Review

The HbA1c and All-Cause Mortality Relationship in Patients with Type 2 Diabetes is J-Shaped: A Meta-Analysis of Observational Studies

Luke W. Arnold, Zhiqiang Wang

Manuscript submitted March 1, 2014; resubmitted March 12, 2014; accepted March 27, 2014; published in print August 10, 2014.

Keywords: type 2 diabetes, HbA1c, all-cause mortality, meta-analysis, non-linear regression, body mass index, risk factor, cardiovascular disease, comorbidity

Abstract

BACKGROUND: Low blood glucose and HbA1c levels are recommended in the literature on management of diabetes. However, data have shown that low blood glucose is associated with serious adverse effects for the patients and the recommendation has been criticized. Therefore, this article revisits the relationship between HbA1c and all-cause mortality by a meta-analysis of observational studies. AIM: The aim of this study is to determine whether there is a J- or U-shaped non-linear relationship between HbA1c and all-cause mortality in type 2 diabetes patients, implying an increased risk to premature all-cause mortality at high and low levels of HbA1c. METHODS: A comprehensive literature search was conducted using PubMed, Medline, and Cochrane Library databases with strict inclusion/exclusion criteria. The published adjusted hazard ratios (HR) with 95% confidence intervals of all-cause mortality for each HbA1c category and per study were analyzed. Fractional polynomial regression was used with random effect modeling to assess the non-linear relationship of the HR trends between studies. Seven eligible observational studies with a total of 147,424 participants were included in the study. RESULTS: A significant J-shaped relationship was observed between HbA1c and all-cause mortality. Crude relative risk for all-cause mortality identified a decreased risk per 1% increase in HbA1c below 7.5% (58 mmol/mol) (0.90, CI 0.86-0.94) and an increased risk per 1% increase in HbA1c above 7.5% (58 mmol/mol) (1.04, CI 1.01-1.06). Observational studies revealed a J-shaped relationship between HbA1c and all-cause mortality, equivalent to an increased risk of mortality at high and low HbA1c levels. CONCLUSIONS: This increased mortality at high and low HbA1c levels has significant implications on investigating optimum clinical HbA1c targets as it suggests that there are upper and lower limits for creating a 'security zone' for diabetes management.

Fulltext: HTML , PDF (530KB)

This article has been cited by other articles:

	Pioglitazone and risk of mortality in patients with type 2 diabetes: results from a European multidatabase cohort study Strongman H, Korhonen P, Williams R, Bahmanyar S, Hoti F, Christopher S, Majak M, Kool-Houweling L, Linder M, Dolin P, Heintjes EM BMJ Open Diabetes Res Care 2017. 5:e000364
	Association of Visit-to-Visit Variability of Systolic Blood Pressure With Cardiovascular Disease and Mortality in Primary Care Chinese Patients With Type 2 Diabetes-A Retrospective Population-Based Cohort Study Wan EY, Fung CS, Yu EY, Fong DY, Chen JY, Lam CL Diabetes Care 2017. 40(2):270-279
	Association of Periodontal Destruction and Diabetes with Mortality Kebede TG, Holtfreter B, Kocher T, Meisel P, Dietrich T, Biffar R, Dörr M, Völzke H, Pink C J Dent Res 2017. 96(1):56-63
	Diabetes control: Incidence of acute myocardial infarction and all-cause mortality among patients with 3-6 years' disease duration Reges O, Leibowitz M, Hoshen M, Leventer-Roberts M, Greenland P, Balicer R Eur J Prev Cardiol 2017. 1:2047487317702041
	A Test in Context: Hemoglobin A1c and Cardiovascular Disease Gore MO, McGuire DK J Am Coll Cardiol 2016. 68(22):2479-2486
	Long-term maintenance of efficacy of dapagliflozin in patients with type 2 diabetes mellitus and cardiovascular disease Leiter LA, Cefalu WT, de Bruin TW, Xu J, Parikh S, Johnsson E, Gause-Nilsson I Diabetes Obes Metab 2016. 18(8):766-774
	Association of variability in hemoglobin A1c with cardiovascular diseases and mortality in Chinese patients with type 2 diabetes mellitus - A retrospective population-based cohort study Wan EY, Fung CS, Fong DY, Lam CL J Diabetes Complications 2016. 30(7):1240-1247
	National guidelines for treatment of diabetic retinopathy: second edition of the national guidelines for treatment of diabetic retinopathy Ziemssen F, Lemmen K, Bertram B, Hammes HP, Agostini H Ophthalmologe 2016. 113(7):623-638
	Association of Hemoglobin A1c Levels With Cardiovascular Disease and Mortality in Chinese Patients With Diabetes Wan EY, Fung CS, Wong CK, Chin WY, Lam CL J Am Coll Cardiol 2016. 67(4):456-458
	Incidence of Acute Myocardial Infarction in Patients with Diabetes and Its Association with Mortality and Cardiopulmonary Complications in Puerto Rico Altamirano R, Caponigro M, Carrion G, Zevallos JC, Castro G, Gonzalez Sanchez JA, Barengo NC Am J Public Health Res 2016. 4(6):196-201
	HbA1c and Risks of All-Cause and Cause-Specific Death in Subjects without Known Diabetes: A Dose-Response Meta-Analysis of Prospective Cohort Studies Zhong GC, Ye MX, Cheng JH, Zhao Y, Gong JP Sci Rep 2016. 6:24071
	Bioactive Oxidised Products of Omega-6 and Omega-3, Excess Oxidative Stress, Oxidised Dietary Intake and Antioxidant Nutrient Deficiencies, in the Context of a Modern Diet Brown RA Fatty Acids 2016. In press
	Determinants of mortality in patients with type 2 diabetes: a review Engelmann J, Manuwald U, Rubach C, Kugler J, Birkenfeld AL, Hanefeld M, Rothe U Rev Endocr Metab Disord 2016. 17(1):129-137
	HbA1c and all-cause mortality risk among patients with type 2 diabetes Li W, Katzmarzyk PT, Horswell R, Wang Y, Johnson J, Hu G Int J Cardiol 2016. 202:490-496
	Investigation of the relationship between patient empowerment and glycaemic control in patients with type 2 diabetes: a cross-sectional analysis Fitzgerald M, O'Tuathaigh C, Moran J BMJ Open 2015. 5(12):e008422
	Improvements in the Management of Diabetic Nephropathy Dounousi E, Duni A, Leivaditis K, Vaios V, Eleftheriadis T, Liakopoulos V Rev Diabet Stud 2015. 12(1-2):119-133