.73 m2), a urine albumin-to-creatinine ratio (UACR) of 200-5000 mg/g, and had received a stable tolerated dose of RASi for ≥4 weeks. The primary composite endpoint of the study was a sustained decrease in eGFR ≥50%, ESKD, death from renal disease or cardiovascular causes; secondary endpoints included renal-specific endpoints (sustained decrease in eGFR ≥50%, death from ESKD or renal disease), cardiovascular endpoints (cardiovascular death) or hospitalization for heart failure), and all-cause death [6].
The DAPA-CKD study had a median follow-up of 2.4 years and was terminated early due to significant efficacy. The findings were published in the New England Journal of Medicine (N Engl J Med) in September 2020 [6]. The results of this study showed that compared with placebo, dapagliflozin treatment had significant efficacy in diabetic and non-diabetic CKD patients, delayed renal disease progression, improved renal and cardiovascular outcomes, reduced all-cause mortality, and had favorable security.
In addition, multiple prespecified subgroup analyses of DAPA-CKD further explored the role of dapagliflozin in populations with different characteristics. The results show:
① In CKD patients with or without diabetes at baseline, CKD due to different etiologies, with or without CVD at baseline, and CKD patients with different ACEi/ARB doses at baseline, dapagliflozin reduced the risk of primary and secondary endpoints, and the trend of benefit Consistent and comparable to placebo in safety [9,10].
②In 270 patients with IgA nephropathy (IgAN), dapagliflozin treatment significantly reduced proteinuria, reducing the risk of the primary endpoint by 71%, the risk of the composite renal endpoint by 76%, and the risk of progression to ESKD by 70% [11].
③ In patients with advanced CKD (CKD stage 4, eGFR<30ml/min/1.73m2), the protective effect and safety of dapagliflozin on the kidney and heart are also consistent with the trend of the benefit of the overall test population [12].
④ The efficacy and safety data of the Asian population are consistent with the benefit trend of other populations [13].
In conclusion, the DAPA-CKD study confirmed that the SGLT2 inhibitor dapagliflozin effectively delays the progression of kidney disease in CKD patients with or without diabetes, and has been confirmed by large clinical trials as a drug that can reduce the risk of all-cause mortality in CKD patients. The approval of dapagliflozin in China will bring more benefits to the majority of Chinese CKD patients.
Dapagliflozin is approved in China for the chronic kidney disease indication to reduce the risk of persistent decline in eGFR, end-stage renal disease, cardiovascular death, and hospitalization for heart failure in adult patients with chronic kidney disease at risk of progression. In CKD patients, dapagliflozin is suitable for patients with eGFR ≥ 25 mL/min/1.73m2; even if the eGFR is less than 25 mL/min/1.73m2, initial treatment is not recommended, but if the patient is taking dapagliflozin treatment, it can be Continue to take 10 mg orally once daily to reduce the risk of eGFR decline, ESKD, CV death, and hHF until dialysis* [14].
Dapagliflozin is approved in China for the treatment of adult patients with CKD. On the one hand, Dapagliflozin delays the progression of renal disease in patients with CKD. A study based on DAPA-CKD data shows that the application of Dapagliflozin can delay the entry of CKD patients. The duration of dialysis is as long as 6.6 years [15], which reduces the economic burden related to dialysis and brings tangible benefits to patients. On the other hand, dapagliflozin reduces cardiovascular adverse events and the risk of death caused by progression to ESKD, which is of great significance for improving the prognosis of Chinese CKD patients, improving the quality of life of patients, and reducing social burden. It is expected that SGLT2 inhibitors will become another sharp edge after relaying RASi in CKD management strategies.
Chronic kidney disease is dominated by drug therapy, nutritional support, and replacement therapy. For end-stage patients, replacement therapy is currently the main treatment, including hemodialysis, peritoneal transplantation, and kidney transplantation [16]. According to the different stages and stages of chronic kidney disease, individualized treatment plans should be given to prevent the occurrence of complications, including anemia, cardiovascular disease, abnormal mineral-bone metabolism, acidosis, infection, homocysteine blood, etc. CKD patients need long-term drug treatment and life adjustment. Effective treatment can prolong the survival period. It is recommended that patients have regular follow-ups with urine routine and renal function tests every year [17].
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