Mechanisms Contributing to Adverse Cardiovascular Events in Patients with Type 2 Diabetes Mellitus and Stage 4 Chronic Kidney Disease Treated with Bardoxolone Methyl

Abstract

Background: Bardoxolone methyl, an Nrf2-activating and nuclear factor-κB-inhibiting semisynthetic oleanane triterpenoid compound, was evaluated in a phase 3 trial (BEACON) in patients with type 2 diabetes mellitus (T2DM) and stage 4 chronic kidney disease (CKD). The trial was terminated because of an increase in heart failure events in the bardoxolone methyl group, many of which appeared related to fluid retention. Thus, additional analyses were conducted to explain these serious adverse events. Methods: Patients (n = 2,185) were randomized to receive once-daily bardoxolone methyl (20 mg) or placebo. Twenty-four-hour urine collections were analyzed in a subset of the BEACON population and from a separate, open-label pharmacology study in patients with stage 3b/4 CKD and T2DM administered 20 mg bardoxolone methyl once daily for 56 consecutive days. Results: Bardoxolone-methyl-treated patients in the BEACON substudy had a clinically meaningful reduction in urine volume and sodium excretion at week 4 relative to baseline (p < 0.05), and a separate study revealed that decreased sodium excretion and urine output occurred in some patients with stage 4 CKD but not those with stage 3b CKD. The clinical phenotype of fluid overload and heart failure in BEACON was similar to that observed with endothelin receptor antagonists in advanced CKD patients, and preclinical data demonstrate that bardoxolone methyl modifies endothelin signaling. Conclusions: The totality of the evidence suggests that through modulation of the endothelin pathway, bardoxolone methyl may pharmacologically promote acute sodium and volume retention and increase blood pressure in patients with more advanced CKD.

Bardoxolone methyl prevents the development and progression of cardiac and renal pathophysiologies in mice fed a high-fat diet

“…For example, mice fed a chronic HF diet develop obesity, which is coupled with an increase in mRNA expression of ETA and increased protein expression of ET-1 in the kidneys (Zhang, d'Uscio et al 2001). BM has been found to suppress the renal endothelin pathway in the kidneys of rodents induced with chronic kidney disease by reducing the protein expression of ETA (Chin, Reisman et al 2014). In this study, we also found that chronic BM administration prevented HF diet-induced increases in mRNA expression of ETA.…”

“…However these positive findings were overshadowed by the recently terminated phase III human clinical trial where there were adverse cardiovascular events seen in patients with advanced chronic kidney disease treated with BM (de Zeeuw, Akizawa et al 2013). The mechanisms contributing to these adverse events in the clinical trial were speculated to be via the modulation of the endothelin pathway (Chin, Reisman et al 2014). However, this pathway was not investigated in the heart tissue and in the kidney following chronic BM treatment, suggesting that further investigation into this drug was vital.…”

Role of Nrf2 Dysfunction in Uremia-Associated Intestinal Inflammation and Epithelial Barrier Disruption

“…Given the accumulating evidence that gut bacterial translocation is associated with systemic inflammation in ESRD patients [15,16], and that the latter is an independent predictor of increased mortality in hemodialysis patients [17][18][19], studies that advance the understanding of gut inflammation are needed as interventions in this area may beneficially impact clinical outcomes. The phase 3 clinical trial of bardoxolone methyl (potent systemic Nrf2 activator) in diabetic CKD patients was terminated early due to unforeseen cardiovascular events in the treatment arm [44], highlighting the need to explore tissue-specific targets for restoration of Nrf2 activity.…”

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…Although the results of the phase II were very encouraging, CDDO-Me was later withdrawn at phase III (BEACON trial) due to cardiovascular safety issues (Zhang, 2013) that were not related to NRF2 but most likely to an off-target alteration of endothelin signaling (de Zeeuw et al, 2013;Chin et al, 2014). Currently, CDDO-Me is under clinical study as potential treatment of Alport syndrome and pulmonary hypertension ( Table 2).…”