Effects of sotagliflozin on anaemia in patients with type 2 diabetes and chronic kidney disease stages 3 and 4

Abstract

Anaemia is frequent in diabetes and advanced chronic kidney disease (CKD). It is associated with adverse cardiovascular (CV) and kidney outcomes, while contributing to increased symptom burden. However, management can be challenging, especially considering mixed results with erythropoietin stimulating agents (ESA). ESAs, and more recently hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF PHI), are also associated with CV risk.¹ Sodium-glucose cotransporter (SGLT) inhibitors consistently increase haemoglobin through multiple mechanisms while improving cardiorenal outcomes.^{2, 3} The objective of our analysis was to examine the effects of sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, on haemoglobin in patients with type 2 diabetes (T2D) and CKD stages 3 and 4, with and without anaemia.

We evaluated the effects of sotagliflozin on haemoglobin in patients with T2D and moderate–severe CKD. Specifically, we performed a post hoc analysis of pooled participant-level data from two clinical trials assessing the effect of sotagliflozin (200 and 400 mg) versus placebo on haemoglobin in participants with T2D and CKD stages 3 or 4 over 26 weeks.^{4, 5} Change from baseline in haemoglobin was compared between sotagliflozin 200 or 400 mg and placebo in the pooled cohort using an analysis of covariance, with the addition of CKD study as a fixed effects variable. In a sensitivity analysis, clinical factors associated with haematopoiesis including baseline estimated glomerular filtration rate (eGFR), baseline use of ‘anti-anaemic preparations’ and baseline use of renal angiotensin system (RAS) inhibition were included in the model as covariates.

Participants with anaemia at baseline were identified based on haemoglobin levels defined as baseline haemoglobin <13 mg/dL for men and <12 mg/dL for women. The change from baseline on haemoglobin, haematocrit, serum albumin, systolic blood pressure (SBP), body weight and estimated glomerular filtration rate (eGFR) was assessed between sotagliflozin (pooled dose) and placebo in participants with and without anaemia. Sotagliflozin doses were pooled for the anaemia subgroup analyses as haemoglobin changes were similar between doses.

Within the entire cohort, baseline mean haemoglobin was 12.7 g/dL and sotagliflozin increased haemoglobin from baseline to week 26 by 0.39 g/dL (200 mg; 95% CI 0.21–0.56) and 0.41 g/dL (400 mg; 95% CI 0.24–0.59) versus placebo (p < 0.0001) (Table 1; Supplemental Figure S1). In the sensitivity analysis adjusting for baseline eGFR, use of ‘anti-anaemic preparations’ and use of RAS inhibition, the placebo-adjusted increase in haemoglobin for the pooled dose of sotagliflozin was 0.43 g/dL (95% CI 0.26 to 0.59, p < 0.0001). Of the 1064 participants randomized, 493 (46.3%) had anaemia at baseline. Participants with anaemia had a lower mean (standard deviation) baseline eGFR compared to those without anaemia (36 [12] mL/min/1.73 m² vs. 43 [11] mL/min/1.73 m²)—a larger proportion of these participants had CKD stage 4 (37% vs. 17%) and moderately increased albuminuria (69% vs. 53%). The effect of sotagliflozin on haemoglobin relative to placebo over 26 weeks was similar in participants with and without anaemia at baseline (p interaction = 0.062; Figure 1A,B). Relative to placebo, sotagliflozin increased mean haemoglobin by 0.27 g/dL in participants with anaemia and by 0.50 g/dL in participants without anaemia (Supplemental Table S1). Sotagliflozin increased the likelihood of anaemia resolving over 26 weeks in participants with anaemia at baseline (odds ratio 1.95; 95% CI 1.13, 3.37, p = 0.017) (Supplemental Figure S2A). There was a nonsignificant decrease in the odds of anaemia developing over 26 weeks in participants without anaemia at baseline with sotagliflozin (odds ratio 0.75; 95% CI 0.39, 1.47, p = 0.41) (Supplemental Figure S2A). Participants without anaemia had greater placebo-adjusted reductions in body weight and blood pressure compared to those without anaemia (p interaction <0.05) (Supplemental Table S1). Safety and tolerability were generally similar between the two anaemia subgroups and consistent with the known profile of sotagliflozin in patients with T2D and CKD^2-4 (Supplemental Table S2).

In a cohort of participants with T2D and moderate–severe CKD, sotagliflozin increased haemoglobin in a rapid and sustained manner, regardless of the presence of anaemia at baseline. In patients with anaemia at baseline, sotagliflozin increased the likelihood of not having anaemia during follow-up period.

These results are consistent with the effects of other SGLT inhibitors on haemoglobin and other red blood cell (RBC) indices, and comparable with lower doses of ESAs and HIF PHIs.¹ SGLT inhibitors are hypothesized to increase RBC indices in several ways. Early rises in haemoglobin and haematocrit may be associated with hemoconcentration due to the natriuresis and plasma volume contraction with proximal renal tubular SGLT2 inhibition. However, based on known effects of SGLT inhibition on natriuresis, these effects are expected to be transient as counterregulatory increases in sodium reabsorption in the proximal tubule and loop of Henle.⁶ Concurrently, anti-inflammatory effects and activation of starvation pathways with SGLT inhibitors may have the effect of promoting iron absorption and mobilization of iron stores.¹ Subsequently, SGLT inhibition may directly stimulate erythropoietin with resulting reticulocytosis and a sustained increase in haemoglobin independent of iron supplementation.^{1, 7}

While the mechanisms through which SGLT inhibition increases erythropoietin are not completely understood, they likely reflect activation of pathways at the cellular and organ level that contribute to CV and kidney protection. Indeed, analyses of SGLT inhibitor outcome trials have identified changes in haemoglobin and haematocrit to be significantly associated with observed reductions in adverse CV and kidney outcomes.⁸

Finally, sotagliflozin was safe and well-tolerated, irrespective of the presence of baseline anaemia. Additionally, the use of SGLT inhibitors, particularly in the context of the management of anaemia, would be expected to contribute to reductions in adverse CV, heart failure and kidney outcomes. In contrast, the use of ESAs and HIF PHIs has been associated with hypertension, CV disease and thrombosis. It must be noted however that SGLT inhibitors are not currently used in the setting of end-stage kidney disease.

There are limitations to these analyses, which were exploratory and post hoc. The relatively short follow-up period precludes us from determining if changes in haemoglobin with sotagliflozin are sustained and if these are associated with clinically meaningful outcomes such as initiation of ESAs. Additionally, in the absence of data on markers of erythropoiesis, we do not have mechanistic insights on how sotagliflozin affects haemoglobin. However, sotagliflozin does work by similar mechanisms as other SGLT inhibitors that have been shown to increase erythropoietin and iron metabolism.

Sotagliflozin increased haemoglobin in patients with T2D and CKD, supporting its potential use in the management of anaemia in this population, in addition to known cardiorenal protective effects.

V. S. S., M. J. D., and D. Z. I. C. contributed to the analysis design and drafted the report. All authors contributed to the interpretation of data, provided critical edits and reviewed and approved the final version. V. S. S. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

V. S. S. has received conference support from Merck Canada. M. J. D., P. B., M. G. and A. C. K. are employees of Lexicon Pharmaceuticals, Inc., and may hold stocks or stock options in the company. D. Z. I. C. has received honoraria from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, Bayer, Prometic, BMS, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon and Novo-Nordisk and has received operational funding for clinical trials from Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Boehring and Novo-Nordisk.