Dapagliflozin cuts renal, CV events in CKD, regardless of diabetes status
Click Here to Manage Email Alerts
In the DAPA-CKD trial, treatment with the SGLT2 inhibitor dapagliflozin reduced risk for worsening renal function and death due to CVD or renal disease in patients with chronic kidney disease, both with and without type 2 diabetes.
“The DAPA-CKD trial has shown dapagliflozin’s potential as a long-awaited new treatment option for patients with chronic kidney disease,” Hiddo J.L. Heerspink, PhD, clinical pharmacologist in the department of clinical pharmacy and pharmacology at University Medical Center Groningen, Netherlands, said during a press conference at the European Society of Cardiology Congress.
During a median follow-up of 2.4 years, the primary composite endpoint of worsening renal function — defined as at least a 50% sustained decline in estimated glomerular filtration rate or onset of end-stage renal disease — or death due to renal disease or CVD was reduced by 39% with dapagliflozin 10 mg (Farxiga, AstraZeneca) compared with placebo (HR = 0.61; 95% CI, 0.51-0.72). Heerspink reported 197 primary endpoint events in the dapagliflozin group vs. 312 events in the placebo group.
More than 67% of patients in DAPA-CKD had diabetes at baseline. The effect of dapagliflozin on the primary endpoint was consistent in patients either with (HR = 0.64; 95% CI, 0.52-0.79) or without (HR = 0.5; 95% CI, 0.35-0.72) type 2 diabetes, Heerspink said during the Hot Line presentation. The effects were also consistent in prespecified subgroup analyses based on urinary albumin creatinine ratio and eGFR at baseline.
In addition, dapagliflozin reduced all three secondary endpoints compared with placebo:
- 44% reduction in worsening renal function or death from renal failure (HR = 0.56; 95% CI, 0.45-0.68).
- 31% reduction in all-cause mortality (HR = 0.69; 95% CI, 0.53-0.88).
- 29% reduction in HF hospitalization or CV death (HR = 0.71; 95% CI, 0.55-0.92).
In addition, Heerspink said dapagliflozin also significantly reduced the prespecified clinically meaningful and patient-oriented endpoint of chronic dialysis, kidney transplantation or renal death.
As Healio previously reported, DAPA-CKD was stopped early in March after investigators reported an “overwhelming benefit” for the primary outcome.
The safety and tolerability of dapagliflozin was consistent with its established profile, he said. Discontinuation of treatment due to an adverse event occurred in 5.5% of the dapagliflozin group vs. 5.7% of the placebo group. The proportion of patients that experienced a serious adverse event was 29.5% with dapagliflozin vs. 33.9% with placebo. Diabetic ketoacidosis was not reported in any patient assigned dapagliflozin, and there were no reports of diabetic ketoacidosis or severe hypoglycemia in patients with diabetes, Heerspink said.
“Last year, we did this [trial] in HF. We now demonstrate similar effects, but in people with chronic kidney disease,” he said during the Hot Line presentation.
The phase 3 DAPA-CKD trial enrolled 4,304 patients at 386 centers in 21 countries. The average age was 62 years and 67% were men. At baseline, all patients had an eGFR 25 and 75 mL/min/1.73 m2, had a urinary albumin creatinine ratio of 200 mg/g to < 5,000 mg/g and were already receiving stable, maximum-tolerated background therapy with an ACE inhibitor or angiotensin receptor blocker for at least 4 weeks.
In May, dapagliflozin was approved by the FDA to reduce risk for CV death and hospitalization for HF in adults with HF with reduced ejection fraction (HFrEF), with and without type 2 diabetes. Dapagliflozin is currently being assessed in patients with HF with preserved EF (HFpEF) in the DELIVERY trial, in patients with both HFrEF and HFpEF in the DETERMINE trial and in patients without type 2 diabetes following an MI in the DAPA-MI trial, according to a press release from AstraZeneca.
