Metabolically "healthy" obesity in postmenopausal women: Unmasking the cardiovascular risk

Abstract

The concept of metabolically healthy obesity (MHO) has attracted growing attention, but its clinical relevance and association with future cardiovascular risk remain unclear. Estrogen deficiency, which signifies the menopause phase, contributes to altered body composition and unfavorable metabolic processes. In this Editorial, we comment on the recent retrospective study by Pingili et al, which used a United States national in-patient population and observed significantly elevated odds of major adverse cardiac and cerebrovascular events in postmenopausal women with MHO compared with their age-matched non-obese counterparts. Of note, disproportionately greater risks were particularly observed among Black patients. These findings along with previous literature data call into question the seemingly benign profile of the MHO state. Obese individuals who appear metabolically healthy present an elevated cardiovascular risk which may be exacerbated in older female populations. These findings emphasize the need for vigilance and improved approaches of risk stratification which would translate into the early application of preventive measures.

Key Words: Obesity; Metabolism; Menopause; Cardiovascular risk; Mortality; Myocardial infarction; Stroke; Biomarkers

Core Tip: Distinct metabolic health states exist among normal-weight and obese individuals and potentially translate into differences in future cardiovascular risk. Menopause is followed by critical metabolic changes, which are associated with a higher risk of metabolic and cardiovascular diseases. Postmenopausal women with a metabolically healthy obesity may represent a subgroup of individuals with exacerbated clinical risk despite a seemingly benign profile of metabolic parameters.

INTRODUCTION

The concept of “metabolically healthy obesity” (MHO) has gained traction over the past two decades, describing a subset of individuals with obesity who, despite excessive adipose tissue, do not exhibit the typical metabolic abnormalities commonly associated with obesity-such as insulin resistance, dyslipidemia, hypertension, and systemic inflammation. The definition is not uniform across studies but generally relies on the absence of cardiometabolic abnormalities, preserved insulin sensitivity, favorable inflammatory profiles, normal hepatic function and cardiorespiratory fitness[1,2]. The prevalence of MHO varies depending on how strictly "metabolically healthy" is defined, but estimates range from 10%-30% of obese individuals[3].

Even though MHO lacks overt metabolic syndrome features, it presents subclinical pathophysiological alterations that may contribute to increased cardiovascular risk. Individuals with MHO often exhibit chronic low-grade inflammation, subclinical endothelial dysfunction, and impaired adipokine secretion (e.g., reduced adiponectin, elevated leptin), which, while more favorable than in metabolically unhealthy obesity (MUO), remain distinct from those in metabolically healthy individuals[4]. Elevated inflammatory biomarkers such as C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6) have been reported even in MHO individuals compared to metabolically healthy normal-weight counterparts, suggesting persistent inflammatory activity despite an ostensibly favorable metabolic profile. Mild hormonal imbalances, such as hyperinsulinemia and elevated sympathetic or renin-angiotensin-aldosterone system activity, further contribute to cardiovascular and metabolic stress[1].

Data from more than 3.5 million participants have demonstrated that individuals with obesity, despite lacking metabolic abnormalities, still confer a greater likelihood of developing coronary heart disease, stroke, and heart failure than metabolically healthy people of normal weight[5]. These results indicate that MHO is not a benign situation and that obesity alone, even in the context of apparent metabolic health, significantly elevates cardiovascular risk. In the Framingham Heart Study, Echouffo-Tcheugui et al[6] observed that approximately 50% of individuals with MHO transitioned to a metabolically unhealthy state over 20 years. Compared to metabolically healthy normal-weight individuals, MHO was associated with a 61% increased risk of cardiovascular disease and a 43% higher risk of all-cause mortality, indicating that MHO is often a transient phenotype with elevated long-term health risks. These conclusions were confirmed by the meta-analysis of Eckel et al[7] including 61000 participants, demonstrating that although MHO individuals are associated with better outcomes than metabolically unhealthy obese people, they still face significantly increased cardiovascular risk by 45% compared to healthy, normal-weight individuals.

