Validation of Time in Range as an Outcome Measure for Diabetes Clinical Trials

Abstract

Objective: This study evaluated the association of time in range (TIR) of 70-180 mg/dL (3.9-10 mmol/L) with the development or progression of retinopathy and development of microalbuminuria using the Diabetes Control and Complications Trial (DCCT) data set in order to validate the use of TIR as an outcome measure for clinical trials.

Research design and methods: In the DCCT, blood glucose concentrations were measured at a central laboratory from seven fingerstick samples (seven-point testing: pre- and 90-min postmeals and at bedtime) collected during 1 day every 3 months. Retinopathy progression was assessed every 6 months and urinary microalbuminuria development every 12 months. Proportional hazards models were used to assess the association of TIR and other glycemic metrics, computed from the seven-point fingerstick data, with the rate of development of microvascular complications.

Results: Mean TIR of seven-point profiles for the 1,440 participants was 41 ± 16%. The hazard rate of development of retinopathy progression was increased by 64% (95% CI 51-78), and development of the microalbuminuria outcome was increased by 40% (95% CI 25-56), for each 10 percentage points lower TIR (P < 0.001 for each). Results were similar for mean glucose and hyperglycemia metrics.

Conclusions: Based on these results, a compelling case can be made that TIR is strongly associated with the risk of microvascular complications and should be an acceptable end point for clinical trials. Although hemoglobin A_1c remains a valuable outcome metric in clinical trials, TIR and other glycemic metrics-especially when measured with continuous glucose monitoring-add value as outcome measures in many studies.

Figure 1

Frequency of development of microvascular complication according to level of TIR (70–180 mg/dL) computed from quarterly seven-point blood glucose testing. A: Retinopathy. B: Microalbuminuria.