Perspective
Back to Top
Janani Rangaswami, MD, FACP, FCRS, FAHA
This trial shows the clear benefits with the SGLT2 inhibitor: a 39% relative risk reduction with respect to reducing the progression of chronic kidney disease, reaching end-stage kidney disease and reduction in kidney and CV deaths.This is importantly an incremental benefit in a population with very high use of current standard-of-care therapies to slow down kidney disease progression, ie, 97% use of ACE inhibitors/angiotensin receptor blockers. We now have a therapy available that slows down CKD progression after 2 decades of lack of newer effective therapies outside the use of ACE inhibitors/angiotensin receptor blockers, BP control and, in patients with diabetes, achieving targets for glycemic control.
The median eGFR of 43 cc/min in this trial and albumin/creatinine ratio of 1 g are very representative of the type of patients seen in a general nephrology practice. The results are also consistent with CREDENCE, which showed similar benefits but in patients with exclusively diabetic kidney disease. The signal for benefit is also consistent with the kidney results from other CV outcome and HF trials, eg, prespecified endpoints from the DAPA-HF and EMPEROR-Reduced trials and post hoc analyses from the CV outcome trials for the first three SGLT2 inhibitors approved by the FDA.
This class of agents changes the landscape of what constitutes standard of care in patients with CKD regardless of underlying diabetes status . In addition to the kidney benefits shown, there is a very relevant benefit of reduction of HF burden, which is a dominant phenotype of CVD in CKD. It is also important to note that patients with lower eGFR all the way down to 25 cc/min were enrolled in DAPA-CKD, and the drug was continued to the point patients reached the need for dialysis. The adverse event profile is overall reassuring, with no significant differences between treatment and placebo arms that would raise concerns for safety. Notably, there were no patients with diabetic ketoacidosis, which is one of the feared complications.
We are now approaching a place where there are high-quality data showing benefits for reduction in adverse CV and kidney events with the SGLT2 inhibitors, as well as other drug classes in this space. However, there remains a major implementation gap with ensuring that high-risk patients appropriately get access to these therapies, and several barriers exist in clinical practice that fuel this trend. It is extremely important to ensure we translate the science into practice as soon as possible and all efforts to implement multidisciplinary cardiorenal metabolic care models to achieve these goals are imperative at this time.
In addition to the SGLT2 inhibitors, other newer agents with cardiorenal benefits such as the GLP-1 receptor agonists as well as newer nonsteroidal mineralocorticoid receptor antagonists such as finerenone (Bayer) are also of big impact in the cardiorenal metabolic space. There are exciting prospects for implementing personalized medicine using combinations of these agents to achieve best outcomes in patients with high cardiorenal risk.
Perspective
Back to Top
Vivek Bhalla, MD, FASN, FAHA
In addition to what Dr. Rangaswami said, another important takeaway from DAPA-CKD and other trials of SGLT2 inhibitors is that they clearly showcase the importance of basic science research to clinical benefits and the interplay between bench and bedside research. Basic research in how glucose was handled in the kidney eventually led to our understanding of SGLT2, and then inhibitors were developed. These drugs have now shown benefits that many were not expecting when glucose transport pathways were first elucidated. Now, we have to take what we have learned at the bedside, to go back to the bench, to understand more about how these drugs are working.
These recent trials, showing lack of appreciable changes in glycemic control, and now, benefit in patients without diabetes, indicate that the mechanisms for the benefits of SGLT2 inhibitors require further exploration. Is energy utilization the primary benefit of SGLT2 inhibitors? Are the benefits to reduction of CV events independent of benefits to kidney function? Not everyone with the same exposure, whether its diabetes or another factor, develops kidney disease. Are differences in energy utilization a key difference between why some people get kidney disease and others do not? Are there other mechanisms at play?
Collapse
Heerspink H. Hot Line: DAPA-CKD. Presented at: European Society of Cardiology Congress; Aug. 29-Sept. 1, 2020 (virtual meeting).
Read more about
Click Here to Manage Email Alerts