Time in Tight Range for Patients With Type 1 Diabetes: The Time Is Now, or Is It Too Soon?

Since the advent of continuous glucose monitoring (CGM), patients with type 1 diabetes (T1D) have been asking a fundamental question. “What should my blood sugar goals be?” It is a seemingly simple question with a lot of nuances and, somewhat surprisingly, not a clear answer. We seem to agree as diabetes providers that keeping your overall average glucose, i.e., A1C, <7% is a place to start. From there, we extrapolate that an average glucose around 150 mg/dL sounds reasonable. But are all A1Cs of a certain value created equal when it comes to long-term complications? In other words, does it matter how you get to that average glucose and what time you spend in different glycemic ranges? These are the questions we are now struggling with, and this leads us to the debate of time in range (TIR) versus time in tight range (TITR).

While the debate around TIR has been going on for over a decade, the term really became a household phrase in the diabetes community in 2019. That year, the Advanced Technologies & Treatments for Diabetes (ATTD) Congress published revised guidelines on CGM glycemic targets, as agreed upon by a global panel of technology experts (1). The panel was tasked with many important issues, starting with what exactly TIR means. The panel settled on defining TIR as time in glucose range 70–180 mg/dL. This range was established considering 1) the lower threshold of 70 mg/dL, below which counterregulatory hormones are secreted; 2) the upper threshold of 180 mg/dL, above which postprandial glucose should not peak; and 3) what could realistically be achieved as a goal for individuals with diabetes, considering the most current technology available at the time (2). From there, the next task was defining targets for each glucose range, with recommendations landing on a goal for most patients as TIR >70% and time below range <4%. These targets were selected since it was felt at the time that these goals could be reasonably achieved with hybrid close-loop (HCL) systems (3–6). HCL systems have enabled tighter glycemic control and reduced the risk of hypoglycemia. These target recommendations were further strengthened by data on associations between TIR and progression of diabetes complications. Beck et al. (7), using 7-point blood glucose profiles from the Diabetes Control and Complications Trial (DCCT) data set, showed that the hazard rate for retinopathy and microalbuminuria progression increased by 64% and 40%, respectively, for each 10% reduction in TIR. Similar associations between retinopathy and TIR were reported in type 2 diabetes by Lu et al. (8), who demonstrated that higher TIR was associated with a decreased rate of retinopathy.

However, before TIR could be fully accepted, a relationship between TIR and A1C needed to be established. Beck et al. (9) analyzed data sets from four randomized trials, encompassing 545 adults with T1D who had measurements of their A1C and CGM metrics. They demonstrated that TIR 70% corresponded with A1C ∼7% and that every 10% increase in TIR corresponded to a 0.6% decrease in A1C. Additionally, a meta-analysis of 18 randomized controlled trials by Vigersky et al. (10) showed a correlation between A1C and TIR across a broad range of subjects, ages, and technologies in which every absolute 10% increase in TIR corresponded to a 0.8% decrease in A1C. Thus, a relationship was established between TIR and A1C. TIR then became the new standard.

Since the ATTD guidelines were published, ∼5 years have passed. Historically, in the world of T1D care, that would be the blink of an eye without much changing. However, technology has boomed since then, with the rapid development of more CGM and HCL systems that offer improvements in essentially all areas of HCL therapy. It is against that backdrop that we ask ourselves, “Can we do better than a goal of 70–180 mg/dL? Is it time to tighten things up?” In this issue of Diabetes Care, we have some data that we can use to start addressing this question. Castañeda et al. (11) studied time in tight range (TITR) (70–140 mg/dL) and its relationship with TIR, with the aim of exploring TITR targets as a novel goal in T1D management. They conducted a retrospective observational analysis using real-world anonymized data in MM780G HCL system users with T1D. The primary end point was the mean percentage of time with glucose levels in the tight range. A total of 13,461 users were included, with 3,762 individuals <15 years old and 9,699 individuals being older (16–28 years, 26.4%; 29–42 years, 29.8%; 43–55 years, 26.1%; >56 years, 17.7%). The median duration of HCL system use, termed post-HCL, was 240 and 229 days for group <15 years old and the older group, respectively.

