Impact of sotagliflozin on glomerular hyperfiltration in people with type 1 diabetes: A post hoc analysis of the <scp>inTandem3</scp> trial

The natural history of kidney dysfunction in diabetes mellitus includes an initial glomerular hyperfiltration phase, followed by elevated urinary albumin excretion and progressive glomerular filtration rate (GFR) decline, eventually leading to chronic kidney disease (CKD) and kidney failure.1 Notably, the presence of glomerular hyperfiltration in people with type 1 diabetes (T1D) corresponds to an increased risk of overt nephropathy,2 kidney function decline,3 and cardiorenal mortality.3 Empagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, was previously shown to attenuate glomerular hyperfiltration (defined as GFR >135 mL/min/1.73 m2) in a small mechanistic clinical trial of people with T1D (3). However, this trial was of a relatively short duration and did not include a placebo group for comparison. Thus, the aim of the current study was to investigate changes in estimated GFR (eGFR) seen during a 24-week randomized, placebo-controlled clinical trial evaluating sotagliflozin, a dual SGLT1/SGLT2 inhibitor, in people with T1D and glomerular hyperfiltration at baseline. This is a post hoc analysis of inTandem3 (NCT02531035), a 24-week phase 3, randomized, double-blind, placebo-controlled multicentre clinical trial that evaluated sotagliflozin 400 mg daily as an adjunct to insulin therapy in people with T1D. This trial received ethical approval at participating institutions and primary outcomes have been published.4 From the original study cohort, individuals with baseline glomerular hyperfiltration (defined as eGFR ≥135 mL/min/1.73 m2)5, 6 were identified and the effects of sotagliflozin or placebo on changes in eGFR throughout the 24-week treatment duration were evaluated. Comparisons between sotagliflozin and placebo were performed by calculating least-squares means with 95% confidence intervals and p-values using a mixed model for repeated measures, with change from baseline eGFR as the dependent variable; treatment, visit, and treatment-by-visit interaction as fixed effects; and baseline eGFR as a covariate. Applicable stratification variables (body mass index at screening, week 2 HbA1c, and use of continuous subcutaneous insulin infusion) were included as fixed effects. All statistical analyses for this observational study were performed with SAS version 9.4 (SAS; Cary, NC). We identified 50 inTandem3 participants (31 in the placebo group and 19 in the sotagliflozin group) with glomerular hyperfiltration. Baseline demographic and biochemical characteristics of the two cohorts are summarized in Table 1. Notably, baseline eGFR was similar between the two cohorts but there were key differences in several variables, including age, sex, race/ethnicity, body mass index, total daily insulin dose, and renin–angiotensin–aldosterone system (RAAS) inhibitor medication use (Table 1). While there was a small numeric difference in baseline RAAS use between groups, we note that overall use was low and consistent with the lack of CKD in this hyperfiltrating cohort. There was a significant decline in eGFR within each treatment cohort at each timepoint (i.e., weeks 4, 8, 16, and 24) (Figure 1). Interestingly, the change in eGFR was significant within each treatment group but did not differ between those receiving sotagliflozin versus placebo. Of note, while the difference in eGFR decline did not differ between the two treatment groups over 24 months, there was a slight increase in eGFR from weeks 16 to 24 in the placebo group. Conversely, a similar pattern was not seen in the sotagliflozin group, suggesting the possibility of a more sustained effect on eGFR reduction. Similar trends were observed for within-group changes in HbA1c over time (Table S1). Although trends in HbA1c in the current analysis were consistent with the overall study cohort,4 the between-group difference in HbA1c was not statistically significant in the current hyperfiltrating cohort (Table S1). Finally, we evaluated effects of each treatment arm on eGFR by various baseline thresholds (Table S2). Notably, there was no change in eGFR at week 24 in either the placebo or sotagliflozin groups for those with baseline eGFR <90 mL/min/1.73 m2. Conversely, there was a significant reduction in eGFR within each group for participants with baseline eGFR 90–135 mL/min/1.73 m2, but this change did not differ between groups (Table S2). Herein we provide what is, to the best of our knowledge, the first placebo-controlled evaluation of SGLT inhibition in people with T1D and glomerular hyperfiltration. Notably, both the sotagliflozin and placebo cohorts experienced significant reductions in eGFR into the normal range and this effect was maintained throughout the 24-week treatment duration for each. The only other study to