The Association of Hypoglycemia with Stroke Risk: A Systematic Review and Meta-Analysis
Association of Hypoglycemia with Stroke Risk
Keywords:
hypoglycemia, mortality, risk, strokeAbstract
Background and aim: The prevalence of stroke continues to increase worldwide, and optimal glucose control remains an important component of acute stroke management. However, the occurrence of hypoglycemia in patients with stroke, particularly hypoglycemia-induced stroke mimics, and its association with mortality remain controversial. This study was conducted to evaluate the occurrence of hypoglycemia in stroke patients, and to assess its association with mortality.
Methods: This systematic review and meta-analysis followed PRISMA guidelines and was registered in PROSPERO (CRD420261306540). PubMed, Scopus, ScienceDirect, Taylor and Francis, ProQuest, EBSCO, and Springer were searched for English-language observational studies involving adults.
Results: A total of 11 studies with 2,024,725 participants were involved. Hypoglycemia was significantly correlated with an increased risk of stroke, with a relative risk (RR) of 1.73 (95% confidence interval [CI]: 1.35–2.22; 95% prediction interval [PI]: 0.81–3.69; p < 0.01). Inter-subgroup analysis showed that severe hypoglycemia (SH) increased the risk by twofold compared to non-severe hypoglycemia (NSH) RR 1.96 (95%CI: 1.38-2.78; p <0.01). In contrast, mild hypoglycemia did not significantly increase the risk of stroke compared to normoglycemia (RR 1.27; 95% CI: 0.79-2.05; p = 0.32). In terms of mortality, hypoglycemia increased the risk of mortality (RR 2.42; 95% CI: 1.59-3.68; p <0.01). Across the analyzed comparisons, severe hypoglycemia was generally associated with higher stroke and mortality risks (RR 2.56; 95%CI: 1.36-4.81; p <0.01).
Conclusion: Hypoglycemia is significantly associated with increased risks of stroke and mortality, with the greatest impact observed in SH episodes, underscoring the clinical importance of preventing SH.
References
1. Feigin VL, Brainin M, Norrving B, Martins SO, Pandian J, Lindsay P, et al. World Stroke Organization: Global Stroke Fact Sheet 2025. Vol. 20, International Journal of Stroke SAGE Publications Inc.; 2025. p. 132–44.
2. Committee ADAPP, ElSayed NA, McCoy RG, Aleppo G, Balapattabi K, Beverly EA, et al. 6. Glycemic Goals and Hypoglycemia: Standards of Care in Diabetes—2025. Diabetes Care. American Diabetes Association; 2025;48(Supplement_1):S128–45. DOI: 10.2337/dc25-S006
3. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al. 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. Vol. 50, Stroke Lippincott Williams and Wilkins; 2019. p. E344–418.
4. Singh RJ, Doshi D, Barber PA. Hypoglycemia Causing Focal Cerebral Hypoperfusion and Acute Stroke Symptoms. Vol. 48, Canadian Journal of Neurological Sciences Cambridge University Press; 2021. p. 550–2.
5. Bree AJ, Puente EC, Daphna-Iken D, Fisher SJ, Fisher S. Diabetes increases brain damage caused by severe hypoglycemia. Am J Physiol Endocrinol Metab. 2009;297:194–201. DOI: 10.1152/ajpendo.91041.2008.-Insulin-induced
6. Denorme F, Portier I, Kosaka Y, Campbell RA. Hyperglycemia exacerbates ischemic stroke outcome independent of platelet glucose uptake. Journal of Thrombosis and Haemostasis. Blackwell Publishing Ltd; 2021;19(2):536–46. DOI: 10.1111/jth.15154
7. Ohshita T, Imamura E, Nomura E, Wakabayashi S, Kajikawa H, Matsumoto M. Hypoglycemia with focal neurological signs as stroke mimic: Clinical and neuroradiological characteristics. J Neurol Sci. Elsevier; 2015;353(1–2):98–101. DOI: 10.1016/j.jns.2015.04.015
8. Hsu PF, Sung SH, Cheng HM, Yeh JS, Liu WL, Chan WL, et al. Association of clinical symptomatic hypoglycemia with cardiovascular events and total mortality in type 2 diabetes: A nationwide population-based study. Diabetes Care. 2013;36(4):894–900. DOI: 10.2337/dc12-0916
9. Lee AK, Warren B, Lee CJ, McEvoy JW, Matsushita K, Huang ES, et al. The association of severe hypoglycemia with incident cardiovascular events and mortality in adults with type 2 diabetes. Diabetes Care. American Diabetes Association Inc.; 2018;41(1):104–11. DOI: 10.2337/dc17-1669
10. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. Vol. 372, BMJ BMJ Publishing Group; 2021.
