Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Sep 30;21(1):681.
doi: 10.1186/s12967-023-04565-x.

Genetically proxied antidiabetic drugs targets and stroke risk

Yahui Zhu  1   2 , Mao Li  2 , Hongfen Wang  2 , Fei Yang  2 , Xinyuan Pang  2   3 , Rongrong Du  2   3 , Jinghong Zhang  1   2 , Xusheng Huang  4   5
Affiliations

Genetically proxied antidiabetic drugs targets and stroke risk

Yahui Zhu et al. J Transl Med. .

Abstract

Background: Previous studies have assessed the association between antidiabetic drugs and stroke risk, but the results are inconsistent. Mendelian randomization (MR) was used to assess effects of antidiabetic drugs on stroke risk.

Methods: We selected blood glucose-lowering variants in genes encoding antidiabetic drugs targets from genome-wide association studies (GWAS). A two-sample MR and Colocalization analyses were applied to examine associations between antidiabetic drugs and the risk of stroke. For antidiabetic agents that had effect on stroke risk, an independent blood glucose GWAS summary data was used for further verification.

Results: Genetic proxies for sulfonylureas targets were associated with reduced risk of any stroke (OR=0.062, 95% CI 0.013-0.295, P=4.65×10－4) and any ischemic stroke (OR=0.055, 95% CI 0.010-0.289, P=6.25×10－4), but not with intracranial hemorrhage. Colocalization supported shared casual variants for blood glucose with any stroke and any ischemic stroke within the encoding genes for sulfonylureas targets (KCNJ11 and ABCC8) (posterior probability>0.7). Furthermore, genetic variants in the targets of insulin/insulin analogues, glucagon-like peptide-1 analogues, thiazolidinediones, and metformin were not associated with the risk of any stroke, any ischemic stroke and intracranial hemorrhage. The association was consistent in the analysis of sulfonylureas with stroke risk using an independent blood glucose GWAS summary data.

Conclusions: Our findings showed that genetic proxies for sulfonylureas targets by lowering blood glucose were associated with a lower risk of any stroke and any ischemic stroke. The study might be of great significance to guide the selection of glucose-lowering drugs in individuals at high risk of stroke.

Keywords: Antidiabetic drugs; Mendelian randomization; Stroke; Sulfonylurea.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
A flow diagram summarizing the study. MR, Mendelian randomization; IVW, inverse variance weighted; GWAS, genome-wide association study; T2DM, type 2 diabetes mellitus; BMI, body mass index; WC, waist circumference; HIP, hip circumference
Fig. 2
Fig. 2
Estimated effects of genetic variants in antidiabetic drugs targets on any stroke and any ischemic stroke
Fig. 3
Fig. 3
Estimated effects of genetic variants in metformin targets on stroke
Fig. 4
Fig. 4
Regional plots for the associations of blood glucose and any stroke within ± 2.5 kb of KCNJ11 and ABCC8
Fig. 5
Fig. 5
Regional plots for the associations of blood glucose and any ischemic stroke within ± 2.5 kb of KCNJ11 and ABCC8
Fig. 6
Fig. 6
Estimated effects of genetic variants in sulfonylureas targets on stroke using an independent blood glucose GWAS summary data
Fig. 7
Fig. 7
Estimated effects of genetic variants in sulfonylureas targets on glucose metabolism-related traits and obesity-related traits
Fig. 8
Fig. 8
Regional plots for the associations of blood glucose and any stroke within ± 100 kb of KCNJ11 and ABCC8 in validation study
Fig. 9
Fig. 9
Regional plots for the associations of blood glucose and any ischemic stroke within ± 100 kb of KCNJ11 and ABCC8 in validation study
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. GBD 2015 DALYs and Hale Collaborators Global, regional, and national disability adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990–2015: a systematic analysis for the global burden of disease study 2015. Lancet. 2016;388:1603–58. doi: 10.1016/S0140-6736(16)31460-X. - DOI - PMC - PubMed
    1. GBD 2015 Mortality and Causes of Death Collaborators Global, regional, and na tional life expectancy, all-cause mortality, and cause-specifific mortality for 249 causes of death, 1980–2015: a systematic analysis for the global burden of disease study 2015. Lancet. 2016;388:1459–544. doi: 10.1016/S0140-6736(16)31012-1. - DOI - PMC - PubMed
    1. Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375:2215–22. doi: 10.1016/s0140-6736(10)60484-9. - DOI - PMC - PubMed
    1. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the american heart association/american stroke association. Stroke. 2014;45:2160–236. doi: 10.1161/str.0000000000000024. - DOI - PubMed
    1. Castilla-Guerra L, Fernandez-Moreno MDC, Leon-Jimenez D, Carmona-Nimo E. Antidiabetic drugs and stroke risk. Current evidence. Eur J Intern Med. 2018;48:1–5. doi: 10.1016/j.ejim.2017.09.019. - DOI - PubMed