Diabetes mellitus and cardiovascular diseases (CVDs) are the major non-communicable diseases, accounting for 74% of global deaths^{1, 2}. The biological mechanisms of diabetes vary between genders, as males are more susceptible to develop type 2 diabetes mellitus (T2DM) than females, majorly due to low testosterone levels. However, gestational diabetes, polycystic ovary syndrome, early menopause (EM) and high testosterone levels in females result in impaired glucose tolerance, and relatively higher risk of cardiovascular (CV) complications and death³. Surprisingly, 50% of CVD-related deaths in women are caused at middle age⁴. The estrogen in women acts as a protective barrier to atherosclerotic diseases, thereby delaying CVD occurrence by 7-10 years, compared to males. A decline in estrogen in post-menopausal women results in loss of vasodilating effect of estrogen and subsequent development of CVDs⁵. This being the reason for better cardio metabolism in females during the early life that gradually exacerbates at mid-life during menopausal transition, when CV risk factors accumulate⁶. Atherogenic dyslipidemia, hypertension, central adiposity, glucose intolerance and non-alcoholic fatty liver disease, caused by reduced endogenous estradiol (E2) in menopausal women are many of the risk factors linked to CVD⁷. Therefore, monitoring the risk factors for T2DM and CVD in middle age to older women is suggested to reduce the complications and deaths related to diminished estrogen⁸. The lack of sufficient knowledge on intricate relationship between menopause and cardiometabolic diseases, CVD and T2DM makes it challenging to develop specific targeted therapies for such scenarios. In view of this, the review paper primarily focuses on the interplay of menopause, diabetes and CVD complications, underlined with their associated pathways. The epidemic correlation of different stages of menopause associated with CVD risk progression is discussed. Clinical evidences of the biomarkers acting as menopause prediction tool and the guideline recommended therapies to prevent the arising health challenges in menopause are reviewed.

MENOPAUSE TRANSITION PREDISPOSES WOMEN TO HIGHER CARDIOVASCULAR DISEASE RISK

The cessation of ovarian reproductive function is termed as menopause, characterized by significantly variable menstrual cycles and menopause-related symptoms. This menopause transition is manifested by significant physiological changes, leading to CVD risk⁹. Premature and early menopause leads to higher risk for developing arterial hypertension and CVD¹⁰. On this account, it is important to understand the epidemiological correlation between the various stages of menopause and their associated cardiometabolic syndrome.

Stages of menopause and cardiovascular diseases

The Indian Menopausal Society (2020) describes Stages of Reproductive Ageing Workshop (STRAW): the reproductive lifetime of a healthy woman undergoing natural menopause consists of reproductive period (stage -5 to -3), the perimenopausal stage or menopausal transition (stage -2 to -1) and the post-menopause period (stage +1 to +2). Early post-menopause stage (+1) is further subdivided into ‘a’ and ‘b’ as one year after final menstrual period and the subsequent 4 years, respectively¹¹. ‘Early menopause’ is menopause experienced before 45 years and ‘premature ovarian insufficiency’ is when menopause occurs even before 40 years¹². The late post-menopause (+2) is a variable period until death^{11, 13}. In high income countries, the natural menopause occurs late at around 50-51 years¹⁴, whereas in Indian population, menopause occurs at an average age of 46.6 years, which is less than the other developing countries¹⁵.

Aging and reduced estrogen levels along with significant increment in gonadotropin follicle-stimulating hormone (FSH) during menopause are the major factors for incident CVDs^{16, 17}. The risk of CVD is more prevalent in women with EM and premature ovarian insufficiency ⁵. Surgical menopause is associated with >20% higher risk of incident CVD than natural menopause¹⁸. Early age at menopause irrespective of natural and surgical menopause is associated with higher CVD risk¹⁹. Early menopause increases the risk of heart failure (HF) than later age of menopause (≥45 years)²⁰. Changes in atherogenic processes during menopause are responsible for elevated levels of total cholesterol, low-density lipoprotein (LDL-C) and triglycerides and decreased level of high-density lipoprotein (HDL-C). In addition to these changes, several features of menopause such as age, stage, vasomotor symptoms (VMS) and sleep disorder are the prime risk factors associated with CVDs²¹. Therefore, identification of EM may offer an opportunity to use appropriate interventions for improving overall CV health.

