Effects of hormone replacement therapy (HRT) in midlife women with type 2 diabetes: a retrospective cohort study

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Introduction There is a lack of outcome data relating to HRT in midlife women with type 2 diabetes (T2DM), particularly concerning cardiovascular risk, gynaecological and oestrogen-related cancers. 1 Methods We performed an active comparator new user design, retrospective cohort study using the TriNetX platform, a global federated database of electronic health records. We preformed three analyses relating to regulator approved HRT dosing: Cohort 1: Impact of T2D in users of HRT with transdermal oestrogen; Cohort 2: Impact of transdermal HRT versus non-users in individuals with T2D; Cohort 3: Impact of oral versus transdermal HRT in individuals with T2D. Cohort 1 was 1:1 propensity score matched (PSM) for age and ethnicity. Cohorts 2 and 3 were PSM for age, ethnicity, HbA1c, BMI and history of essential hypertension (SSMD <0.1). Outcomes of interest were pulmonary embolism (PE), deep venous thrombosis (DVT), ischaemic heart disease (IHD), cerebral infarction, and breast, ovarian and endometrial carcinoma. Analysis started from initiation of HRT or a statin for controls. Follow up was 5 years. Results Study population (n=7,600, Cohort 1: n=2,650; Cohort 2: n=2,298; Cohort 3: n=2,652). Follow-up ranged from 1,523±568 to 1,713±332 days. Mean ages ranged from 58.3±9.9 to 59.0±10.8 years. There was a significant selection bias to White women across all cohorts consistent with all menopause research (75% White, 17% Black and 2% Asian). Cohort 1: compared with HRT users without T2DM, transdermal HRT in women with T2DM was associated with a greater risk of PE (HR 2.70, 95% CI 1.14–6.42, p=0.019), DVT (HR 1.95, 95% CI 1.13–3.33, p=0.014), IHD (HR 2.13, 95% CI 1.74–2.60, p<0.001) and cerebral infarction (HR 1.88, 95% CI 1.17–3.03, p=0.008), but no differences in rates of breast, ovarian or endometrial carcinoma. Cohort 2: For individuals with T2DM, use of transdermal HRT, compared with non-users, was associated with a reduced risk of IHD (HR 0.78, 95% CI 0.61–0.99, p=0.047), and no difference in risk of PE, DVT, cerebral infarction, breast, ovarian or endometrial carcinoma. Cohort 3: Oral, compared with transdermal HRT in individuals with T2D, was associated with an increased risk of IHD (HR 1.34, 95% CI 1.08–1.66, p=0.008) and cerebral infarction (HR 1.59, 95% CI 1.07–2.39, p=0.022), but no difference in risk of PE, DVT, breast, ovarian or endometrial carcinoma. Discussion Midlife women with T2DM using HRT have a greater risk of PE, IHD and ischaemic stroke compared with non-diabetic HRT users. Our data suggest that transdermal HRT use in T2DM is associated with no additional PE/DVT/IHD/ischaemic stroke risk compared with non-HRT users with T2DM. Women with T2DM using HRT do not have increased risks of breast or gynaecological cancers compared with non-diabetic HRT users, but we did not match for type of HRT (combined versus oestrogen only). Conclusions Up to 5 years of regulator-approved doses of transdermal HRT appear safe in a large cohort of midlife women with T2DM. Given increased risks with oral HRT, we propose that women with T2DM should not be prescribed oral oestrogen therapy.

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