Hemoglobin A1c variability as an independent correlate of cardiovascular disease in patients with type 2 diabetes: a cross-sectional analysis of the Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study

Background: Previous reports have clearly indicated a significant relationship between hemoglobin (Hb) A(1c) change from one visit to the next and microvascular complications, especially nephropathy (albuminuria and albuminuric chronic kidney disease, CKD). In contrast, data on macrovascular disease are less clear. This study was aimed at examining the association of HbA(1c) variability with cardiovascular disease (CVD) in the large cohort of subjects with type 2 diabetes from the Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study. Methods: Serial (3-5) HbA(1c) values obtained during the 2-year period preceding recruitment, including that obtained at the enrolment, were available from 8,290 subjects from 9 centers (out of 15,773 patients from 19 centers). Average HbA(1c) and HbA(1c) variability were calculated as the intra-individual mean (HbA(1c)-MEAN) and standard deviation (HbA(1c)-SD), respectively, of 4.52 +/- 0.76 values. Prevalent CVD, total and by vascular bed, was assessed from medical history by recording previous documented major acute events. Diabetic retinopathy (DR) was assessed by dilated fundoscopy. CKD was defined based on albuminuria, as measured by immunonephelometry or immunoturbidimetry, and estimated glomerular filtration rate, as calculated from serum creatinine. Results: HbA(1c)-MEAN, but not HbA(1c)-SD, was significantly higher (P<0.0001) in subjects with history of any CVD (n. 2,133, 25.7%) than in those without CVD (n. 6,157, 74.3%). Median and interquartile range were 7.78 (7.04-8.56) and 7.49 (6.81-8.31), respectively, for HbA(1c)-MEAN, and 0.47 (0.29-0.75) and 0.46 (0.28-0.73), respectively, for HbA(1c)-SD. Logistic regression analyses showed that HbA(1c)-MEAN, but not HbA(1c)-SD (and independent of it), was a significant correlate of any CVD. Similar findings were observed in subjects with versus those without any coronary or cerebrovascular event or myocardial infarction. Conversely, none of these measures were associated with stroke, whereas both correlated with any lower limb vascular event and HbA(1c)-SD alone with ulceration/gangrene. All these associations were independent of known CVD risk factors and microvascular complications (DR and CKD). Conclusions: In patients with type 2 diabetes, HbA(1c) variability has not a major impact on macrovascular complications, at variance with average HbA(1c), an opposite finding as compared with microvascular disease, and particularly nephropathy. Trial registration: ClinicalTrials.Gov NCT00715481