SP104DECREASES IN WEIGHT WITH BARDOXOLONE METHYL IN OBESE PATIENTS WITH CHRONIC KIDNEY DISEASE STAGE 4 AND TYPE 2 DIABETES - POST-HOC ANALYSES FROM BEACON

Abstract

INTRODUCTION AND AIMS: Obesity increases the risk for chronic kidney disease (CKD) and its progression to end-stage renal disease. In animal models of obesity, the anti-inflammatory effects of bardoxolone methyl (BARD) have been shown to reduce fat accumulation by decreasing fatty acid synthesis and improving metabolism. Treatment with BARD in a multinational, randomized, double-blind, placebo-controlled phase 3 trial, Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), resulted in increases in estimated glomerular filtration rate (eGFR) as well as decreases in body weight. We performed post-hoc analyses to further characterize decreases in weight with BARD. METHODS: Patients with type 2 diabetes and CKD stage 4 (eGFR 15 to 29 mL/min/ 1.73m2) in BEACON (n=2185) were randomized 1:1 to receive once-daily BARD (20 mg) or placebo. We compared the change in body weight, waist circumference, and Quetelet's (body mass) index. A subset of the BEACON population (n = 174) consented to additional 24-hour urine collections; to assess if weight loss was derived from muscle mass, we examined changes in 24-hour excretion of urinary creatinine. RESULTS: The mean BMI and weight at baseline were 33.867.1 kg/m2 and 95.26 21.5 kg for patients enrolled in BEACON. Patients treated with BARD had a significant decrease in weight compared to placebo. In the BARD-treated patients, the rate and amount of weight loss was proportional to the initial BMI. Weight plateaued at 32 weeks in the ideal BMI group (18.5 to 24.9 kg/m2), while it continued to decline in the higher BMI groups. BARD also significantly reduced waist circumference after 24 weeks of treatment (relative change:-4.168.0 cm). Mean (6SD) 24-hour urinary creatinine excretion in patients randomized to BARD was unchanged from baseline at Week 4 (11326394 mg versus 11916339 mg at baseline; n=61) and was not significantly different from changes in placebo patients (p=0.3). CONCLUSIONS: BARD treatment resulted in significant weight loss in this obese, CKD patient population with type 2 diabetes, with the magnitude and rate being dependent on baseline BMI. Unchanged 24-hr urinary creatinine excretion (a proxy for muscle mass) are consistent with the hypothesis that bardoxolone methyl led to a loss of adipose tissue rather than muscle, a finding further supported in the entire patients sample by changes in waist circumference. Although the mechanism of weight loss with BARD treatment in humans is not fully understood, it is hypothesized that BARD increases lipolysis of peripheral lipid stores, as has been observed in preclinical studies.