Kevin Fowler provides his perspective on the DAPACKD trial below
Background
Despite the fact that nearly 700 million people globally have chronic kidney disease, there has been a paucity of clinical trials. Moreover, interventional trials to slow down the progression of kidney disease have been in short supply. Until the approval of tolvaptan in 2018, the only classes of medications proven to slow decline in kidney function were angiotensin-converting-enzyme inhibitors (ACEi) and angiotensin-receptor blockers (ARBs). The majority of this evidence was established in type 2 diabetes.
Similar to the ACEi/ARBs and tolvaptan, the sodium-glucose co-transporter 2 (SGLT2) inhibitors were not designed to slow down the progression of kidney disease. Instead, they were developed to treat type 2 diabetes based upon their ability to decrease glucose levels. In 2019, the CREDENCE trial demonstrated that long-term use of canagliflozin provided not just cardiovascular but also renal protection in type 2 diabetes patients with chronic kidney disease. Thereby, providing nephrologists the opportunity to combine two medications to slow down the progression of diabetic kidney disease. Moreover, it provided a large patient population tangible hope.
Although the mechanism of SGLT2 inhibitors to preserve kidney function is not fully established, it is postulated that SGLT2 inhibitors have additional mechanism of actions that confer renal protection. Because of this hypothesis, the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) was designed to study the potential benefit of dapagliflozin in other CKD patient populations. The objective of the DAPA-CKD was to study dapagliflozin in CKD patients with or without diabetes.
Study Design
The DAPA-CKD was a randomized double-blind, placebo controlled multicenter trial. The sponsor of the global trial was AstraZenaca. The trial was conducted at 386 sites in 21 countries. Inclusion criteria included an estimated glomerular filtration rate (GFR) between 25-75. All of the study participants were required to be on either an ACE or ARB four weeks before screening. Exceptions were granted for participants who could not tolerate an ACE or ARB. Study candidates were excluded if the cause of their chronic kidney disease was polycystic kidney disease, type 1 diabetes, lupus nephritis, or antineutrophil cytoplasmic anti-body associated vasculitis. Participants were randomized to receive dapagliflozin 10mg once daily or placebo. Randomization was monitored to ensure that study participants included at least 30% CKD patients without diabetes.
The primary composite outcome was the first occurrence of any of the following:
A decline of at least 50% in the estimated GFR
The onset of End Stage Kidney Disease (ESKD)
Death from renal or cardiovascular causes
Secondary outcomes were in hierarchical order:
The composite kidney outcome of a sustained decline in the estimated GFR of at least 50%
ESKD or death from renal causes
Composite cardiovascular outcome defined as hospitalization for heart failure or death
Death from any cause
Results
A little over 4000 study participants were randomized to the DAPA=CKD trial. The mean age of the patients was 61 with a mean estimated GFR of 43.1. Approximately 2/3 of the study enrollees had type 2 diabetes with CKD. In contrast to the CREDENCE trial, approximately 1/3 of the participants had CKD without diabetes. The independent data monitoring terminated the trial prematurely because of the clear efficacy benefit in the dapagliflozin treatment arm. When the study ended, the median follow up was 2.4 years.
The primary composite outcome occurred in 9.2% of the dapagliflozin arm and 14.5% in the placebo group. Within the composite endpoint, event rates all favored the dapagliflozin treatment arm. The number of participants who needed to be treated to prevent one outcome was 19.
The incidence of each secondary outcome was lower in the dapagliflozin group than the placebo arm. The hazard ratio for the kidney composite of sustained decline was .56. The estimated GFR slopes from baseline to 30 months in the treatment arm and placebo arm were -2.86+-0.11 and -3.79+-0.11 per minute per 1.73m2 per year respectively. During the first 2 weeks there was a greater reduction in the dapagliflozin arm than with placebo (-3.97+-0.15 vs -.82+-0.15 ml per minute per 1.73 m2). From that point on the annual change in the mean GFR was smaller with dapagliflozin than with placebo (-1.67+-0.11 and -3.59+-0.11 ml per minute 1.73 m2 respectively).
Discussion
The DAPA-CKD trial was well designed in both the scope, and its attempt to understand the role of SGLT2 inhibitors beyond people with chronic kidney disease and diabetes. While the study demonstrated again the benefit of using dapagliflozin with ACEi/ARBs, it bears repeating again that the clinical utilization of ACEi/ARBs remain sub optimal in the United States. This is puzzling considering the wide and affordable access to ACEi/ARBs. None the less, the DAPA-CKD trial confirms the kidney protective benefits of SGLT2 inhibitors in CKD patients without type 2 diabetes. These results open up the possibility of studying the SGLT2 inhibitors in additional patient populations: other glomerular diseases not included in DAPA-CKD, pediatric CKD, and even kidney transplant recipients. As someone living with a kidney transplant, the possibility of clinical trials offers me hope.
The SGLT2 inhibitors in combination with ACREi/ARBs offer the opportunity to improve health equity for vulnerable patient populations such as the African American and Latinx communities. Based upon the disparities in kidney disease care, the nephrology community and the pharma manufacturers need to take an intentional community-based approach so that the concept of kidney health is advanced, and is understood by nephrology and patient communities.
The fact that DAPA-CKD was studied and safely used in GFRs below 30 challenges the concept of renalism. Renalism hangs over nephrology like a black cloud, and the results in this trial effectively disrupts the status quo. The investigators should be commended for including a GFR of 25 rather than the usual of 30 or often even higher. It is also notable that there were no cases of ketoacidosis. I find this especially encouraging to me. Last year, I participated in a Consensus Conference on SGLT2 inhibitors sponsored by the National Kidney Foundation. At that meeting, several nephrologists stated that ketoacidosis would be a barrier to adoption.
Personal Recommendations
I have listed my recommendations to the nephrology and patient community:
Clinical Trials: I would like to see the SGLT2 inhibitors studied in glomerular diseases, pediatric kidney disease, and in adult and pediatric kidney transplant recipients. There is an unmet need in all of these patient populations, and clinical trials would be welcome by all of these patient communities.
Burden of Kidney Disease: The term kidney health has been the centerpiece language describing the President’s Executive Order, Advancing American Kidney Health. Before describing the benefits of kidney health, I don’t believe the nephrology community fully understands the true physical and mental burden across the spectrum of kidney diseases. Allow me to describe one aspect to illustrate the point. While living with CKD some patients experience cognitive impairment. If this person progresses to ESKD, and then hemodialysis, it is very common for that cognition to become worse while on hemodialysis. If this same person is fortunate to survive dialysis and receive a kidney transplant, the transplant medications can make cognition worse through their neurotoxicity.
Health Equity: The SGLT2 inhibitors should be seen as a catalyst to advance health equity. To do so requires a commitment by both the nephrologists, the pharma companies, and the patients themselves to work together with a shared outcome. Namely, a future where patients in vulnerable populations have expanded patient choice, and no longer have to bear the disproportionate burden of dialysis.
Patient Voice Feature from Kevin Fowler