The Healthy Women Bias and Hormone Replacement Therapy in Women With Type 2 Diabetes Free

A cross-sectional study by Ferrara et al. (1), recently published in Diabetes Care suggests that hormone replacement therapy (HRT) is associated with a decreased HbA_1c level in women with diabetes. The “healthy women bias” always becomes an issue to be discussed in cross-sectional studies related with HRT. It is well known that women willing to initiate and continue taking any form of HRT are usually more concerned about their health, more educated, visit their doctors more often, and have lower blood pressure and lipid levels. Furthermore, compared with the rest of women, they are physically trained and usually do not smoke tobacco or drink alcohol in excess.

The results presented by the authors clearly show that this bias may explain a large percent of the HRT-related benefit on HbA_1c levels. Case subjects had significantly higher education and lower rates of smoking. Also, they practiced regular exercise and capillary glucose measurements more often than the control subjects. The authors tried to avoid the confounding effect of this bias by using a generalized estimating equation model. After controlling some of these variables, HRT remained as an independent predictor for the HbA_1c levels. The “healthy women bias” results from the sum of a large number of measurable and nonmeasurable confounders (2). The only way to avoid it is the use of randomized control trials. Unfortunately, few papers had prospectively analyzed the effect of HRT on glucose control in women with type 2 diabetes. Most of them (3) had included small number of cases with a wide range in HbA_1c levels. Also, the inclusion of a progestin may result in different conclusions.

Data published by our group (4) clearly showed that HRT might have different effects on glucose control depending on the baseline HbA_1c level. A total of 54 postmenopausal women were included. After a 6-week run-in period on diet, case subjects were randomized to receive either placebo (HbA_1c <8%, n = 13; >8%, n = 17) or HRT (HbA_1c <8%, n = 11; >8%, n = 13) during 12 weeks. HRT consisted in cyclical conjugated estrogens at 0.625 mg/day plus medrogestone at 5 mg/day. At baseline and during the study, hyperglycemic cases had an HbA_1c level significantly higher than the near-normoglycemic control subjects (baseline 10.2 ± 2.9 vs. 6.5 ± 0.7%, P < 0.01). In the normoglycemic cases, a small increase in HbA_1c was observed (6.5 ± 0.7 vs. 7.4 ± 1%, P = 0.04). No further deterioration in glucose control resulted from HRT in hyperglycemic women (10.5 ± 2.7 vs. 10.6 ± 3.5, NS). However, the triglycerides response was significantly higher in the hyperglycemic group.

These observations are proof that randomized controlled trials (instead of cross-sectional reports) are urgently needed to assess the short- and long-term safety in women with type 2 diabetes who have a clear indication for receiving HRT.