History of Severe Hypoglycemia in Type 2 Diabetes Mellitus Unmasked Significant Atherosclerotic Coronary Artery Disease

A Comparative Case Control Study





hypoglycemia, coronary artery disease, type 2 diabetes mellitus, C-reactive protein


Objectives. A history of severe hypoglycemia (SH) is associated with cardiovascular (CV) events among patients with type 2 diabetes mellitus (T2DM). In this study, we compared the severity of atherosclerotic coronary artery disease (ACAD) in T2DM patients with and without a history of SH.

Methodology. We conducted a comparative case-control study involving 28 T2DM patients with a history of SH within the last 5 years with no documented ACAD, and matched them with 28 T2DM patients with no history of SH. All subjects underwent coronary artery calcium scoring (CACS) with or without coronary computed tomographic angiography (CCTA) to evaluate the severity of ACAD. 

Results. A history of SH in T2DM was associated with a higher prevalence of significant ACAD (79% versus 46%, p=0.026). A high CACS (≥100) was seen in a greater number of patients with a history of SH compared to those without (75% versus 43%, p=0.029). Similarly, there was a  higher prevalence of obstructive CAD in those with a history of SH compared to those without (72% versus 39%, p=0.036). Median C-reactive protein level was also higher among patients with a history of SH (0.41 mg/dL versus 0.16 mg/dL, p=0.029).

Conclusion.  In patients with T2DM, a history of SH is significantly associated with ACAD compared to those without SH. A history of SH warrants screening for ACAD.


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Author Biographies

Mohd Asyiq Raffali, UKM Medical Centre, Kuala Lumpur, Malaysia

Department of Medicine

Syawal Faizal Muhammad, UKM Medical Centre, Kuala Lumpur, Malaysia

Department of Medicine

Hamzaini Abdul Hamid, UKM Medical Centre, Kuala Lumpur, Malaysia

Department of Radiology

Azmawati Mohammed Nawi, UKM Medical Centre, Kuala Lumpur, Malaysia

Department of Community Health

Nor Azmi Kamaruddin, UKM Medical Centre, Kuala Lumpur, Malaysia

Department of Medicine


Bedenis R, Price AH, Robertson CM, et al. Association between severe hypoglycemia, adverse macrovascular events, and inflammation in the Edinburgh Type 2 Diabetes Study. Diabetes Care. 2014;37(12):3301-8. https://www.ncbi.nlm.nih.gov/pubmed/25239782. https://doi.org/10.2337/dc14-0908.

McCoy RG, Van Houten HK, Ziegenfuss JY, Shah ND, Wermers RA, Smith SA. Increased mortality of patients with diabetes reporting severe hypoglycemia. Diabetes Care. 2012;35(9):1897-901. https://www.ncbi.nlm.nih.gov/pubmed/22699297. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3425008. https://doi.org/10.2337/dc11-2054.

ORIGIN Trial Investigators; Mellbin LG, Rydén L, Riddle MC, et al. Does hypoglycaemia increase the risk of cardiovascular events? A report from the ORIGIN trial. Eur Heart J. 2013;34(40):3137-44. https://www.ncbi.nlm.nih.gov/pubmed/23999452. https://doi.org/10.1093/eurheartj/eht332.

Zoungas S, Patel A, Chalmers J, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med. 2010;363(15):1410-8. https://www.ncbi.nlm.nih.gov/pubmed/20925543. https://doi.org10.1056/NEJMoa1003795.

Hutton RA, Mikhailidis D, Dormandy KM, Ginsburg J. Platelet aggregation studies during transient hypoglycaemia: A potential method for evaluating platelet function. J Clin Pathol. 1979;32(5):434-8. https://www.ncbi.nlm.nih.gov/pubmed/469000. https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC1145703. https://doi.org/10.1136/jcp.32.5.434.

