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Appropriateness of Time in Range as a Measure of Diabetes Outcomes

Dec 22, 2018
 
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Michael Zaccaro, Pharm. D. Candidate 2019, LECOM School of Pharmacy

Time in glycemic range inversely correlated to risk of developing vascular complications in patients with diabetes.

Ever since the Diabetes Control and Complications Trial (DCCT) demonstrated the strong correlation between risk of vascular complications in diabetes and hemoglobin A1C levels, A1C has become the gold standard for assessing glycemic control in patients with diabetes.

The ease and accuracy with which hemoglobin A1C can be measured has made it an invaluable clinical tool for the treatment of patients with diabetes. However, hemoglobin A1C does have some inherent drawbacks. For instance, since it is an average of glycemic levels over the life of the patient’s red blood cells, it does not provide a good measure of the variability of glycemic levels. The advent of continuous glucose monitoring has since made it possible to see what person’s glucose level is at any point throughout the day. Consequently, a new endpoint for glycemic control has come into popularity: time in range, which is the percentage of time a patient’s glucose level is within a range of 70 to 180 mg/dL. Despite its perceived clinical value by clinicians and patients alike, the Food and Drug Administration (FDA) has not recognized it as a valid outcome in order to prove efficacy. The reasoning behind this is that there is little evidence proving an association between time in glycemic range and risk of vascular complications.

Therefore, the aim of this study is to determine if there is an association between time in range and risk of vascular complications in patients with diabetes.

The previously mentioned DCCT compared the observed hemoglobin A1C with the corresponding development of retinopathy and microalbuminuria. The DCCT also required participants to measure blood glucose at 7 points (before each meal, 90 minutes after each meal, and at bedtime) one day every 3 months during the trial. The authors of this study concluded that there was sufficient data collected in the DCCT to allow for a high-quality retrospective cohort comparing time in range with the occurrence of retinopathy and microalbuminuria. The DCCT assessed its participants for retinopathy and microalbuminuria every 6 and 12 months respectively. For this study, the average time in range was calculated from the raw data collected during the DCCT and compared against occurrence of retinopathy / microalbuminuria. In order to determine statistical significance, 2 cox proportional hazards regression models were used to assess the association of retinopathy and microalbuminuria with time in glycemic range separately.

Overall, the average time in glycemic range for the 1,440 participants was 41%. When compared against the occurrence of retinopathy, it was determined that each 10% decrease in time in range was associated with a 64% increase in retinopathy occurrence (p < 0.001). Likewise, each 10% decrease was also associated with a 40% increase in microalbuminuria occurrence (p < 0.001).

The results of this study indicate that, like hemoglobin A1C, time in range is correlated with risk of developing retinopathy and/or microalbuminuria. This correlation indicates that time in range is a valid clinical outcome for determining risk of vascular complications of diabetes. The FDA will likely require further corroborating research in order to fully accept this conclusion. However, the evidence suggests that time in glycemic range is a valid measure of risk of developing vascular complications in patients with diabetes and therefore can be appropriately used as a clinical endpoint.

Practice Pearls:

  • Time in range is the percentage of time a patient is within the glycemic range of 70 to 180 mg/dL.
  • Evidence suggests that time in range is inversely correlated to risk of developing vascular complications in patients with diabetes.
  • Time in range may be used as an appropriate clinical endpoint in diabetes research and as a measure of glycemic control in patients.

References:

Nathan DM, Genuth S, Lachin J, et al., “Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.” New England Journal of Medicine, vol. 329, 1993, pp. 977–986

Beck RW, Bergenstal RM, et al., Validation of Time in Range as an Outcome Measure for Diabetes Clinical Trials.” Diabetes Care, 2018, doi: 10.2337/dc18-1444

Michael Zaccaro, Pharm. D. Candidate 2019, LECOM School of Pharmacy

 

For more information on blood glucose control, and the effects of good, intensive, and poor glucose control, visit the Diabetes in Control Blood Glucose Control/A1c Therapy Center.