Regression from prediabetes to normoglycaemia and the role of cardiometabolic risk factors on the subsequent risk of developing type 2 diabetes

Abstract Aims/hypothesis We aimed to investigate the association between reversion to normoglycaemia among individuals with prediabetes (fasting plasma glucose 5.6–6.9 mmol/l in the absence of other criteria for type 2 diabetes) and the subsequent risk of type 2 diabetes, and to examine whether concurrent favourable cardiometabolic risk factor profiles modify this association. Methods We used individual-level data from prospective cohorts in the USA, Australia and Asia. Participants with prediabetes at baseline, with at least two follow-ups (n=8191) at median intervals of 2.9 years (IQR 2.3–9.0) and 3.1 years (IQR 2.6–3.6), were classified into restoration of normoglycaemia and persistent prediabetes groups based on the glucose status at the first follow-up (normoglycaemia or prediabetes). Type 2 diabetes occurrence was assessed at subsequent follow-ups. Hierarchical mixed-effects proportional hazards Weibull models estimated type 2 diabetes risk, adjusting for age, sex and cardiometabolic risk factors. A subgroup analysis evaluated the combined association of normoglycaemia restoration and normal cardiometabolic risk factor levels on subsequent type 2 diabetes risk. Results In individuals with prediabetes, normoglycaemia restoration compared with persistent prediabetes was associated with a 51% lower risk of developing type 2 diabetes. Even lower risks were observed among individuals with concurrent favourable cardiometabolic profiles, including non-smokers (HR 0.20, 95% CI 0.10, 0.31), and those with normal BMI (0.16, 95% CI 0.06, 0.27), waist circumference (0.22, 95% CI 0.12, 0.33), waist-to-height ratio (0.15, 95% CI 0.03, 0.26), WHR (0.17, 95% CI 0.05, 0.28), and systolic (0.20, 95% CI 0.11, 0.30) and diastolic (0.25, 95% CI 0.12, 0.38) blood pressure, triacylglycerol (0.24, 95% CI 0.13, 0.35) and HDL-cholesterol levels (0.21, 95% CI 0.13, 0.29). Weight loss combined with normoglycaemia restoration was also associated with lower type 2 diabetes risk (0.18, 95% CI 0.07, 0.30) compared with weight gain and persistent prediabetes. Conclusions/interpretation Our results suggest that prioritising normoglycaemia restoration during the prediabetes stage in clinical guidelines may contribute to reducing the risk of type 2 diabetes, particularly when accompanied by favourable cardiometabolic health profiles. Graphical Abstract