Albuminuria-Lowering Effect of Dapagliflozin, Eplerenone, and Their Combination in Patients with Chronic Kidney Disease: A Randomized Crossover Clinical Trial. Issue 8 (August 2022)

• Record Type: Journal Article
• Authors: Provenzano, Michele; Puchades, Maria Jesús; Garofalo, Carlo; Jongs, Niels; D'Marco, Luis; Andreucci, Michele; De Nicola, Luca; Gorriz, Jose Luis; Heerspink, Hiddo J.L.
• Other Names: author non-byline.; Pennino Luigi author non-byline.; De Gregorio Ilaria author non-byline.; Polese Lucio author non-byline.; Caturano Alfredo author non-byline.; Minutolo Roberto author non-byline.; Sasso Ferdinando author non-byline.; Gagliardi Ida author non-byline.; Zicarelli Mariateresa author non-byline.; Crugliano Giuseppina author non-byline.; Civera Elena Gimenez author non-byline.; Panizo Nayara author non-byline.; Sen Taha author non-byline.; Xie Di author non-byline.
• Is Part Of: Journal of the American Society of Nephrology. Volume 33:Issue 8(2022)
• Page Start: 1569
• Page End: 1580
• Publication Date: 2022-08
• Subjects: albuminuria -- aldosterone -- chronic kidney disease -- randomized controlled trials -- sodium glucose co transporter -- mineralocorticoid receptor antagonist -- dapagliflozin -- eplerenone
• DOI: 10.1681/ASN.2022020207
• Languages: English
• ISSNs: 1046-6673

Abstract

Significance Statement: In this randomized crossover clinical trial in patients with CKD with and without type 2 diabetes, we assessed the albuminuria-lowering effect of the sodium glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin and mineralocorticoid receptor antagonist (MRA) eplerenone individually and in combination. We demonstrated that the albuminuria-lowering effects of dapagliflozin and eplerenone alone are additive when they are used in combination, resulting in a clinically relevant albuminuria reduction of 53% after 4 weeks of dapagliflozin-eplerenone treatment. The incidence of hyperkalemia was significantly less with combination treatment compared with eplerenone alone. These data support future clinical trials to confirm long-term efficacy and safety of combined SGLT2 inhibitor and MRA treatment. Visual Abstract: Abstract : Background: Sodium glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists (MRAs) reduce the urinary albumin-to-creatinine ratio (UACR) and confer kidney and cardiovascular protection in patients with CKD. We assessed efficacy and safety of the SGLT2 inhibitor dapagliflozin and MRA eplerenone alone and in combination in patients with CKD. Methods: We conducted a randomized open-label crossover trial in patients with urinary albumin excretion ≥100 mg/24 hr, eGFR 30–90 ml/min per 1.73 m 2, who had been receiving maximum tolerated stable doses of an ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB). Patients were assigned to 4-week treatment periods with dapagliflozin 10 mg/day, eplerenone 50 mg/day, or their combination in random order, separated by 4-week washout periods. Primary outcome was the correlation in UACR changes between treatments. Secondary outcome was the percent change in 24-hour UACR from baseline. Results: Of 57 patients screened, 46 were randomly assigned (mean eGFR, 58.1 ml/min per 1.73 m 2 ; median UACR, 401 mg/g) to the three groups. Mean percentage change from baseline in UACR after 4 weeks of treatment with dapagliflozin, eplerenone, and dapagliflozin-eplerenone was –19.6% (95% confidence interval [CI], –34.3 to –1.5), –33.7% (95% CI, –46.1 to –18.5), and –53% (95% CI, –61.7 to –42.4; P <0.001 versus dapagliflozin; P =0.01 versus eplerenone). UACR change during dapagliflozin or eplerenone treatment did not correlate with UACR change during dapagliflozin-eplerenone ( r =–0.13; P =0.47; r =–0.08; P =0.66, respectively). Hyperkalemia was more frequently reported with eplerenone ( n =8; 17.4%) compared with dapagliflozin ( n =0; 0%) or dapagliflozin-eplerenone ( n =2; 4.3%; P between-groups =0.003). Conclusions: Albuminuria changes in response to dapagliflozin and eplerenone did not correlate, supporting systematic rotation of these therapies to optimize treatment. Combining dapagliflozin with eplerenone resulted in a robust additive UACR-lowering effect. A larger trial in this population is required to confirm long-term efficacy and safety of combined SGLT2 inhibitor and MRA treatment. Clinical Trial registry name and registration number: European Union Clinical Trials Register, EU 2017–004641–25.