Variability in Glycated Hemoglobin and Risk of Poor Outcomes Among People With Type 2 Diabetes in a Large Primary Care Cohort Study

OBJECTIVE Diabetes guidelines focus on target glycated hemoglobin (HbA1c) levels. Long-term variability in HbA1c may be predictive of hospitalization or mortality, but its importance at different average levels or trajectories is unclear. RESEARCH DESIGN AND METHODS Using English primary care data, 58,832 patients with type 2 diabetes had HbA1c average (mean of annual means), variability (coefficient of variation), and trajectory (annual regression slope) estimated during 2006–2009. Hazard ratios (HRs) for mortality and emergency hospitalization during 2010–2015, with adjustment for age, sex, smoking, BMI, duration of diabetes, and deprivation, were estimated using Cox regression. The simultaneous impact of HbA1c average, variability, and trajectory was estimated using percentiles. RESULTS In mutually adjusted models, HbA1c variability showed a consistent dose-response relationship with all-cause mortality, while average level was only important among individuals in the highest or lowest 10% of the distribution, and trajectory had no independent effect. Individuals with the most unstable HbA1c (top 10%) were almost twice as likely to die (HR 1.93 [95% CI 1.72–2.16]) than were those with the most stable (bottom 10%)-an association attenuated but not explained by hypoglycemia. For emergency hospitalizations, similar trends were seen except for coronary artery disease (CAD) and ischemic stroke (IS), where increasing average rather than variability was predictive. CONCLUSIONS HbA1c variability was strongly associated with overall mortality and emergency hospitalization and not explained by average HbA1c or hypoglycemic episodes. Only for CAD and IS hospitalizations was no association found, with average HbA1c strongly predictive. Targets should focus on both stability and absolute level of HbA1c.