CGM-Phenotyped Circadian Glycemic Vulnerability Windows to Personalize Meal Timing and Postprandial Activity in Prediabetes : A Randomized Controlled Trial

Prediabetes is a high-risk metabolic state in which postprandial glucose excursions and glycemic variability may contribute to progression toward type 2 diabetes. Although lifestyle modification can reduce diabetes risk, conventional advice is usually generic and does not account for individual differences in the timing of glucose intolerance across the day. Emerging evidence suggests that circadian biology, meal timing, sleep timing, and postprandial activity may influence glucose regulation, but it remains unclear whether continuous glucose monitoring can be used to personalize the timing of meals and brief activity in adults with prediabetes.

CLOCK-PRIME is a single-center, two-arm, randomized controlled trial in adults with prediabetes. Participants will undergo a 10-day blinded observational run-in period using continuous glucose monitoring, wrist actigraphy, and timestamped meal-photo logging. Run-in data will be used to classify participants into pre-specified circadian glycemic phenotypes based on postprandial glucose incremental area under the curve during morning and evening windows. Participants will be categorized as morning-vulnerable, evening-vulnerable, or globally variable.

After phenotype classification, participants will be randomized to either a phenotype-guided intervention or an attention-matched active control group. The intervention group will receive personalized guidance to shift the highest glycemic-load meal away from the participant's highest-vulnerability window and toward the lowest-vulnerability window. Participants will also be advised to perform a 10-minute brisk walk within 30 minutes after the meal occurring in their highest-vulnerability window. The control group will receive standardized sleep hygiene advice and a general step-count goal, without meal-timing or postprandial walking instructions.

The primary endpoint is the change from baseline to week 4 in vulnerable-window postprandial glucose incremental area under the curve measured by continuous glucose monitoring. Secondary endpoints include time in range, time above range, glucose coefficient of variation, mean postprandial peak glucose, nocturnal mean glucose, sleep regularity, social jetlag, and actigraphy-derived activity patterns. Exploratory mechanistic outcomes include fasting dried-blood-spot measures of cortisol:insulin ratio and selected primary bile acids to assess whether changes in neuroendocrine or enterohepatic metabolic pathways accompany improvement in glycemic vulnerability.

The study is designed to determine whether CGM-derived circadian glycemic vulnerability windows can support a feasible precision lifestyle strategy for reducing postprandial glycemic burden in adults with prediabetes.