Skip to main content
SpringerLink
Log in

Metformin treatment and acute ischemic stroke outcomes in patients with type 2 diabetes: a retrospective cohort study

  • Original Article
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

Background and purpose

Preclinical studies have shown that metformin has neuroprotective actions in stroke. However, the optimal treatment timing and duration remain unknown. Herein, we examined the efficacy of metformin treatment on prognosis in acute ischemic stroke (AIS) patients, and assessed the optimal treatment timing and duration.

Methods

AIS patients with type 2 diabetes mellitus were retrospectively enrolled. Patients were grouped into those who never received metformin (MET − group), those who received metformin continuously before stroke and after admission (pre-stroke + /post-stroke + group), those who only received metformin before stroke onset (pre-stroke + /post-stroke − group), and those who only received metformin after admission (pre-stroke − /post-stroke + group). The all MET + group represents the sum of the three metformin treatment groups. The efficacy outcome was the 90-day modified Rankin Scale (mRS) score.

Results

In total, 309 eligible patients were included (MET − [N = 130], pre-stroke + /post-stroke + [N = 94], pre-stroke + /post-stroke − [N = 30], pre-stroke − /post-stroke + [N = 55]; all MET + [N = 179]). The all MET + group had a trend toward a lower 90-day mRS score compared with that in the MET − group (1 [0–2] vs 1 [0–3], unadjusted odds ratio [OR] = 0.652, P = 0.041; adjusted OR = 0.752, P = 0.218). In the three metformin treatment groups, only the pre-stroke + /post-stroke + group had a significantly lower 90-day mRS score (1 [0–1] vs 1 [0–3], adjusted OR = 0.497, 95%CI = 0.289–0.854; P = 0.011) and higher proportion of mRS score 0–1 (78.7% vs. 61.5%, adjusted OR = 2.278, 95%CI = 1.108–4.680; P = 0.025) than the MET − group.

Conclusion

AIS patients with type 2 diabetes mellitus who receive continuous metformin treatment before stroke onset and after admission have improved functional outcome at 90 days.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. GBD (2019) Stroke Collaborators (2021) Global, regional, and national burden of stroke and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol 20(10):795–820. https://doi.org/10.1016/S1474-4422(21)00252-0

    Article  Google Scholar 

  2. Alfred C, Pierre A, Goldstein Larry B et al (2011) Risk of stroke and cardiovascular events after ischemic stroke or transient ischemic attack in patients with type 2 diabetes or metabolic syndrome: secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Arch Neurol 68(10):1245–1251. https://doi.org/10.1001/archneurol.2011.146

    Article  Google Scholar 

  3. Lv Z, Guo Y (2020) Metformin and its benefits for various diseases. Front Endocrinol (Lausanne) 11:191. https://doi.org/10.3389/fendo.2020.00191

    Article  PubMed  Google Scholar 

  4. Zeng J, Zhu L, Liu J et al (2019) Metformin protects against oxidative stress injury induced by ischemia/reperfusion via regulation of the lncRNA-H19/miR-148a-3p/Rock2 Axis. Oxid Med Cell Longev 2019:8768327. https://doi.org/10.1155/2019/8768327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ashabi G, Khalaj L, Khodagholi F et al (2015) Pre-treatment with metformin activates Nrf2 antioxidant pathways and inhibits inflammatory responses through induction of AMPK after transient global cerebral ischemia. Metab Brain Dis 30(3):747–754. https://doi.org/10.1007/s11011-014-9632-2

    Article  CAS  PubMed  Google Scholar 

  6. Liu Y, Tang G, Li Y et al (2014) Metformin attenuates blood-brain barrier disruption in mice following middle cerebral artery occlusion. J Neuroinflammation 11:177. https://doi.org/10.1186/s12974-014-0177-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Venna VR, Li J, Hammond MD et al (2014) Chronic metformin treatment improves post-stroke angiogenesis and recovery after experimental stroke. Eur J Neurosci 39(12):2129–2138. https://doi.org/10.1111/ejn.12556

    Article  PubMed  PubMed Central  Google Scholar 

  8. Li J, Benashski SE, Venna VR et al (2010) Effects of metformin in experimental stroke. Stroke 41(11):2645–2652. https://doi.org/10.1161/STROKEAHA.110.589697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Jin Q, Cheng J, Liu Y et al (2014) Improvement of functional recovery by chronic metformin treatment is associated with enhanced alternative activation of microglia/macrophages and increased angiogenesis and neurogenesis following experimental stroke. Brain Behav Immun 40:131–142. https://doi.org/10.1016/j.bbi.2014.03.003

    Article  CAS  PubMed  Google Scholar 

  10. Westphal LP, Widmer R, Held U et al (2020) Association of prestroke metformin use, stroke severity, and thrombolysis outcome. Neurology 95(4):e362–e373. https://doi.org/10.1212/WNL.0000000000009951

    Article  CAS  PubMed  Google Scholar 

  11. Tu WJ, Liu Z, Chao BH et al (2022) Metformin use is associated with low risk of case fatality and disability rates in first-ever stroke patients with type 2 diabetes. Ther Adv Chronic Dis 13:20406223221076896. https://doi.org/10.1177/20406223221076894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. American Diabetes Association (2014) Diagnosis and classification of diabetes mellitus. Diabetes Care 37:S81-90. https://doi.org/10.2337/dc14-S081

    Article  Google Scholar 

  13. Powers WJ, Rabinstein AA, Ackerson T et al (2019) Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 50(12):e344–e418. https://doi.org/10.1161/STR.0000000000000211

