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Cited by 282Diabetes Management and ResearchDiabetes Treatment and ManagementDiabetes, Cardiovascular Risks, and Lipoproteins

Time in Range in Relation to All-Cause and Cardiovascular Mortality in Patients With Type 2 Diabetes: A Prospective Cohort Study

Open access
Lu, Jingyi, Wang, Chunfang, Shen, Yun, Chen, Lei, Zhang, Lei, Cai, Jinghao, Lu, Wei, Zhu, Wei +3 more·2021·Diabetes Care
DOI 10.2337/dc20-1862PMC PMC9162101

Published version of a preprint

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Abstract

OBJECTIVE: There is growing evidence linking time in range (TIR), an emerging metric for assessing glycemic control, to diabetes-related outcomes. We aimed to investigate the association between TIR and mortality in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 6,225 adult patients with type 2 diabetes were included from January 2005 to December 2015 from a single center in Shanghai, China. TIR was measured with continuous glucose monitoring at baseline, and the participants were stratified into four groups by TIR: >85%, 71–85%, 51–70%, and ≤50%. Cox proportional hazards regression models were used to estimate the association between different levels of TIR and the risks of all-cause and cardiovascular disease (CVD) mortality. RESULTS: The mean age of the participants was 61.7 years at baseline. During a median follow-up of 6.9 years, 838 deaths were identified, 287 of which were due to CVD. The multivariable-adjusted hazard ratios associated with different levels of TIR (>85% [reference group], 71–85%, 51–70%, and ≤50%) were 1.00, 1.23 (95% CI 0.98–1.55), 1.30 (95% CI 1.04–1.63), and 1.83 (95% CI 1.48–2.28) for all-cause mortality (P for trend <0.001) and 1.00, 1.35 (95% CI 0.90–2.04), 1.47 (95% CI 0.99–2.19), and 1.85 (95% CI 1.25–2.72) for CVD mortality (P for trend = 0.015), respectively. CONCLUSIONS: The current study indicated an association of lower TIR with an increased risk of all-cause and CVD mortality among patients with type 2 diabetes, supporting the validity of TIR as a surrogate marker of long-term adverse clinical outcomes.

AI snapshot

Written from the paper’s full text.

TL;DR

In 6,225 adults with type 2 diabetes, lower baseline time in range (TIR) measured by continuous glucose monitoring was associated with higher all-cause and cardiovascular disease (CVD) mortality over a median 6.9 years. The findings support TIR as a surrogate marker of long-term adverse clinical outcomes.

Key findings

  • During median 6.9 years of follow-up, 838 deaths occurred, including 287 from CVD. Multivariable-adjusted hazard ratios across TIR categories >85% (reference), 71–85%, 51–70%, and ≤50% were 1.00, 1.23 (95% CI 0.98–1.55), 1.30 (95% CI 1.04–1.63), and 1.83 (95% CI 1.48–2.28) for all-cause mortality (P for trend <0.001), and 1.00, 1.35 (95% CI 0.90–2.04), 1.47 (95% CI 0.99–2.19), and 1.85 (95% CI 1.25–2.72) for CVD mortality (P for trend = 0.015).
  • When TIR was analyzed continuously, each 10% decrease was associated with an adjusted HR of 1.08 (95% CI 1.05–1.12) for all-cause mortality and 1.05 (95% CI 1.00–1.11) for CVD mortality.
  • The inverse association with all-cause mortality was present in most subgroups except women; there was a significant interaction by sex (P for interaction <0.05). HbA1c showed a J-shaped association with all-cause and CVD mortality.

Methods

  • Prospective cohort study of 6,225 adult inpatients with type 2 diabetes recruited from a single center in Shanghai, China, from January 2005 to December 2015; participants were followed until death or 31 December 2018.
  • TIR was measured at baseline with 72-h continuous glucose monitoring, defined as percentage of time in 3.9–10.0 mmol/L, and categorized as >85%, 71–85%, 51–70%, and ≤50%.
  • Cox proportional hazards regression models estimated associations with all-cause and CVD mortality, adjusted first for age and sex and then for smoking, diabetes duration, BMI, systolic blood pressure, lipids, history of cancer/CVD, and medication use; restricted cubic splines assessed continuous TIR.

