Glycemic Control in Diabetes: A Tale of Three Studies

Abstract

Much of the controversy at the American Diabetes Association Scientific Sessions, held 6–10 June 2008 in San Francisco, California, pertained to questions raised about the benefits of intensive glycemic control by three large clinical studies: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, the Action in Diabetes and Vascular Disease (ADVANCE) trial, and the Veterans’ Administration Diabetes Trial (VADT). All three presented somewhat negative study results. David Goff (Winston-Salem, NC) discussed the ACCORD study design. The goal of ACCORD was to determine whether cardiovascular disease (CVD) event rates could be reduced by intensively treating three important risk factors (hyperglycemia, dyslipidemia, and high blood pressure) in a double 2 × 2 factorial design. For glycemia, the question of A1C <6 vs. 7–7.9% was addressed. Goff reviewed previous studies that led to the decision to aim for the low A1C target. In the UK Prospective Diabetes Study (UKPDS), insulin and sulfonylurea treatment achieved a mean A1C level of 7%, with 7.9% in a control group. The 16% CVD reduction just missed statistical significance. Metformin treatment in this study achieved a mean A1C level of 7.4% with 8% in a control group, associated with a significant 39% CVD reduction. (Goff did not mention that, compared with sulfonylureas alone, the other UKPDS metformin substudy showed that metformin with a sulfonylurea was associated with 96, 60, and 9% increases in diabetes-related and all-cause mortality and in myocardial infarction [1].) A nonsignificant CVD risk reduction of ∼50% was seen in the Kumamoto study, while there was also a nonsignificant CVD risk increase of ∼50% in the Veterans’ Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes (VACSDM); both studies showed A1C 7.1% in the treatment group and 9.3–9.4% in the control group. Analysis of a number of observational studies …