Long-term Visit-to-Visit Variability in Hemoglobin A1c and Kidney-Related Outcomes in Persons With Diabetes
Yang Xu1, Shujie Dong2, Edouard L Fu3
1Peking University Clinical Research Institute, Peking University First Hospital, Beijing, People's Republic of China; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Insights
Increased hemoglobin A1c variability is linked to higher risks of kidney disease progression, acute kidney injury, and worsening albuminuria in diabetes patients. This finding suggests glycemic variability is a key factor in kidney complications.
Area of Science:
- Endocrinology and Metabolism
- Nephrology
- Clinical Epidemiology
Background:
- Current diabetes management guidelines primarily focus on average hemoglobin A1c (HbA1c) levels.
- Long-term glycemic variability may offer additional predictive value for adverse outcomes.
- Kidney complications are a significant concern in patients with diabetes.
Purpose of the Study:
- To investigate the association between long-term visit-to-visit HbA1c variability and the risk of adverse kidney outcomes.
- To determine if glycemic variability predicts kidney disease progression, acute kidney injury, and albuminuria worsening independently of mean HbA1c levels.
Main Methods:
- An observational study involving 93,598 adults with diabetes in Stockholm, Sweden.
- HbA1c variability was quantified using a score (HVS) based on percentage of measures varying by >0.5% over a 3-year window.
- Multivariable Cox proportional hazards regression was used to analyze associations with CKD progression, AKI, and albuminuria.
Main Results:
- Higher HbA1c variability was significantly associated with increased risk of CKD progression, AKI, and worsening albuminuria compared to low variability.
- Patients with the highest variability (81%-100% HVS) showed adjusted HRs of 1.6 for CKD progression, 1.23 for AKI, and 1.28 for albuminuria worsening.
- These associations remained consistent across various subgroups and sensitivity analyses.
Conclusions:
- Elevated long-term visit-to-visit HbA1c variability is a consistent predictor of adverse kidney outcomes in patients with diabetes.
- Glycemic variability may play a crucial role in the pathogenesis of diabetic kidney disease.
- HbA1c variability could serve as a valuable metric for kidney risk stratification in clinical practice.
Rationale & Objective:
To characterize associations between long-term visit-to-visit variability of hemoglobin A1c (HbA1c) and risk of adverse kidney outcomes in patients with diabetes.
Study Design:
Observational study.
Setting & Participants:
93,598 adults with diabetes undergoing routine care in Stockholm, Sweden.
Exposures And Predictors:
Categories of baseline and time-varying HbA1c variability score (HVS, the percentage of total HbA1c measures that vary by>0.5% [5.5mmol/mol] during a 3-year window): 0-20%, 21%-40%, 41%-60%, 61%-80%, and 81%-100%, with 0-20% as the reference group.
Outcome:
Chronic kidney disease (CKD) progression (composite of>50% estimated glomerular filtration rate [eGFR] decline and kidney failure), acute kidney disease (AKI by clinical diagnosis or transient creatinine elevations according to KDIGO criteria), and worsening of albuminuria.
Analytical Approach:
Multivariable Cox proportional hazards regression.
Results:
Compared with persons showing low HbA1c variability (HVS 0-20%), any increase in variability was associated with a higher risk of adverse kidney outcomes beyond mean HbA1c. For example, for patients with a baseline HbA1c variability of 81%-100%, the adjusted HR was 1.6 (95% CI, 1.47-1.74) for CKD progression, 1.23 [1.16-1.3] for AKI, and 1.28 [1.21-1.36] for worsening of albuminuria. The results were consistent across subgroups (diabetes subtypes, baseline eGFR, or albuminuria categories), in time-varying analyses and in sensitivity analyses including time-weighted average HbA1c or alternative metrics of variability.
Limitations:
Observational study, limitations of claims data, lack of information on diet, body mass index, medication changes, and diabetes duration.
Conclusions:
Higher long-term visit-to-visit HbA1c variability is consistently associated with the risks of CKD progression, AKI, and worsening of albuminuria.
Plain-Language Summary:
The evidence for current guideline recommendations derives from clinical trials that focus on a single HbA1c as the definitive measure of efficacy of an intervention. However, long-term visit-to-visit fluctuations of HbA1c may provide additional value in the prediction of future kidney complications. We evaluated the long-term fluctuations in glycemic control in almost 100,000 persons with diabetes undergoing routine care in Stockholm, Sweden. We observed that higher long-term HbA1c fluctuation is consistently associated with the risks of chronic kidney disease progression, worsening of albuminuria and acute kidney injury. This finding supports a role for long-term glycemic variability in the development of kidney complications and illustrates the potential usefulness of this metric for risk stratification at the bedside beyond a single HbA1c test.
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