Spotlight on the Diabetes Prevention Program

Recently published studies used data from the Diabetes Prevention Program (DPP) Outcomes Study to assess the impact of diabetes prevention efforts on cognition and coronary artery calcium.

The DPP was a randomized trial that enrolled 3,234 participants between 1996 and 1999. All were considered at risk for diabetes, with a body mass index of 24 kg/m² or more (22 kg/m² in Asian Americans), a fasting plasma glucose level between 95 and 125 mg/dL, and impaired glucose tolerance. They were randomized to placebo, metformin, or a lifestyle intervention, with the interventions lasting 2.8 years on average. After the conclusion of the DPP, participants were bridged to the DPP Outcomes Study, which offered all patients some continuing lifestyle interventions. The new studies are based on data gathered 12 to 14 years after randomization.

The cognition study, published by Diabetes Care on May 12, included 2,280 DPP participants (749 in the lifestyle group, 776 in the metformin group, 755 in the placebo group). Researchers assessed participants' cognition with the Spanish English Verbal Learning Test, letter fluency and animal fluency tests, the Digit Symbol Substitution Test, and a composite cognitive score. They found no difference in cognition among the interventions. Development of diabetes was also not associated with cognition, but patients who had higher HbA1c levels at the time of cognition testing did show worse cognitive results. The overall findings led the authors to conclude that exposure to intensive lifestyle intervention or metformin was not related to cognition.

A previous Finnish study found a similar lack of effect on cognition from a successful lifestyle intervention to prevent diabetes, the authors noted. These findings argue against hypotheses that declines in cognitive performance can be prevented by preventing or treating diabetes, they added. The results do also suggest that metformin is cognitively safe among people with or at risk for diabetes. It's not clear why worse glycemia would be associated with worse cognition, despite the lack of effect of the interventions on cognition, the authors said. Possibilities include that it takes longer than the study period for glycemia to affect cognition, that the causal direction is reversed (that is, that cognitive impairment causes hyperglycemia), or that glycemia and cognitive decline have other common determinants.

The other study, published by Circulation on May 5, measured coronary artery calcium among 2,029 DPP Outcomes Study participants. Coronary artery calcium was measured 14 years after randomization and was categorized by severity and presence. No difference in severity or presence of calcium was found between the lifestyle and placebo groups. However, among men, there was a significant difference between the metformin and placebo groups (age-adjusted mean coronary artery calcium severity, 39.5 vs. 66.9 Agatston units [P=0.04]; calcium presence, 75% vs. 84% [P=0.02]). This effect wasn't influenced by demographic, anthropometric, or metabolic factors, the development of diabetes, or use of statins. No metformin effect was seen in women.

The authors noted that the effect of metformin was most prominent in younger men and those with lower coronary calcium scores, which could suggest that metformin has the most effect on smaller and newer plaques. The finding that the effect was independent of the development of diabetes suggests that metformin's effect on coronary artery calcium does not depend on diabetes prevention and supports “the notion that use of metformin within a few years before and after diabetes development has a beneficial effect on early stages of atherosclerosis in men,” the authors said. They noted that the lack of effect of the lifestyle intervention is somewhat surprising but might be explained by the limited length of follow-up or the limited length of the lifestyle intervention itself.