Long-term Visit-to-Visit Variability in Hemoglobin A_1c and Kidney-Related Outcomes in Persons With Diabetes

Rationale & objective: To characterize associations between long-term visit-to-visit variability of hemoglobin A_1c (HbA_1c) 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 HbA_1c variability score (HVS, the percentage of total HbA_1c 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 HbA_1c variability (HVS 0-20%), any increase in variability was associated with a higher risk of adverse kidney outcomes beyond mean HbA_1c. For example, for patients with a baseline HbA_1c 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 HbA_1c 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 HbA_1c 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 HbA_1c as the definitive measure of efficacy of an intervention. However, long-term visit-to-visit fluctuations of HbA_1c 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 HbA_1c 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 HbA_1c test.