Representation of women in randomized controlled trials of novel antidiabetic drugs: A cohort study

Abstract

Underrepresentation of women in clinical trials significantly impairs the precision and advancement of medical knowledge, particularly given the physiological differences between sexes.¹ This disparity constrains the development of reliable, safe and effective medical interventions for women. In diabetes, sex differences lead to significant variations in diabetes complications.² Consequently, pharmacological treatments may work differently in men and women. The aim of this study, therefore, was to examine the representation of women in clinical trials for novel diabetes drugs, focusing specifically on studies where cardiac and renal events were the primary outcomes.

A total of 25 studies met the inclusion criteria. Of those, eight evaluated renal outcomes (SGLT2 inhibitors: seven studies; GLP-1RAs: one study), and 17 evaluated cardiac outcomes (SGLT2 inhibitors: 10 studies; GLP-1RAs: seven studies). The median (IQR) number of participants across all studies was 3533 (2474–8793), with a median (IQR) age of 64.6 (63.9–68.1) years. The median (IQR) proportion of female participants was 35% (30.8%–43.7%). Five studies did not address the primary outcome by gender.

The global estimated male-to-female ratio for the group of studies examining CKD was 1.68 (Table 1). For the group of studies examining cardiovascular outcomes, the global estimated male-to-female ratio was 1.67 (Table 2).

The median (IQR) PPR for women with diabetes and CKD was 0.74 (0.49–0.93; p = 0.018 [Table 1]), and for women with both diabetes and heart disease the median (IQR) PPR was 0.79 (0.62–0.83; p < 0.001 [Table 2]).

There is a current global trend aimed at reducing the gap in participation in clinical trials between men and women. Despite these efforts, our study, which assessed clinical research in novel diabetes mellitus drugs in recent years, observed an opposite trend with a significant underrepresentation of women and a PPR of approximately 70% (e.g., proportion of women in trials representing 70% of the actual proportion of the examined condition in the general population).

Moreover, the results of clinical trials according to gender were often not readily accessible to readers, and in five of the 25 included studies (20%), the primary outcome was not reported by gender in the main study publication; this was often relegated to the supplementary section of the article. In studies not exclusively focusing on patients with diabetes, gender-specific distribution among those patients was not specified, complicating accurate extrapolation for calculations and understanding of the study results for those patients.

To calculate the PPR, an extensive literature search was conducted to determine the prevalence of both diabetic kidney disease and heart disease by gender. This proved to be extremely challenging due to inconsistent and conflicting data. The IDF Atlas, which summarizes the prevalence of diabetes and its complications, does not clearly state the prevalence of these complications by gender.

Sex differences and the underrepresentation of women in diabetes studies were highlighted in a 2020 report that summarized five CVOT studies starting in 2008 on SGLT2 inhibitors, dipeptidyl peptidase-4 inhibitors and GLP-1RAs.¹² The report issued a call to action to enhance the recruitment of women in clinical studies on diabetes. Despite this, a significant number of studies on cardiovascular and renal outcomes have been published since then, yet female participants continue to be underrepresented in these studies. While the limitation in enrolling women of childbearing potential may contribute to this gender imbalance, the argument is weakened by the fact that the average age of all recruited patients is well over the age of menopause.

Evidence-based medicine predominantly relies on male-dominated studies despite significant physiological differences between men and women. Women with diabetes are more prone to developing CKD but progress more slowly to end-stage renal disease compared to men. They also face higher risks of mortality, myocardial infarction, and vascular diseases.² Despite these findings, our study highlights a persistent trend of female underrepresentation, potentially contributing to suboptimal medical practice.

This study has several limitations. First, it included a limited number of clinical trials. Second, because the published distribution of kidney and heart disease in women with diabetes is conflicting, it was difficult to set a specific number for the calculation of the PPR. We therefore set the number based on extensive literature review and clinical experience. However, this number, particularly with regard to heart disease, might be higher in women, making the underrepresentation even more significant. A different choice of male-to-female ratio may have resulted in different results, although most likely without a change in trend. Third, two studies with primary renal outcomes and five studies with primary cardiovascular outcomes included patients with and without diabetes. Even though the percentage of patients with diabetes in these studies was high (45%–68%), it could have distorted this analysis. Nevertheless, excluding all studies that were not specifically conducted in patients with diabetes would have resulted in a significant loss of data. Fourth, data on the retention of women in trials were not collected.

In conclusion, this study highlights a significant underrepresentation of women in guideline-setting clinical research, possibly perpetuating inaccuracies in treatment. We recommend that future researchers prioritize recruiting women in proportions reflective of their representation in the population, thereby enhancing the precision and relevance of medical interventions.

Genya Aharon-Hananel and Noam Tau were involved in the conception, methodology, design, and conduct of the study. Yovel Cohen handled acquisition of data and performed the statistical analysis. All authors contributed to the interpretation of the results and critical revision of the manuscript and approved the final version of the manuscript. Genya Aharon-Hananel is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

No funding was received for this study.

Genya Aharon-Hananel reports previous Advisory Board membership for Sanofi, is a current investigator in several randomized controlled trials conducted by Novo Nordisk, Eli Lilly and Bayer through Hadassah Medical Center, has received travel support from Novo Nordisk through Hadassah Medical Center, and AstraZeneca through Sheba Medical Center, and has served on Speaker's Bureau for AstraZeneca, Novo Nordisk, Eli Lilly and Sanofi. Yovel Cohen and Noam Tau have no conflicts of interest to declare.