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


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

In This Article


Of the 196 patients enrolled in the extension study, 127 had a history of diabetes (70 in the veverimer group and 57 in the placebo group). In the veverimer and placebo groups, respectively, 97.3% (111/114) and 90.0% (74/82) of patients completed the study (Supplementary data, Figure S3). The mean daily dose in the veverimer group was 7.9 (1.8) g/day. Dosing compliance, defined as >80% of the prescribed doses taken, was 100% and 99% in the veverimer and placebo groups, respectively.

Baseline characteristics within the diabetes subgroup and the overall study population, including demographics, serum bicarbonate, eGFR and the urine albumin to creatinine ratio (ACR) were generally balanced across treatment groups (Table 1). Among patients with diabetes, the mean age was 63.2 years and the mean serum bicarbonate was 17.3 mmol/L; 10.2% were on background oral alkali. Most patients with diabetes were on anti-diabetic drug treatments (90% in the veverimer group and 80% in the placebo group), most commonly sulfonylurea drugs, insulin and metformin (Table 1). No patients received phosphate binders during the study.

Among patients with diabetes, a significantly greater percentage of patients in the veverimer group at Week 52 had a ≥4 mmol/L increase, or normalization, in serum bicarbonate than the placebo group (64% versus 38%, P < 0.01; Figure 1A), and patients in the veverimer group had a significantly greater least squares mean increase from baseline in serum bicarbonate than the placebo group [4.4 (0.4) versus 2.9 (0.5) mmol/L, P < 0.05] (Figure 1B). These findings were nearly identical to those observed in the overall study population (Figure 1).

Figure 1.

Veverimer effects on serum bicarbonate. (A) Percent of patients achieving an increase in serum bicarbonate of ≥4 mmol/L or serum bicarbonate in the normal range (22–29 mmol/L) at Week 52. (B) Serum bicarbonate change from baseline to Week 52. LS, least squares; SE, standard error.

In the diabetes subgroup, patient-reported limitations of physical function on the KDQoL-PFD, which measured daily activities such as walking several blocks and climbing a flight of stairs, improved significantly in the veverimer group versus the placebo group (+12.5 versus +0.3 points, respectively, P < 0.001; Figure 2A) as did objectively measured physical performance on the repeated chair stand test at Week 52 (P < 0.0001; Figure 2B). These findings were nearly identical to those observed in the overall study population (Figure 2). Formal testing of interaction by diabetes showed that there was no significant effect of the presence or absence of diabetes on the effect of veverimer on improvement in either measure of physical function (rank-based ANCOVA, P ≥ 0.6).

Figure 2.

Veverimer effects on physical function. (A) Change from baseline in KDQoL-PFD. (B) Change from baseline in time to complete the repeated chair stand test. S, seconds.

Examination of the individual items of the KDQoL-PFD in the overall study population revealed that patients in the veverimer group reported significant improvements in all items related to walking, climbing a flight of stairs and bending/kneeling/stopping compared with patients in the placebo group.[13] These activities require lower body strength and use muscle groups that are also needed to perform the repeated chair stand test.

In the overall population, long-term treatment with veverimer was well tolerated, with a safety profile that was not different from placebo.[13] Two patients died and both were in the placebo group. Fewer patients in the veverimer group than in the placebo group discontinued treatment prematurely (3% versus 10%, respectively), and no patient in the veverimer group discontinued due to an AE. SAEs occurred in 2% of patients in the veverimer group and 5% of patients in the placebo group; no SAE was considered by the investigator as related to the study drug. The only AE with a between-group difference of >5% was headache, which was more common in the placebo group.[13] Renal system AEs, which included only events related to worsening kidney function (other than one event of proteinuria), were reported for 8% of patients in the veverimer group and 15% in the placebo group. An increase in serum bicarbonate to >30 mmol/L occurred in only one patient (in the veverimer group) and this increase occurred in the context of over-diuresis. There was little change in hemoglobin A1c during the study in either group. Veverimer showed no apparent off-target effects including on other electrolytes, lipids, vital signs or electrocardiogram intervals.[13]

Among patients with diabetes, AEs, SAEs and treatment-related AEs were reported with similar frequency in the veverimer and placebo groups (Table 2); there was one death (in the placebo group).