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Predictions of diabetes complications and mortality using hba1c variability: a 10-year observational cohort study

Abstract

Introduction

Emerging evidence suggests that HbA1c variability, in addition to HbA1c itself, can be used as a predictor for mortality. The present study aims to examine the predictive power of mean HbA1c and HbA1c variability measures for diabetic complications as well as mortality.

Methods

The retrospective observational study analyzed diabetic patients who were prescribed insulin at outpatient clinics of the Prince of Wales Hospital and Shatin Hospital, Hong Kong, from 1 January to 31 December, 2009. Standard deviation (SD), root mean square (RMS), and coefficient of variation were used as measures of HbA1c variability. The primary outcomes were all-cause and cardiovascular mortality. Secondary outcomes were diabetes-related complications.

Results

The study cohort consists of 3424 patients, including 3137 patients with at least three HbA1c measurements. The low mean HbA1c subgroup had significantly shorter time-to-death for all-cause mortality (P < 0.001) but not cardiovascular mortality (P = 0.920). The high Hba1c subgroup showed shorter time-to-death for all-cause (P < 0.001) and cardiovascular mortality (P < 0.001). Mean Hba1c and Hba1c variability predicted all-cause as well as cardiovascular-specific mortality. In terms of secondary outcomes, mean HbA1c and HbA1c variability significantly predicted diabetic ketoacidosis/hyperosmolar hyperglycemic state/diabetic coma, neurological, ophthalmological, and renal complications. A significant association between dichotomized HbA1c variability and hypoglycemia frequency was found (P < 0.0001).

Conclusion

High HbA1c variability is associated with increased risk of all-cause and cardiovascular mortality, as well as diabetic complications. The association between hypoglycemic frequency, HbA1c variability, and mortality suggests that intermittent hypoglycemia resulting in poorer outcomes in diabetic patients.

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References

  1. 1.

    Saeedi P, Petersohn I, Salpea P et al (2019) Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9(th) edition. Diabetes Res Clin Pract 157:107843. https://doi.org/10.1016/j.diabres.2019.107843

    Article  PubMed  Google Scholar 

  2. 2.

    King P, Peacock I, Donnelly R (1999) The UK prospective diabetes study (UKPDS): clinical and therapeutic implications for type 2 diabetes. Br J Clin Pharmacol 48(5):643–648. https://doi.org/10.1046/j.1365-2125.1999.00092.x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Heller SR, Group AC (2009) A summary of the advance trial. Diabetes Care 32(Suppl 2):S357–S361. https://doi.org/10.2337/dc09-S339

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Huang ES, Davis AM (2015) Glycemic control in older adults with diabetes mellitus. JAMA 314(14):1509–1510. https://doi.org/10.1001/jama.2015.8345

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Buse JB, Bigger JT et al (2007) Action to control cardiovascular risk in diabetes (ACCORD) trial: design and methods. Am J Cardiol. 99(12A):21i–33i. https://doi.org/10.1016/j.amjcard.2007.03.003

    Article  PubMed  Google Scholar 

  6. 6.

    Currie CJ, Peters JR, Tynan A et al (2010) Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study. Lancet 375(9713):481–489. https://doi.org/10.1016/S0140-6736(09)61969-3

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Anyanwagu U, Mamza J, Donnelly R, Idris I (2019) Relationship between HbA1c and all-cause mortality in older patients with insulin-treated type 2 diabetes: results of a large UK cohort study. Age Ageing 48(2):235–240. https://doi.org/10.1093/ageing/afy178

    Article  PubMed  Google Scholar 

  8. 8.

    Arnold LW, Wang Z (2014) The HbA1c and all-cause mortality relationship in patients with type 2 diabetes is J-shaped: a meta-analysis of observational studies. Rev Diabet Stud 11(2):138–152. https://doi.org/10.1900/RDS.2014.11.138

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    American Diabetes A (2020) 12. Older adults standards of medical care in diabetes-2020. Diabetes Care 43(Suppl 1):S152–S162. https://doi.org/10.2337/dc20-S012

    Article  Google Scholar 

  10. 10.