    Article  PubMed  Google Scholar 

  14. Kleindorfer DO, Towfighi A, Chaturvedi S et al (2021) 2021 Guideline for the Prevention of stroke in patients with stroke and transient ischemic attack: a Guideline From the American Heart Association/American Stroke Association. Stroke 52(7):e364–e467. https://doi.org/10.1161/STR.0000000000000375

    Article  PubMed  Google Scholar 

  15. Adams HP Jr, Bendixen BH, Kappelle LJ et al (1993) Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 24(1):35–41. https://doi.org/10.1161/01.str.24.1.35

    Article  PubMed  Google Scholar 

  16. Akhtar N, Singh R, Kamran S et al (2022) Diabetes: Chronic Metformin Treatment and Outcome Following Acute Stroke. Front Neurol 13:849607. https://doi.org/10.3389/fneur.2022.849607

    Article  PubMed  PubMed Central  Google Scholar 

  17. Li W, Qu Z, Prakash R et al (2013) Comparative analysis of the neurovascular injury and functional outcomes in experimental stroke models in diabetic Goto-Kakizaki rats. Brain Res 1541:106–114. https://doi.org/10.1016/j.brainres.2013.10.021

    Article  CAS  PubMed  Google Scholar 

  18. Elgebaly MM, Prakash R, Li W et al (2010) Vascular protection in diabetic stroke: role of matrix metalloprotease-dependent vascular remodeling. J Cereb Blood Flow Metab 30(12):1928–1938. https://doi.org/10.1038/jcbfm.2010.120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Deng T, Zheng YR, Hou WW et al (2016) Pre-stroke metformin treatment is neuroprotective involving AMPK reduction. Neurochem Res 41(10):2719–2727. https://doi.org/10.1007/s11064-016-1988-8

    Article  CAS  PubMed  Google Scholar 

  20. Ghadernezhad N, Khalaj L, Pazoki-Toroudi H et al (2016) Metformin pretreatment enhanced learning and memory in cerebral forebrain ischaemia: the role of the AMPK/BDNF/P70SK signalling pathway. P Pharm Biol 54(10):2211–2219. https://doi.org/10.3109/13880209.2016.1150306

    Article  CAS  PubMed  Google Scholar 

  21. Zhu XC, Jiang T, Zhang QQ et al (2015) Chronic metformin preconditioning provides neuroprotection via suppression of NF-κB-mediated inflammatory pathway in rats with permanent cerebral ischemia. Mol Neurobiol 52(1):375–385. https://doi.org/10.1007/s12035-014-8866-7

    Article  CAS  PubMed  Google Scholar 

  22. Kumari R, Willing L, Kimball SR et al (2022) The effect of chronic exposure to metformin in a new type-2 diabetic NONcNZO10/LtJ mouse model of stroke. Pharmacol Rep 74(4):696–708. https://doi.org/10.1007/s43440-022-00382-z

    Article  CAS  PubMed  Google Scholar 

  23. Karimipour M, Shojaei Zarghani S, Mohajer Milani M et al (2018) Pre-treatment with metformin in comparison with post-treatment reduces cerebral ischemia reperfusion induced injuries in rats. Bull Emerg Trauma 6(2):115–121. https://doi.org/10.29252/beat-060205

    Article  PubMed  PubMed Central  Google Scholar 

  24. Mima Y, Kuwashiro T, Yasaka M et al (2016) Impact of metformin on the severity and outcomes of acute ischemic stroke in patients with type 2 diabetes mellitus. J Stroke Cerebrovasc Dis 25(2):436–446. https://doi.org/10.1016/j.jstrokecerebrovasdis.2015.10.016

    Article  PubMed  Google Scholar 

  25. Bres-Bullrich M, Fridman S, Sposato LA (2021) Relative Effect of stroke severity and age on outcomes of mechanical thrombectomy in acute ischemic stroke. Stroke 52(9):2846–2848. https://doi.org/10.1161/STROKEAHA.121.034946

    Article  PubMed  Google Scholar 

  26. Phan TG, Clissold BB, Ma H et al (2017) Predicting disability after ischemic stroke based on comorbidity index and stroke severity-from the virtual international stroke trials archive-acute collaboration. Front Neurol 8:192. https://doi.org/10.3389/fneur.2017.00192

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Justin Mark Dean from Liwen Bianji, Edanz Group China (www.liwenbianji.cn/ac), for editing the English text of a draft of the manuscript.

Funding

This work was supported by grants from the National Natural Science Foundation of China (NSFC, Grant code: 81971116) and Shaanxi Provinical Key Research and Development Project of China (Grant code: 2019ZDLSF01-04).

Author information

Authors and Affiliations

  1. Department of Neurology, the Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 Xiwulu Xi’an, Shaanxi, 710004, China

    Yating Jian, Heying Wang, Lili Zhao, Tao Li, Lei Zhang, Xiaoya Wang, Yiheng Zhang, Ye Li, Meijuan Dang, Ziwei Lu, Jialiang Lu, Yuxuan Feng, Yang Yang & Guilian Zhang

Authors
  1. Yating Jian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Heying Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lili Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaoya Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yiheng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ye Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Meijuan Dang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ziwei Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jialiang Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yuxuan Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Guilian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the conception of the work and the acquisition, analysis, and interpretation of data. All authors approved the final version of the manuscript to be published.

Corresponding author

Correspondence to Guilian Zhang.

Ethics declarations

Ethical approval

All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and national research committee and adhered to the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the local ethics committees.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jian, Y., Wang, H., Zhao, L. et al. Metformin treatment and acute ischemic stroke outcomes in patients with type 2 diabetes: a retrospective cohort study. Neurol Sci 44, 989–997 (2023). https://doi.org/10.1007/s10072-022-06491-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10072-022-06491-0

Keywords

Search

Navigation