In this multicenter, randomized, blinded, placebo-controlled study of up to 52 weeks in patients with CKD and metabolic acidosis, veverimer, a novel non-absorbed HCl binder, was effective in treating metabolic acidosis and improving both patient-reported and objectively measured physical function. This posthoc subgroup analysis of the 127 patients with diabetes enrolled in this trial showed that the veverimer-treated group, compared with placebo, had significant improvement in serum bicarbonate and physical function, similar to improvements observed in the overall study population. Veverimer was well-tolerated and had a high treatment adherence, no treatment discontinuations due to AEs and an overall safety profile not different from placebo. While this study was not designed to evaluate CKD progression or mortality, fewer fatal events and AEs related to worsening kidney function were reported in the veverimer group than the placebo group. These findings are consistent with those of several single-center studies showing that treatment of metabolic acidosis slows CKD progression[16–18] and the observations that metabolic acidosis is associated with higher mortality. Longer and larger trials are required to further evaluate these findings.
Improvement in the ability to conduct activities of daily living and to rise from a chair are important clinical and patient-centric outcomes. Loss of these abilities has important health, social and economic consequences because they can gauge whether a patient can continue to live independently. Prior studies showed that metabolic acidosis leads to bone loss and increased protein degradation; and correction of acidosis increases bone density and reduces protein degradation.[20,21] Others have suggested that metabolic acidosis contributes to frailty, fractures and failure to thrive in patients with CKD.[22,23] Our study provides evidence that treatment of metabolic acidosis in patients with CKD improves physical function. The observed effects on physical function in this study were both statistically and clinically significant. The observed improvement in patient-reported physical function on the KDQoL-PFD in the veverimer group (+11.4 points in the overall study population and +12.5 points in the diabetes subgroup) exceeded the minimal clinically important difference of 3–5 points for this subscale.[24–26] Similarly, the improved physical performance on the repeated chair stand test (−4.3 s in the overall population and −4.1 s in the diabetes subgroup) exceeded the 1.7 s minimally reported difference for this instrument. Moreover, the chair stand time decrease of 4.3 s in the veverimer group between baseline and Week 52 was larger than the 3.4 s difference in mean expected performance between 80- to 89-year-olds and 60- to 69-year-olds (i.e. ~20-year age difference). While this was not a mechanistic study, our findings of reduced limitations in physical functions, particularly those related to lower extremity strength, are consistent with the expected clinical manifestations of reduced muscle protein catabolism and bone loss.
Current strategies for treatment of metabolic acidosis in patients with CKD include decreasing metabolic acid production through increasing base-producing dietary fruits and vegetables and neutralizing accumulated acid with alkali supplements such as sodium bicarbonate. Based on evidence that chronic metabolic acidosis is associated with increased protein catabolism, muscle wasting, uremic bone disease, chronic inflammation, impaired glucose homeostasis, impaired cardiac function, progression of CKD and increased mortality, the International Nephrology Clinical Practice guidelines: KDIGO recommends treating patients with CKD whose serum bicarbonate is <22 mmol/L, and Kidney Disease Outcomes Quality Initiative (KDOQI) suggests that it is reasonable to maintain serum bicarbonate between 24 and 26 mmol/L. However, despite these guidelines, only a minority of patients are currently treated with alkali supplements. In the US-based prospective Chronic Renal Insufficiency Cohort study, for example, only 2.7% of patients with a serum bicarbonate <22 mmol/L and CKD were receiving treatment with oral alkali. Sodium bicarbonate treats metabolic acidosis by entering the systemic circulation to supply bicarbonate that neutralizes retained acid. However, there is an obligatory sodium load delivered that may be absolutely or relatively contraindicated in the many patients with CKD, especially those whose blood pressure is above target levels, have edema and/or have heart failure.[31,32] Compared with patients without diabetes, the risk of heart failure in patients with diabetes is doubled and cardiovascular outcomes, hospitalization and prognosis are worse. Thus, patients with diabetes may have greater susceptibility to adverse consequences of excess sodium intake. The current KDOQI nutrition guideline for sodium intake is <2.3 g/day and the American College of Cardiology and American Heart Association target is <1.5 g/day. To increase serum bicarbonate by 3–4 mmol/L with sodium bicarbonate in an 80 kg individual, for example, requires 6–8 g/day of sodium bicarbonate, which has a sodium content of 1.7–2.2 g. The mechanism of action of veverimer represents an alternative strategy for the treatment of metabolic acidosis in which acid is bound and removed from the gastrointestinal tract, leading to a net increase in serum bicarbonate. Because veverimer is not an ion-exchange resin, unwanted ions such as sodium are not introduced.
The strengths of this study include its multicenter, randomized, blinded, placebo-controlled design, the rigor of evaluation of both serum bicarbonate and physical function endpoints, and the 1-year treatment duration. The primary limitation of the present analysis is that it was conducted posthoc in a subgroup of patients and therefore results should be viewed as hypothesis-generating. The subgroup findings were highly consistent with those of the overall study population, however. Racial homogeneity was another limitation. While diet data were not collected, all patients were required to undergo dietary counseling at specific time points in accordance with dietary recommendations for CKD patients and the potential confounding effects of diet was excluded based on 24-h urea urine nitrogen measurements at baseline and post-baseline timepoints.[13,14]
Management of patients with diabetes and CKD is challenging. Progression of CKD and accompanying decline in physical function have multiple ramifications on patients' lives and influence the decision to initiate dialysis. Few interventions for patients with diabetes and CKD have successfully improved patient quality or life or physical functioning. Our study suggests that veverimer is an effective treatment for metabolic acidosis in patients with diabetes and CKD. Treatment with veverimer significantly improved how these patients felt and functioned.
The authors would like to thank Jun Shao (Tricida, Inc.) for graphic design of the figures and reviewing the manuscript. The authors would also like to thank Deborah M. Lidgate for editing, formatting and reviewing the manuscript.
This study was funded by Tricida, Inc.
Data Availability Statement
The data for this study have not been made publically available.
Nephrol Dial Transplant. 2022;37(7):1302-1309. © 2022 Oxford University Press