Using time in range to optimize insulin therapy in patients with T2DM

Time spent within target blood glucose range (ie, time in range [TIR]) evaluated through continuous glucose monitoring (CGM) has emerged as an important complementary metric for assessing day-to-day glycaemic control in diabetic patients. In an interview with MIMS Doctor, Dr Tin-Wai Wong, Specialist in Endocrinology, Diabetes & Metabolism at the Ruttonjee Hospital in Hong Kong, discussed the importance of TIR as an adjunct to other glycaemic parameters and shared case studies on how TIR may help fine-tune insulin therapy in patients with type 2 diabetes mellitus (T2DM).

TIR complementary to HbA_1c
“HbA_1c has been the standard indicator of glycaemic control in patients with diabetes and remains an important surrogate marker of macrovascular and microvascular complications,” noted Wong. “However, HbA_1c does not provide a measure of glycaemic variability [ie, patterns of hypoglycaemia and hyperglycaemia].” [Diabetes Care 2019;42:1593-1603; Diabetes Care 2023;46(Suppl 1):S97-S110]

“Hypoglycaemia, in particular, is an important concern,” she shared. “It can result in falls, concomitant fractures and other serious or fatal events in elderly patients. While hypoglycaemia may be associated with inconvenient symptoms [eg, shakiness, irritability, confusion, tachychardia, and hunger], it can go undetected during sleep.” [Diabetes Care 2023;46(Suppl 1):S97-S110]

“For patients at increased risk of glycaemic variability [eg, those with severe insulin deficiency], TIR metrics based on CGM data for a recommended 14 days may be used to complement HbA_1c in assessing glycaemic control,” explained Wong. [Diabetes Care 2019;42:1593-1603; Diabetes Care 2023;46(Suppl 1):S97-S110]

According to guidelines of the American Diabetes Association, the recommended TIR target for most diabetic patients is >70 percent of time spent in the target blood glucose range of 3.9–10.0 mmol/L. Other metrics related to TIR include time below range (TBR; percentage of time spent in glucose level <3.9 mmol/L) and time above range (TAR; percentage of time spent in glucose level >10.0 mmol/L). (Figure 1) Glycaemic variability (target percentage of coefficient of variation, ≤36 percent), glucose management indicator (GMI; target <7 percent), and daily glucose profiles may also be derived from CGM data. [Diabetes Care 2019;42:1593-1603; Diabetes Care 2023;46(Suppl 1):S97-S110]

“Based on CGM data, an ambulatory glucose profile [AGP] report illustrates patients’ TIR metrics, which can be used in conjunction with HbA_1c and other glucose parameters to guide pharmacologic adjustments to optimize glycaemic control and reduce blood glucose variability,” Wong continued.

“TIR monitoring through CGM may be beneficial for patients on intensive [antidiabetic] therapy with multiple insulin injections, or those with fluctuating glycaemic control [eg, experiencing both hypoglycaemic and hyperglycaemic events], discordance between home blood glucose monitoring [BGM] and HbA_1c values, or poor record of home BGM,” commented Wong.

Clinical implications of TIR targets
“Achieving the recommended TIR targets has important implications on clinical outcomes,” Wong noted. “Since HbA_1c and TIR are shown to be at least moderately correlated with each other, TIR may have similar associations with diabetic complications predicted with HbA_1c monitoring. In fact, each 5 percent increase in TIR has been associated with clinically significant benefits for patients with type 1 or type 2 diabetes.” [Diabetes Care 2019;42:1593-1603; J Diabetes Sci Technol 2019;13:614-626; Diabetes Technol Ther 2019;21:81-85]

In a post hoc analysis of the DEVOTE study (n=5,774), T2DM patients with derived TIR >70 percent had a significantly lower estimated rate of first major adverse cardiovascular event (MACE) vs those with TIR ≤70 percent (hazard ratio [HR], 0.73; 95 percent confidence interval [CI], 0.59–0.90; p<0.01) or TIR ≤50 percent (HR, 0.69; 95 percent CI, 0.52–0.91; p<0.01). Derived TIR was also significantly associated with time to first severe hypoglycaemic episode (p<0.0001) and microvascular event (p=0.019) for those with TIR >70 percent and TIR >50–≤70 percent vs those with TIR ≤50 percent. [Bergenstal RM, et al, ADA 2020, poster 21-LB]

These results show that TIR may be a valid surrogate endpoint for long-term clinical outcomes in patients with T2DM.

Fine-tuning insulin therapy based on TIR
“TIR metrics are particularly useful parameters for insulin dose adjustments and re-evaluation of patients’ treatments,” said Wong. [Diabetes Care 2023;46(Suppl 1):S97-S110]

The 41-week, randomized, crossover, open-label, multicentre, active-controlled SWITCH PRO trial compared TIR values with insulin degludec (IDeg) 100 U/mL vs insulin glargine (IGlar) 100 U/mL in basal insulin–treated T2DM patients with ≥1 hypoglycaemia risk factor. [Diabetes Obes Metab 2021;23:2572-2581]

“IDeg is a long-acting basal insulin analogue administered subcutaneously QD at any time of the day, preferably at the same time every day,” noted Wong.“This flexibility is due to IDeg’s longer duration of action [>42 hours] and comparatively lower risk of hypoglycaemia vs earlier basal insulin analogues in diabetic patients.” [Tresiba Hong Kong Prescribing Information; Lancet 2012;379:1498-1507; N Engl J Med 2017;377:723-732; Diabetes Care 2012;35:2464-2471; Diabetes Obes Metab 2013;15:175-184; JAMA 2017;318:33-44; JAMA 2017;318:45-56]

SWITCH PRO results confirmed noninferiority and superiority of IDeg vs IGlar for TIR (mean, 72.1 percent vs 70.7 percent; estimated treatment difference [ETD], 1.43 percent [equivalent to 20.6 minutes/day]; 95 percent CI, 0.12–2.74; p=0.03). Overall time in tight glycaemic range (ie, 3.9–7.8 mmol/L) also favoured IDeg vs IGlar (ETD, 1.5 percent [equivalent to 21.9 minutes/day); 95 percent CI, 0.15–2.89). [Diabetes Obes Metab 2021;23:2572-2581]

“Importantly, IDeg reduced nocturnal TBR [<3.9 mmol/L] vs IGlar [ETD, -0.88 percent (equivalent to -12.7 minutes/night); 95 percent CI, -1.34 to -0.42; post hoc analysis],” noted Wong.“IDeg was also associated with significantly fewer nocturnal hypoglycaemic episodes of <3.0 mmol/L [vs IGlar].”

Practical tips on switching to IDeg from human insulin
“IDeg effectively improves glycaemic control,” Wong commented.“When switching to IDeg from human insulin, the insulin dose should be carefully titrated every week, and the starting dose is typically based on patients’ HbA_1c values.”

“In patients who achieve target HbA_1c [ie, ≤7.0 percent], the starting dose of IDeg can be slightly lower than that of human insulin. However, patients with fair or suboptimal glycaemic control may receive an IDeg dose equivalent to or higher than the human insulin dose,” Wong advised. “Patient education remains important for increasing awareness of hypoglycaemia.”

Summary
TIR is complementary to HbA_1c and provides more actionable information (ie, glycaemic variability). This allows patients and their doctors to better evaluate individual responses to therapy, assess if glycaemic targets are safely met, and promptly make treatment changes to improve glycaemic control and reduce variability.