Sex Hormones May Influence Heart Disease Risk in Type 2 Diabetes

Understanding the connection between type 2 diabetes and heart health is crucial, as individuals with this condition face an increased risk of heart disease. Recent research suggests that sex hormones may play a role in why women with diabetes experience a higher risk of cardiovascular problems compared to men. This insight is particularly relevant as the healthcare community seeks to personalize prevention strategies for those affected.

Why it matters

The increased incidence of heart attacks and strokes among people with type 2 diabetes is a growing concern for healthcare providers and patients alike. Recognizing that these risks may be influenced by biological differences linked to sex hormones opens new avenues for understanding heart health. Personalized healthcare approaches could improve outcomes by tailoring prevention strategies to individual needs based on factors like hormone levels, alongside traditional risk factors such as cholesterol and smoking.

A new prospective study led by researchers from John Hopkins Medicine explored whether sex hormones like testosterone and estradiol help explain differences linked to risk in cardiovascular problems. Data from the LookAHEAD trial were used to analyze how weight loss in people (n = 2,260) with type 2 diabetes affected heart health outcomes. Sex hormones and sex hormone binding globulin (SHBG) were analyzed at the beginning of the trial and one year after enrollment. A total of 488 cardiovascular events occurred in the total cohort. Following the analysis, researchers saw clear and distinct differences in the male participants. Male participants who had higher testosterone levels when they initially joined the study had a lower risk of heart disease compared to those with lower levels of initial testosterone. Interestingly, in the same male participants, increases in estradiol levels after one year into the study led to a higher risk of heart disease. Male participants who had a weight loss total of ≥7% also had increases in SHBG and inversely associated CV risk scores. Comparatively, in the female cohort, researchers did not find meaningful links between the hormone levels collected and the cardiovascular outcomes revealed.

The results of this study add to the ever-expanding body of research and literature that help to explain our understanding of how tracking sex hormones in people with diabetes can meaningfully add to what we already know about traditional heart disease risk factors.

Heart Disease and Hormones

Curiosity in the ties between heart disease, hormones, and type 2 diabetes has been floating around the research community for over 20 years. Recent research goes as far as comparing the gut microbiome between men and women with coronary artery disease. Researchers found that while men tend to have more bacteria linked to inflammation, women often have bacteria that may support a healthier gut and immune system. These slight differences may be the answer to why and how men and women respond to inflammation over time. This research is an important addition to the work being done on sex hormones and heart disease risk. Researchers propose the sex-based microbial and metabolic disparities within the gut-heart axis in coronary artery disease. As with any newly emerging scientific hypothesis, future research will need to be conducted in order to fully understand the underlying mechanisms at work.

Future Work

In the near future, clinicians can personalize heart disease prevention and treatment strategies. The National Heart, Lung, and Blood Institute (NHLBI) is currently working on several clinical trials that span heart and vascular research, which includes heart failure, heart attacks, coronary heart disease, and obesity.

Who it affects

This issue primarily impacts individuals diagnosed with type 2 diabetes, particularly women who may be at higher risk for heart problems. It also concerns healthcare professionals who monitor and manage diabetes, as well as public health policymakers aiming to address the broader implications of cardiovascular wellness in chronic illnesses.

Per the Centers for Disease Control and Prevention (CDC), people with diabetes have twice the risk for heart disease, and the longer a patient has diabetes, the higher the risk of developing heart disease climbs. Diabetes affects the heart by consistently high blood sugar, damaging the blood vessels and nerves that control the heart. Individuals with diabetes are also more likely to have other conditions that raise the risk for heart disease.

Although the research study led by researchers at John Hopkins failed to reveal any clinically significant results in the women’s cohort, there is additional evidence provided by the NHLBI that reveals just how different heart disease looks in women.

