title: 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.
abstract: BACKGROUND
  Previous reports have clearly indicated a significant relationship between hemoglobin (Hb) A1c 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 HbA1c 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) HbA1c 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 HbA1c and HbA1c variability were calculated as the intra-individual mean (HbA1c-MEAN) and standard deviation (HbA1c-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
  HbA1c-MEAN, but not HbA1c-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 HbA1c-MEAN, and 0.47 (0.29-0.75) and 0.46 (0.28-0.73), respectively, for HbA1c-SD. Logistic regression analyses showed that HbA1c-MEAN, but not HbA1c-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 HbA1c-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, HbA1c variability has not a major impact on macrovascular complications, at variance with average HbA1c, an opposite finding as compared with microvascular disease, and particularly nephropathy.
  
  
  BACKGROUND
  ClinicalTrials.Gov NCT00715481.
authors.affiliation: Department of Clinical and Molecular Medicine, "La Sapienza" University, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Penno
authors.forename: Anna
authors.initials: A
authors.lastname: Solini
authors.forename: Giacomo
authors.initials: G
authors.lastname: Zoppini
authors.forename: Emanuela
authors.initials: E
authors.lastname: Orsi
authors.forename: Cecilia
authors.initials: C
authors.lastname: Fondelli
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Zerbini
authors.forename: Susanna
authors.initials: S
authors.lastname: Morano
authors.forename: Franco
authors.initials: F
authors.lastname: Cavalot
authors.forename: Olga
authors.initials: O
authors.lastname: Lamacchia
authors.forename: Roberto
authors.initials: R
authors.lastname: Trevisan
authors.forename: Monica
authors.initials: M
authors.lastname: Vedovato
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pugliese
mesh_terms: D000368:Aged; D002318:Cardiovascular Diseases / Q000097:blood* / Q000150:complications; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000150:complications; D003928:Diabetic Nephropathies; D003930:Diabetic Retinopathy; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D012307:Risk Factors
chemical_list: D006442:Glycated Hemoglobin; C517652:hemoglobin A1c protein, human