Age at menopause and incident cardiovascular events 

A meta-analysis of 32 observational studies recorded higher risk of coronary heart disease (CHD) and CVD death with EM²². A study from Atherosclerosis Risk in Communities (ARIC) reported that acute myocardial infarction is at a surge among women aged below 55 years²³. A pooled analysis of post-menopausal women (n=9374) has shown significantly higher crude rates (incidence/1000 woman-years) of CHD, atherosclerotic CVD (ASCVD) and HF with EM, compared to menopause at ideal age²⁴. A cohort study observed that women who encounter EM at the age of 45-49 years or premature menopause before the age of 45 years are at high risk of developing ischemic heart disease (IHD)-related mortality. Ten person-year total CVD rate, ischemic CVD, CHD, stroke, ischemic stroke and hemorrhagic stroke was found to be 5.9, 5.4, 2.7, 3.6, 3.0, and 0.5/1000 woman-years, respectively in women having premature menopause²⁵. Hysterectomy before natural menopause results in EM and the consequent CVD onset. The Korean National Health Insurance Service data showed higher risk of CVD (especially stroke) in women with median age of 45 years, having hysterectomy, compared to non-hysterectomy (HR, 1.25; 95% CI, 1.09–1.44)²⁶. Shin et al. reported increased risk of HF (HR, 1.33; 95% CI, 1.26–1.40) and atrial fibrillation (HR, 1.09; 95% CI, 1.02–1.16) in women with EM at a mean age of 36.7±2.6 years than women who aged ≥50 years²⁷. A summary of the risk of CVDs in post-menopausal women is presented in Table 1.

Table 1: A summary of cardiovascular disease risk in post-menopausal women

BMI: Body Mass Index; CABG: Coronary Artery Bypass Grafting; CHD: Coronary Heart Disease; CVD: Cardiovascular disease; EM: Early Menopause; PCI: Percutaneous Coronary Intervention; T2DM: Type 2 Diabetes Mellitus; UK: United Kingdom; USA: United States of America

Menopause and diabetes: A challenging bidirectional association

Diabetes is a major public health concern of the twenty-first century. According to the International Diabetes Federation (IDF), approximately 537 million adults in the world had diabetes in 2021, which is estimated to increase up to 783 million by 2045³⁵. Globally, the diabetes prevalence (standardized to the 2021 UN world population) in females aged 20–79 years is 10.2%³⁵. The inconsistencies in regulation of blood glucose level during and after menopause lead to hyperglycemia and greater glucose variability that further aggravates diabetes associated complications¹⁷. A meta-analysis by Guo et al. demonstrated an inverse linear correlation between age at menopause and T2DM, with 10% reduced T2DM risk for every 5 years increase in natural menopausal age³⁶.

Diabetes predisposes women to early menopause

Diabetes results in ovarian dysfunction during the entire reproductive span³⁷. The European Prospective Investigation into Cancer and Nutrition (EPIC) study reported EM with early onset of diabetes, i.e. before the age of 20 years than the non-diabetic women³⁸. Women with T2DM encounter menopause earlier, compared to non-diabetic women (41% vs. 36%)²⁴. The average age of menopause has decreased to 45 years for 26% Indian women with T2DM³⁹. A study from a south Indian tertiary care center suggested that T2DM increases the risk of EM (at an average age of 44.65 years than 48.2 years in non-diabetic women), hence early diagnosis and prolonged treatment of diabetes is crucial for the well-being of a woman⁴⁰.

