Reappraising Cardiovascular Risks of Tibolone in Postmenopausal Women: A Response to the Editorial by Lee and Kim

We read with interest the editorial by Lee and Kim [1] regarding the cardiovascular disease (CVD) risks associated with tibolone use in postmenopausal women, which serves as a commentary on our study [2]. While the Korean Society of Menopause’s perspective is appreciated, several points merit reconsideration to better reflect the totality and quality of current evidence.

METHODOLOGICAL LIMITATIONS IN KEY RANDOMIZED CONTROLLED TRIALS

The authors cite the long-term intervention on fractures with tibolone (LIFT) trial by Cummings et al. [3] as evidence that tibolone’s stroke risk varies with age. However, LIFT randomized women aged 60–85 to tibolone 1.25 mg daily (half the usual marketed 2.5 mg dose) and still found a significant increase in stroke (hazard ratio [HR] 2.19, 95% confidence interval [CI] 1.14–4.23), prompting early termination. While this absolute excess (2.3 strokes per 1,000 person-years) is modest in women aged 60 years, such an increase can translate into a meaningful number of additional events at the population level. Furthermore, the absence of any demonstrated cardiovascular benefit and the presence of a clear signal of harm in this age group do not justify presuming safety or cardiovascular neutrality in substantially younger postmenopausal women.

Similarly, the livial intervention following breast cancer; efficacy, recurrence and tolerability endpoints (LIBERATE) trial by Kenemans et al. [4] enrolled breast cancer patients with distinct clinical characteristics that limit its generalizability [5]. Approximately 70% of participants had received chemotherapy, which can independently affect CVD risk [4,5]. Moreover, as noted by Johansson et al. [6] 2024, the LIBERATE study was designed primarily to assess breast cancer recurrence, with CVD outcomes as secondary endpoints. The limited sample size (n = 3,098) and low event rates (14 cardiovascular events in tibolone group vs. 10 in placebo group) rendered the study underpowered to detect meaningful CVD differences, potentially overlooking significant risks related to cerebrovascular and coronary artery disease [4,6].

Consequently, the findings from these trials in older populations (LIFT) or breast-cancer survivors (LIBERATE) cannot be used to presume cardiovascular safety or neutrality in younger postmenopausal women (age < 60 years or < 10 years since menopause).

PROSPECTIVE EVIDENCE FROM YOUNGER WOMEN

A large prospective Swedish nationwide register-based emulated target trial published in 2024 in The British Medical Journal (BMJ), including 919,614 women aged 50–58, found that tibolone initiation was associated with a significantly increased risk of CVD (HR 1.52, 95% CI 1.11–2.08) (CVD defined as the composite of ischaemic heart disease, myocardial infarction, or cerebral infarction/ischaemic stroke; venous thromboembolism was analysed separately and was not included in this composite) [6]. This finding provides crucial evidence from the demographic most relevant to clinical practice, namely younger postmenopausal women initiating hormone therapy. In addition, a BMJ rapid response from the Million Women Study investigators reported that standardized death rates for stroke were significantly higher in current tibolone users than in users of other hormone therapies (relative risk 1.58, 95% CI 1.06–2.37), and critically, this excess persisted regardless of age group [7]. Specifically, the relative risk for stroke mortality in tibolone users was similar in women younger than 60 and those aged 60 or older (about 1.47 and 1.72, respectively), indicating elevated cerebrovascular risk even under 60 years.

CONCERNS WITH SUPPORTING KOREAN STUDIES

The editorial cites Baek et al. [8] 2024 (a nested case–control study) as evidence that tibolone reduces stroke risk, raises significant questions. This study directly contradicts not only the LIFT study but also the recent findings from the Swedish nationwide emulated target trial [3,6]. Importantly, another large-scale Korean cohort study conducted by our research group (an independent cohort distinct from the study addressed in this letter) published in BJOG (an International Journal of Obstetrics and Gynaecology) in 2024 (n = 1,120,705), demonstrated an increased risk of CVD associated with tibolone use, particularly among women in their 50s (HR 1.167, 95% CI 1.130–1.205) in a multivariableadjusted analysis that excluded women with baseline CVD [9]. This finding has been consistently replicated in our subsequent analysis (Health Insurance Database in South Korea [HISK]-2 cohort) involving 134,298 propensity score-matched pairs (after excluding women with prior CVD or antithrombotic use) which showed tibolone use associated with a 38% increased CVD risk (HR 1.38, 95% CI 1.27–1.50) [2,9]. Although both Korean studies were conducted by the same research group, they analyzed two separate nationwide datasets (National Health Insurance Service [NHIS] and Health Insurance Review & Assessment Service [HIRA]) and demonstrated consistent findings regarding tibolone-associated cardiovascular risk. More recently, an independent Korean nationwide cohort study from Yonsei University College of Medicine (Gangnam Severance Hospital) involving 19,055 Korean women aged 45–60 years without prior cardiovascular disease reported that current tibolone users had a markedly higher risk of ischemic stroke (adjusted HR 3.52, 95% CI 2.05–6.03) compared with never-users [10].

The findings by Baek et al. [8], which suggested a reduced stroke risk, differ not only from the LIFT study and the recent Swedish nationwide emulated target trial but also from several larger cohort studies that used the same Korean National Health database (NHIS and HIRA) [2,3,6,8,9,10]. These findings should be interpreted with caution in light of the study’s design and the contrasting results from more extensive cohort analyses.

INCONSISTENCIES IN OTHER HORMONE THERAPIES

Additionally, the editorial did not discuss in detail why tibolone uniquely increases CVD risk, whereas other forms of menopausal hormone therapy (estrogen–progestin therapy and estrogen therapy) do not demonstrate similar increases in CVD in the same populations [1,2]. This selectivity requires explanation and suggests distinct mechanisms of CVD risk specific to tibolone. Unlike standard estrogen-based therapies, tibolone possesses androgenic properties that can lower high-density lipoprotein (HDL) cholesterol and has been associated with increased C-reactive protein levels, potentially contributing to atherosclerotic plaque instability and arterial thrombotic risk [11,12].

CLINICAL IMPLICATIONS

While the editorial correctly notes that absolute risk differences remain relatively small, the consistent pattern of increased CVD risk across multiple large-scale studies, including prospective evidence from younger women, warrants careful consideration [3,6,13]. The CVD safety profile of tibolone appears distinct from other menopausal hormone therapies, particularly in women under 60 years of age.

CONCLUSION

Clinicians should consider exercising caution when prescribing tibolone, particularly in the context of CVD risk, based on current evidence that includes recent prospective data in younger postmenopausal women and findings from large Korean cohorts. While menopausal hormone therapy remains an important option, tibolone’s distinct CVD risk profile warrants an individualized, case-by-case risk–benefit assessment rather than routine use for cardiovascular risk mitigation.