Clinical Researcher—June 2024 (Volume 38, Issue 3)

PEER REVIEWED

Kirti Salunkhe, MD; Tara Coffin, PhD, MEd, CIP; Sharad Adekar, MD, PhD, CIP

Transgender and gender diverse (TGGD) individuals face an increased risk of cardiovascular disease (CVD). There is an unmet need to identify the root causes of CVD health disparities in this population. More research and evidence-based strategies are needed. Additional factors to be addressed include possible bias and discrimination in healthcare settings, paucity of representation of TGGD competent care providers, and insufficient resources to encourage and accommodate TGGD individuals wanting to participate in clinical research. Regulatory authorities, notably the U.S. Food and Drug Administration (FDA), have critical roles to play, as do institutional review boards (IRBs), sponsors, investigators, and patient advocates. Recommendations include adopting community-based research methods; employing scientifically and ethically sound study design; revising participant-facing recruitment and research materials to utilize gender-inclusive language; providing TGGD continuing medical education for staff; and engaging patient advocates familiar with issues faced by TGGD individuals. These measures should help to increase TGGD representation in CVD clinical studies, leading to improved treatment options and health outcomes.

Background

Good cardiovascular health is central to overall wellbeing. Over the years, research has supported the development of evidence-based treatments for conditions ranging from hypertension to genetic and congenital malformations; from use of medical devices to formulation of life-saving drugs, and advancement of strategies aimed at improving prevention of CVD. CVD is an equal opportunity condition, affecting both cis-men and cis-women, and is the leading cause of human mortality and morbidity.{1–5}

Decades of data from CVD trials have identified important risk factors fueling CVD rates, including tobacco use, hormone therapies, weight gain, poor dietary choices, and lack of physical exercise.{6} These risk factors are applicable across the sex and gender spectrum. However, clinical research also highlights the presence of sex-specific risk factors and treatment outcomes associated with CVD. For example, there are lower implantation rates of electronic cardiac devices in cis-gender women when compared to cis-gender men despite comparable indications, and less use of drug-eluting stents in women, despite demonstrated efficacy.{7–9} Similarly, sex-specific research indicates that there is an increase in cardiac risks from tobacco use in pre-menopausal people assigned female at birth (AFAB). Unfortunately, these findings are often limited to the cis-gendered populations represented in the clinical research setting and lack generalizability to TGGD individuals.

TGGD individuals face additional barriers to obtaining safe and accessible healthcare, and poorer health outcomes when compared to cis-gendered individuals.{10} This trend persists when it comes to cardiac health. For example, recent data indicate that for AFAB individuals and those who identify as transgender, the odds of developing CVD in their lifetime are 2.66 times higher than cis-gender women. Similarly, for gender non-conforming individuals, the odds of developing CVD are 2.21 times higher than cis-gender individuals.{11} TGGD individuals are also at a higher risk of encountering significant barriers to safe and responsive healthcare services, compounding disparities in disease prevalence and contributing to poorer health outcomes overall.{12}

Many of these trends can be attributed to bias and discrimination in the healthcare setting, a lack of TGGD competent care providers, and a general dearth of clinical knowledge.{12,13} These trends are also explained in part by the lack of representation in clinical research. Without representation in cardiac research, important risk factors are overlooked and options for care for a population experiencing higher rates of CVD remain limited.

Additional research is needed to build an understanding of how the social determinants of health contribute to poorer outcomes. There is also an unmet need to identify how hormone therapy and other gender affirming care may influence risk factors or responses to other care. This work is critical to ensure TGGD individuals have access to safe and appropriate healthcare.

Current State of CVD in TGGD

Current guidelines speak to CVD risk factors common to all populations, including active or passive tobacco use, physical activity, diet/nutrition, weight management, lipid profile, glycemic status, and blood pressure. However, these fail to capture the social determinants of health that may uniquely impact TGGD individuals, nor do they capture variables presented with the uptake of gender-affirming care, such as gender-affirming hormone replacement therapy (GAHT). While limited, current research does indicate that GAHT may impact cardiac health. For example, one study noted that transgender men receiving hormone therapy had a three to five times higher risk of thrombosis and twice as high risk for stroke as compared to cis-gender men. There was also an elevated risk for myocardial infarction in transgender women undergoing GAHT compared to cis-gender women.{14,15}

Optimal cardiovascular outcomes are dependent upon markers of physical health, but they are also strongly linked with parameters for emotional and mental well-being. Many TGGD individuals speak to the impact of family rejection, bullying, and lack of social acceptance, leading to an increase in stress responses and maladaptive coping mechanisms. This in turn can lead to increased lipid levels, a predisposition to diabetes, depression, anxiety, and loneliness.{16,17} Yet data about these factors and how they affect members of the TGGD community are lacking.

