Does Gender-Affirming Hormone Therapy Affect T2D Risk?

Transfeminine (TF) people may be at a higher risk for type 2 diabetes (T2D) compared with cisgender females (CF), according to results of a cohort study. However, the corresponding difference in T2D risk was not discernable when compared with cisgender males (CM), and little evidence exists attributing T2D in TF or transmasculine (TM) persons to gender-affirming hormone therapy (GAHT), researchers found.

The manuscript was published online in The Journal of Clinical Endocrinology & Metabolism.

“Our study findings provide some reassurance that gender-affirming therapy does not increase the risk of [T2D], but our analysis was not designed to evaluate more subtle subclinical changes. For this reason, health care providers should continue monitoring the metabolic status of individuals receiving gender-affirming therapy,” said study author Noreen Islam, MD, MPH, of Emory University School of Medicine in Atlanta, Georgia.

Nearly 1 million individuals in the United States identify as transgender, and the number of those who report identifying as transgender and gender diverse (TGD) is growing. As it is increasingly likely that providers will encounter TGD patients in their practice, a better understanding of the health issues facing these individuals is becoming increasingly important, authors explained.

One priority of TGD health research is to elucidate the metabolic changes induced by GAHT, as “there is evidence that GAHT may affect glucose metabolism, and body weight, but how these changes influence the risk of [T2D] is unclear,” they added.

To evaluate the occurrence of T2D in a cohort of TGD people receiving GAHT, investigators assessed data from the Study of Transition Outcomes and Gender (STRONG). This cohort is comprised of electronic health records of TGD patients receiving care at 3 Kaiser Permanente health systems in California and Georgia.

TGD patients were matched with up to 10 male and 10 female cisgender patients based on race/ethnicity, year of birth, and other characteristics. All study participants were at least 18 years old at index date, and data reported between 2006 and 2014 were included in the analysis; a follow-up period extended through the end of 2016.

Of the 5002 TGD individuals included, 2869 (57%) were TF and 2133 (43%) were TM; patients were matched with 28,300 CF and 28,258 CM patients, and 20,997 CF and 20,964 CM referents, respectively.

Analyses revealed:

• The TM cohort members were on average younger than their TF counterparts and more than half of participants (54% for TF and 60% for TM) were non-Hispanic White.
• The proportions of participants with normal body mass index at baseline were about the same in the TF and TM cohorts (36% vs 34%).
• Approximately 32% of TF and 24% of TM individuals were on GAHT on or before the index date.
• Both prevalent and incident T2D was more common in the TF cohort relative to CF referents with odds ratio (OR) and HR estimates of 1.3 (95% CI, 1.1-1.5) and 1.4 (95% CI, 1.1-1.8), respectively.
• 175 (61%) of the 287 TF patients and 77 (59%) of the 131 TM patients had a diagnosis of T2D at baseline (on or before the index date) and the rest developed diabetes at some time after the index date.
• No significant differences in prevalence or incidence of T2D were observed across the remaining comparison groups, both overall and in TGD persons with evidence of GAHT receipt.
• Previous studies have explored the impact of GAHT on laboratory markers of insulin resistance and glucose metabolism. One investigation found GAHT can induce insulin resistance in TM and TF individuals, but only if insulin levels remained within physiologic range. An additional study “reported that TF persons experienced increases in glucose utilization following GAHT initiation, whereas the same result for TM study participants demonstrated no discernable changes from the baseline.” However, both studies included small sample sizes.

“The published literature indicates that measures of glucose metabolism and insulin resistance do not appear to be adversely influenced by testosterone in TM individuals but may be affected by estradiol therapy among TF individuals,” researchers explained. They continued, “these observations notwithstanding, the clinical significance of the reported associations is not clear, and it is possible that small GAHT-related changes in laboratory parameters do not translate into higher risk of overt T2D.”

In the current analysis, data were not collected at specified intervals and the algorithm utilized did not explicitly distinguish between T2D and type 1 diabetes (T1D), although cases with T1D-specific diagnostic codes were excluded. Some misclassifications could have taken place, marking a limitation to the study.

Data on other T2D risk factors such as family history, socioeconomic status, and adverse childhood experiences were also not included. Past research has indicated sexual and gender minority stress are associated with higher incidence of cardiovascular disease, while data link stressful experiences to T2D and poor glycemia control, authors explained.

“Taking into consideration the apparent absence of the association between GAHT receipt and T2D incidence in our study, additional research should focus on the hypothesized effect of gender minority stress and its interaction with lifestyle related metabolic risk factors among TGD people,” they concluded. Future larger, more detailed studies with longer follow-up periods are warranted.

Reference

Islam N, Nash R, Zhang Q, et al. Is there a link between hormone use and diabetes incidence in transgender people? Data from the STRONG cohort. J Clin Endocrinol Metab. Published online November 30, 2021. doi: 10.1210/clinem/dgab832