Comment on Lachin et al. Association of Estimated Time-in-Range Capillary Glucose Levels Versus HbA_1c With Progression of Microvascular Complications in the Diabetes Control and Complications Trial. Diabetes Care 2022;45:2445–2448

In their article, Lachin et al. (1) report that in the Diabetes Control and Complications Trial study the estimated time in range (TIR) and HbA_1c are strongly and inversely correlated and that this correlation results in a lack of prognostic value for TIR when HbA_1c is added as a covariate. They thus conclude that HbA_1c remains the preferred outcome in clinical studies of type 1 diabetes (T1D) complications. However, we believe that some considerations are missing.

First, the authors considered the development of retinopathy and of albuminuria as the only outcomes. In this respect, it is well recognized that HbA_1c has a strong prognostic role for the development of microvascular outcomes, while such association is less straightforward when considering macrovascular diseases. Indeed, patients with T1D with well-controlled HbA_1c still have an increased cardiovascular risk compared with the general population, which is hardly explainable without the use of additional glucose-related metrics (2,3).

Second, the authors used estimated TIR and not device-derived TIR. A TIR derived from seven points might not be representative of the time spent by patients in the normoglycemic range each day (3).

Third, it must be considered that glycemia has a two-dimensional nature, with the magnitude of the excursion and the time spent at each level being equally important. Indeed, it is not surprising that HbA_1c and TIR are inversely related, since HbA_1c integrates the mean values of glycemia in the last 2–3 months (3). However, the variability of glucose is not captured by either of the two metrics, and the variability of HbA_1c is not considered in this study. HbA_1c variability was recently shown to be an independent risk factor for cardiovascular complications, particularly in people having HbA_1c at target (4). Similarly, glucose variability has been demonstrated to be a risk factor for diabetes complications, also independently of TIR (5).

In conclusion, the work by Lachin et al. (1) is meritorious since it explores the possible redundancy of two metrics of glycemic control for the development of microvascular diseases in T1D. However, examples of additive and synergic prognostic value among different glucose-related metrics are continuously emerging (3). Thus, HbA_1c alone should no longer be considered the only reference to evaluate overall glycemic control in diabetes. More research is needed to explore which combination of glycemic metrics is the most effective in predicting the development of diabetes complications and that thus should be employed as the main outcome measure in clinical studies assessing glycemic control. Meanwhile, improving TIR and avoiding glucose variability should still be considered therapeutic options for the prevention of complications in diabetes, considering also that TIR monitoring often results in improvement of HbA_1c values (3).