The 59th European Annual Conference on Nephrology (ERA-EDTA) came to an end on 22 May 2022 in Paris, France. This conference brought together many experts and scholars in the field of nephrology to talk about the latest research progress and diagnosis and treatment plan optimization of kidney disease.
Since the DAPA-CKD study published in 2020, the sodium-glucose synergistic transporter 2 (SGLT2) inhibitor dapagliflozin has become a bright star in the field of chronic kidney disease (CKD), the clinical response has been enthusiastic. However, there are also some confusions in clinical practice, and the post-mortem analysis of two DAPA-CKD studies published at the ERA-EDTA Annual Meeting answers two common clinical confusions: Is the benefit of dapagliflozin in patients with CKD partly attributed to the background of the application of angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor antagonists (ARBs)? How much is it safe to have transient estimation of a decrease in glomerular filtration rate (eGFR) at the beginning of dapagliflozin application? Professor Fu Ping of West China Hospital of Sichuan University was invited to interpret the two latest studies released at the conference. This article collates the research essentials and shares them with readers!
Expert Profiles
Professor Fu Ping
Director of the Department of Nephrology, West China Hospital, Sichuan University
Director of West China Institute of Nephrology
PhD/Postdoctoral Co-Supervisor
8.9.10 Standing Committee Member of the Nephrology Branch of the Chinese Medical Association
Member of the Standing Committee of the Nephrology Branch of the Chinese Medical Doctor Association
Member of the Standing Committee of the Blood Purification Center Management Branch of the Chinese Hospital Association
Chairman of the Chinese Medicine Development Research Committee for Kidney Disease of The Chinese Materia Medica Association
Vice President of the World Association of Chinese Nephrologists
Vice Chairman of the Integrative Medicine Nephrology Branch of the Chinese Medical Doctor Association
Member of the Standing Committee of the Nephrology Prevention and Control Branch of the China Association for the Promotion of Medical Exchanges
Member of the Standing Committee of the Dialysis Committee of Kidney Disease of the China Association of Non-public Medical Institutions
Former and alternate chairman of the Nephrology Committee of Sichuan Medical Association
Former and elective president of the Nephrologist Branch of Sichuan Medical Doctor Association
Chairman of the Nephrology Committee of sichuan Association for the Promotion of International Medical Exchanges
International Nephrologist (ISN Scholar)
He is a member of the editorial board of 23 journals, including the English Edition of the Chinese Medical Journal
The benefits of dapagliflozin are not affected by the background of RASI applications
Randomized, placebo-controlled, double-blind DAPA-CKD studies[1] have demonstrated that in patients with CKD with or without type 2 diabetes mellitus (T2DM), the dapagliflozin group significantly reduced the risk of developing a CKD patient with or without T2DM compared with a placebo group compared with a 39% risk of end-stage renal disease (ESKD), renal death, or cardiovascular death based on renin angiotensin system blocker (RASI) compared with placebo group.[a sustained decline in eGFR ≥50%, end-stage renal disease (ESKD), kidney death, or cardiovascular death] (P<0.001), and this benefit was present regardless of whether the patient had type 2 diabetes or not. In terms of secondary endpoints, the risk of renal complex endpoints (≥50% decrease in eGFR, ESKD, renal death) was significantly reduced by 44% (P<0.001), the risk of hospitalization for cardiovascular death/heart failure was 29% (P=0.009), and the risk of all-cause death was 31% (P=0.004) compared with the placebo group.
RASI is a commonly used clinical treatment for CKD, ACE and ARB have antihypertensive and renal protective effects independent of antihypertensive. ACEI or ARB are recommended for patients with CKD with 30 to 300 mg/day of urinary albumin and diabetes mellitus. When urinary albumin > 300 mg/day, ACEI or ARB is recommended for patients with CKD, regardless of whether diabetes mellitus is present or not[2].
The benefits of dapa-CKD studies shown to have been obtained on the background therapy of RASI, so is the benefit of dapagliflozin still true when not combined with RASI or when using low-dose RASI? The research data [3] released at the ERA-EDTA Annual Meeting attempts to answer this question. The study conducted a post-event analysis of the DAPA-CKD study, with an analysis of the timing of the event based on baseline prescription and ACEI or ALB treatment dose. In the DAPA-CKD study, 4296 (99.9%) subjects had available ACEI/ARB dose data, 1231 (28.7%) received the target dose ("target dose") drug, 1867 (43.5%) received ≥50% to 100% of the target dose <, 1068 (24.9%) received a target dose of 0 to <50%, and 130 (3.0%) did not apply ACEI/ARB.
The results of the analysis showed that in the placebo group, subjects who did not use ACEI/ARB had the highest risk of primary outcome event (Figure 1), which is consistent with previous cognition that the risk of CKD without ACEI/ARB treatment was higher than that of receiving ACEI/ARB.
More importantly, the benefits of dapagliflozin for primary compound outcomes were consistent with or without the use of the target dose of ACEI/ARB. Secondary results maintain this consistency (Figure 1). Compared with placebo, dapagliflozin changed the downward trend of eGFR to 0.93 ml/min/1.73 m2 [95% confidence interval (CI) 0.61 to 1.25]. This effect was present with or without the use of the target dose of ACEI/ARB (interaction P= 0.877). It can be seen that regardless of the use or dosage of ACEI/ARB, dapagliflozin is equally effective in reducing the main adverse renal and cardiovascular outcomes in subjects with CKD.