Limitations

  • Stated: observational design means causality can only be inferred and residual confounding is possible; 3-day CGM with an older sensor and a standard inpatient diet may not reflect real-life or historical glycemic control, precluded time-dependent or updated mean TIR analyses, and may have underestimated the association.
  • Stated: smoking status, CVD history, and cancer history were self-reported and may be misclassified; socioeconomic and lifestyle data were unavailable; participants were hospitalized patients, so results may not generalize to other diabetes populations.
  • Evident from the text: the single-center, inpatient recruitment and baseline-only TIR measurement further limit generalizability and causal inference.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.2337/dc20-1862

Cites

33 of 33 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 12 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In patients with type 2 diabetes, compared with TIR >85%, TIR 51-70% was not significantly associated with cardiovascular mortality (multivariable-adjusted HR 1.47, 95% CI 0.99-2.19).

    “Model 2 | 1.00 | 1.35 (0.90–2.04) | 1.47 (0.99–2.19) | 1.85 (1.25–2.72) | 0.015 | 1.05 (1.00–1.11)”
    Quote in the paperSubstantial claim
  • Findingown data

    In patients with type 2 diabetes, compared with TIR >85%, TIR ≤50% was associated with a higher risk of all-cause mortality (multivariable-adjusted HR 1.83, 95% CI 1.48-2.28).

    “Model 2 | 1.00 | 1.23 (0.98–1.55) | 1.30 (1.04–1.63) | 1.83 (1.48–2.28) | <0.001 | 1.08 (1.05–1.12)”
    Quote in the paperSubstantial claim
  • Findingown data

    When TIR was examined as a continuous variable using restricted cubic splines, an inverse association of TIR with the risk of all-cause mortality was observed.

    “When TIR was examined as a continuous variable by using restricted cubic splines, an inverse association of TIR with the risk of all-cause mortality was observed (Fig. 2)”
    Quote in the paperSubstantial claim
  • Findingown data

    There were no significant interactions of TIR with age, history of CVD or cancer, use of insulin, or use of antihypertensive drugs on the risk of all-cause mortality.

    “There were no significant interactions of TIR and age, history of CVD or cancer, use of insulin, and use of antihypertensive drugs on the risk of all-cause mortality.”
    Quote in the paperSubstantial claim
  • Findingown data

    The inverse association between TIR and all-cause mortality was present in all subgroups except women.

    “When stratified by age, sex, history of CVD or cancer, use of insulin, and use of antihypertensive drugs, this inverse association between TIR and the risk of all-cause mortality was still present in all subgroups except for women (Table 3).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 9
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Findingown data

    HbA1c was correlated with mean glucose (r = 0.53) and inversely correlated with TIR (r = −0.53) (P < 0.001).

    “The correlation coefficients were 0.53 for HbA1c and mean glucose (P < 0.001) and −0.53 for HbA1c and TIR (P < 0.001).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Compared with HbA1c 6.0-6.9%, HbA1c <6% and ≥8% were associated with increased risks of all-cause and cardiovascular mortality.

    “with increased risks of all-cause and CVD mortality observed among patients with HbA1c <6% and ≥8% compared with those with HbA1c of 6.0–6.9%.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    During a median follow-up of 6.9 years, 838 deaths occurred among the 6,225 participants, of which 287 were due to cardiovascular disease.

    “During a median follow-up of 6.9 years, 838 deaths were identified, 287 of which were due to CVD.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    A recent international consensus recommended that 14 days of continuous glucose monitoring with at least 70% of data available are needed for accurate and meaningful interpretation.

    “A recent international consensus (5) recommended that 14 days of CGM with at least 70% of data available are needed for accurate and meaningful interpretation”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Battelino, 2019, Clinical targets for continuous glucose monitoring data interpretation: recommendations from the international consensus on time in range, Diabetes Care source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    TIR can provide valuable information that is not captured by HbA1c.

