Chang-Sheng Sheng1,2, Jingyan Tian3,4, Ya Miao1,4, Yi Cheng1,2, Yulin Yang1,4, Peter D Reaven5, Zachary T Bloomgarden6, Guang Ning3,4. 1. State Key Laboratory of Medical Genomics, Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. 2. Center for Epidemiological Studies and Clinical Trials and Center for Vascular Evaluation, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. 3. State Key Laboratory of Medical Genomics, Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China gning@sibs.ac.cn tianjypaper@163.com. 4. Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. 5. Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ. 6. Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
Abstract
OBJECTIVE: The association between high glycemic variability and all-cause mortality has been widely investigated in epidemiological studies but rarely validated in glucose-lowering clinical trials. We aimed to identify the prognostic significance of visit-to-visit HbA1c variability in treated patients in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial population. RESEARCH DESIGN AND METHODS: We studied the risk of all-cause mortality in relation to long-term visit-to-visit HbA1c variability, expressed as coefficient of variation (CV), variability independent of the mean (VIM), and average real variability (ARV), from the 8th month to the transition from intensive to standard glycemic therapy. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratio (HR) and 95% CI. RESULTS: Compared with the standard therapy group (n = 4,728), the intensive therapy group (n = 4,755) had significantly lower mean HbA1c (6.6% [49 mmol/mol] vs. 7.7% [61 mmol/mol], P < 0.0001) and lower CV, VIM, and ARV (P < 0.0001). In multivariate adjusted analysis, all three HbA1c variability indices were significantly associated with total mortality in all patients as well as in the standard- and intensive-therapy groups analyzed separately. The hazard ratios for a 1-SD increase in HbA1c variability indices for all-cause mortality were 1.19 and 1.23 in intensive and standard therapy, respectively. Cross-tabulation analysis showed the third tertile of HbA1c mean and VIM had significantly higher all-cause mortality (HR 2.05; 95% CI 1.17-3.61; P < 0.01) only in the intensive-therapy group. CONCLUSIONS: Long-term visit-to-visit HbA1c variability was a strong predictor of all-cause mortality. HbA1c VIM combined with HbA1c mean conferred an increased risk for all-cause mortality in the intensive-therapy group.
RCT Entities:
OBJECTIVE: The association between high glycemic variability and all-cause mortality has been widely investigated in epidemiological studies but rarely validated in glucose-lowering clinical trials. We aimed to identify the prognostic significance of visit-to-visit HbA1c variability in treated patients in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial population. RESEARCH DESIGN AND METHODS: We studied the risk of all-cause mortality in relation to long-term visit-to-visit HbA1c variability, expressed as coefficient of variation (CV), variability independent of the mean (VIM), and average real variability (ARV), from the 8th month to the transition from intensive to standard glycemic therapy. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratio (HR) and 95% CI. RESULTS: Compared with the standard therapy group (n = 4,728), the intensive therapy group (n = 4,755) had significantly lower mean HbA1c (6.6% [49 mmol/mol] vs. 7.7% [61 mmol/mol], P < 0.0001) and lower CV, VIM, and ARV (P < 0.0001). In multivariate adjusted analysis, all three HbA1c variability indices were significantly associated with total mortality in all patients as well as in the standard- and intensive-therapy groups analyzed separately. The hazard ratios for a 1-SD increase in HbA1c variability indices for all-cause mortality were 1.19 and 1.23 in intensive and standard therapy, respectively. Cross-tabulation analysis showed the third tertile of HbA1c mean and VIM had significantly higher all-cause mortality (HR 2.05; 95% CI 1.17-3.61; P < 0.01) only in the intensive-therapy group. CONCLUSIONS: Long-term visit-to-visit HbA1c variability was a strong predictor of all-cause mortality. HbA1c VIM combined with HbA1c mean conferred an increased risk for all-cause mortality in the intensive-therapy group.
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