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Validation of Time in Range as an Outcome Measure for Diabetes Clinical Trials

Open access
Beck, Roy W., Bergenstal, Richard M., Riddlesworth, Tonya D., Kollman, Craig, Li, Zhaomian, Brown, Adam S., Close, Kelly L.·2019·Diabetes Care
DOI 10.2337/dc18-1444PMC PMC6905478
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Abstract

OBJECTIVE: This study evaluated the association of time in range (TIR) of 70–180 mg/dL (3.9–10 mmol/L) with the development or progression of retinopathy and development of microalbuminuria using the Diabetes Control and Complications Trial (DCCT) data set in order to validate the use of TIR as an outcome measure for clinical trials. RESEARCH DESIGN AND METHODS: In the DCCT, blood glucose concentrations were measured at a central laboratory from seven fingerstick samples (seven-point testing: pre- and 90-min postmeals and at bedtime) collected during 1 day every 3 months. Retinopathy progression was assessed every 6 months and urinary microalbuminuria development every 12 months. Proportional hazards models were used to assess the association of TIR and other glycemic metrics, computed from the seven-point fingerstick data, with the rate of development of microvascular complications. RESULTS: Mean TIR of seven-point profiles for the 1,440 participants was 41 ± 16%. The hazard rate of development of retinopathy progression was increased by 64% (95% CI 51–78), and development of the microalbuminuria outcome was increased by 40% (95% CI 25–56), for each 10 percentage points lower TIR (P < 0.001 for each). Results were similar for mean glucose and hyperglycemia metrics. CONCLUSIONS: Based on these results, a compelling case can be made that TIR is strongly associated with the risk of microvascular complications and should be an acceptable end point for clinical trials. Although hemoglobin A1c remains a valuable outcome metric in clinical trials, TIR and other glycemic metrics—especially when measured with continuous glucose monitoring—add value as outcome measures in many studies.

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  • Glucose time in range (70-180 mg/dl [3.9-10.0 mmol/l]) and time in hypoglycemia (<70 mg/dl [3.9 mmol/l] and <54 mg/dl [3.0 mmol/l]) have been used as outcomes for clinical trials and have been endorsed as appropriate metrics for clinical care.

    “In particular, glucose time in range (70 -180 mg/dl [3.9 -10.0 mmol/l]) and time in hypoglycemia ( &lt; 70 mg/dl [3.9 mmol/l] and &lt; 54 mg/dl [3.0 mmol/l]) have been used as outcomes for clinical trials 259,260 and have been endorsed as appropriate metrics for clinical care. 229”

    From KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease (2022) · cites this paper as [259]

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  • More recent studies have begun to examine the relationship between time in target range and long-term complications and have provided the basis for glycemic targets with newer glucose monitoring technologies.

    “Although the evidence of HbA 1c reduction remains the most robust measure associated with chronic diabetes complications and is the only measure that is prospectively validated, more recent studies have begun to examine the relationship between time that glucose is within the target range and long-term complications and have provided the basis for glycemic targets with newer glucose monitoring”

    From The management of type 1 diabetes in adults. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) (2021) · cites this paper as [45]

    The Abstract and Conclusions report that time in range is associated with retinopathy progression and microalbuminuria, and discuss its relevance to continuous glucose monitoring (CGM). The paper describes an existing consensus target range and argues that time in range should be an acceptable clinical-trial outcome; it does not establish that these studies provided the basis for glycemic targets using newer monitoring technologies. (LLM, conf=0.78)

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  • GMI is calculated based on average sensor glucose over the last 14 days and provides an approximation of laboratory-measured HbA1c in some individuals, but may be higher or lower than actual HbA1c in others.

    “GMI is calculated based on the average sensor glucose over the last 14 days and provides an approximation of a laboratory-measured HbA 1c in some individuals, but it may be higher or lower than actual HbA 1c in others (45).”

    From The management of type 1 diabetes in adults. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) (2021) · cites this paper as [45]

    The Abstract (page unavailable) describes substantial individual variation between mean glucose and A1C, supporting the warning that a glucose-based estimate may differ from measured A1C. The Conclusions (page unavailable) say 10–14 days of CGM data can estimate TIR and other metrics, but our copy does not identify GMI or state that it is calculated from the last 14 days of average sensor glucose. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • TIR is associated with microvascular complications.

    “TIR is associated with microvascular complications (45,46), and a TIR of 70% roughly corresponds to an HbA 1c of 53 mmol/mol (7.0%).”

    From The management of type 1 diabetes in adults. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) (2021) · cites this paper as [45]

  • SGLT-2 agents help individuals with type 1 diabetes increase TIR.

    “Most recently, the beneficial effects of new medications, such as sodium glucose cotransporter-2 (SGLT-2) agents have helped individuals with type 1 diabetes increase TIR (49-51).”

    From Clinical Targets for Continuous Glucose Monitoring Data Interpretation: Recommendations From the International Consensus on Time in Range (2019) · cites this paper as [50]

    The TIR and Conclusions sections report higher time in range with intensive versus conventional treatment in the DCCT, but do not address SGLT-2 agents. Searches for “SGLT-2” and “SGLT” found no passage linking those agents to increased TIR in type 1 diabetes. (LLM, conf=0.76)

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Authors
Beck, R. W., Bergenstal, R. M., Riddlesworth, T. D., Kollman, C., Li, Z., Brown, A. S., & Close, K. L.
Affiliations
  • Jaeb Center for Health Research (US)
  • Park Nicollet Health Services (US)
  • Close Concerns (United States) (US)
  • The diaTribe Foundation, San Francisco, CA
Corresponding author
Beck, Roy W.
ORCID
Venue
Diabetes Care
Publisher
American Diabetes Association
Published
2018-10-23
Volume
42
Issue
3
Pages
400-405
ISSN
  • 0149-5992 (ISSN-L)
  • 1935-5548
DOI
10.2337/dc18-1444
PMC
PMC6905478
OpenAlex
W2897457722
Cited by
793
References
29
Citations by year
2026: 73 · 2025: 93 · 2024: 87 · 2023: 106 · 2022: 138 · 2021: 134 · 2020: 103 · 2019: 54 · 2018: 2 · 2014: 1
FWCI
57.92
Type
journal article
Language
en
Open access
Licence
www.diabetesjournals.org/content/license (vor, 120 d)
Locations
  • Diabetes Care (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Jaeb Center for Health Research Foundation
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
time in range, glycemic control, retinopathy progression, microalbuminuria, microvascular complications, outcome measure validation, Diabetes Control and Complications Trial, continuous glucose monitoring, HbA1c, glycemic metrics
MeSH terms
Adult, Blood Glucose, Clinical Trials as Topic, Diabetes Mellitus, Female, Glycated Hemoglobin, Humans, Longitudinal Studies, Male, Middle Aged, Patient Care Planning, Prognosis, Research Design, Time Factors, Blood Glucose Self-Monitoring, Treatment Outcome, Outcome Assessment, Health Care, Disease Progression, Diabetes Complications

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