Dapagliflozin is a Potential Treatment Option for Chronic Kidney Disease Patients

DAPA-CKD trial results indicate a significant benefit for SGLT2 inhibitor dapagliflozin in reducing chronic kidney disease progression and mortality caused by kidney failure and cardiovascular disease, regardless of diabetes status.  

Diabetes is a progressive disease that can lead to chronic kidney failure and cardiovascular complications if poorly controlled. Medication management is implemented for a diabetes patient to help reduce these unwanted, adverse events. Angiotensin-converting enzyme inhibitor (ACEI) and angiotensin-receptor blocker (ARB) has been the mainstay therapy for diabetes patients to reduce vascular resistance. Ultimately, these treatments improve renal function, heart failure, and hypertension. Another treatment, dapagliflozin, has shown promising results in the DAPA-CKD trial, which would enhance glucose levels, slow down the progression of kidney failure, and reduce kidney and cardiovascular death. Hiddo J.L Heerspeek, Ph.D., a clinical pharmacologist, stated during the European Society of Cardiology congress that the DAPA-CKD trial had shown dapagliflozin to be a potential long-awaited new treatment option for patients with chronic kidney disease. The FDA approves AstraZeneca’s dapagliflozin to treat heart failure with reduced ejection fraction (HFrEF) for patients with or without diabetes. This treatment can help many patients with type 2 diabetes, reducing hospital stay due to heart failure and improving their quality of life.  

The DAPA-CKD trial was a double-blinded placebo-controlled study that enrolled 4,304 patients. The average participant age was 61.8 years old, and they were recruited from 386 centers spanning 21 countries. The participants all had an estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73m2, urinary albumin to creatine ratio (UACR) >200 with the median eGFR of 43.1ml/min/1.73 m2 and UACR of 949mg/g. Also, participants were randomized to receive dapagliflozin 10mg daily or a placebo. 4174 patients (97%) received an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, 1882 (43.7%) diuretics, 229 (5.3%) mineralocorticoid receptor antagonist, and 122 (2.8%) glucagon-like peptide 1 receptor agonist. There was a total of 2,906 (68%) patients who had type 2 diabetes. Also, this trial enrolled participants whose chronic kidney disease was not caused by diabetes.  

The median follow-up was 2.4 years. The primary composite endpoint was indicated as the worsening of kidney function, sustained a >50% decline in eGFR, event of end-stage kidney disease, and death due to cardiovascular or renal disease. 197 patients had primary endpoint with dapagliflozin and 312 with placebo. A 39% reduction in death due to CVD or renal disease in the dapagliflozin group and hazard ratio for the primary endpoint was 0.61 (95% CI 0.51–0.72) compared with placebo. The results were compatible with both the patients with and without diabetes. Also, dapagliflozin successfully reduced all three secondary endpoints compared to the placebo. First, a 44% reduction in worsening renal function or death from renal failure (HR=0.56, 95% CI 0.45–0.68). Second, a 29% reduction in HF hospitalization or CV death (HR=0.71, 95% CI = 0.55-0.92). Finally, a 31% reduction in all-cause mortality (HR=0.69, 95% CI 0.53-0.88) was achieved. Due to its rapid, outstanding results, this trial was concluded before its anticipated end date due to the massive benefits shown in the primary outcome when using dapagliflozin. The SGLT2 agent has been shown to decrease cardiorenal risk, and it can be used as an alternative agent for chronic kidney disease patients regardless of diabetes status. Dapagliflozin was discontinued due to an adverse event in 5.5% of the dapagliflozin group and 5.7% of the placebo. Also, 29.5% in dapagliflozin and 33.9% with a placebo experienced a serious adverse effect. There was no ketoacidosis among any participants in the trial.  

This data shows promising results for using SGLT2 drug dapagliflozin to reduce adverse kidney and CV events. Dapagliflozin can be an alternative for patients using an ACE inhibitor and ARB therapy. This is a new treatment option for chronic kidney disease patients who have an increased chance of developing cardiovascular adverse events. Dapagliflozin continues to be assessed in the DELIVERY trail, DETERMINE trial, and DAPA-MI trail to analyze further the impact that it can have on cardiovascular disease. 

Practice Pearls:  

• Patients achieved a 39% relative risk reduction in mortality due to CVD or renal disease using dapagliflozin.  
• Dapagliflozin proved beneficial in reducing adverse CV and kidney events in patients with CKD, regardless of diabetes status. 
• The primary endpoint of lower eGFR, renal disease, and cardiovascular-related death was coherent for patients with and without diabetes.   

Wheeler, David C, et al. Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) Trial: Baseline Characteristics. August 30, 2020, academic.oup.com/ndt/advance-article/doi/10.1093/ndt/gfaa234/5899227.  

DAPA-CKD Trial Meets Primary Endpoint in Patients with Chronic Kidney Disease.   www.escardio.org/The-ESC/Press-Office/Press-releases/DAPA. 

Aleksandra Kusic, PharmD Candidate, Florida A&M University, College of Pharmacy and Pharmaceutical Sciences