Observational study finds higher testosterone associated with lower heart disease risk in men — Evidence Review
Published in Diabetes Care, by researchers from Johns Hopkins University School of Medicine
Researched by
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Table of Contents
People with type 2 diabetes face increased heart disease risk, but a new study suggests that among men, higher testosterone levels are linked to lower cardiovascular risk, while changes in estradiol may signal higher risk; these hormone-risk relationships were not observed in women. Most related studies agree that sex differences exist in cardiovascular risk and outcomes among people with diabetes, but the role of sex hormones in these differences remains unclear, with some research reporting conflicting results on testosterone's effects (1, 2, 6, 7). For more detail, see the original publication in Diabetes Care.
- Several large cohort studies confirm that cardiovascular risk factors—including diabetes—affect men and women differently, often with greater relative risk in women, but biological explanations have been elusive (1, 2, 4).
- Meta-analyses and randomized trials report inconsistent findings on testosterone's cardiovascular impact: some show increased risk with supplementation, while others find neutral or even beneficial effects depending on population and baseline risk (6, 7, 8, 9).
- The new study's finding of a sex-specific association between endogenous hormones and heart disease risk in diabetes adds nuance to the literature, highlighting the need for more research on how hormone dynamics interact with traditional and non-traditional risk factors (5, 9).
Study Overview and Key Findings
Understanding why women with type 2 diabetes have a greater risk of cardiovascular disease compared to men is a longstanding question in endocrine and cardiovascular research. The Johns Hopkins-led study examined whether endogenous sex hormones—specifically testosterone and estradiol—could help explain these observed sex differences in heart disease risk among people with diabetes. By leveraging longitudinal hormone measurements from the Look Ahead study, the researchers aimed to clarify if changes in these hormones over time relate to future cardiovascular events, potentially guiding more personalized prevention strategies.
| Property | Value |
|---|---|
| Organization | Johns Hopkins University School of Medicine |
| Journal Name | Diabetes Care |
| Authors | Wendy Bennett, M.D., M.P.H., Teresa Gisinger, M.D., Ph.D., Jiahuan Helen He, M.H.S., Chigolum Oyeka, MBBS, M.P.H., Jianqiao Ma, ScM, Nityasree Srialluri, M.D., M.S., M.H.S., Mark Woodward, Ph.D., Erin D. Michos, M.D., M.H.S., Rita R. Kalyani, M.D., M.H.S., Jeanne M. Clark, M.D., M.P.H., Alexandra Kautzky-Willer, M.D., Dhananjay Vaidya, MBBS, Ph.D., M.P.H. |
| Population | People with type 2 diabetes |
| Methods | Observational Study |
| Outcome | Hormone levels and heart disease risk |
| Results | Higher testosterone linked to lower heart disease risk in men. |
Literature Review: Related Studies
To situate this study within the broader scientific context, we searched the Consensus paper database, which includes over 200 million research papers. The following search queries guided the literature review:
- heart disease risk gender differences
- testosterone effects cardiovascular health men
- type 2 diabetes heart disease mechanisms
The search identified several key themes and findings, summarized in the table below.
| Topic | Key Findings |
|---|---|
| How do heart disease risk factors differ between men and women? | - Women with diabetes may have a higher relative risk of cardiovascular disease (CVD) compared to men, though men still have higher absolute rates (1, 2, 4). - Clinical presentation and treatment of heart disease can differ by sex, with women often underdiagnosed or undertreated and underrepresented in trials (1, 4, 5). |
| What is the relationship between testosterone (endogenous or therapy) and CVD risk? | - Some meta-analyses suggest testosterone therapy can increase cardiovascular risk in men, especially with high doses or in frail populations (6, 9). - Other studies report that normal testosterone levels are associated with lower cardiovascular risk and mortality, and testosterone therapy may have neutral or beneficial effects in some groups (7, 8, 9, 10). |
| What mechanisms link type 2 diabetes to increased cardiovascular risk? | - Type 2 diabetes exacerbates atherosclerosis and heart failure via metabolic, inflammatory, and hormonal pathways (11, 12, 13, 14, 15). - Glycemic control alone does not fully mitigate cardiovascular risk, suggesting other factors (including hormones) contribute to disease (12, 13, 14, 15). |
| Do sex hormones explain differences in heart disease risk in diabetes? | - Declines in estrogen and testosterone with age are associated with increased CVD risk in both sexes, but hormone replacement therapy has not clearly reduced CVD events in women (3, 7, 9). - The biological mechanisms by which sex hormones influence diabetes-related CVD risk remain incompletely understood and appear to differ by sex (2, 3, 5, 9). |
How do heart disease risk factors differ between men and women?
Sex differences in cardiovascular risk are well documented, with diabetes conferring a proportionally greater increase in risk for women compared to men. Still, men generally experience higher absolute rates of myocardial infarction and other CVD events. The new study builds on this foundation by exploring potential hormonal explanations for these disparities.
