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. 2024 Jul;14(7):e3624.
doi: 10.1002/brb3.3624.

Sodium-glucose cotransporter 1/2 inhibition and risk of neurodegenerative disorders: A Mendelian randomization study

Jinxin Liu  1 , Xinxiu Shi  1 , Yankun Shao  1
Affiliations

Sodium-glucose cotransporter 1/2 inhibition and risk of neurodegenerative disorders: A Mendelian randomization study

Jinxin Liu et al. Brain Behav. 2024 Jul.

Abstract

Introduction: This study aims to evaluate the effects of sodium-glucose cotransporter 1 inhibitors (SGLT1i) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) on neurodegenerative disorders and to investigate the role of hemoglobin A1c (HbA1c) levels.

Methods: Utilizing drug target Mendelian randomization, we employed single nucleotide polymorphisms (SNPs) proximal to the SLC5A1 and SLC5A2 genes to analyze the influence of SGLT1i and SGLT2i on Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), frontotemporal dementia (FTD), Lewy body dementia (LBD), and amyotrophic lateral sclerosis (ALS), with type 2 diabetes (T2D) as a positive control. An additional analysis examined the impact of HbA1c levels on the same disorders.

Results: SGLT1i exhibited a significant association with decreased risk for ALS and MS. Conversely, SGLT2i were linked to an increased risk of AD, PD, and MS. Elevated HbA1c levels, independent of SGLT1 and SGLT2 effects, were associated with an increased risk of PD. Sensitivity analyses supported the robustness of these findings.

Conclusion: Our study suggests that SGLT1i may confer protection against ALS and MS, whereas SGLT2i could elevate the risk of AD, PD, and MS. Additionally, elevated HbA1c levels emerged as a risk factor for PD. These findings underscore the importance of personalized approaches in the utilization of SGLT inhibitors, considering their varying impacts on the risks of neurodegenerative diseases.

Keywords: Mendelian randomization; drug target; hemoglobin A1c; neurodegenerative disorders; sodium‐glucose cotransporter.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

FIGURE 1
FIGURE 1
Study design. Diagram of the two steps of MR models: primary analysis, to establish the causal effect of SGLT1/2 inhibition on neurodegenerative disorders and T2D, and additional analysis, to establish the causal effect of the HbA1c on neurodegenerative disorders and T2D. SGLT, sodium‐glucose cotransporter; HbA1c, hemoglobin A1c; AD, Alzheimer's disease; PD, Parkinson's disease; MS, multiple sclerosis; ALS, amyotrophic lateral sclerosis; FTD, frontotemporal dementia; LBD, Lewy body dementia; T2D, type 2 diabetes.
FIGURE 2
FIGURE 2
MR estimates and forest plot of the effect of SGLT1/2 inhibition on neurodegenerative disorders and T2D. Asterisk (*) represents the linkage disequilibrium parameter in the selection of IVs changes from r 2 < 0.3 to r 2 < 0.1. nsnp, number of single nucleotide polymorphisms; pval, p value; OR, odds ratio; CI, confidence Intervals; HbA1c, hemoglobin A1c; AD, Alzheimer's disease; PD, Parkinson's disease; MS, multiple sclerosis; ALS, amyotrophic lateral sclerosis; FTD, frontotemporal dementia; LBD, Lewy body dementia; T2D, type 2 diabetes; SGLT, sodium‐glucose cotransporter; IVW, inverse variance weighted.
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