Early menopause and risk of type 2 diabetes

Early onset of menopause is an independent risk factor for T2DM. At menopausal age of <40, 40-44 and 45-55 years, the hazard ratio for the association between age at menopause and T2DM were found to be 3.65 (95% CI 1.76, 7.55), 2.36 (95% CI 1.30, 4.30) and 1.62 (95% CI 0.96, 2.76), respectively, compared to menopause after the age of 55 years⁴¹. A recent study by Ko et al. recorded increased risk of T2DM with EM at <40 years (HR, 1.13; 95% CI, 1.08-1.18) and 40-44 years (HR, 1.03; 95% CI, 1.00-1.06) than menopause at the age of 50 years or older⁴². In addition to EM, Yazdkhasti et al. found that odds of T2DM increased with late menopausal age (OR, 1.14, 95% CI, 1.03–1.26) vs. normal menopausal age. The study also reported higher risk of T2DM with EM (HR, 1.31, 95% CI, 1.05–1.64)⁴³. Therefore, targeted health strategies aiming T2DM prevention in post-menopausal women should be undertaken.

Menopause and diabetes: Combined impact on cardiovascular complications

A significant link between EM and increased CV risk exists in women with diabetes⁴⁴. An estimated 2.1 million women worldwide die of diabetes, majorly because of CV issues, compared to 1.8 million deaths in diabetic men. Additionally, diabetic women have 1.81-fold higher chances of mortality from myocardial infarction and 5-fold of HF; diabetic men have 2-fold risk of HF²¹. A diabetic woman in her midlife is more susceptible to develop CVD than a healthy woman. Consequently, a post-menopausal diabetic woman is 2.5 to 3.5-times more likely to encounter stroke or CHD²¹. High fasting blood glucose level is significantly associated with high chances of stroke in post-menopausal women⁴⁵. Elevated risk of CVD in diabetic women having EM indicates the need for intervention that targets CVD delay or prevention⁴⁴.

Underlying pathways of menopause leading to diabetes and cardiovascular disease

The onset of T2DM generally coincides with the women’s menopausal transition period. This is marked by a swift fluctuation in the metabolic profile, body composition and body fat distribution⁴⁶. A rapid decline in ovarian follicular activity and hormonal abnormalities with decreased E2 and elevated FSH levels are observed between perimenopause and after the final menstrual period⁴⁷. A positive correlation between FSH, waist circumference and adipocyte distribution during menopausal transition are attributed to the lowered activation of E2^{10, 48}. This diminished E2 up-regulates lipoprotein lipase activity and lowers the lipolysis¹⁰. The menopausal transition leads to increased fat mass in women that further leads to production of proinflammatory cytokines and reactive oxygen species, and high circulating free fatty acids that promote insulin resistance⁴⁹. The resultant post-menopausal body fat increases insulin resistance by 50%¹⁰. Moreover, evidence support that an enhanced overall androgenicity that occurs in post-menopausal women due to increase in testosterone, also leads to insulin resistance. Sex hormone-binding globulin decreases, which is associated with impaired glucose tolerance and diabetes⁵⁰. Increased testosterone and decreased sex hormone-binding globulin levels increase ASCVD risk in post-menopausal women⁵¹. Diminished endogenous E2 during menopausal transition leads to paracardial fat deposition, i.e. fat outside the pericardium, increasing the CVD risk⁹. Women become more prone to metabolic syndrome (MetS) post-menopause as a result of abnormal glucose metabolism and central abdominal obesity⁵. The European Menopause and Andropause Society (EMAS) clinical guide reported prevalence of MetS between 14% and 45% in premenopausal women and 30-70% in post-menopausal women, resulting in insulin resistance, impaired glucose metabolism, hypertension, dyslipidemia and central obesity after menopause⁴⁹. According to the IDF criteria for Asian population, MetS is significantly more prevalent in post-menopausal women (55%) than the premenopausal women⁵¹. The initiation of such metabolic changes leads to an increased cardiometabolic risk in women¹⁶. A pictorial representation of progression of T2DM and CVD depending on stages of menopause is shown in Figure 1.