Wright RJ, Newby DE, Stirling D, Ludlam CA, Macdonald IA, Frier BM. Effects of acute insulin-induced hypoglycemia on indices of inflammation: Putative mechanism for aggravating vascular disease in diabetes. Diabetes Care. 2010;33(7):1591-7. https://www.ncbi.nlm.nih.gov/pubmed/20587725. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2890364. https://doi.org/10.2337/dc10-0013.

Dalsgaard-Nielsen J, Madsbad S, Hilsted J. Changes in platelet function, blood coagulation and fibrinolysis during insulin-induced hypoglycaemia in juvenile diabetics and normal subjects. Thromb Haemost. 1982;47(3):254-8. https://www.ncbi.nlm.nih.gov/pubmed/7051410.

Dandona P, Chaudhuri A, Dhindsa S Proinflammatory and prothrombotic effects of hypoglycemia. Diabetes Care. 2010;33(7):1686-7. https://www.ncbi.nlm.nih.gov/pubmed/20587729. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2890381. https://doi.org/10.2337/dc10-0503.

Joy NG, Hedrington MS, Briscoe VJ, Tate DB, Ertl AC, Davis SN. Effects of acute hypoglycemia on inflammatory and pro-atherothrombotic biomarkers in individuals with type 1 diabetes and healthy individuals. Diabetes Care. 2010;33(7):1529-35. https://www.ncbi.nlm.nih.gov/pubmed/20587723. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2890354. https://doi.org/10.2337/dc09-0354.

Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S49-73. https://www.ncbi.nlm.nih.gov/pubmed/24222018. https://doi.org/10.1161/01.cir.0000437741.48606.98.

D’Agostino RB Sr, Vasan RS, Pencina MJ, et. al. General cardiovascular risk profile for use in primary care: The Framingham Heart Study. Circulation. 2008;117(6):743-53. https://www.ncbi.nlm.nih.gov/pubmed/18212285. https://doi.org/10.1161/CIRCULATIONAHA.107.699579.

Kamath DY, Xavier D, Sigamani A, Pais P. High sensitivity C-reactive protein (hsCRP) & cardiovascular disease: An Indian perspective. Indian J Med Res. 2015;142(3): 261-8. https://www.ncbi.nlm.nih.gov/pubmed/26458341. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669860. https://doi.org/10.4103/0971-5916.166582.

Pfützner A, Forst T. High-sensitivity C-reactive protein as cardiovascular risk marker in patients with diabetes mellitus. Diabetes Technol Ther. 2006;8(1):28-36. https://www.ncbi.nlm.nih.gov/pubmed/16472048. https://doi.org/10.1089/dia.2006.8.28.

Dollery CM, McEwan JR, Henney AM. Matrix metalloproteinases and cardiovascular disease. Circ Res. 1995;77(5):863-8. https://www.ncbi.nlm.nih.gov/pubmed/7554139. https://doi.org/10.1161/01.res.77.5.863.

Kalela A, Koivu TA, Sisto T, et al. Serum matrix metalloproteinase-9 concentration in angiographically assessed coronary artery disease. Scand J Clin Lab Invest. 2002;62(5):337-42. https://www.ncbi.nlm.nih.gov/pubmed/12387578. https://doi.org/10.1080/00365510260296483.

Garvin P, Jonasson L, Nilsson L, Falk M, Kristenson M. Plasma matrix metalloproteinase-9 levels predict first-time coronary heart disease: An 8-year follow-up of a community-based middle-aged population. PLoS One. 2015;10(9):e0138290. https://www.ncbi.nlm.nih.gov/pubmed/26389803. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4577098. https://doi.org/10.1371/journal.pone.0138290.

Messerli FH. TIMPs, MMPs and cardiovascular disease. Eur Heart J. 2004;25(17):1475-6. https://www.ncbi.nlm.nih.gov/pubmed/15342163. https://doi.org/10.1016/j.ehj.2004.07.015.

