Genetic Variation in Targets of Antidiabetic Drugs and Amyotrophic Lateral Sclerosis Risk
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Updated: Jun 3, 2025
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Mengxia Wan1,2, Linjing Zhang1, Junyan Huo1
1Department of Neurology, Peking University Third Hospital, Beijing 100191, China.
Background:
Previous studies have suggested that antidiabetic drug use may be associated with amyotrophic lateral sclerosis. However, these studies are limited by many confounding and reverse causality biases. We aimed to determine whether antidiabetic drug use has causal effects on ALS.
Methods:
Drug-target Mendelian randomization analysis was conducted to evaluate the association between genetic variation in the targets of antidiabetic drugs and ALS risk. The antidiabetic drugs included sulfonylureas, GLP-1 analogues, thiazolidinediones, insulin/insulin analogues, metformin, and SGLT2 inhibitors. Summary statistics for ALS were retrieved from previous genome-wide association studies comprising 27,205 ALS patients and 55,058 controls. The instrumental variables for these drugs are from previous published articles.
Results:
Genetic variation in SGLT2 inhibition targets was associated with lower risk of ALS (odds ratio [OR] = 0.32, 95% CI = 0.14-0.74; p = 0.008). We did not find that genetic variation in metformin targets was associated with ALS (OR = 1.61, 95% CI = 0.94-2.73; p = 0.081). Nevertheless, mitochondrial complex I, a target of metformin, was associated with a higher risk of ALS (OR = 1.83, 95% CI = 1.01-3.32; p = 0.047). The analysis showed that genetic variation in sulfonylureas, GLP-1 analogues, thiazolidinediones, insulin or insulin analogues targets was not associated with ALS (all p > 0.05).
Conclusions:
The complex interaction between hypoglycemic, antioxidation, and anti-inflammatory effects may account for the different results across antidiabetic drug types. These findings provide key evidence to guide the use of antidiabetic drugs and will help to identify novel therapeutic targets in ALS.
Insights
Antidiabetic drug use may influence amyotrophic lateral sclerosis (ALS) risk. SGLT2 inhibitors show a potential protective effect, while metformin
Area of Science:
- Genetics
- Pharmacology
- Neurology
Background:
- Previous research suggested a link between antidiabetic drug use and amyotrophic lateral sclerosis (ALS).
- Prior studies were limited by confounding factors and reverse causality, necessitating further investigation.
- This study aimed to establish a causal relationship between antidiabetic drug use and ALS risk.
Purpose of the Study:
- To investigate the potential causal effects of antidiabetic drug use on amyotrophic lateral sclerosis (ALS) risk.
- To utilize drug-target Mendelian randomization to assess genetic associations between antidiabetic drug targets and ALS.
Main Methods:
- Drug-target Mendelian randomization analysis was employed to assess genetic associations.
- Genetic variations in targets of sulfonylureas, GLP-1 analogues, thiazolidinediones, insulin/analogues, metformin, and SGLT2 inhibitors were examined.
- ALS summary statistics from genome-wide association studies (27,205 cases, 55,058 controls) were utilized.
Main Results:
- Genetic variation in SGLT2 inhibition targets was associated with a reduced risk of ALS (OR = 0.32, p = 0.008).
- Metformin's target, mitochondrial complex I, was linked to an increased ALS risk (OR = 1.83, p = 0.047).
- No significant associations were found for genetic variations in targets of sulfonylureas, GLP-1 analogues, thiazolidinediones, or insulin/analogues with ALS risk.
Conclusions:
- Findings suggest differential impacts of antidiabetic drug classes on ALS risk, potentially mediated by hypoglycemic, antioxidant, and anti-inflammatory pathways.
- This research provides crucial evidence for guiding antidiabetic drug use in the context of ALS.
- The study may help identify novel therapeutic targets for amyotrophic lateral sclerosis.
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