Figure 1: Menopause to type 2 diabetes mellitus and cardiovascular disease progression. CVD: Cardiovascular disease; CHD: Coronary heart disease; E2: Estradiol; FMP: Final menstrual period; FSH: Follicle stimulating hormone; HDL: High-density lipoprotein; IHD: Ischemic heart disease; LDL: Low-density lipoprotein; MI: Myocardial infarction; SHBG: Sex hormone-binding globulin; T2DM: Type 2 diabetes mellitus

Menopause onset prediction: Solution to the emerging health complications

The prediction of the menopause phases is important in a woman’s life since both early and late menopause might have adverse health implications. Early menopause is associated with osteoporosis, lower bone density, and increased risk of T2DM, CVD and all-cause mortality while late menopause might lead to breast, endometrial or ovarian cancer⁵². Therefore, estimation of the age at onset of natural menopause can help to estimate the chances of the different adverse complications, aid in family planning and menopausal treatments⁵³.  Prediction of age at natural menopause not only helps in identifying EM, risk for CVD and CV-death, but also depression and bone health⁵⁴. Several prediction models, including concentration of anti-mullerian hormone (AMH), FSH, E2, antral follicle count, menstrual cycle irregularities and lifestyle factors have been evaluated⁵⁵.

Anti-mullerian hormone is the most widely used biomarker for the prediction of onset of natural menopause⁵⁵. Anti-mullerian hormone level indicates ovarian aging and decline in follicle reserve across time⁵⁶. Anti-mullerian hormone has a significant association with measures of atherosclerosis in middle-aged diabetic women⁵⁷. Follicle stimulating hormone and E2 has similar C-statistic as AMH for predicting ovarian aging⁵⁵. High levels of FSH and luteinizing hormone (LH) are potential risk prediction biomarkers of MetS in post-menopausal women. Serum FSH and LH levels are negatively linked with MetS severity in perimenopausal as well as in post-menopausal women. Moreover, in post-menopausal women, serum FSH levels and diabetes have a negative relationship; low serum FSH is also associated with high blood pressure⁵⁸. However, predicting accurate onset of natural menopause can be challenging because of the inter-individual differences in onset of natural menopause along with irregular and long period of menopausal transition⁵⁵. Therefore, the 2024 National Institute for Health and Care Excellence (NICE) guideline has not recommended AMH in routine diagnosis of menopause⁵⁹.

Protein biomarkers, such as hemopexin, adrenomedullin, adipsin and beta-2 microglobulin are distinct predictors of natural EM, and helps in prognosticate hypertension, HF, coronary artery disease and CVD states. Elevated inflammatory biomarkers, complement C3, ceruloplasmin and fibrinogen (-a and -b) are related to ovarian insufficiency as well as natural EM. An association between EM and high levels of C-reactive protein and beta-2 microglobulin has been found⁶⁰. A higher level of C-reactive protein and interleukin-6 was reported in women having EM (44.2±3.5 years) than the typical menopause (52.1±2.8 years) group⁴⁴. Both C-reactive protein and beta-2 microglobulin predict CV-death, incidence of HF and all-cause mortality⁶⁰.

Management of cardiovascular health in post-menopausal women with diabetes

Higher prevalence of dyslipidemia, hypertension and CVD are the major health concerns faced by the post-menopausal women with diabetes, compared to non-diabetic women⁶¹. The Indian Menopausal Society, 2020 and the American Heart Association (AHA), 2017 have recommended lifestyle intervention as the first line therapy or key strategy for the betterment of CV health^{9, 13}. According to the AHA consensus statement (2017), physical activity, weight loss, heart-healthy diet and smoking cessation improve the lipid profile in women at mid-life. Moreover, these changes cease CVD complications, preventing CV-mortality⁹. Modified fat diet refines levels of LDL, total cholesterol, systolic blood pressure, fasting blood sugar or apolipoprotein A⁶². Moreover, the AHA recommended plant-based diets, weight-loss diets and paleolithic diet with favourable effects in CVD prevention⁶². The different management therapies in menopausal women with diabetes, experiencing CV complications are summarized in Figure 2.