11. Bedenis R, Price AH, Robertson CM, Morling JR, Frier BM, Strachan MWJ, et al. Association Between Severe Hypoglycemia, Adverse Macrovascular Events, and Inflammation in the Edinburgh Type 2 Diabetes Study. Diabetes Care. American Diabetes Association; 2014;37(12):3301–8. DOI: 10.2337/dc14-0908
12. Rana JS, Moffet HH, Liu JY, Karter AJ. Severe Hypoglycemia and Risk of Atherosclerotic Cardiovascular Disease in Patients With Diabetes. Diabetes Care. American Diabetes Association; 2021;44(3):e40–1. DOI: 10.2337/DC20-2798
13. Nunes AP, Iglay K, Radican L, Engel SS, Yang J, Doherty MC, et al. Hypoglycaemia seriousness and weight gain as determinants of cardiovascular disease outcomes among sulfonylurea users. Diabetes Obes Metab. Blackwell Publishing Ltd; 2017;19(10):1425–35. DOI: 10.1111/dom.13000
14. Christou MA, Christou PA, Kyriakopoulos C, Christou GA, Tigas S. Effects of Hypoglycemia on Cardiovascular Function in Patients with Diabetes. Int J Mol Sci. 2023;24(11):9357. DOI: 10.3390/ijms24119357
15. Hanefeld M, Frier BM, Pistrosch F. Hypoglycemia and Cardiovascular Risk: Is There a Major Link? Diabetes Care. 2016;39(Supplement_2):S205–9. DOI: 10.2337/dcS15-3014
16. Rickels MR. Hypoglycemia‐associated autonomic failure, counterregulatory responses, and therapeutic options in type 1 diabetes. Ann N Y Acad Sci. 2019;1454(1):68–79. DOI: 10.1111/nyas.14214
17. Chow E, Bernjak A, Williams S, Fawdry RA, Hibbert S, Freeman J, et al. Risk of Cardiac Arrhythmias During Hypoglycemia in Patients With Type 2 Diabetes and Cardiovascular Risk. Diabetes. 2014;63(5):1738–47. DOI: 10.2337/db13-0468
18. Cryer PE. Hypoglycemia-associated autonomic failure in diabetes. In: Handbook of Clinical Neurology. 2013. DOI: 10.1016/B978-0-444-53491-0.00023-7
19. Bonds DE, Miller ME, Bergenstal RM, Buse JB, Byington RP, Cutler JA, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ. 2010;340(jan08 1):b4909–b4909. DOI: 10.1136/bmj.b4909
20. Zoungas S, Patel A, Chalmers J, de Galan BE, Li Q, Billot L, et al. Severe Hypoglycemia and Risks of Vascular Events and Death. New England Journal of Medicine. 2010;363(15):1410–8. DOI: 10.1056/NEJMoa1003795
21. Nakhleh A, Shehadeh N. Hypoglycemia in diabetes: An update on pathophysiology, treatment, and prevention. World J Diabetes. 2021;12(12):2036–49. DOI: 10.4239/wjd.v12.i12.2036
22. Mattishent K, Loke YK. Meta-Analysis: Association Between Hypoglycemia and Serious Adverse Events in Older Patients Treated With Glucose-Lowering Agents. Front Endocrinol (Lausanne). Frontiers Media S.A.; 2021;12. DOI: 10.3389/fendo.2021.571568
23. Yeh JS, Sung SH, Huang HM, Yang HL, You LK, Chuang SY, et al. Hypoglycemia and risk of vascular events and mortality: a systematic review and meta-analysis. Acta Diabetol. Springer-Verlag Italia s.r.l.; 2016;53(3):377–92. DOI: 10.1007/s00592-015-0803-3
24. Li J, Ji C, Zhang W, Lan L, Ge W. Effect of new glucose-lowering drugs on stroke in patients with type 2 diabetes: A systematic review and Meta-analysis. Vol. 37, Journal of Diabetes and its Complications Elsevier Inc.; 2023.
25. Rajati F, Rajati M, Rasulehvandi R, Kazeminia M. Prevalence of stroke in the elderly: A systematic review and meta-analysis. Vol. 32, Interdisciplinary Neurosurgery: Advanced Techniques and Case Management Elsevier B.V.; 2023.
26. Pirscoveanu DFV, Olaru DG, Hermann DM, Doeppner TR, Ghinea FS, Popa-Wagner A. Immune genes involved in synaptic plasticity during early postnatal brain development contribute to post-stroke damage in the aging male rat brain. Biogerontology. Springer Science and Business Media B.V.; 2025;26(2). DOI: 10.1007/s10522-025-10203-4
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