Spotlight on intensive glycemic control

Three recent studies reanalyzed past data about the effects of intensive glycemic control and published new findings about how and which patients may benefit.

In the June 4 New England Journal of Medicine, the Veterans Affairs Diabetes Trial (VADT) investigators reported on 5 years of new follow-up data from their study, in which 1,791 veterans with type 2 diabetes were randomized to intensive or standard glucose control for an average of 7.5 years. They found that 3 years after the active trial ended, HbA1c levels between groups differed by only 0.2 to 0.3 percentage points (compared to 1.5 percentage points during the trial). However, the intensive group had a significantly lower risk of a first major cardiovascular event (hazard ratio, 0.83; 95% CI, 0.70 to 0.99; P=0.04). There was no significant difference between groups in cardiovascular or total mortality during follow-up, however. The effect on cardiovascular events would work out to a reduction of 8.6 per 1,000 person-years, the study authors concluded, but given the lack of impact on mortality, the benefits should be weighed against potential harms of intensive control. Possibly due to their clinical heterogeneity, the major studies of intensive glycemic control (VADT, ACCORD, ADVANCE, and UKPDS) have found very different results regarding mortality outcomes, the study authors noted.

The ACCORD trial found that intensive control was associated with increased mortality, and 2 recent studies examined potential explanations for that finding, using data from the original trial. In the first study, published in the June Diabetes Care, researchers entered the study patients' fasting plasma glucose level at baseline into a linear regression equation to calculate a predicted HbA1c level. Hemoglobin glycation index was then determined by subtracting the predicted HbA1c from the observed HbA1c at baseline. They found that patients with a high hemoglobin glycation index (a large difference between predicted and observed HbA1c) had higher mortality on intensive treatment than standard treatment. In contrast, participants with low or moderate hemoglobin glycation indices had reductions in cardiovascular events and mortality on standard treatment. This suggests that intensive treatment's benefits for some patients may have been masked by the detrimental effects on the subgroup with high hemoglobin glycation index, the study authors concluded, reminding clinicians that “HbA1c is not a one-size-fits all indicator.”

In the other study, researchers compared ACCORD participants who had severe hypoglycemia and failed to achieve an HbA1c below 6% with controls, who were those study patients that achieved an HbA1c below 6% without hypoglycemia. Results were published in the June Diabetologia. The patients in the first group were significantly more likely to test positive at baseline for insulin deficiency (adjusted odds ratio, 23.2; 95% CI, 9.0 to 59.5; P<0.0001) and various islet autoantibodies (including glutamic acid decarboxylase, tyrosine phosphatase-related islet antigen 2, insulin, and zinc transporter 8). Quantifying insulin deficiency in type 2 diabetes may be important, and C-peptide and islet autoantibodies may serve as biomarkers to predict the risk of severe hypoglycemia under intensified treatment, the study authors concluded.