Strengths and Limitations
The current prospective study describes a cohort derived from a large population, which was well characterized and closely followed up. All end points were independently adjudicated according to predefined criteria, including separate reporting of nephropathy and retinopathy end points. This is one of the first studies to show that subtle subclinical differences in cardiac biomarkers may run concurrently with or even precede peripheral microvascular disease. Prediction of microvascular end points is a novel application of the data. Participants in the ADVANCE study, like those from other randomized controlled trial populations, represent a selected cohort, and our results may not be generalizable to all patients with diabetes. For instance, ADVANCE participants were required to have a history of CVD or CVD risk factors, and although efforts to adjust for these confounding factors were made, residual confounding remains possible. As such, our findings should be considered hypothesis generating. Our results relating to clinical risk predictors are, however, consistent with other data from an ethnically distinct cohort (7), and the baseline characteristics of the ADVANCE cohort are very comparable with those in several observational studies at the community level (33). Although the large study population and case-cohort design ensure considerable statistical power and allow reliable correction for many potential confounding factors, other possible confounders may be present, leading to an overestimate of risk associations. Levels of hsTnT and NT-proBNP were measured only once, and it would be useful to address the effects of serial changes in levels in the future. We speculate on the mechanisms linking cardiac biomarkers to microvascular outcomes but have no data to examine cardiac perfusion specifically. The NRI models that we have constructed are necessarily based on somewhat artificial cutoffs, but they contain most of the pertinent information that might typically be used to estimate the cardiovascular risk of patients with diabetes. NT-proBNP and hsTnT were measured on stored serum samples, and although we cannot rule out the potential for differential sample degradation that biases our results, both of these markers appear fairly stable in long-term storage (34,35).