Focusing on specific age groups, adults aged 55 and older classified as MHO individuals, were found to present a 62% higher risk of cardiovascular disease (hazard ratio: 1.62), whereas metabolically unhealthy obese individuals presented a 100% higher risk (hazard ratio: 2.00), compared to metabolically healthy normal-weight individuals[8]. Of note, metabolic dysregulation with distinct states of metabolic health may also exist early in life in children/adolescents both with normal weight and obesity, and are reflected by alterations in biomarkers for metabolic homeostasis[9].

MHO IN POSTMENOPAUSAL WOMEN: A MULTIFACETED VULNERABLE PHENOTYPE

Menopause represents a critical transition in a woman's life, associated with hormonal alterations and mechanisms primarily derived by estrogen deficiency contributing to the development of obesity and metabolic dysregulation, and affecting body composition, lipid metabolism, and vascular function. Loss of estrogen receptors’ regulatory and protective control on appetite, lipid metabolism, glucose homeostasis, and mitochondrial function, promotes vulnerability to adipocyte hypertrophy, chronic inflammation, and insulin resistance; this pattern is strongly associated with increased risk for cardiovascular disease, type 2 diabetes, and metabolic syndrome[10-12]. Even though both aging and hormonal changes, contribute to deteriorating metabolic health, evidence suggests that estrogen deficiency independently exacerbates glucose intolerance, endothelial dysfunction, and vascular inflammation, which are key drivers of cardiovascular disease and type 2 diabetes in postmenopausal women[13].

Menopause affects women differently, with nationality playing a significant role. In the Study of Women's Health across the Nation, up to 80% of midlife women experienced vasomotor symptoms-hot flashes and night sweats-with a median duration of 7.4 years, sometimes lasting over a decade. African American women had the highest prevalence and severity, while Asian women had the lowest[14].

In a cohort of more than 90000 postmenopausal women followed for 16.4 years, even metabolically healthy overweight and obese individuals had a higher heart failure risk, namely, 32% and 39%, respectively compared to healthy normal-weight women. The risk rose to 72% in metabolically unhealthy obese women, highlighting that excess weight alone increases heart failure risk[15].

In the recent issue of the World Journal of Cardiology, Pingili et al[16] published the interesting article: Prevalence and impact of MHO on cardiovascular outcomes in postmenopausal women and disparities: An age-matched study. This study focuses on the subset of metabolically healthy postmenopausal women, and investigates the incidence of major adverse cardiovascular events according to the presence of obesity, further emphasizing the need for precision in risk stratification and individualized care.

In this recent large-scale retrospective study, the authors derived the study population from the 2020 United States National Inpatient Sample, and identified approximately 1.3 million hospitalized women aged ≥ 55 years old (i.e. considered to be post-menopausal) without hypertension, hyperlipidemia and diabetes mellitus, thereby reflecting a metabolically healthy status. Then, Pingili et al[16] distinguished those with and without obesity (11.4% and 88.6%, respectively) using International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) coding, and constructed their final study population after propensity score matching for age (n = 148250 in each of the two cohorts with and without obesity). The analysis primarily focused on the incidence of in-hospital major adverse cardiac and cerebrovascular events (MACCE) including all-cause mortality, myocardial infarction, cardiac arrest, and acute ischemic stroke, while multivariable regression models were used to reduce confounding for demographic and hospital-level variables. The principal finding of the study indicated that postmenopausal women with MHO have an overall increased risk for in-hospital MACCE events compared to metabolically healthy counterparts without obesity. Despite the metabolically healthy state, those classified as obese still demonstrated increased odds by 8% for MACCE (P = 0.028) according to the multivariable logistic regression analysis but there was no significant difference in all-cause mortality (adjusted odds ratio [aOR]: 1.23, P = 0.621) according to the discharge status; unfortunately, separate aORs for the other components of MACCE were not provided while crude incidence rates provided in the article are not clear. Of note, when the analysis was stratified according to race, the difference in odds for MACCE was significant only in the black population (aOR: 1.23, P = 0.035) and non-significant in any of the other populations (white, Hispanic, Asian/pacific islander, and native American).