    Gorst C, Kwok CS, Aslam S et al (2015) Long-term glycemic variability and risk of adverse outcomes: a systematic review and meta-analysis. Diabetes Care 38(12):2354–2369. https://doi.org/10.2337/dc15-1188

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Forbes A, Murrells T, Mulnier H, Sinclair AJ (2018) Mean HbA1c, HbA1c variability, and mortality in people with diabetes aged 70 years and older: a retrospective cohort study. Lancet Diabetes Endocrinol 6(6):476–486. https://doi.org/10.1016/S2213-8587(18)30048-2

    Article  PubMed  Google Scholar 

  12. 12.

    Li S, Nemeth I, Donnelly L, Hapca S, Zhou K, Pearson ER (2020) Visit-to-visit HbA1c variability is associated with cardiovascular disease and microvascular complications in patients with newly diagnosed type 2 diabetes. Diabetes Care 43(2):426–432. https://doi.org/10.2337/dc19-0823

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Su JB, Zhao LH, Zhang XL et al (2018) HbA1c variability and diabetic peripheral neuropathy in type 2 diabetic patients. Cardiovasc Diabetol 17(1):47. https://doi.org/10.1186/s12933-018-0693-0

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Luk AO, Ma RC, Lau ES et al (2013) Risk association of HbA1c variability with chronic kidney disease and cardiovascular disease in type 2 diabetes: prospective analysis of the Hong Kong diabetes registry. Diabetes Metab Res Rev 29(5):384–390. https://doi.org/10.1002/dmrr.2404

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Waden J, Forsblom C, Thorn LM et al (2009) A1C variability predicts incident cardiovascular events, microalbuminuria, and overt diabetic nephropathy in patients with type 1 diabetes. Diabetes 58(11):2649–2655. https://doi.org/10.2337/db09-0693

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Wright RJ, Frier BM (2008) Vascular disease and diabetes: is hypoglycaemia an aggravating factor? Diabetes Metab Res Rev 24(5):353–363. https://doi.org/10.1002/dmrr.865

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Kahal H, Halama A, Aburima A et al (2020) Effect of induced hypoglycemia on inflammation and oxidative stress in type 2 diabetes and control subjects. Sci Rep 10(1):4750. https://doi.org/10.1038/s41598-020-61531-z

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Wang J, Alexanian A, Ying R et al (2012) Acute exposure to low glucose rapidly induces endothelial dysfunction and mitochondrial oxidative stress: role for AMP kinase. Arterioscler Thromb Vasc Biol 32(3):712–720. https://doi.org/10.1161/ATVBAHA.111.227389

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Li CK, Xu Z, Ho J et al (2020) Association of NPAC score with survival after acute myocardial infarction. Atherosclerosis 301:30–36. https://doi.org/10.1016/j.atherosclerosis.2020.03.004

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Ju C, Lai RWC, Li KHC et al (2019) Comparative cardiovascular risk in users versus non-users of xanthine oxidase inhibitors and febuxostat versus allopurinol users. Rheumatology (Oxford). https://doi.org/10.1093/rheumatology/kez576

    Article  Google Scholar 

  21. 21.

    UK Prospective Diabetes Study (UKPDS) Group (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352(9131):854–865

    Article  Google Scholar 

  22. 22.

    Andersson C, van Gaal L, Caterson ID et al (2012) Relationship between HbA1c levels and risk of cardiovascular adverse outcomes and all-cause mortality in overweight and obese cardiovascular high-risk women and men with type 2 diabetes. Diabetologia 55(9):2348–2355. https://doi.org/10.1007/s00125-012-2584-3

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Action to Control Cardiovascular Risk in Diabetes Study G, Gerstein HC, Miller ME et al (2008) Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 358(24):2545–2559. https://doi.org/10.1056/NEJMoa0802743

    Article  Google Scholar 

  24. 24.

