The male predominance of cardiovascular disease is overridden by the presence of diabetes, as the sex-related burden of cardiovascular disease increases in postmenopausal women with diabetes (1). Sexual dimorphism in cardiovascular autonomic neuropathy (CAN) might contribute to these findings (1).
We conducted a cross-sectional study hypothesizing that 1) the prevalence of CAN is different among women and men with type 1 diabetes, 2) such a difference is dependent on the pre- or postmenopausal status of women, and 3) sex steroids show opposite associations with CAN depending on sex.
In this study, we recruited 279 consecutive patients with type 1 diabetes attending our clinic (ClinicalTrials.gov identifier NCT02910271) (2,3). Inclusion and exclusion criteria are detailed elsewhere (2,3). Assuming a global prevalence of CAN of ∼30% in our population of patients with type 1 diabetes (2) and setting α at 0.05 and β at 0.20 for a two-sided test, the inclusion of at least 160 men and 120 women was enough to identify a difference in prevalence among them above 15% (www.imim.cat/ofertadeserveis/software-public/granmo/).
The study protocol conformed to the ethical guidelines of the Declaration of Helsinki and was approved by the local ethics committee of Hospital Universitario Ramón y Cajal (approval date 22 January 2016, protocol ID 464/15). Informed consent was obtained from all participants included in the study. Patients did not receive any economic compensation for their participation.
For all study subjects, we reviewed medical history and clinical parameters of the patients at recruitment. Then, participants were submitted to a physical examination and biochemical assessments. Serum for sex steroid measurements was frozen at −80°C until thawed for analysis. Technical characteristics of the assays used for biochemical and hormone measurements have been described in detail elsewhere (2,4). We performed hormone assays at the same time using kits from the same production lots. Cardiovascular autonomic function was assessed using Ewing tests (Monitor OneDx System device; Qmed, Inc., Eatontown, NJ) and by the changes in blood pressure and heart rate after active standing (3).
Data are shown as means ± SD or counts (percentage) with 95% CI (lower limit; upper limit). Patients were classified by age using a cutoff of 45 years. Analysis of discrete variables used logistic binary regressions, and continuous variables were submitted to two-way ANOVA tests. We assessed the association between sex steroids and Ewing tests by Spearman correlations. Statistical significance was set at a P value <0.05.
The features of participants are detailed in Table 1. In women, CAN was early/mild in 39 cases (32%) and definitive in 4 (3%). In men, CAN was early/mild in 40 cases (25%) and definitive in 2 (1%). On the whole, the prevalence of CAN was not significantly different between men and women (Table 1). However, it was much more frequent in women >45 years of age than in younger women or in men regardless of age. The odds ratio of CAN was 4.5 (95% CI 1.4; 14.1) in older women compared with older men, 5.4 (95% CI 2.0; 14.7) compared with younger women, and 6.4 (95% CI 2.4; 17.2) compared with younger men.
Men with CAN showed lower total testosterone (T) and T/estradiol (E2) ratios than those without CAN. T and T/E2 ratios were directly correlated with Ewing scores. Women with CAN had higher T/E2 ratios than those without CAN. A significant correlation was observed between free T and orthostatism test values.
According to our findings, women with type 1 diabetes >45 years of age show a marked increase in the risk of suffering from CAN with respect to other subgroups of patients. In agreement with our previous hypothesis (5), we also observed that circulating T and its relation to E2 may have opposite associations with CAN in men and women. The higher concentrations of T in our women with CAN suggest that androgen excess might be associated with autonomic dysfunction, although the T/E2 ratio increase largely relied on the profound decrease of E2 found in older women. Conversely, T was positively associated with heart rate variability in men, and those men with CAN had lower T levels.
Nonetheless, our older women also had more cardiovascular risk factors than the other study subgroups. Whether this fact was related only to the estrogen decline of menopause is unclear (1). We have to bear in mind that these women also had a longer duration of diabetes, which is one of the most important predictors for cardiovascular outcomes. However, older men also had a longer duration of diabetes but did not show an increased prevalence of CAN.
If confirmed in other populations, the very large prevalence of CAN among postmenopausal women with type 1 diabetes in our study, despite the obvious limitations of its relatively small sample size and observational design, would make CAN screening mandatory for the accurate stratification of their cardiovascular risk. The consequences of the management of male hypogonadism and female hyperandrogenism in patients with type 1 diabetes merit further research.
H.F.E.-M. and M.L.-R. contributed equally to this work.
Article Information
Acknowledgments. The authors thank Belén Arias Zamorano from the Diagnostic and Therapeutic Facilities of the Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, for her excellent technical help.
Funding. This work was supported by grants from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitiveness (PI1400649, PI151686, and PIE1600050). CIBERDEM is also an initiative of Instituto de Salud Carlos III, partially supported by the European Regional Development Fund.
The funding organization played no role in the study design; collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the report for publication.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.
Author Contributions. L.N.-C. recruited subjects, researched and analyzed data, and wrote the manuscript. H.F.E.-M. and M.L.-R. designed the study, researched and analyzed data, contributed to the discussion, and reviewed and edited the final version. S.A.D. recruited patients, researched data, and contributed to the discussion. L.J.-M. and A.G.-C. processed and assayed samples and contributed to the discussion. E.F.-D. and B.D.A. recruited patients, processed samples, and contributed to the discussion. All the authors approved the final version of the manuscript. L.N.-C. and M.L.-R. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Prior Presentation. A preliminary report of this study was presented in abstract form at the 79th Scientific Sessions of the American Diabetes Association, San Francisco, CA, 7–11 June 2019.
