Individualizing Time-in-Range Goals in Management of Diabetes Mellitus and Role of Insulin: Clinical Insights from a Multinational Panel
Diabetic patients are always motivated to achieve glycemic targets to prevent chronic complications associated with diabetes. Although HbA1c is a gold standard for measuring glycemic control, there is a need for more effective and accurate diabetes management, the development of an integrated approach with second-generation basal insulin and glucometrics involving glycemic variability (GV) and time-in-range (TIR). Sanjay Kalra and colleagues published a research paper under the title “Individualizing Time-in-Range Goals in Management of Diabetes Mellitus and Role of Insulin: Clinical Insights from a Multinational Panel” in the Diabetes Therapy journal. The summary of this paper is given below:
• To provide clinical insights into the individualization of TIR targets
• To elaborate on the role of the second-generation basal insulin analogues in addressing TIR.
A multinational group of diabetologists and endocrinologists reviewed the existing recommendation on TIR and basal insulin strategies in diabetes management. The panel also provided clinical insights, which are summarized in this article.
TIR Recommendations for Different Populations and Life Phases:
• In 2/3rd of cases, oral antidiabetic drugs (OADs) inadequacy is observed within 5 years. TIR is a useful metric in OADs.
• In T1DM, the lower cutoff may be 80 mg/dL to prevent hypoglycemia.
• Tighter glycemic control is recommended for adults T2DM with no complications: > 80% in 70–160 mg/dL, as this group is usually on metformin treatment and with low hypoglycemic risk; hence, 70 mg/dL is the acceptable lower limit and above target glucose range (TAR) < 15%, below target glucose range (TBR) < 5%.
• It is recommended that the definition of target glucose range (TIR) should be individualized particularly in pregnancy, organ dysfunction, and the elderly.
TIR recommendations based on the 4 phases of life i.e. adolescents T1DM/ T2DM (10–18 years), adults (>18 years), pregnancy, and elderly are as follow:
For adolescents: In both T1DM and T2DM, the target range of 70–180 mg/dL is acceptable. It is not recommended to set the lower limit to a value above 70 mg/dL as it will suspend insulin too early. As T1DM individuals are more prone to GV because of reduced endogenous insulin, higher TIR is recommended for them.
(i) In T1DM: > 80% TIR in a target blood glucose of 70–180 mg/dL; <15% TAR and, <5% TBR
(ii) In T2DM: > 70% TIR in a target blood glucose of 70–180 mg/dL; <25% TAR and <5% TBR
For adults: considering the majority of people falling into this category, it is better to strive for tighter control in adults. Hence, two recommendations can be considered for TIR in adults and individualized as needed:
(i) Same as Advanced Technologies and Treatments for Diabetes (ATTD) consensus recommendations for T1DM and T2DM: >70% TIR in a target blood glucose of 70–180 mg/dL; <25% TAR and <5% TBR
(ii) Tighter control: >80% TIR in a target blood glucose of 70–160 mg/dL; <15% TAR and <5% TBR. Tighter control is recommended in people who are newly diagnosed, highly motivated, do not have comorbidities, and have a long life expectancy.
For pregnancy: Considering the target range similar to ATTD consensus recommendations, the time spent in the target range should be increased by 10%, because it has the potential to lead to better outcomes: > 80% TIR in a target blood glucose of 63–140 mg/ dL; <15% TAR and <5% TBR.
For elderly: As this group is more susceptible to hypoglycemia, targets need to be relaxed with more time spent in the relaxed range; >80% TIR in a target blood glucose of 90–200 mg/dL; < 15% TAR, <5% TBR (<90 mg/dL) \ 1% (<70 mg/dL).
• 80–90% of children aged <10 years aren’t aware of hypoglycemia. Thus, the lower limit of TIR should be relaxed.
• CGM reading differences with an increase in temperature should be taken into account both during physiological and pathological conditions.
• The variation between CGM and SMBG is most evident during times when blood glucose levels are rapidly changing.
Clinical Insights on TIR Recommendations for Different Complications:
• CGM should be considered in pregnancy, inconsistency between HbA1c, renal failure, and clinical features/SMBG
• TIR is an ‘‘additional’’ measure (along with other glycemic parameters), mainly if more accessible parameters are inconclusive.
• In order to establish TIR as a substitution for complications, more longitudinal studies are required.
For individuals at high risk of hypoglycemia (renal/hepatic disease):
A relaxed target range comprising of high lower limit is recommended; >70% TIR in a target blood glucose of 90–180 mg/dL; <25% TAR and <5% TBR.
With micro-/macrovascular complications:
(i) Microvascular: Same as adults; >70% TIR in a target blood glucose of 70–180 mg/dL; <25% TAR and <5% TBR or >80% TIR in a target blood glucose of 70–160 mg/dL; <15% TAR and <5% TBR.
(ii) Macrovascular: Same target as microvascular complications or relaxed as following > 70% TIR in a target blood glucose of 80–180 mg/dL; <25% TAR and <5% TBR. While strict control has shown microvascular benefits, there may be a high risk of hypoglycemia in people with macrovascular complications, and hence relaxed targets are recommended.
With concomitant acute infections:
(i) Non-hospitalized: > 75% TIR in a target blood glucose of 80–180 mg/dL; <20% TAR and <5% TBR.
(ii) Hospitalized: >80% TIR in a target blood glucose of 140–180 mg/dL; <15% TAR and <5% TBR. The cutoffs are kept in this range, in consideration of the use of antipyretics such as acetaminophen in acute infections that can have an effect on CGM readings, giving a false higher value.
• Those with fever consuming antipyretics and on CGM should undergo cross-check with the finger-stick method.
• In patients with sepsis in ICU: TAR (>180 mg/dL) should be minimized to <5% and the lower limit of 70 mg/dL should be pushed to 80 mg/dL to minimize mortality.
Management of GV as the Stepping-Stone in Diabetes Management:
Following factors have been proposed to help reduce GV in individuals who are on insulin treatment:
• Timely insulinization
• Choice of insulin
• Initiation dose
• Proper timing of injection of prandial insulin
• Systematic and adequate titration
• Prompt intensification (using prandial insulin) when indicated
• Stepwise intensification
• Simple regimen
• Dosing flexibility
Clinical Insights on TIR Recommendations, Based on Modality of Treatment
• Second-generation basal insulin scores better than insulin regimens in terms of improved quality of life, increased duration of action, prevention of cognitive dysfunction, lesser GV, better adherence, reduction of diabetes distress, and long-term complications.
• In practice, for equivalent glucose levels, second-generation basal insulin brings down blood glucose with lower hypoglycemia compared to first-generation insulin.
• TIR recommendations remain the same in spite of the modality of treatment. The treatment should be focused on achieving TIR. This can be attained with basal insulins, especially second-generation basal insulins.
• TIR targets remain the same regardless of whether the patient was on insulin or OADs (taking into consideration age group, a specific population, and associated complications).