Unmet Need: The Lack of Data

Despite the implications of increased CVD risk among TGGD individuals, there remains a dearth of research specifically identifying the underlying causes or developing equitable interventions. This may be due to a limited understanding of the nuances of CVD in TGGD individuals by the medical device and biopharmaceutical companies that facilitate clinical trials. However, this deficit is also observed in the wider healthcare setting, manifesting as limited continuing medical education on CVD in TGGD individuals, as well as a lack of representative providers, researchers, site-level staff, patient advocates, and research participants. This underrepresentation may cause harms associated with a lack of safe and appropriate treatment options.

Bridging the Research Gap: Roles of Continuing Medical Education, Sponsors, Investigators, and Regulatory Authorities

The reality is that increased cardiovascular morbidity and mortality among TGGD individuals is driven by both physical and psychosocial etiologies. Research gaps and the relative lack of safe, appropriate clinical care compound these issues.

Providing Investigators with Continuing Medical Education to Address Issues Related to TGGD Individuals

There is a need to provide healthcare professionals and investigators with relevant continuing education and training about possible cardiovascular health disparities associated with TGGD individuals. This can be done by updating the current medical school curriculum and adding appropriate, required continuing medical education. These updates should be facilitated by advocates, community leaders, and other key stakeholders from the TGGD population.

Developing and Assessing Eligibility Criteria

It is also important for sponsors to design clinical trials for TGGD populations, either by focusing research objectives and recruitment on TGGD patients or by ensuring that existing clinical studies recruit a representative sample that includes these individuals. This requires careful consideration of eligibility criteria, accurately reflecting the intent to enroll individuals across the sex/gender spectrum. Throughout protocol development, sponsors and investigators are also urged to critically assess research methods and approaches, to avoid perpetuating discrimination and microaggressions that may otherwise go overlooked.{18} This includes careful consideration of research outreach and recruitment methods.

TGGD populations are often defined as “difficult to reach” in terms of research recruitment. While this may, in part, be due to ineffective outreach and recruitment methods, recent data indicate that there may be other barriers prohibiting participation. One study found that researchers viewed interactions with potential minority participants as challenging. Importantly, this perception ultimately led to providers withholding clinical trial opportunities.{19} With such findings in mind, bias (common in the clinical research setting), must be accounted for. Community-based participatory research methods can be utilized to identify and resolve any potential bias. There is specific emphasis placed on the importance of integrating community members from the beginning, to ensure research objectives and methods align with the needs and concerns of the intended community. By partnering with TGGD individuals, sponsors and investigators can ensure that research objectives address concerns and needs expressed within the specific community, optimizing the contextualization of lessons learned over the course of the research.{20,21}

Regulatory authorities and IRBs can play important roles in assessing accessibility of clinical trials for TGGD populations. A key component of assessing the criteria for research approval is considering the equitable selection of research participants. The Belmont Report emphasizes that no one group should be explicitly targeted or excluded from research, without sound scientific or ethical rationale.{22} Institutional and commercial IRBs are responsible for assessing whether the explanation provided is scientifically and ethically sound to achieve objectives of the research study.

TGGD individuals are not considered a traditionally vulnerable population from a regulatory perspective. However, given the documented harm associated with being misgendered in the health setting, among other risks associated with access to general medical care, IRBs should ensure appropriate safeguards and protections as well as reasonable accommodations and assistance for this study population.{23}

Modernizing Data Collection Practices

Sponsors and investigators are encouraged to employ questionnaires and survey instruments that have been validated across gender diverse populations, when possible. If appropriately validated instruments are not available, selected questionnaires should be adapted whenever possible to improve access. When conducting ethical review, an IRB should consider the appropriateness of selected scales in terms of gendered language and intended measurements. A scale might be validated, but that doesn’t mean it is applicable to all participants.

Use of Gender Inclusive Language in Participant-Facing Materials

Finally, when designing protocol documents, including any participant-facing materials such as advertisements, consent forms, questionnaires, and other forms, sponsors and investigators should incorporate gender inclusive language as applicable. This means using gender inclusive pronouns, including “they/them,” along with inclusive phrasing. Similarly, binary language should be avoided, unless clinically relevant.

Conclusions

There is an unmet need to identify the root cause of CVD health disparities in TGGD individuals. There are not enough, or sufficient, evidence-based strategies which can be used to improve CVD health in such individuals. To address such disparities, more research is needed. Sponsors, investigators, regulatory authorities, and IRBs all play critical roles in developing solutions to this health disparity. Actionable steps may include the application of community-based participatory research methods in trial development and implementation, but should also encompass ethically and scientifically sound and equitable eligibility criteria.

Providing continuing medical education to healthcare professionals, sponsors, investigators, and research staff regarding specific cardiovascular health disparities in this population, collaborating with patient advocates who are familiar with issues related to TGGD individuals, and actively working to expand the ease of approaches and recruitment for this community will also help. Actions such as these have the potential to improve the representation of this population in clinical research, with specific findings that cascade into the clinical setting. These findings may contribute to evidence-based guidance and new treatment options to positively impact cardiovascular health outcomes in TGGD individuals.

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