1. Matthew C. Riddle, MD¹,
2. Walter T. Ambrosius, PHD²,
3. David J. Brillon, MD³,
4. John B. Buse, MD, PHD⁴,
5. Robert P. Byington, MPH, PHD²,
6. Robert M. Cohen, MD⁵,
7. David C. Goff Jr., MD, PHD²,
8. Saul Malozowski, MD, PHD⁶,
9. Karen L. Margolis, MD, MPH⁷,
10. Jeffrey L. Probstfield, MD⁸,
11. Adrian Schnall, MD⁹,
12. Elizabeth R. Seaquist, MD¹⁰ and
13. for the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Investigators*

+Author 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.

1. Corresponding author: Matthew C. Riddle, [email protected].

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.