Uric acid lowering in relation to HbA1c reductions with the SGLT2 inhibitor tofogliflozin

Abstract

An integrated analysis was performed with data from 4 phase 2 and phase 3 studies of tofogliflozin in which patients with type 2 diabetes mellitus received the sodium‐glucose cotransporter 2 inhibitor tofogliflozin for up to 24 weeks. Sex differences, baseline haemoglobin A1c (HbA1c) and serum uric acid (UA) levels, and log10‐transformed urinary N‐acetyl‐β‐D‐glucosaminidase ratio were significantly correlated with the reduction in serum UA levels at both 4 and 24 weeks in multivariate analysis (respectively, P < .0001). The decrease in HbA1c levels was greatest in the group with the highest baseline HbA1c level (quartile 4; HbA1c > 8.6%) and lowest in the group with the lowest baseline HbA1c level (quartile 1; HbA1c ≤ 7.4%). The decrease in serum UA levels was greatest in the quartile 1 group and lowest in the quartile 4 group. In most groups, the maximum decrease in serum UA levels was seen in the first 4 weeks, while the maximum decrease in HbA1c was seen at week 24. Thus, serum UA levels were significantly decreased in patients with moderate HbA1c levels.

Unaccounted for regression to the mean renders conclusion of article titled “Uric acid lowering in relation to HbA1c reductions with the SGLT2 inhibitor tofogliflozin” unsubstantiated

“…In conclusion, the data presented by Ouchi et al are insufficient to arrive at the conclusion that treatment with tofogliflozin causes greater reductions in serum UA or HbA1c among people with higher baseline levels of serum UA or HbA1c. Careful consideration of the effects of RTM as well as of potential pitfalls in the study design and statistical methods are warranted in conducting clinical studies and also in the peer review process.…”

“…Ouchi et al reported the aggregated outcomes of four clinical trials that examined the effects of the sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor tofogliflozin (vs placebo) on glycated haemoglobin (HbA1c) and serum uric acid levels. The authors reported that the individuals with highest levels of HbA1c experienced greater reductions in HbA1c than did those with lower baseline HbA1c levels within the tofogliflozin arm.…”

“…Additionally, the inappropriate conclusions resulting from RTM can be aggravated when study samples are segregated based on extreme criteria (eg, HbA1c ≥ 7.0%) and when repeated measurements (eg, post‐ vs pre‐intervention) of such extreme samples are compared . Ouchi et al stratified their sample into four quartile‐defined categories based on the pre‐intervention HbA1c levels and compared the effects of intake of tofogliflozin on the post‐ vs pre‐intervention changes in HbA1c without taking RTM into consideration. Moreover, in this sample, HbA1c quartile‐defined categories and the serum UA levels had a significant inverse association prior to the intervention (ie, the group with the highest level of HbA1c had the lowest level of serum UA, and vice versa).…”

This is in reply to the Letter by Kahathuduwa et al. titled “Unaccounted for regression to the mean renders conclusion of article titled ‘Uric acid lowering in relation to HbA1c reductions with the SGLT2 inhibitor Tofogliflozin’ unsubstantiated”

“…We thank Dr Chanaka N. Kahathuduwa and colleagues for their thoughtful comments on our recent article which appeared in Diabetes, Obesity and Metabolism . We completely understand the points made by Kahathuduwa et al Certainly, if the authors' conclusion is based only on the impact of regression to the mean, RTM might generally be insufficient.…”

“…In this study, we included Supporting Information and Figures in addition to presenting the results of multivariate analysis of subjects who received tofogliflozin. The degree of reduction in serum uric acid (UA) levels was greater in the subjects who received tofogliflozin than in those who received placebo (Figure S2).…”