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      Epidemiologic Relationships Between A1C and All-Cause Mortality During a Median 3.4-Year Follow-up of Glycemic Treatment in the ACCORD Trial

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      , MD 1 , , PHD 2 , , MD 3 , , MD, PHD 4 , , MPH, PHD 2 , , MD 5 , , MD, PHD 2 , , MD, PHD 6 , , MD, MPH 7 , , MD 8 , , MD 9 , , MD 10 , for the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Investigators
      Diabetes Care
      American Diabetes Association

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          Abstract

          OBJECTIVE

          Randomized treatment comparing an intensive glycemic treatment strategy with a standard strategy in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was ended early because of an unexpected excess of mortality in the intensive arm. As part of ongoing post hoc analyses of potential mechanisms for this finding, we explored whether on-treatment A1C itself had an independent relationship with mortality.

          RESEARCH DESIGN AND METHODS

          Participants with type 2 diabetes ( n = 10,251 with mean age 62 years, median duration of diabetes 10 years, and median A1C 8.1%) were randomly assigned to treatment strategies targeting either A1C <6.0% (intensive) or A1C 7.0–7.9% (standard). Data obtained during 3.4 (median) years of follow-up before cessation of intensive treatment were analyzed using several multivariable models.

          RESULTS

          Various characteristics of the participants and the study sites at baseline had significant associations with the risk of mortality. Before and after adjustment for these covariates, a higher average on-treatment A1C was a stronger predictor of mortality than the A1C for the last interval of follow-up or the decrease of A1C in the first year. Higher average A1C was associated with greater risk of death. The risk of death with the intensive strategy increased approximately linearly from 6–9% A1C and appeared to be greater with the intensive than with the standard strategy only when average A1C was >7%.

          CONCLUSIONS

          These analyses implicate factors associated with persisting higher A1C levels, rather than low A1C per se, as likely contributors to the increased mortality risk associated with the intensive glycemic treatment strategy in ACCORD.

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          Most cited references7

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          Diabetes and cardiovascular disease. The Framingham study.

          Based on 20 years of surveillance of the Framingham cohort relating subsequent cardiovascular events to prior evidence of diabetes, a twofold to threefold increased risk of clinical atherosclerotic disease was reported. The relative impact was greatest for intermittent claudication (IC) and congestive heart failure (CHF) and least for coronary heart disease (CHD), which was, nevertheless, on an absolute scale the chief sequela. The relative impact was substantially greater for women than for men. For each of the cardiovascular diseases (CVD), morbidity and mortality were higher for diabetic women than for nondiabetic men. After adjustment for other associated risk factors, the relative impact of diabetes on CHD, IC, or stroke incidence was the same for women as for men; for CVD death and CHF, it was greater for women. Cardiovascular mortality was actually about as great for diabetic women as for diabetic men.
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            Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial.

            To assess predictors of CVD mortality among men with and without diabetes and to assess the independent effect of diabetes on the risk of CVD death. Participants in this cohort study were screened from 1973 to 1975; vital status has been ascertained over an average of 12 yr of follow-up (range 11-13 yr). Participants were 347,978 men aged 35-57 yr, screened in 20 centers for MRFIT. The outcome measure was CVD mortality. Among 5163 men who reported taking medication for diabetes, 1092 deaths (603 CVD deaths) occurred in an average of 12 yr of follow-up. Among 342,815 men not taking medication for diabetes, 20,867 deaths were identified, 8965 ascribed to CVD. Absolute risk of CVD death was much higher for diabetic than nondiabetic men of every age stratum, ethnic background, and risk factor level--overall three times higher, with adjustment for age, race, income, serum cholesterol level, sBP, and reported number of cigarettes/day (P < 0.0001). For men both with and without diabetes, serum cholesterol level, sBP, and cigarette smoking were significant predictors of CVD mortality. For diabetic men with higher values for each risk factor and their combinations, absolute risk of CVD death increased more steeply than for nondiabetic men, so that absolute excess risk for diabetic men was progressively greater than for nondiabetic men with higher risk factor levels. These findings emphasize the importance of rigorous sustained intervention in people with diabetes to control blood pressure, lower serum cholesterol, and abolish cigarette smoking, and the importance of considering nutritional-hygienic approaches on a mass scale to prevent diabetes.
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              Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus.