In the DAPA-CKD study, dapagliflozin has been shown to have a benefit in reducing the risk of cardio-renal events and all-cause death in patients with CKD, and this study further suggests that the benefits of patients are not changed by ACEI/ARB background therapy: for patients with CKD who have received ACEI/ARB therapy, dapagliflozin can further reduce the risk of cardiac and kidney events; more importantly, for some patients with CKD who cannot tolerate ACEI/ARB therapy, The emergence of dapagliflozin provides patients with another cardioprotective drug option that breaks through the mechanism. In addition, the lower eGFR limit of patients included in the DAPA-CKD study is 25 ml/min/1.73 m2, and perhaps we can expect that in the future, patients with moderate and severe renal impairment can also benefit from treatment with this drug, delaying the progression to renal failure.
Figure 1 The benefits of dagliflozin are not affected by the context of ACEI/ARB applications
There is no need to worry about a transient reduction in renal function eGFR at the beginning of the drug, and the safety of dapagliflozin has been re-verified
Some clinicians, especially primary physicians, often have some misunderstandings, and some believe that dapagliflozin cannot be applied when renal function eGFR is reduced, which the DAPA-CKD study has given solid evidence that patients with CKD (eGFR> 25 ml/min/1.73 m2) can also use dapagliflozin. Another group of physicians, when there is a transient renal function eGFR decrease (elevated serum creatinine) in the short term after the application of dapagliflozin, directly choose to discontinue dapagliflozin, so that patients with CKD who have already received cardiac and renal protection suddenly lose the cardionephrenic effect. Admittedly, some patients will experience a transient reduction in eGFR after initiation of treatment, so to what extent is it safe to reduce it? Will it lead to serious consequences? Another pre-programmed secondary analysis of the DAPA-CKD study presented at the ERA-EDTA Annual Meeting [4] answered this question.
In this pre-programmed secondary analysis, the correlation between changes in the acute phase of eGFR (from baseline to week 2 of treatment) in the DAPA-CKD study was analyzed in the dapa-CKD study in the primary and secondary stages, and the effect of changes in the acute phase of dapagliflozin and placebo eGFR on primary and secondary endpoint outcomes was assessed.
The results of the analysis showed that a significant acute reduction in eGFR was independently associated with an increased risk of primary and secondary endpoint outcomes in randomly assigned to placebo, but not in both the dagliflozin group and primary and secondary endpoint outcomes were not associated with an increased risk (Figure 2).
Figure 2 Acute decrease in dapagliflozin eGFR is not associated with an increased risk of primary and secondary endpoint outcomes
In patients with CKD treated with dapagliflozin, an acute decline in eGFR from baseline to week 2 of treatment was associated with a lower rate of CKD progression. In the placebo group, an acute decrease in eGFR was associated with a higher rate of CKD progression. In addition, an acute decline in eGFR was not associated with an increased risk of adverse events.
DAPA-CKD results[5] show that eGFR reaches its lowest point 2-4 weeks after initiation of treatment with dapagliflozin, followed by a slow rise in eGFR recovery, eGFR begins to stabilize gradually after 2 to 4 months, and then eGFR declines consistently slower than in the placebo group. Transient decrease in eGFR associated with dapagliflozin may be related to its hemodynamic changes (tube-ball feedback mechanism). The new study suggests that a transient eGFR decline in renal function after medication, as long as the eGFR decline is within 30% (such as the secondary analysis preset by the DAPA-CKD study), it is safe and effective, and there is no need to worry about medication.
Summary:
The benefit of dapagliflozin to patients with CKD has been confirmed by a number of studies, era-EDTA newly released research suggests: the benefit of dapagliflozin in CKD population is not affected by ACEI / ARB background drugs; even if there is a transient eGFR decline in the short term after initiation, there is no need to worry, as long as within a reasonable range (a decrease of <30%), the safety and efficacy of the drug are still guaranteed, and long-term application can make the heart and kidney of CKD patients get long-term protection.
A few years after its marketing, the SGLT2 inhibitor dapagliflozin has become a treatment for three major categories of diseases, including type 2 diabetes, heart failure, and chronic kidney disease, and even a preventive drug to reduce the onset of new diabetes with CKD [6-8]. It is believed that with the continuous disclosure of research, dapagliflozin will become the preferred cardioprotective drug for patients with CKD.
bibliography
[1] Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020, 383(15): 1436-1446.
Shanghai Chronic Kidney Disease Early Detection and Standardized Diagnosis and Treatment and Demonstration Project Expert Group. Guidelines for the Screening, Diagnosis and Prevention of Chronic Kidney Disease. CJT, 2017, 37(1): 28-34.
[3] ERA-EDTA 2022.Effects of dapagliflozin in patients with chronic kidney disease according to background angiotensin-converting enzyme inhibitor and angiotensin receptor blocker dose.
[4] ERA-EDTA 2022. Correlates and consequences of an acute change in eGFR in response to the SGLT2 inhibitor dapagliflozin in patients with chronic kidney disease.
[5] ProfHiddo J L Heerspink，Niels Jongs，Prof Glenn MChertow, et al, Effect of dapagliflozin on the rate of decline in kidney function in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial，The Lancet Diabetes & Endocrinology (2021) doi：10.1016/S2213-8587(21)00242-4.
[6] Peter Rossing, et al, . Dapagliflozin and new-onset type 2 diabetes in patients with chronic kidney disease or heart failure: pooled analysis of the DAPA-CKD and DAPA-HF trials. Lancet Diabetes Endocrinol. DOI: https://doi.org/10.1016/S2213-8587(21)00295-3.
[7] Adapted from Heidenreich PA et al. Central Illustration. Online ahead of print. J Am Coll Cardiol. 2022.
[8] FDA/EMA dipagliflozin specification.