Aim Approximately half of the participants in the Diabetes Prevention Outcomes Study (DPPOS) had diabetes after 15 years of follow‐up, whereas nearly all the others remained with pre‐diabetes. We examined whether formerly unexplored factors in the DPPOS coexisted with known risk factors that posed additional risk for, or protection from, diabetes as well as microvascular disease. Methods Cox proportional hazard models were used to examine predictors of diabetes. Sequential modelling procedures considered known and formerly unexplored factors. We also constructed models to determine whether the same unexplored factors that associated with progression to diabetes also predicted the prevalence of microvascular disease. Hazard ratios (HR) are per standard deviation change in the variable. Results In models adjusted for demographics and known diabetes risk factors, two formerly unknown factors were associated with risk for both diabetes and microvascular disease: number of medications taken (HR = 1.07, 95% confidence intervals (95% CI) 1.03 to 1.12 for diabetes; odds ratio (OR) = 1.10, 95% CI 1.04 to 1.16 for microvascular disease) and variability in HbA1c (HR = 1.02, 95% CI 1.01 to 1.03 for diabetes; OR = 1.06, 95% CI 1.04 to 1.09 for microvascular disease per sd). Total comorbidities increased risk for diabetes (HR = 1.10, 95% CI 1.04 to 1.16), whereas higher systolic (OR = 1.22, 95% CI 1.13 to 1.31) and diastolic (OR = 1.14, 95% CI 1.05 to 1.22) blood pressure, as well as the use of anti‐hypertensives (OR = 1.41, 95% CI 1.23 to 1.62), increased risk of microvascular disease. Conclusions Several formerly unexplored factors in the DPPOS predicted additional risk for diabetes and/or microvascular disease – particularly hypertension and the use of anti‐hypertensive medications – helping to explain some of the residual disease risk in participants of the DPPOS. What's new? The Diabetes Prevention Outcomes Study (DPPOS) is the largest global trial to date aimed at preventing or delaying diabetes onset in a high‐risk group. We have retained ˜ 85% of the original participants for nearly 20 years. At the time of the most recent data lock, ˜ 50% of participants had developed diabetes, whereas the others had not. This analysis examines residual risk factors for diabetes and microvascular disease not formerly explored in the DPPOS. Simple clinical information, such as the number of medications taken and glycaemic variability, are associated with increased risk for diabetes and microvascular disease. Hypertension and use of anti‐hypertensive medication predicted composite microvascular disease independent of diabetes status.
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