Figure 2:  Management therapies in menopausal women with diabetes experiencing cardiovascular complications. CVD: Cardiovascular disease; DPP-4i: Dipeptidyl peptidase-4 inhibitors; GLP-1RA: Glucagon-like peptide-1 receptor agonists; VMS: Vasomotor symptoms; SGLT-2i: Sodium-dependent glucose transporter 2 inhibitor; TZD: Thiazolidinedione

Hormonal therapy: The most promising treatment in menopausal women

Menopausal symptoms like hot flashes, depression, anxiety, sleep disruption and night sweats that occur often in post-menopausal stage, demand proper medications⁶³. Several guidelines such as the EMAS clinical guide (2018), the AHA consensus statement (2020) and the NICE guidelines (2024) have recommended the use of hormonal therapy to alleviate the VMS and to manage menopausal transition^{9, 49, 59}. However, association of hormonal therapy with IHD, stroke, venous thromboembolism, breast cancer and lung cancer in menopausal or post-menopausal women should be considered⁶⁴. The NICE guidelines (2024) recommend use of estrogen with progestogen in women with a uterus and estrogen alone in women without a uterus for managing VMS after discussing risk-benefit profile of hormonal therapy⁵⁹. The Indian Menopausal Society advised that apart from screening and laboratory testing, transvaginal scan of the endometrium is crucial before starting hormonal therapy¹³.

Clinical studies over the years have debated the risk and benefits of hormonal therapy in CVD. An age-stratified analysis of Women Health Initiative (WHI) study demonstrated lower CV risk in younger women (aged 50-59 years) using hormonal therapy (conjugated equine estrogens + medroxyprogesterone acetate) than the older women (aged 70-59 years), who started hormonal therapy 10 years post-menopause⁶⁵. The Early versus Late Intervention Trial with Estradiol (ELITE) also noted time-dependent beneficial effects of hormonal therapy (exogenous estrogen) on the progression of atherosclerosis⁶⁶. The Kronos Early Estrogen Prevention Study (KEEPS) showed that combined estrogen/ progestin hormonal therapy for 4 years halted the advancement of carotid intima-media thickness and atherosclerosis in women during EM. There was improvement in menopausal symptoms and CV health with no rise in adverse events and no evidence of cardiometabolic risk after 10 years⁶⁷. Although estrogen therapy evidently reduces the risk of CV event, it is not recommended in women with pre-existing diabetes or higher CVD risk⁶².

Management of lipid profile in post-menopausal women

Significant improvement in total cholesterol, LDL-C and HDL-C levels with overall favourable changes in lipid profile in post-menopausal women was reported by the Selective Estrogens, Menopause, and Response to Therapy (SMART-1) trial. The intervention was a third generation selective estrogen receptor modulator, a conjugation of estrogen/ bazidoxifene⁶⁸. Low doses of tibolone, a transdermal hormone therapy is safe in reducing hypertriglyceridemia; however, oral hormone therapy is preferred to achieve benefits on lipid profile⁶⁹. Three months treatment with E2 with norethisterone acetate was reported to reduce plasma levels of lipoprotein-a, apolipoprotein A1, apolipoprotein B, total cholesterol, HDL-C, LDL-C, total cholesterol/HDL-C and LDL-C/HDL-C ratio in post-menopausal women aged below 70 years⁷⁰.

Dyslipidemia, systemic inflammation and National Institutes of Health Stroke Scale scores appear higher in post-menopausal women than pre-menopausal women. Atorvastatin, a widely used statin therapy provide beneficial effect in improving the atherosclerotic CVD in post-menopausal women⁷¹. Rosuvastatin has remarkable effect on atherosclerosis in asymptomatic post-menopausal women with lowered risk of dyslipidemia. It improves the functional and morphological markers associated with atherosclerosis⁷². In almost 5-10% Indian population, statin therapy is suggested for ASCVD (cholesterol >140 mg/dl or LDL-C >70 mg/dl) in premature menopause (<40 years)⁷³. The Indian Menopause Society has also recommended initiation of statin therapy to both women with CVD risk (LDL-C >100 and >130 mg/dL)¹³.

