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Endocrinología, Diabetes y Nutrición (English ed.)
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Inicio Endocrinología, Diabetes y Nutrición (English ed.) What if chromosome sex was a variable of importance at the time of individualizi...
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Vol. 70. Issue S2.
Pages 70-71 (June 2023)
Letter to the Editor
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What if chromosome sex was a variable of importance at the time of individualizing treatment in diabetes mellitus?
¿Y si el sexo cromosómico supusiera una variable de importancia a la hora de individualizar el tratamiento en la diabetes mellitus?
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Virginia González Hidalgoa,
Corresponding author
virginiagonhid@gmail.com

Corresponding author.
, Jesús Manuel Morán Lópezb
a Servicio de Medicina Interna, Hospital Virgen del Puerto, Plasencia (Cáceres), Spain
b Servicio de Endocrinología y Nutrición, Hospital Virgen del Puerto, Plasencia (Cáceres), Spain
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Table 1. Cardiovascular outcomes stratified by gender.
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Vol. 70. Issue S2
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Dear Editor,

Diabetes mellitus (DM) is a field of knowledge that continues to experience exponential growth. As a result, the management paradigms have changed, shifting the glucocentric view of the disease towards a vision in which different variables (social, age, organic) are taken into account when determining the treatment objective. The development of new families of drugs (SGLT2 inhibitors, GLP-1 analogues) and their benefits beyond their hypoglycaemic effect also influence our treatment algorithms.1,2 However, there is a non-modifiable factor that we may not be taking into account when making our decisions: the influence of the gender factor (as a biological and social factor).

There is a large body of evidence suggesting that the expression of the disease and its complications are not the same in males and females: disease onset is earlier age in males, but as age advances it becomes equal in both genders3 and the male/female ratio is projected to reach around 1:1 in the coming years; females can develop a specific type of diabetes (gestational diabetes mellitus), which leads to a 9.51 times higher risk of developing diabetes outside pregnancy (P < .001; 95% CI: 7.14–12.67),4 and differences have also been described in the complications tree.3 In general terms, males have a higher incidence and severity of microvascular complications (both in DM1 and DM2),5 while with macrovascular complications, the opposite is the case; it is striking that both the incidence and mortality rate due to coronary complications are distinctly higher in females than in males (increase in the incidence of coronary artery disease of 3–5 times in females and 1–3 times in males with DM2 compared to individuals without DM,5,6 with 6.4 years of life lost in females under 50 compared to 5.8 years of life lost in males).3 It seems that cerebrovascular disease is also more prevalent and fatal in women (without being as evident as in coronary disease).5,6

While there are no conclusive data on peripheral arterial disease in DM1,5 in young women with DM2 it leads to a higher mortality risk than in their male counterparts, although, in absolute terms, it is more common and causes more deaths in males.6

Since 2007, with its resolution WHA60.25 and the subsequent “Strategy for integrating gender analysis and actions into the work of WHO”,7 the World Health Organization has been committed to integrating gender analysis into all its actions and pressing for the data from its studies to be broken down by such variables as gender and age. It also advocates following the same recommendations when publishing the results of scientific research.

If we look back at the results of the cardiovascular safety studies for the drugs approved for the treatment of DM published since the Food and Drug Administration resolution in 2008, we can conclude that, in general, the number of females included in these studies represented 30%–40% of the total number of participants.8 A review published in 2018 by Gerstein and Shah8 analysed the cardiovascular outcomes from the safety studies published to date stratified by gender (Table 1). Although all the drugs analysed have proven to be safe in females, from a statistical point of view, cardiovascular benefit is described with pioglitazone and degludec. Since that review, we have seen the publication of the REWIND study (dulaglutide)9 showing cardiovascular safety, but without superiority of its primary composite endpoint (myocardial infarction or non-fatal stroke or death from cardiovascular causes; P = .90; 95% CI: 0.79–1.04), while in the studies of the VERTIS series (ertugliflozin),10 the data published were not stratified by gender.

Table 1.

Cardiovascular outcomes stratified by gender.