- Heart disease is the leading cause of death for women in the United States - Women in their 40s, 30s, and even sometimes, 20s, can be at risk for heart disease - There is an increased risk in women who were diagnosed with preeclampsia or high blood pressure - Before menopause, the hormone estrogen provides women with some protection against heart disease - As women age, their risk for coronary heart disease increases through the use of hormones to relieve symptoms of menopause - Women who experience early menopause, especially after surgical removal of the uterus, are more likely to develop heart disease than women of the same age who have not yet experienced menopause - A woman’s heart and blood vessels are smaller, and the muscular walls of women’s hearts are thinner than men’s - Women are more likely to have heart disease in the tiny arteries of the heart, called coronary microvascular disease – this can make the disease harder to identify and cause delays in treatment - Symptoms of heart disease also differ in women: 1. Different activities bring on chest pain. In men, angina tends to worsen with physical activity and go away with rest. 2. Women are also more likely to have angina while they are doing routine daily activities rather than during exercise. 3. The location and type of pain may differ between men and women. Pain symptoms are different for each person. Both women and men having angina (chest pain) or a heart attack often describe their chest pain as crushing, or that it feels like pressure, squeezing, or tightness. Women may also have pain in the chest, neck, and throat. 4. Microvascular angina events may last longer and be more painful than other types of angina. 5. Mental stress is more likely to trigger angina pain in women than in men. 6. Other symptoms common for women include nausea, vomiting, shortness of breath, abdominal pain, sleep problems, tiredness, and lack of energy.

Future Care and Treatments

As research and real-world evidence (RWE) continue to discover similarities and overlaps in patient care accessibility and better shared decision-making process will be formed. Popular treatments like glucagon-like peptide 1 receptor agonists (GLP-1s) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have cross-functionally beneficial effects that may lead to less polypharmacy, better adherence, and overall better patient health. Initial investigations into the cardiovascular safety effects of glucose-lowering medications in patients with type 2 diabetes revealed an unexpected reduction in CV complications and mortality with the use of GLP-1s and SGLT2is. Patients with diabetes at risk of heart disease may benefit from additional research that also takes into account sex hormones and changes.

Following more data and studies, the treatment of type 2 diabetes has shifted from a blood sugar-centric approach to a broader cardio-renal-metabolic strategy, emphasizing the prevention of cardiovascular and renal events and the improvement of metabolic aspects beyond the promotion of weight loss.

Although both GLP-1s and SGLT2-inhibitors work to treat type 2 diabetes, they do so through different mechanisms of action.

• SGLT2 inhibitors decrease the plasma glucose levels by inhibiting renal reabsorption in the proximal tubule by increasing the renal excretion of glucose. The reduction in plasma glucose enhances insulin sensitivity and beta (β)-cell function.
• GLP-1s help to promote insulin secretion while inhibiting glucagon release from the pancreas, leading to glucose-dependent reductions in blood glucose levels.

Both therapies help regulate postprandial glucose by suppressing its production in the liver and delaying gastric emptying. When it comes to weight loss, both agents assist in weight loss through different mechanisms of action. GLP-1s help slow gastric emptying and directly act on the central nervous system to suppress a patient’s appetite. While SGLT2 inhibitors stimulate weight loss by inducing osmotic diuresis, which in turn reduces body water and increases urinary excretion. At this time, the selection of treatment is determined by the clinician and patient while taking comorbidities and other preferences into account.

What changes**

• Healthcare providers may begin incorporating hormone level assessments into routine care for patients with type 2 diabetes to better gauge cardiovascular risk.
• Interprofessional care teams consisting of clinicians and support staff well-trained in both diabetes and heart disease management may provide better care for comorbid patients.
• Future research could lead to targeted prevention strategies, focusing on menstrual and hormonal health (perimenopause and menopause) in women as part of diabetes management.
• The findings emphasize the importance of a comprehensive approach to cardiovascular health, which considers both traditional risk factors and new biological insights, including sex hormones and sex hormone binding globulin (SHBG).
• Additional research that includes different age ranges and comorbidities will prove useful in differentiating the variability between men and women with diabetes and their risk of heart disease.

References

1. https://pubmed.ncbi.nlm.nih.gov/41582527/
2. https://clinicaltrials.gov/study/NCT00017953
3. https://pubmed.ncbi.nlm.nih.gov/16537739/
4. https://pubmed.ncbi.nlm.nih.gov/41618437/
5. https://www.nhlbi.nih.gov/research/research-topics
6. https://www.cdc.gov/diabetes/diabetes-complications/diabetes-and-your-heart.html#
7. https://www.nhlbi.nih.gov/health-topics/education-and-awareness/heart-truth
8. https://www.nhlbi.nih.gov/health/coronary-heart-disease/women