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

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.