Association Between Glycemic Control and Adverse Outcomes in People With Diabetes Mellitus and Chronic Kidney Disease: A Population-Based Cohort Study

Study Questions:

What is the effect of a lower glycated hemoglobin (HbA1c) level on outcomes in people with diabetes mellitus (DM) and chronic kidney disease (CKD)?

Methods:

From all people with serum creatinine measured as part of routine care in a single Canadian province from 2005 through 2006, the authors identified those with CKD based on laboratory data (estimated glomerular filtration rate [eGFR], <60.0 ml/min/1.73 m2) and DM using a validated algorithm applied to hospitalization and claims data. Patients were classified based on their first HbA1c measurement; Cox regression models were used to assess independent associations between HbA1c level and five study outcomes (death, progression of kidney disease based on a doubling of serum creatinine level, or new end-stage renal disease [ESRD], cardiovascular events, all-cause hospitalization).

Results:

The investigators identified 23,296 people with DM and an eGFR lower than 60.0 ml/min/1.73 m2. The median HbA1c level was 6.9% (range, 2.8%-20.0%), and 11% had an HbA1c value higher than 9%. Over the median follow-up period of 46 months, 3,665 people died, and 401 developed ESRD. Regardless of baseline eGFR, a higher HbA1c level was strongly and independently associated with excess risk of all five outcomes studied (p < 0.001 for all comparisons). However, the association with mortality was U-shaped, with increases in the risk of mortality apparent at HbA1c levels lower than 6.5% and higher than 8.0%. The increased risk of ESRD associated with a higher HbA1c level was attenuated at a lower baseline eGFR (p value for interaction, < 0.001). Specifically, among those with an eGFR of 30.0-59.9 ml/min/1.73 m2, the risk of ESRD was increased by 22% and 152% in patients with HbA1c levels of 7-9% and higher than 9%, respectively, compared with patients with an HbA1c level lower than 7% (p < 0.001), whereas corresponding increases were 3% and 13%, respectively, in those with an eGFR of 15.0-29.9 ml/min/1.73 m2.

Conclusions:

The authors concluded that appropriate and timely control of HbA1c level in people with DM and CKD may be more important than previously realized.

Perspective:

This study suggests strong and independent associations between higher levels of HbA1c and multiple clinically relevant outcomes, including mortality, cardiovascular events, hospitalization, and progression to kidney failure. Consistent with findings from trials in the general population with DM, the study also reports that levels of HbA1c greater than 8.0% as well as levels lower than 6.5% were associated with increased mortality. Overall, the study is consistent with the hypothesis that better glycemic control in patients with stage 3-4 CKD tends to improve clinical outcomes, but that overly intensive therapy (i.e., HbA1c target level lower than 7%) may be harmful, but needs confirmation in an adequately powered randomized trial. For now, clinicians should follow guidelines, which recommend achieving good control of blood pressure and cholesterol and glucose levels, while minimizing the potential for serious adverse effects of the treatment regimens, including intensive glycemic control.

Clinical Topics: Dyslipidemia, Lipid Metabolism, Nonstatins

Keywords: Hemoglobin A, Follow-Up Studies, Kidney Function Tests, Canada, Blood Pressure, Creatinine, Cholesterol, Renal Insufficiency, Proportional Hazards Models, Biological Markers, Blood Glucose, Glomerular Filtration Rate, Disease Progression


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