Low mean HbA1c does not increase all-cause and cardiovascular mortality in patients with diabetes: Effect-modifications by anemia and chronic kidney disease stages

BACKGROUND: Previous studies reported that low levels of glycated hemoglobin A1c (HbA1c) were associated with increased mortality. We investigated rates and risks of all-cause and cardiovascular mortality in association with mean HbA1c levels with stratification of anemia and chronic kidney disease (CKD) stages, major causes of low HbA1c. METHODS: 47,145 patients with prescription of antidiabetic agents >6 months in the outpatient visits (2003–2018) were linked to Taiwan’s National Death Registry to identify all-cause and cardiovascular mortality. Poisson assumption was used to estimate the mortality rates, and the Cox proportional hazard regression model was used to evaluate the relative hazards of respective mortality in relation to mean HbA1c in different statuses of anemia and CKD stages. RESULTS: All-cause and cardiovascular mortality rates were the lowest in non-anemic stages 1–2 CKD patients, and the highest in anemic stages 3–5 CKD patients. In stages 1–2 CKD, excessive HRs observed in those with mean HbA1c <6.0% (Hazard Ratio [HR]) 1.58; 95% Confidence Interval [CI] 1.18–2.12) became inconsequential after adjustment of medications and laboratory results (HR: 1.26; 95% CI 0.89–1.79). The similar patterns were observed in anemic stages 1–2 CKD, anemic or non-anemic stages 3–5 CKD. Low HbA1c was not related to cardiovascular mortality in any anemia status or CKD staging. CONCLUSIONS: Higher risks associated with low mean HbA1c and all-cause mortality were attenuated by adjustment of medications and comorbidities. It is imperative for the diabetologists to consider confounding effects of underlying illness before concluding low HbA1c associated higher mortality.