    Li W, Katzmarzyk PT, Horswell R, Wang Y, Johnson J, Hu G (2016) HbA1c and all-cause mortality risk among patients with type 2 diabetes. Int J Cardiol 202:490–496. https://doi.org/10.1016/j.ijcard.2015.09.070

    Article  PubMed  Google Scholar 

  25. 25.

    Carson AP, Fox CS, McGuire DK et al (2010) Low hemoglobin A1c and risk of all-cause mortality among US adults without diabetes. Circ Cardiovasc Qual Outcomes 3(6):661–667. https://doi.org/10.1161/CIRCOUTCOMES.110.957936

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Crane PK, Walker R, Hubbard RA et al (2013) Glucose levels and risk of dementia. N Engl J Med 369(6):540–548. https://doi.org/10.1056/NEJMoa1215740

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Rogers SC, Zhang X, Azhar G, Luo S, Wei JY (2013) Exposure to high or low glucose levels accelerates the appearance of markers of endothelial cell senescence and induces dysregulation of nitric oxide synthase. J Gerontol A Biol Sci Med Sci 68(12):1469–1481. https://doi.org/10.1093/gerona/glt033

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Zaslavsky O, Walker RL, Crane PK, Gray SL, Larson EB (2016) Glucose levels and risk of frailty. J Gerontol A Biol Sci Med Sci 71(9):1223–1229. https://doi.org/10.1093/gerona/glw024

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Gu J, Pan JA, Fan YQ, Zhang HL, Zhang JF, Wang CQ (2018) Prognostic impact of HbA1c variability on long-term outcomes in patients with heart failure and type 2 diabetes mellitus. Cardiovasc Diabetol 17(1):96. https://doi.org/10.1186/s12933-018-0739-3

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Cheng D, Fei Y, Liu Y et al (2014) HbA1C variability and the risk of renal status progression in diabetes mellitus: a meta-analysis. PLoS ONE 9(12):e115509. https://doi.org/10.1371/journal.pone.0115509

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Monnier L, Mas E, Ginet C et al (2006) Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA 295(14):1681–1687. https://doi.org/10.1001/jama.295.14.1681

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Costantino S, Paneni F, Battista R et al (2017) Impact of glycemic variability on chromatin remodeling, oxidative stress, and endothelial dysfunction in patients with type 2 diabetes and with target HbA1c levels. Diabetes 66(9):2472–2482. https://doi.org/10.2337/db17-0294

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Tse G, Lai ET, Tse V, Yeo JM (2016) Molecular and electrophysiological mechanisms underlying cardiac arrhythmogenesis in diabetes mellitus. J Diabetes Res 2016:2848759. https://doi.org/10.1155/2016/2848759

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Tse G, Yan BP, Chan YW, Tian XY, Huang Y (2016) Reactive oxygen species, endoplasmic reticulum stress and mitochondrial dysfunction: the link with cardiac arrhythmogenesis. Front Physiol 7:313. https://doi.org/10.3389/fphys.2016.00313

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Skriver MV, Sandbaek A, Kristensen JK, Stovring H (2015) Relationship of HbA1c variability, absolute changes in HbA1c, and all-cause mortality in type 2 diabetes: a Danish population-based prospective observational study. BMJ Open Diabetes Res Care 3(1):e000060. https://doi.org/10.1136/bmjdrc-2014-000060

    Article  PubMed  PubMed Central  Google Scholar 

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Correspondence to Wing Tak Wong or Gary Tse.

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This single-center retrospective observational study was approved by The Joint Chinese University of Hong Kong – New Territories East Cluster Clinical Research Ethics Committee.

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Informed consent was waived by the Ethics Committee due to the retrospective, observational nature of the study.

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Lee, S., Liu, T., Zhou, J. et al. Predictions of diabetes complications and mortality using hba1c variability: a 10-year observational cohort study. Acta Diabetol 58, 171–180 (2021). https://doi.org/10.1007/s00592-020-01605-6

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