Drug  Study  Percentage by gender (%)  Primary composite endpoint (HR) overall (M and F)  Effects of the cardiovascular intervention stratified by gender 
Nateglinide  NAVIGATOR  F: 51  0.94 (0.82−1.09)  F: 1.05 (0.82−1.33) 
    M: 49    M: 0.90 (0.75−1.07) 
Prandial insulin  HEART 2D  F: 37  0.98 (0.80−1.21)  N/A 
    M: 63    N/A 
Insulin glargine  ORIGIN  F: 35  1.02 (0.94−1.11)  F: 1.11 (0.94−1.31) 
    M: 65    M: 0.98 (0.89−1.09) 
Insulin degludec  DEVOTE  F: 37  0.91 (0.78−1.06)  F: 0.76 (0.59−0.99) 
    M: 63    M: 0.99 (0.83−1.20) 
Pioglitazone  PROACTIVE  F: 34  0.90 (0.80−1.02)   
    M: 66     
Pioglitazone  IRIS  F: 35  0.76 (0.62−0.93)  F: 0.65 (0.46−0.93) 
    M: 65    H: 0.81 (0.64−1.03) 
Alogliptin  EXAMINE  F: 32  0.96 (<1.16)  F: 0.87 (0.67−1.12) 
    M: 68    M: 1.02 (0.84−1.24) 
Sitagliptin  TECOS  F: 29  0.98 (0.89−1.08)  F: 0.95 (0.78−1.15) 
    M: 71    M: 0.99 (0.88−1.10) 
Saxagliptin  SAVOR  F: 33  1.00 (0.89−1.12)  F: 0.97 (0.78−1.20) 
    M: 67    M: 1.01 (0.89−1.16) 
Lixisenatide  ELIXA  F: 31  1.02 (0.89−1.17)  F: 1.10 (0.90−1.30) 
    M: 69    M: 0.95 (0.75−1.20) 
Liraglutide  LEADER  F: 36  0.87 (0.78−0.97)  F: 0.88 (0.72−1.08) 
    M: 64    M: 0.86 (0.75−0.98) 
Semaglutide  SUSTAIN 6  F: 39  0.74 (0.58−0.95)  F: 0.68 (0.50−0.92) 
    M: 61    M: 0.84 (0.54−1.31) 
Empagliflozin  EMPA-REG  F: 29  0.86 (0.74−0.99)  F: 0.83 (0.62−1.11) 
    M: 71    M: 0.87 (0.73−1.02) 
Canagliflozin  CANVAS  F: 36  0.86 (0.75−0.97)  F: 0.84 (0.66−1.06) 
    M: 64    M: 0.86 (0.74−1.00) 
Dulaglutide  REWIND  F: 46.6  0.88 (0.79−0.99)  F: 0.85 (0.71−1.02) 
    M: 53.4    M: 0.90 (0.79−1.04) 

F: female; HR: hazard ratio; M: male.

Adapted from World Health Organization7 and Gernstein and Reema.8

Looking at these data, the question we asked as title to this letter seems all the more important. Specific studies in female subjects are needed to guide us towards the best therapeutic decision-making for women and girls with DM.

Funding

No funding was received.

References
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R. Reyes-García, Ó. Moreno-Pérez, C. Tejera-Pérez, D. Fernández-García, V. Bellido-Castañeda, M. López de la Torre Casares.
Documento de abordaje integral de la diabetes tipo 2.
Endocrinol Diabetes Nutr., 66 (2019), pp. 443-458
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Summary of revisions: Standards of Medical Care in Diabetes 2022.
Diabetes Care., 45 (2022), pp. S4-S7
[3]
Federación Internacional de Diabetes. Atlas de diabetes. 9ª edición. 2019 [accessed 6 Feb 2022]. Available from: www.diabetesatlas.org.
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E. Vounzoulaki, K. Khunti, S.C. Abner, B.K. Tan, M.J. Dvies, C.L. Gilles.
Progression to type 2 diabetes in women with a known history of gestational diabetes: systematic review and meta-analysis.
BMJ., 369 (2020), pp. m1361
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Sex differences in micro- and macro-vascular complications of diabetes mellitus.
Clin Sci., 131 (2017), pp. 833-846
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Organización Mundial de la Salud. Género y salud. 2018 [accessed 6 Feb 2022]. Available from: https://www.who.int/es/news-room/fact-sheets/detail/gender.
[8]
H.G. Gerstein, S. Reema.
Cardiovascular outcomes trials of glucose-lowering drugs or strategies in type 2 diabetes.
Endocrinol Metab Clin N Am., 47 (2018), pp. 97-116
[9]
H.G. Gerstein, H.M. Colhoun, G.R. Dagenais, R. Diaz, M. Lakshmanan, P. Pais, et al.
Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
Lancet., 394 (2019), pp. 121-130
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C.P. Cannon, R. Pratley, S. Dagogo-Jack, J. Mancuso, S. Huyck, U. Masiukiewicz, et al.
VERTIS CV Investigators. Cardiovascular outcomes with ertugliflozin in type 2 diabetes.
N Engl J Med., 383 (2020), pp. 1425-1435
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