Regulation of blood glucose in menopausal women with cardiovascular disease risk

Hormone therapy has demonstrated improvement in glycemic control and is associated with the decreased prevalence of MetS⁶¹. Menopausal hormone therapy has benefits on glucose metabolism in both diabetic- and non-diabetic women but should be administered after assessing CVD risk⁴⁹. Various hypoglycaemic agents have been used since ages for the management of diabetes mellitus, which target decreased insulin secretion and sensitivity, and increased gluconeogenesis. The EMAS guidelines, 2018 have recommended metformin as the preferred first line pharmacotherapy in post-menopausal women with T2DM as it increases insulin sensitivity and improves glycemic index. The recommended second line treatment involves dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists. Other most commonly used medications for post-menopausal women are sodium-dependent glucose transporter-2 inhibitor, insulin, sulfonylureas and thiazolidinediones (not recommend to women with osteoporosis)⁴⁹. Aspirin therapy is primarily recommended for prevention of CVD in diabetic women aged ≥50 years⁷⁴.

Clinical evidences on effective therapies in post-menopausal women with or without diabetes and a risk of CVDs is presented in Table 2.

Table 2: Effective treatments for post-menopausal women with risk for diabetes and cardiovascular diseases

Apo: Apolipoprotein; ASCVD: Atherosclerotic cardiovascular disease; CEE: Conjugated equine estrogens; CHD: Coronary Heart Disease; CV: Cardiovascular; CVD: Cardiovascular disease; E2: Estradiol; HF: Heart failure; HDL-C: High-density lipoprotein cholesterol; HOMA-IR: Homeostatic model assessment of insulin resistance; LDL-C: Low-density lipoprotein cholesterol; MPA: Medroxyprogesterone acetate; RCT: Randomized controlled trial; T2DM: Type 2 Diabetes Mellitus; TC: Total cholesterol; TG: Triglycerides; VLDL-C: Very low-density lipoprotein cholesterol

Menopausal transition is a critical period in a woman’s life, marked by VMS and the predisposition to diabetes and CVDs.  Post-menopausal women with pre-existing diabetes are highly prone to encounter a CV event. Moreover, a diabetic woman is likely to experience EM and evidently, the chances of CV events are higher in early menopausal women. This bidirectional nature of menopause highlights the importance of evaluating the onset of CVD risk factors through indication of reproductive aging as well as overall physical aging. Various strategies including lifestyle modification, hormone therapy and pharmacological intervention help in reducing VMS, impaired glucose metabolism and CV complications.  Menopausal hormone therapy has been suggested as strategy for the alleviation of VMS and the management of lipid profile. In addition, targeted interventions include statin therapy in menopausal women with T2DM and intermediate or high risk of CVD. This study underscores the necessity of understanding the complex interplay between menopause, CVD and diabetes for recommending targeted intervention in the menopausal women. Limited clinical evidences contemplated the need for advanced research and clinical trials on diabetes and CV risks in post-menopausal women and their management.

Declaration

Author contributions: Author SB, PBJ, SD, AHZ, AB, ND, AT, AA, SJ and OS contributed equally to the conception or design of the work; drafting, writing and revising of the manuscript; interpretation of data; and approved the submitted version. All authors agree to be accountable for their contributions as well as for all aspects of the study.

Funding: The study received no funding.

Acknowledgments: Alembic Pharmaceuticals Ltd provided funds for medical writing support. The authors thank WorkSure^® India for providing the medical writing and editing assistance for this manuscript.

Conflicts of interest: Author OS and SJ are full-time employees of Alembic Pharmaceuticals Ltd. The other authors report no conflicts of interest.

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