Spain
Spain (España)
Leave it to La Furia Roja to assemble a powerhouse squad for The Tournament. Despite having won only one World Cup, Spain has appeared in sixteen (16) of twenty-two (22) World Cups (73% qualification rate). This year's NephroWorldCup equipo combines two of the most impactful developments in cardiovascular, renal, and metabolic disorders (CVRM): SGLT2 inhibitors and mineralocorticoid receptor antagonists (MRA). A combination that only Spain could pull off.
In the last five (5) years the CVRM space has seen an explosion in positive results from both SGLT2i and MRAs (Figure 1). These trials have led many to wonder how best to utilize these agents: alone (and in what sequence) or in combination. This year's Spanish squad, ROTATE-3, tries to answer this question (Videos 1 and 2).
Figure 1: CREDENCE v FIDELIO-DKD v DAPA-CKD | Courtesy of Dr. Rajesh Raj (zoom in for details)
La Furia Roja starts us off in an open-label randomized crossover trial. Nearly forty-six (46) patients with moderate CKD (eGFR 31-89 mL/min/1.73 square-meter) and albuminuria (100-3500 mg/24h) were randomized to either:
dapagliflozin 10 mg daily, or
eplerenone 50 mg daily, or
both
All patients were on stable doses of either ACE inhibition or ARB therapy. Each treatment was administered for four (4) weeks, followed by a four (4) week washout period before moving onto the next arm. The primary outcome was the change in albuminuria from baseline values (Figure 2).
Figure 2: Summary of the ROTATE-3 trial | Courtesy of the Journal of the American Society of Nephrology
Figure 3: Odds ratios of the three treatment arms on albuminuria | Courtesy of Dr. Irwing Benites (zoom in for details)
With both dapagliflozin or eplerenone monotherapy, albuminuria at four (4) weeks decreased by 19.6% and 33.7%, respectively. The combination of both resulted in an impressive 53.0% reduction. And once all medications were discontinued, albuminuria increased. Perhaps most interesting, the odds ratio of a ≥ 30% reduction on albuminuria with combination therapy was 4.5 compared to eplerenone alone; 3.4 for dapagliflozin versus eplerenone alone (Figure 3). Those odds ratios remained similar for ≥ 50% albuminuria reduction as well (Figure 3).
Spain puts forth a significant effort that goes far, but not far enough. The question of which option is best for controlling moderate, albuminuric CKD (SGLT2i alone, MRA alone, or both) is clarified but not fully answered. Using the surrogate marker of albuminuria, the combination of SGLT2i and MRA is better than either alone. Unfortunately, the combination of a surrogate endpoint with a short interval (four weeks) in a small cohort of patients (N < 50) and using eplerenone as a comparator (instead of the non-steroidal MRA finerenone) limit La Furia Roja's impact (Carousel 1).
Carousel 1: CONFIDENCE trial design | Courtesy of Dr. Alfonso Valle (click enter full screen for details)
Videos 1 (EN) and 2 (ES): The ROTATE-3 trial | Courtesy of Dra. Maria Soler and Beatriz Fernandez