Effects of Veverimer on Serum Bicarbonate and Physical Function in Diabetic Patients With Chronic Kidney Disease and Metabolic Acidosis

Subgroup Analysis From a Randomized, Controlled Trial

Vandana S. Mathur; Elizabeth Li; Donald E. Wesson

Disclosures

Nephrol Dial Transplant. 2022;37(7):1302-1309. 

In This Article

Abstract and Introduction

Abstract

Graphical Abstract

Background: Metabolic acidosis is a complication of chronic kidney disease (CKD) that increases risk of CKD progression, and causes bone demineralization and muscle protein catabolism. Patients with diabetes are prone to metabolic acidosis and functional limitations that decrease quality of life. Veverimer, an investigational, non-absorbed polymer that binds and removes gastrointestinal hydrochloric acid, is being developed as treatment for metabolic acidosis. This post hoc subgroup analysis evaluated effects of veverimer on metabolic acidosis and physical function among patients with diabetes.

Methods: This was a Phase 3, multicenter, randomized, blinded, placebo-controlled trial in 196 patients with CKD (estimated glomerular filtration rate 20–40 mL/min/1.73 m2) and metabolic acidosis who were treated for up to 1 year with veverimer or placebo.

Results: At Week 52, veverimer-treated patients with diabetes (n = 70), had a significantly greater increase in mean serum bicarbonate than the placebo group (n = 57) (4.4 versus 2.9 mmol/L, P < 0.05). Patient-reported limitations of physical function on the Kidney Disease and Quality of Life-Physical Function Domain (e.g. walking several blocks and climbing a flight of stairs) improved significantly in the veverimer versus placebo group (+12.5 versus +0.3, respectively, P < 0.001) as did objective physical performance on the repeated chair stand test (P < 0.0001).

Conclusions: Few interventions for patients with diabetes and CKD have successfully improved quality of life or physical functioning. Our study demonstrated that veverimer effectively treated metabolic acidosis in patients with diabetes and CKD, and significantly improved how these patients felt and functioned.

Introduction

Acid produced daily through metabolism and diet is initially neutralized through titration and reduction of serum bicarbonate, which must ultimately be excreted to maintain normal acid–base homeostasis. Normally functioning kidneys maintain this homeostasis through acid excretion and regeneration of new bicarbonate to replace the titrated bicarbonate and thereby restore serum bicarbonate to normal. Patients with chronic kidney disease (CKD) develop metabolic acidosis due to acid retention from impaired kidney acid excretion due in part to reduced kidney ammoniagenesis.[1] Reduced renin–aldosterone–angiotensin II system activity and reduced responsiveness to aldosterone (Type IV renal tubular acidosis) further contribute to metabolic acidosis in patients with diabetes.[2] Metabolic acidosis increases the risk of CKD progression and causes bone demineralization, muscle protein catabolism and loss of muscle mass.[3] Acidemia directly stimulates glutamine extraction from blood by several fold[4] and increases proximal tubule glutamine catabolism—a process that generates new bicarbonate, which is transported into the blood and ammonia, which is excreted into the urine.[5] The increased need for glutamine to support maximal renal ammoniagenesis is met, in part, by metabolic acidosis-induced skeletal muscle protein catabolism.[4] While skeletal muscle protein catabolism facilitates acid excretion, bones facilitate acid buffering. Bone is a large repository of carbonate and phosphate, which when released into the blood can serve as an acid buffer.[6] Metabolic acidosis induces direct dissolution of bone and activation of osteoclasts, which break down bone leading to release of carbonate and phosphate from the skeleton, reducing bone density and strength.[6] In patients with CKD and metabolic acidosis the bone histology is predominantly osteomalacia and it is not reversible with calcitriol treatment.[7] In patients with CKD, both low bone mineral density and annual percent decline in bone mineral density have been shown to be significant predictors of incident fractures.[8]

Insulin normally inhibits muscle protein degradation but patients with CKD and metabolic acidosis have reduced sensitivity to the suppression of protein catabolism by insulin.[9] These defects may change body tissue composition analogous to fasting and/or low energy intake that overlap with alterations in insulin sensitivity that occur with aging.[9] As such, metabolic acidosis in patients with diabetes and CKD may contribute to the premature functional decline observed clinically in these patients. Data from a nationally representative sample of community-dwelling US adults found that in patients ≥60 years with diabetes, 32% of women and 15% of men reported an inability to walk a quarter of a mile, climb stairs or do housework compared with 14% of women and 8% of men without diabetes.[10] The effect of treating metabolic acidosis on physical function in patients with diabetes and CKD has not been reported previously.

Veverimer is a non-absorbed orally administered polymer drug that selectively binds protons and chloride in the gastrointestinal tract and thereby removes hydrochloric (HCl) acid via fecal excretion. The veverimer molecule has free amines that first bind protons, becoming positively charged, and then binds chloride, the most abundant anion in the gastrointestinal tract. The selective chloride binding is a function of the highly crosslinked structure of veverimer that prevents all but the smallest gastrointestinal tract anion (chloride) from binding.[11] The removal of HCl from the gastrointestinal tract is the equivalent of a net gain of bicarbonate in the blood because chloride secretion into the stomach is accompanied by generation of bicarbonate, which is transported into the blood. Veverimer is not an ion-exchange resin and thus does not introduce unwanted cations such as sodium or potassium. In a prior study of patients with CKD and metabolic acidosis conducted in an inpatient research unit, veverimer significantly increased serum bicarbonate within 24 h of treatment initiation, with increases in serum bicarbonate of 3–4 mmol/L after 2 weeks of treatment.[12]

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