Negative Association of Time in Range and Urinary Albumin Excretion Rate in Patients with Type 2 Diabetes Mellitus: A Retrospective Study of Inpatients
Introduction
Type 2 diabetes mellitus (T2DM) is a growing global health concern, with complications such as diabetic nephropathy contributing significantly to morbidity and mortality. Diabetic nephropathy, characterized by elevated urinary albumin excretion rate (UAER), is a leading cause of end-stage renal disease. While glycosylated hemoglobin A1c (HbA1c) remains the gold standard for assessing glycemic control, it fails to capture glycemic variability, hypoglycemic episodes, or daily glucose patterns. Time in range (TIR), defined as the percentage of time spent within a target glucose range (3.90–10.00 mmol/L), has emerged as a complementary metric to evaluate glycemic management. This study aimed to investigate the relationship between TIR and the severity of UAER in hospitalized T2DM patients.
Methods
Study Design and Participants
A retrospective analysis was conducted on 1,014 inpatients with T2DM from the Department of Endocrinology and Metabolism at Peking University International Hospital (2018–2019). Participants were ≥18 years old, diagnosed with T2DM per WHO criteria, and on stable glucose-lowering regimens for ≥3 months. Exclusion criteria included diabetic ketoacidosis, hyperosmolar hyperglycemic state, recent severe hypoglycemia, malignancy, or severe organ dysfunction.
Data Collection
Blood glucose was measured six times daily (pre-meal, post-meal, fasting, and overnight) for three consecutive days. TIR was calculated as the percentage of readings within 3.90–10.00 mmol/L. Glycemic variability metrics, including coefficient of variation (CV) and mean amplitude of glycemic excursions (MAGE), were also computed.
UAER was assessed using 24-hour urine samples collected over three days. Immunoturbidimetry quantified albumin levels, with severity categorized as:
- Normal: <30 mg/g creatinine,
- Microalbuminuria: 30–300 mg/g creatinine,
- Macroalbuminuria: >300 mg/g creatinine.
Baseline clinical parameters (age, sex, BMI, blood pressure, HbA1c, lipid profile, creatinine) were extracted from electronic medical records.
Statistical Analysis
Continuous variables were analyzed using ANOVA or Jonckheere-Terpstra tests. Multinomial logistic regression assessed associations between TIR and UAER severity, adjusting for confounders (age, sex, BMI, diabetes duration, systolic blood pressure, HbA1c, triglycerides, creatinine). Patients were stratified into TIR quartiles: Q1 (83%).
Results
Baseline Characteristics
The cohort had a mean age of 55.6 years, diabetes duration of 8.9 years, BMI of 26.0 kg/m², and HbA1c of 8.4%. Patients with macroalbuminuria were older (61.3 vs. 54.4 years), had longer diabetes duration (15.2 vs. 7.9 years), higher systolic blood pressure (141.5 vs. 130.5 mmHg), and elevated creatinine (94.4 vs. 67.1 mmol/L) compared to those with normal UAER (all P < 0.001).
TIR and UAER Severity
The overall mean TIR was 70% ± 20%. TIR decreased progressively with worsening UAER:
- Normal: 70% ± 20%,
- Microalbuminuria: 50% ± 20%,
- Macroalbuminuria: 30% ± 20% (all P < 0.001).
Stratification by TIR quartiles revealed significant trends:
- Microalbuminuria prevalence: 41.1% (Q1), 21.6% (Q2), 7.1% (Q3), 5.5% (Q4),
- Macroalbuminuria prevalence: 24.2% (Q1), 1.1% (Q2), 1.4% (Q3), 0% (Q4) (all P < 0.001).
Multivariate Analysis
After adjusting for confounders, each 10% increase in TIR was associated with reduced odds of microalbuminuria (OR: 0.58, 95% CI: 0.52–0.65) and macroalbuminuria (OR: 0.26, 95% CI: 0.18–0.38). These associations persisted even after accounting for glycemic variability metrics (CV, MAGE).
Discussion
This study demonstrates a robust inverse relationship between TIR and UAER severity in T2DM patients. Lower TIR values correlated strongly with higher risks of micro- and macroalbuminuria, independent of traditional risk factors like HbA1c, blood pressure, and diabetes duration.
Clinical Implications
TIR provides granular insights into glycemic patterns that HbA1c cannot capture. For instance, two patients with identical HbA1c may have vastly different TIR due to fluctuations between hyperglycemia and hypoglycemia. The findings align with prior studies linking TIR to microvascular complications. For example, the Diabetes Control and Complications Trial (DCCT) reported that every 10% decrease in TIR increased retinopathy progression by 64% and microalbuminuria risk by 40%. Similarly, Lu et al. (2018) found TIR assessed via continuous glucose monitoring (CGM) predicted diabetic retinopathy in T2DM.
Mechanistic Insights
Chronic hyperglycemia and glycemic variability induce oxidative stress and endothelial dysfunction, contributing to renal damage. TIR’s inverse association with UAER suggests that sustained glucose control within the target range mitigates these pathways. Notably, the near-absence of macroalbuminuria in the highest TIR quartile (Q4: >83%) underscores the potential renal benefits of optimizing TIR.
Limitations
The study’s retrospective design, single-center cohort, and short observation period limit generalizability. Daytime-focused glucose measurements may underestimate nocturnal fluctuations. Additionally, fingerstick glucose sampling, while practical, is less comprehensive than CGM.
Conclusion
TIR is a clinically meaningful metric strongly associated with UAER severity in T2DM. Optimizing TIR may reduce the risk of early diabetic nephropathy, offering a complementary strategy to HbA1c for glycemic management. Future prospective studies using CGM-derived TIR are warranted to validate these findings across diverse populations.
doi.org/10.1097/CM9.0000000000001914
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