The investigators demonstrated that the initiation of this particular HCL system resulted in an absolute increase in TITR of ∼12% in both groups (about 2.5 h per day). Interestingly, the increase in TIR had roughly the same magnitude of increase, and the percent time in the 140- to 180-mg/dL range was maintained post-HCL in both groups (∼22% to ∼25%). In other words, when glucose improved, it was generally because of an increase in time between 70 and 140 mg/dL and not due to an increase in the time spent in the 140- to 180-mg/dL range. The authors go on to make a critical addition to the literature, which is to correlate findings between TITR and A1C values. Specifically, they report that TITR treatment targets of ∼45%, ∼50%, and ∼55% correlated with glucose management indicator estimates of <7.0%, <6.8%, and <6.5%, respectively. The result of these findings is that aiming for TITR of ∼45% would align with a predicted A1C of <7%. Is 45% the new 70%? This has not been determined yet.

A key question that this study raises is the following. Yes, we can establish what a TITR goal might be, but would recommending that patients strive for this goal be beneficial? The current study cannot answer this question, as it was not an interventional trial in which patients were instructed to aim for this goal. It is our concern that should that goal be implemented, the result would be an increase in hypoglycemia. We want to be very clear on this point. In the current study, patients were documented as having a certain TTIR, but that was achieved while targeting standards of care—presumably based on current TIR recommendations. Therefore, we cannot speculate what rates of hypoglycemia would be if patients were told to aim for glucose values <140 mg/dL. It is a reasonable concern that this would elicit more correction boluses, “fake carb” entry, and generally more aggressive insulin dosing that could induce hypoglycemia. A common T1D patient phenotype is the patient who strives for perfect glycemic control and, as a result, is constantly hypoglycemic. These are some of the most challenging patients to treat, and they often concern providers the most. As a medical community, we need to be careful not to heighten fears of hyperglycemia by redefining what hyperglycemia is for our patients. Changing our guidelines from staying between 70 and 180 mg/dL to staying between 70 and 140 mg/dL without documented data on the benefits would be represent a major shift in our current management and messaging to patients.

Some recent publications have shed some light on how meaningful the TITR metric is. Beck et al. (12) looked at CGM data collected from 9 studies using Dexcom sensors, totaling 912 patients with T1D. They found that TIR and TITR were highly correlated, suggesting that for any given TIR, TITR can be predicted with a high degree of accuracy. As these two metrics are highly correlated, it may ultimately be very difficult to determine if one predicts complications better than the other. This point was further highlighted in a article by Shah et al. (13) that looked at 71 T1D patients with a new diagnosis of diabetic retinopathy. They looked back at up to 7 years of CGM data and found that the Spearman correlations between TIR, TITR, and mean glucose were all ≥0.97. Importantly, improvements in TIR and TITR both were associated with lower odds of retinopathy.

Overall, there is certainly good news here. Technological advancements are now offering the possibility of achieving glucose levels close to euglycemia. However, doing so introduces a new dimension of anxiety related to the constant vigilance required to maintain tight glycemic control with all the associated emotional and psychological issues. Balancing the pursuit of tight glycemic control with quality of life is a crucial aspect of individualizing glycemic goals. To incorporate the findings of this study into new glycemic target goals, it is essential to replicate the data using alternative HCL systems across diverse age-groups, particularly those with higher risk of hypoglycemia. To bring about a fundamental shift in clinical care using these new metrics, it is imperative to establish their correlation to clinical outcomes and long-term complications. Therefore, prospective studies detailing how aiming for TITR impacts time spent within specific CGM glycemic ranges (specifically hypoglycemia), diabetes complications, and other outcomes are required.

The final question we are left with is this: “Is TITR an interesting new metric, or is it the new standard?” For us, it is too early to make TITR a new recommendation for the masses. It may come with time, but not yet.