    “Since TIR can provide valuable information that is not captured by hemoglobin A1c (HbA1c), it has been advocated as a key metric of glycemic control (5)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Battelino, 2019, Clinical targets for continuous glucose monitoring data interpretation: recommendations from the international consensus on time in range, Diabetes Care source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    The study had a large sample size and long follow-up time, which allowed for high statistical power and the ability to perform stratified analyses.

    “There are several strengths in our study, including the large sample size and long follow-up time, which allowed for high statistical power and the ability to perform stratified analyses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    Due to the observational design, causality between TIR and mortality can only be inferred and residual confounding remains possible.

    “First, due to the observational design of the study, the causality between TIR and mortality can only be inferred and the presence of residual confounding remains a possibility.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Only 3 days of continuous glucose monitoring were conducted in this study with a less accurate former-generation glucose sensor.

    “However, only 3 days of CGM were conducted in our study with a less accurate former-generation glucose sensor.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    TIR is regarded by patients with diabetes as a crucial measure in diabetes management.

    “and is regarded by patients with diabetes to be a crucial measure in diabetes management (6).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Runge, 2018, Does time-in-range matter? Perspectives from people with diabetes on the success of current therapies and the drivers of improved outcomes, Clin Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The results support the validity of TIR as a surrogate marker of long-term adverse clinical outcomes and an end point in future clinical trials.

    “These results support the validity of TIR as a surrogate marker of long-term adverse clinical outcomes and an end point in future clinical trials.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 3-day continuous glucose monitoring measurement of TIR during hospitalization is a valid proxy for the long-term glycemic exposure relevant to mortality risk.

  • May combine two claims.

    Study design and conductreasoning

    The study design precluded exploration of the association between mortality and TIR as a time-dependent variable or updated mean TIR, which might have underestimated the strength of the association.

    “Second, as we discussed above, the glucose profiles observed in the study may not necessarily reflect the historical glycemic control of the enrolled subjects, and the study design precluded the exploration of the association between mortality and TIR as a time-dependent variable or the updated mean TIR, which might have underestimated the strength of the association.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In a post hoc analysis of the Diabetes Control and Complications Trial, TIR was significantly associated with the development of diabetic retinopathy and microalbuminuria.

    “In a post hoc analysis from the Diabetes Control and Complications Trial (DCCT), Beck et al. (8) calculated TIR with seven-point fingerstick glucose values and demonstrated significant associations of TIR with the development of diabetic retinopathy and microalbuminuria.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Beck, 2019, Validation of time in range as an outcome measure for diabetes clinical trials, Diabetes Care source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In pregnant women with type 1 diabetes, TIR was significantly linked to large-for-gestational-age and adverse neonatal outcomes.

    “Moreover, in pregnant women with type 1 diabetes, TIR was observed to be significantly linked to large-for-gestational-age and adverse neonatal outcomes (9).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Kristensen, 2019, Continuous glucose monitoring in pregnant women with type 1 diabetes: an observational cohort study of 186 pregnancies, Diabetologia source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In a previous cross-sectional study, TIR was negatively associated with the prevalence of diabetic retinopathy and carotid intima-media thickness.

    “In our previous cross-sectional study with a large sample of patients with type 2 diabetes, TIR was found to be negatively associated with the prevalence of diabetic retinopathy and carotid intima-media thickness (7).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Lu, 2020, Comparison of multiple cut points for time in range in relation to risk of abnormal carotid intima-media thickness and diabetic retinopathy, Diabetes Care source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Socioeconomic and lifestyle data were not available in the study.

    “In addition, socioeconomic and lifestyle data were not available in the current study.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The multivariable-adjusted models adjusted for age, sex, smoking, diabetes duration, BMI, systolic blood pressure, triglycerides, HDL cholesterol, LDL cholesterol, history of cancer, history of cardiovascular disease, and use of antihypertensive drugs, aspirin, and statins.