Pletcher MJ, Tice JA, Pignone M, Browner WS. Using the coronary artery calcium score to predict coronary heart disease events: A systematic review and meta-analysis. Arch Intern Med. 2004;164(12):1285-92. https://www.ncbi.nlm.nih.gov/pubmed/15226161. https://doi.org/ 10.1001/archinte.164.12.1285.

Mieres JH, Makaryus AN, Redberg RF, Shaw LJ. Noninvasive coronary imaging. Am Fam Physician. 2007;75(8):1219-28. https://www.ncbi.nlm.nih.gov/pubmed/17477105.

Westwood ME, Raatz HDI, Misso K, et al. Systematic review of the accuracy of dual-source cardiac CT for detection of arterial stenosis in difficult to image patient groups. Radiology. 2013;267(2):387-95. https://www.ncbi.nlm.nih.gov/pubmed/23392425. https://doi.org/10.1148/radiol.13121136.

Mowatt G, Cummins E, Waugh N, et al. Systematic review of the clinical effectiveness and cost-effectiveness of 64-slice or higher computed tomography angiography as an alternative to invasive coronary angiography in the investigation of coronary artery disease. Health Technol Assess. 2008;12(17):iii-iv, ix-143. https://www.ncbi.nlm.nih.gov/pubmed/18462576. https://doi.org/10.3310/hta12170.

Agarwal S, Cox AJ, Herrington DM, et al. Coronary calcium score predicts cardiovascular mortality in diabetes: Diabetes Heart Study. Diabetes Care. 2013;36(4): 972-7. https://www.ncbi.nlm.nih.gov/pubmed/23230101. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609509. https://doi.org/10.2337/dc12-1548.

Edridge CL, Dunkley AJ, Bodicoat DH, et al. Prevalence and incidence of hypoglycaemia in 532,542 people with type 2 diabetes on oral therapies and insulin: A systematic review and meta-analysis of population based studies. PLoS One. 2015;10(6):e0126427. https://www.ncbi.nlm.nih.gov/pubmed/26061690. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465495. https://doi.org/10.1371/journal.pone.0126427.

Budoff MJ, Dowe D, Jollis JG, et al. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: Results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. J Am Coll Cardiol. 2008;52(21):1724-32. https://www.ncbi.nlm.nih.gov/pubmed/19007693. https://doi.org/10.1016/j.jacc.2008.07.031.

Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol. 1990;15(4):827-32. https://www.ncbi.nlm.nih.gov/pubmed/2407762. https://doi.org/10.1016/0735-1097(90)90282-t.

Grandhi GR, Mirbolouk M, Dardari ZA, et al. Interplay of coronary artery calcium and risk factors for predicting CVD/CHD mortality: The CAC Consortium. JACC Cardiovasc Imaging. 2020;13(5):1175-86. https://www.ncbi.nlm.nih.gov/pubmed/31734198. https://doi.org/10.1016/j.jcmg.2019.08.024.

Maffei E, Seitun S, Martini C, et al. Prognostic value of CT coronary angiography in diabetic and non-diabetic subjects with suspected CAD: Importance of presenting symptoms. Insights Imaging. 2011;2(1):25-38. https://www.ncbi.nlm.nih.gov/pubmed/22865423. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3288971. https://doi.org/10.1007/s13244-010-0053-4.

Einarson TR, Acs A, Ludwig C, Panton UH. Prevalence of cardiovascular disease in type 2 diabetes: A systematic literature review of scientific evidence from across the world in 2007-2017. Cardiovasc Diabetol. 2018;17(1):83. https://www.ncbi.nlm.nih.gov/pubmed/29884191. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994068. https://doi.org/10.1186/s12933-018-0728-6.

Goto A, Goto M, Terauchi Y, Yamaguchi N, Noda M. Association between severe hypoglycemia and cardiovascular disease risk in Japanese patients with type 2 diabetes. J Am Heart Assoc. 2016;5(3):e002875. https://www.ncbi.nlm.nih.gov/pubmed/26961698. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4943262. https://doi.org/10.1161/JAHA.115.002875.

