We thank Chan et al. (1) for their interest in our work (2) and their relevant comments. We agree that there is still much to be learned about the relationship between homocysteine and atherosclerosis, as was recently stressed by Christen et al. (3). We also agree that homocysteine metabolism is altered for a few days after acute ischemic events, as reported by Egerton et al. (4) and Lindgren et al. (5). Therefore, patients with acute cardiovascular events were excluded from our analysis and could not interfere with the interpretation of our results.

Chan et al. (1) pertinently mention the role of fibrates and metformin as potential confounders of homocysteine concentrations. Our data in type 2 diabetic patients confirm that fibrates significantly increased homocysteine levels, whereas there was no influence from metformin treatment.

Chan et al. (1) also comment aptly on postmenopausal use of estro-progesterone hormone replacement therapy (HRT). Recent reports show that homocysteine levels increase after menopause (6,7) and that HRT lowers homocysteine concentrations (8,9).

In our cohort, 84% of women (n = 68) had reached menopause, and reliable information on both menopause and HRT status was available for 46 of them. A total of 20 (43%) of the latter patients were treated with HRT (HRT+ group), whereas 26 had no hormonal substitution (HRT group). Age, diabetes duration, BMI, smoking prevalence, HbA1c, and creatinine clearance were comparable between the two groups. In contrast, menopause duration was significantly shorter in HRT+ group than in the HRT group (16 ± 4 vs. 22 ± 6 years, P = 0.002). There was a nonsignificant trend for lower homocysteine levels in patients with HRT (13.2 ± 5.3 vs. 17.4 ± 9.9 μmol/l, P = 0.07). Folic acid and vitamin B12 concentrations were comparable (7.4 ± 3.9 vs. 7.2 ± 3.6 ng/ml and 398 ± 167 vs. 521 ± 298 pg/ml) in the HRT+ and the HRT groups, respectively. Plasma cholesterol (C), LDL-C, and triglycerides were also similar in the HRT+ and the HRT groups, whereas HDL-C and C/HDL ratio were 58 ± 17 vs. 49 ± 13 mg/dl (P = 0.058) and 4.0 ± 0.9 vs. 5.0 ± 2.5 (P = 0.068) in patients with and without HRT, respectively. It is of interest to mention that macroangiopathy was significantly less frequent in HRT + than in HRT – patients (10 vs. 39%, P = 0.04), as also observed in nondiabetic subjects (10).

In view of the trend in association between the use of HRT and lower homocysteine levels, as well as the reduced prevalence of macroangiopathy in HRT+ women, we agree with Chan et al. (1) that it could be of interest to measure homocysteine in postmenopausal type 2 diabetic patients as another incentive for selective use of HRT when high homocysteine is found.

In summary, our findings demonstrate the current importance of homocysteine determination in routine initial evaluations of all patients at risk for macroangiopathy. Additional caution is needed when interpreting such data because of various confounding factors, including the use of HRT.

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Address correspondence to Prof. M. Buysschaert, Service d’Endocrinologie et Nutrition, Cliniques Universitaires St Luc Avenue Hippocrate 54, UCL 54.74 B-1200 Brussells, Belgium. E-mail: buysschaert@diab.ucl.ac.be.