Researchers urged to warn about women with type 2 diabetes taking oral HRT

In women with type 2 diabetes, use of hormone replacement therapy (HRT) skin patches is not associated with a higher risk of blood clots or stroke.

However, an increased cardiovascular risk was found for oral HRT, according to a large real-world study presented at this year’s Annual Meeting of The European Association for the Study of Diabetes (EASD), Vienna (15-19 Sept).  

Among the findings are an analysis revealing women with type 2 diabetes who took the oral form of HRT doubled their risk of developing a pulmonary embolism (PE - when a blood clot blocks an artery in the lung) and faced a 21 per cent increased risk of heart disease compared with those receiving transdermal HRT (skin patches).  

“Our study suggests that up to five years of regulator-approved doses of transdermal HRT appears safe in a large cohort of women in midlife with type 2 diabetes and that the use of HRT skin patches is not associated with an excess increased risk of cardiovascular complications or oestrogen-sensitive cancers when compared to women with type 2 diabetes who did not use HRT,” said lead author Dr Matthew Anson from the University of Liverpool and University Hospitals of Liverpool Group, UK. “However, given increased risks with oral HRT, we propose that women with type 2 diabetes should not be prescribed oral oestrogen therapy.” 

HRT is regularly prescribed to women suffering from the effects of menopause to relieve symptoms such as hot flushes and night sweats.

Treatments include tablets containing oestrogen only, or a combination of oestrogen and progesterone, as well as patches, gels and creams. Approximately 2.6 million UK women were taking HRT in 2023-2024.

Some previous trials have suggested a link between HRT and an increased risk of cardiovascular disease and some cancers, but information on risk in women with type 2 diabetes in midlife is lacking, despite the increasing prevalence of post-menopausal women with type 2 diabetes.  

Moreover, large-scale randomised controlled trials using modern formulations of HRT in women with type 2 diabetes are unlikely to ever be funded.

To address this, researchers conducted three analyses using real-world data to examine regulator approved oral and transdermal (through the skin) HRT doses and the risk of cardiovascular disease and gynaecological and oestrogen-related cancers in women with type 2 diabetes.

They used electronic health records from the TriNetX global database of 140 healthcare organisations from across Europe and the USA to identify 36,855 women initiating HRT + statin or a statin alone (controls) between April 8, 2000 and April 8, 2020, with follow up for five-years. 

Participants were followed for an average of five years after HRT or statin initiation for PE, DVT, ischaemic heart disease, ischaemic stroke, and breast, ovarian and endometrial cancers. 

The first analysis compared the impact of HRT with transdermal oestrogen in 8,316 women with and without type 2 diabetes who were matched in a 1:1 ratio based on age and ethnicity. The findings showed that in women with type 2 diabetes, HRT with transdermal oestrogen was associated with a 90 per cent greater risk for DVT, a 77 per cent increased risk of heart disease, and an 89 per cent greater risk of stroke compared to women without type 2 diabetes.

However, the risk of PE and breast and gynaecological cancers were not increased. The authors note that a substantial part of the increased risk for certain conditions is because women with type 2 diabetes are already at much higher risk of cardiovascular disease due to the type 2 diabetes itself, before any other factors are included, compared to women without type 2 diabetes. 

The second analysis examined the impact of transdermal HRT versus no HRT use in 8,354 women all with type 2 diabetes who were matched in a 1:1 ratio based on age, ethnicity, HbA1c (average blood glucose levels over the previous few months), body mass index (BMI) and history of essential hypertension (high blood pressure not caused by other diseases). 

Compared to women not taking HRT, women using HRT had a 25 per cent reduced risk of heart disease, but no difference in risk for PE, DVT, stroke, or cancer.

The final analysis investigated whether this risk varies according to the method of administration of HRT (i.e., oral vs skin patches) in 8,316 women with type 2 diabetes matched in a 1:1 ratio based on age, ethnicity, HbA1c, BMI and history of essential hypertension. The findings, as mentioned above, revealed women who took the oral form of HRT doubled their risk of developing a PE and faced a 21 per cent increased risk of heart disease compared with those receiving transdermal HRT.

However, no difference in risk between the two methods of administration was found for DVT, stroke, heart disease, breast, ovarian or endometrial cancer.

The authors suggest that the reason for the difference in risk of developing PE and heart disease between oral and transdermal HRT might be due to the different way oestrogen is absorbed.

When taken orally, much of the oestrogen is broken down by the liver before entering the circulation, which might impair the balance between clotting and anti-clotting proteins.

In contrast, when given in patch form, oestrogens are given in lower doses and are absorbed directly through the skin and into the circulation.

“The decision to use HRT, even for a short period of time, is very difficult for many women," said Dr Anson. "We hope our data will provide the increasing number of postmenopausal women living with type 2 diabetes and their physicians with more evidence to consider when weighing the risks versus benefits of the most appropriate HRT formulation." 

Despite the important findings, this is a retrospective study and the authors cannot rule out the possibility that other unmeasured factors may have influenced the results despite efforts to reduce confounding bias via propensity score matching.

The authors also note that the majority of participants were White women potentially limiting the generalisability of their findings.  

They also acknowledge inherent limitations of real-world data often result from inconsistent patient reporting in electronic medical records, and lack of granularity provided by big data platforms.