              In persons with diabetes, chronic hyperglycemia (assessed by glycosylated hemoglobin level) is related to the development of microvascular disease; however, the relation of glycosylated hemoglobin to macrovascular disease is less clear. To conduct a meta-analysis of observational studies of the association between glycosylated hemoglobin and cardiovascular disease in diabetic persons. Search of the MEDLINE database by using Medical Subject Heading search terms and key words related to glycosylated hemoglobin, diabetes, and cardiovascular disease. Prospective cohort studies with data on glycosylated hemoglobin levels and incident cardiovascular disease. Relative risk estimates were derived or abstracted from each cohort study that met the inclusion criteria. Adjusted relative risk estimates for glycosylated hemoglobin (total glycosylated hemoglobin, hemoglobin A1, or hemoglobin A1c levels) and cardiovascular disease events (coronary heart disease and stroke) were pooled by using random-effects models. Three studies involved persons with type 1 diabetes (n = 1688), and 10 studies involved persons with type 2 diabetes (n = 7435). The pooled relative risk for cardiovascular disease was 1.18; this represented a 1-percentage point increase in glycosylated hemoglobin level (95% CI, 1.10 to 1.26) in persons with type 2 diabetes. Results in persons with type 1 diabetes were similar but had a wider CI (pooled relative risk, 1.15 [CI, 0.92 to 1.43]). This review largely reflects the limitations of the literature. Important concerns were residual confounding, the possibility of publication bias, the small number of studies, and the heterogeneity of study results. Pending confirmation from large, ongoing clinical trials, this analysis shows that observational studies are consistent with limited clinical trial data and suggests that chronic hyperglycemia is associated with an increased risk for cardiovascular disease in persons with diabetes.
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                Author and article information

                Journal
                Diabetes Care
                diacare
                dcare
                Diabetes Care
                Diabetes Care
                American Diabetes Association
                0149-5992
                1935-5548
                May 2010
                : 33
                : 5
                : 983-990
                Affiliations
                [1] 1Division of Endocrinology, Diabetes, and Clinical Nutrition, Oregon Health and Science University, Portland, Oregon;
                [2] 2Wake Forest University School of Medicine, Winston-Salem, North Carolina;
                [3] 3Weill Cornell Medical College of Cornell University, New York, New York;
                [4] 4University of North Carolina School of Medicine, Chapel Hill, North Carolina;
                [5] 5University of Cincinnati College of Medicine, Cincinnati, Ohio;
                [6] 6National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland;
                [7] 7Health Partners Research Foundation, Minneapolis, Minnesota;
                [8] 8University of Washington School of Medicine, Seattle, Washington;
                [9] 9Case Western Reserve University School of Medicine, Cleveland, Ohio;
                [10] 10University of Minnesota School of Medicine, Minneapolis, Minnesota.
                Author notes
                Corresponding author: Matthew C. Riddle, riddlem@ 123456ohsu.edu .

                *The entire list of the ACCORD investigators can be found in an appendix to ref. 11.

                Article
                1278
                10.2337/dc09-1278
                2858202
                20427682
                a73f6c7f-1577-47e1-905b-748ce5b0cce4
                © 2010 by the American Diabetes Association.

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

                History
                : 29 July 2009
                : 7 February 2010
                Funding
                Funded by: National Institutes of Health
                Award ID: N01-HC-95178
                Award ID: N01-HC-95179
                Award ID: N01-HC-95180
                Award ID: N01-HC-95181
                Award ID: N01-HC-95182
                Award ID: N01-HC-95183
                Award ID: N01-HC-95184
                Award ID: IAA-Y1-HC-9035
                Award ID: IAA-Y1-HC-1010
                Categories
                Original Research
                Clinical Care/Education/Nutrition/Psychosocial Research

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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