evaluate this question was an 8-week investigation of empagliflozin 25 mg daily in 40 people (27 with glomerular hyperfiltration and 13 with normal filtration) with T1D.7 In that study, empagliflozin lessened glomerular hyperfiltration via tubuloglomerular feedback mechanisms but there was no placebo group available for comparison.7 The ability of the SGLT inhibitor medications to normalize eGFR in those with glomerular hyperfiltration may be one (but far from the only) pathway whereby they provide cardiorenal benefits. For example, glomerular hyperfiltration has been linked to worsening kidney function2, 3 and cardiorenal mortality3 in people with T1D. Recent studies have also linked glomerular hyperfiltration to incident cardiovascular disease (particularly heart failure) in middle-aged healthy individuals,8 people with hypertension,9 and people with type 2 diabetes.10 As previously noted, in this hyperfiltrating cohort both the placebo and the sotagliflozin groups saw normalization of eGFR in the inTandem3 Trial and there was no difference in eGFR reduction between groups. One interesting and somewhat unexpected finding in the current report is that the inTandem3 placebo group also experienced a significant decline in eGFR during the 24-week intervention. We noted that RAAS medication use was numerically higher in the placebo group and this could have contributed to some eGFR reduction; however, overall use of these medications was quite low. We also evaluated whether changes in glycaemic control were a contributing factor, but there were no between-group differences in HbA1c reduction in this small, hyperfiltrating cohort. In addition, the duration of diabetes in the current analysis was fairly short and more than half of the cohort was diagnosed after age 18 years (Table 1). Baek et al. have reported that kidney function decline in people with T1D is more prominent with greater disease duration and that early-age onset of disease is an independent risk of nephropathy.11 It is conceivable that this cohort with later disease onset and shorter disease duration may have had ‘recoverable’ renal function when compared to those with T1D and longer disease duration. While our study has numerous strengths, there are a few important limitations that should be considered when interpreting results from this post hoc analysis. First, our study had a relatively small sample size in general and there was an unequal distribution of those with glomerular hyperfiltration between the two treatment groups. The small sample size limits the statistical power to detect true treatment differences; thus, larger studies with more balanced comparative groups are needed before firm conclusions can be drawn. A second key limitation to consider is the 24-week treatment duration. While this is an adequate period to assess glycaemic outcomes (which was the study's original aim), our post hoc analysis would benefit from a longer monitoring period. We found that both placebo and sotagliflozin significantly reduced eGFR in a small cohort of people with T1D and baseline glomerular hyperfiltration from the inTandem3 Trial. Larger and longer studies with more balanced comparator groups are needed to better evaluate this question. Given the relationship of glomerular hyperfiltration with numerous adverse outcomes and the challenges faced by many people with T1D to achieve glycaemic targets, our results also highlight the urgent need to develop safe administration strategies for SGLT inhibitors in this patient population. MBH, MJD, and WBH developed the concept and designed the analysis. MG performed the analysis. All authors reviewed the results and interpreted the findings. AP wrote the first draft of the manuscript. MBH, MG, MJD, and WBH reviewed/edited the manuscript. All authors approved the final version of the manuscript. MJD is the guarantor of the work and, as such, had full access to all data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis. The authors thank the participants and investigators in the inTandem3 trial. MBH, MG, and MJD are employees of Lexicon Pharmaceuticals, Inc. and may hold stock or stock options in the company. AP and WBH declare no conflicts of interest. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.70266. The data that support the findings of this study are available from Lexicon Pharmaceuticals, Inc. but restrictions apply to the availability of these data and therefore are not publicly available. Data are, however, available from the authors upon reasonable request and with permission of Lexicon Pharmaceuticals, Inc. Table S1. Change in HbA1c within each hyperfiltrating treatment group throughout the 24-week inTandem3 trial. Table S2. Change in eGFR by varying baseline eGFR thresholds within each treatment group throughout the 24-week inTandem3 trial. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.