- Multiple studies show that women with diabetes have higher relative risk for heart disease than men, but men have higher absolute incidence (1, 2).
- Women are less likely to receive aggressive treatment or be included in clinical trials, leading to potential gaps in evidence and care (1, 4, 5).
- Sex-specific clinical presentations may complicate diagnosis and timely intervention for cardiovascular events in women (1, 5).
- The current study complements this literature by investigating whether endogenous hormone levels (rather than just traditional risk factors) may explain some observed sex differences in cardiovascular outcomes (2, 5).
What is the relationship between testosterone (endogenous or therapy) and CVD risk?
The cardiovascular effects of testosterone are debated. Some studies link testosterone therapy to increased cardiovascular events, particularly at high doses or in older, frail men. Others suggest that normal endogenous testosterone levels are associated with lower cardiovascular risk, and that appropriately managed therapy may be neutral or even beneficial.
- Meta-analyses demonstrate increased cardiovascular risk associated with testosterone therapy in certain populations, especially in non-industry funded trials and with supra-physiological dosing (6, 9).
- Large randomized trials indicate testosterone replacement does not increase the risk of major adverse cardiovascular events in men with low testosterone and high CVD risk (8).
- Observational studies and some clinical trials find that men with higher endogenous testosterone have lower CVD risk and mortality (7, 9).
- The new study's finding that higher baseline testosterone is associated with lower CVD risk in men with diabetes aligns with some observational research, but the lack of a clear effect in women or with estradiol is notable and warrants further study (7, 9, 10).
What mechanisms link type 2 diabetes to increased cardiovascular risk?
Type 2 diabetes increases cardiovascular risk through a range of mechanisms beyond hyperglycemia, including insulin resistance, inflammation, and metabolic dysregulation. Hormonal changes, such as declining sex hormones, may contribute to these mechanisms.
- Diabetes accelerates atherosclerosis and heart failure via multiple metabolic and inflammatory pathways (11, 12, 13, 14, 15).
- Standard glycemic control strategies alone do not sufficiently reduce cardiovascular events, suggesting that other factors—potentially including sex hormones—play key roles (12, 13, 14, 15).
- Preclinical and clinical studies have identified targets beyond glucose lowering, such as anti-inflammatory and antifibrotic agents, but hormone modulation remains an area of ongoing investigation (13, 14, 15).
- The new study provides evidence that monitoring endogenous hormone changes may inform cardiovascular risk stratification and prevention strategies in people with diabetes (11, 13).
Do sex hormones explain differences in heart disease risk in diabetes?
Declines in sex hormones with age are linked to increased cardiovascular risk in both men and women, but hormone replacement therapies have not reliably improved outcomes. The interplay between hormones, diabetes, and CVD risk appears complex and sex-specific.
- Older women may have a greater risk of CVD than age-matched men, associated with postmenopausal declines in estrogen, but hormone replacement has not consistently reduced CVD risk (3).
- Several studies report an inverse relationship between endogenous testosterone and CVD risk in men, but effects of hormone therapy are inconsistent and may depend on dose and patient characteristics (7, 9).
- The new study finds that changes in sex hormones over time are linked to CVD risk in men (but not women) with diabetes, highlighting the need for sex-specific research and personalized prevention (2, 3, 9).
- Biological mechanisms underlying these sex-specific effects remain incompletely understood and are an important target for future research (3, 5, 9).
Future Research Questions
Although this study advances our understanding of how sex hormones might influence cardiovascular risk in people with type 2 diabetes, significant gaps remain. Future research should clarify causal mechanisms, explore the clinical utility of hormone monitoring, and identify whether interventions can reduce risk in specific subgroups. Addressing these questions will be critical for developing personalized prevention strategies.
| Research Question | Relevance |
|---|---|
| Do endogenous sex hormone changes predict cardiovascular events in women with type 2 diabetes? | The current study did not find strong associations in women; understanding whether other hormonal patterns or measurement timepoints are relevant could help address sex-specific prevention gaps (2, 3). |
| Can monitoring sex hormones improve personalized cardiovascular risk stratification in type 2 diabetes? | Incorporating hormone levels with traditional risk factors may enhance prediction and guide individualized prevention, but clinical utility and cost-effectiveness require validation (7, 9). |
| What are the long-term effects of testosterone therapy on cardiovascular outcomes in men with diabetes? | Randomized trials provide mixed results on safety and efficacy, often with limited follow-up; long-term impacts in diabetic populations remain unclear (6, 8, 9). |
| How do weight loss and metabolic interventions interact with hormonal changes to affect heart disease risk in diabetes? | The parent Look Ahead study focused on weight loss; understanding how metabolic improvements and hormone dynamics jointly influence risk could reveal new intervention targets (10, 13, 14). |
| What biological mechanisms underlie sex-specific differences in diabetes-related cardiovascular risk? | Elucidating molecular and hormonal pathways may uncover new targets for prevention in both sexes, particularly as existing therapies do not fully address the excess risk seen in diabetes (11, 13, 15). |