Nematollahi LR, Kitabchi AE, Stentz FB, et al. Proinflammatory cytokines in response to insulin-induced hypoglycemic stress in healthy subjects. Metabolism. 2009;58(4):443-8. https://www.ncbi.nlm.nih.gov/pubmed/19303962. https://doi.org/10.1016/j.metabol.2008.10.018.

Sommerfield AJ, Wilkinson IB, Webb DJ, Frier BM. Vessel wall stiffness in type 1 diabetes and the central hemodynamic effects of acute hypoglycemia. Am J Physiol Endocrinol Metab. 2007;293(5):E1274-9. https://www.ncbi.nlm.nih.gov/pubmed/17726149. https://doi.org/10.1152/ajpendo.00114.2007.

Standl E, Stevens SR, Armstrong PW, et al. Increased risk of severe hypoglycemic events before and after cardiovascular outcomes in TECOS suggests an at-risk type 2 diabetes frail patient phenotype. Diabetes Care. 2018;41(3):596-603. https://www.ncbi.nlm.nih.gov/pubmed/29311155. https://doi.org/10.2337/dc17-1778.

Pieber TR, Marso SP, McGuire DK, et al. DEVOTE 3: Temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality. Diabetologia. 2018;61(1):58-65. https://www.ncbi.nlm.nih.gov/pubmed/28913543. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002964. https://doi.org/10.1007/s00125-017-4422-0.

Yun JS, Park YM, Han K, Cha SA, Ahn YB, Ko SH. Severe hypoglycemia and the risk of cardiovascular disease and mortality in type 2 diabetes: A nationwide population-based cohort study. Cardiovasc Diabetol. 2019;18(1):103. https://www.ncbi.nlm.nih.gov/pubmed/31412855. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694505. https://doi.org/10.1186/s12933-019-0909-y.

Clinical practice guidelines on primary and secondary prevention of cardiovascular disease 2017. Ministry of Health of Malaysia. https://www.malaysianheart.org/files/597736485dd17.pdf.

Muhlestein JB, Lappé DL, Lima JAC, et al. Effect of screening for coronary artery disease using CT angiography on mortality and cardiac events in high-risk patients with diabetes: The FACTOR-64 randomized clinical trial. JAMA. 2014;312(21):2234-43. https://www.ncbi.nlm.nih.gov/pubmed/25402757. https://doi.org/10.1001/jama.2014.15825.

Turrini F, Scarlini S, Mannucci C, et al. Does coronary Atherosclerosis Deserve to be Diagnosed earlY in Diabetic patients? The DADDY-D trial. Screening diabetic patients for unknown coronary disease. Eur J Intern Med. 2015;26(6):407-13. https://www.ncbi.nlm.nih.gov/pubmed/26058988. https://doi.org/10.1016/j.ejim.2015.05.006.

Bauters C, Lemesle G. Screening for asymptomatic coronary artery disease in patients with diabetes mellitus: A systematic review and meta-analysis of randomized trials. BMC Cardiovasc Disord. 2016;16:90. https://www.ncbi.nlm.nih.gov/pubmed/27165687. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862116. https://doi.org/10.1186/s12872-016-0256-9.

Matsuhisa M, Kuroda A. New risk factors of severe hypoglycemia. J Diabetes Investig. 2019;10(2):219-20. https://www.ncbi.nlm.nih.gov/pubmed/30175462. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400149. https://doi.org/10.1111/jdi.12925.



How to Cite

Raffali, M. A. ., Muhammad, S. F., Abdul Hamid, H., Mohammed Nawi, A., & Kamaruddin, N. A. (2021). History of Severe Hypoglycemia in Type 2 Diabetes Mellitus Unmasked Significant Atherosclerotic Coronary Artery Disease: A Comparative Case Control Study. Journal of the ASEAN Federation of Endocrine Societies, 36(1), 37–44. https://doi.org/10.15605/jafes.036.01.15



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