    “The analyses were first carried out after adjustment for age and sex (model 1) and then further for smoking, diabetes duration, BMI, systolic blood pressure, triglycerides, HDL cholesterol, LDL cholesterol, history of cancer, history of CVD, and use of antihypertensive drugs, aspirin, and statins (model 2).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    This is the first cohort study to investigate the association between TIR assessed by continuous glucose monitoring and the risk of mortality in patients with type 2 diabetes.

    “This is the first cohort study to investigate the association between TIR assessed by CGM and the risk of mortality in patients with type 2 diabetes.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The relationship between TIR and mortality among patients with type 2 diabetes had not been previously investigated.

  • May combine two claims.

    Interpretationreasoning

    The subjects were hospitalized patients with type 2 diabetes, so the results may not be generalizable to other populations with diabetes.

    “Finally, the subjects included in the analysis were hospitalized patients with type 2 diabetes. Thus, the results of the study may not be generalizable to other populations with diabetes.”
    Quote in the paperNot a substantial claim
18 of 18

  • The paper relies on this without support.

    The 3-day continuous glucose monitoring measurement of TIR during hospitalization is a valid proxy for the long-term glycemic exposure relevant to mortality risk.

    “However, only 3 days of CGM were conducted in our study with a less accurate former-generation glucose sensor.”
    “Consequently, the glucose profiles captured in the current study may not fully represent the patients’ glucose control in the real life.”

  • The paper relies on this without support.

    The relationship between TIR and mortality among patients with type 2 diabetes had not been previously investigated.

    “However, the relationship between TIR and mortality among patients with type 2 diabetes has not been previously investigated.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The results align with existing literature emphasizing the clinical benefits of higher TIR, including reduced complications and improved overall health outcomes for individuals with diabetes.

    “These results align with existing literature that emphasizes the clinical benefits of higher TIR, including reduced complications and improved overall health outcomes for individuals with diabetes19,22–24.”

    From Impact of digital health interventions on glycemic control and weight management. (2025) · cites this paper as [23]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • TIR category is labeled both 50-70% and 51-70%

    Minor

    The results describe a 50-70% TIR group, which overlaps the ≤50% group at 50%. The corresponding group in Table 2 is labeled 51-70%.

1 of 1

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Related

Authors
Lu, J., Wang, C., Shen, Y., Chen, L., Zhang, L., Cai, J., Lu, W., Zhu, W., Hu, G., Xia, T., & Zhou, J.
Affiliations
  • Shanghai Jiao Tong University (CN)
  • Shanghai Municipal Center For Disease Control Prevention (CN)
  • Pennington Biomedical Research Center (US)
Corresponding author
  • Xia, Tian
  • Zhou, Jian
ORCID
Venue
Diabetes Care
Publisher
American Diabetes Association
Published
2020-10-23
Volume
44
Issue
2
Pages
549-555
ISSN
  • 0149-5992 (ISSN-L)
  • 1935-5548
DOI
10.2337/dc20-1862
PMC
PMC9162101
OpenAlex
W3094028309
Cited by
282
References
33
Citations by year
2026: 35 · 2025: 71 · 2024: 46 · 2023: 59 · 2022: 40 · 2021: 29 · 2020: 2
FWCI
24.51
Type
journal article
Language
en
Open access
Licence
www.diabetesjournals.org/content/license (vor, 89 d)
Locations
  • Diabetes Care (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Civil War Book Review (submittedVersion)
Funders
  • National Key R&D Program of China (2018YFC2001004)
  • National Natural Science Foundation of China (31971485)
  • Shanghai Municipal Education Commission (20161430)
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, type 2 diabetes, all-cause mortality, cardiovascular mortality, glycemic control, continuous glucose monitoring, glycemic variability
MeSH terms
Adult, Blood Glucose, Cardiovascular Diseases, China, Diabetes Mellitus, Type 2, Humans, Middle Aged, Prospective Studies, Risk Factors, Blood Glucose Self-Monitoring, Proportional Hazards Models

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