Although the data from Pingili et al[16] were derived retrospectively from a national United States dataset of hospitalized patients, thereby limiting the generalizability of the findings to the broader outpatient population, and a cross-sectional type of analysis was employed regarding simple associations with in-hospital outcomes, rather than a longitudinal analysis with patient follow-up which would substantiate a more causative relationship, they provide supportive evidence regarding the non-benign nature of obesity even when some criteria are met for a metabolically healthier profile, and are overall in accordance with the above-mentioned data from the Women’s Health Initiative[15]. However, we need to acknowledge that the higher risk for MACCE may be particularly present in some patient populations such as the Black race. This is also in line with the data presented from the Shizuoka Study in a Japanese population[17], according to which stroke incidence (9.2 vs 10.5 per 10000 person-years), myocardial infarction (3.7 vs 3.1 per 10000 person-years), and all-cause mortality (26.6 vs 23.3 per 10000 person-years) were not significantly different in MHO and non-MHO individuals, respectively.

It is also worthwhile noting that the definition of a metabolically healthy status and obesity per se may differ between studies and may not be robust especially in population studies and more so when data are collected retrospectively. Instead of strict metabolic criteria (such as the homeostatic model assessment for insulin resistance; the triglyceride, high-density lipoprotein cholesterol and fasting blood glucose levels; and measures of systolic and diastolic pressure), Pingili et al[16] merely excluded patients with a known history of diabetes, hypertension and hyperlipidemia to identify metabolically healthy hospitalized patients. Interestingly, in registry data from the National Health and Nutrition Examination Survey III and the United Kingdom Biobank, the combination of systolic blood pressure and waist-to-hip ratio was found to be the most effective in predicting lower risks of cardiovascular disease and total mortality among individuals with MHO, thereby supporting a new simpler definition of metabolic health[18]. Lastly, Pingili et al[16] used hospital classification codes corresponding to a body mass index above 30 kg/m², whereas obese individuals in the Shizuoka Study were classified according to a body-mass-index above 25 kg/m²[17]; it may be important to distinguish obese from overweight and normal-weight individuals relating to various levels of cardiovascular risk. Such differences may contribute to the significance (vs non-significance) of associations among studies.

The lack of detailed patient-level data (which would go beyond discharge diagnoses and classification codes) in the population study by Pingili et al[16], also limits any efforts for an explanatory analysis of these observations. Data on detailed lifestyle variables (e.g., physical activity, dietary habits) seem to differ among metabolic phenotypes[19]. Furthermore, meta-analytic literature data suggest that MHO individuals exhibit higher levels of inflammatory markers such as TNF-α, IL-6, and CRP compared to metabolically healthy non-obese individuals, signifying that MHO may carry an increased risk for inflammation-related complications[20]. Such pieces of evidence could be critical for understanding the pathophysiology behind distinct cardiovascular risk levels of metabolically healthy normal-weight, MHO, and metabolically unhealthy obese individuals.

CLINICAL IMPLICATIONS

Given that postmenopausal women are already at a relatively elevated baseline cardiovascular risk, available data underline the importance of accurate risk stratification in the clinical setting. In that respect, the attribution of a metabolically healthy state to an obese postmenopausal woman may be misleading, as it underplays the risk for future disease progression and major adverse events. Therefore, the presence of obesity per se may be the critical phenotypic characteristic which determines biological vulnerability and future cardiovascular risk irrespective of minimal or advanced dysregulation according to specific metabolic indices/biomarkers.

Whether fine-tuned risk stratification tools, which account for subclinical cardiovascular vulnerability in individuals who are metabolically healthy by standard definitions but remain at high risk due to other factors, could be developed, that remains to be pursued in future investigations. To this end, prospective, longitudinal studies, incorporating metabolic biomarkers, dedicated imaging such as visceral fat quantification, and lifestyle data, are needed to investigate the potential transitions from MHO to MUO, and any causative relationships with cardiovascular outcomes, particularly in aging female populations. Lastly, future research must also focus on determining the therapeutic value of targeted interventions, namely, pharmacological (e.g., glucagon-like peptide-1 agonists)[21], lifestyle, or surgical, in the MHO subgroup to prevent or delay transition to metabolically unhealthy states and reduce long-term cardiovascular risk.

A key limitation in understanding and managing MHO is the absence of a standardized definition. Criteria for metabolic health vary widely-ranging from strict exclusion of all metabolic abnormalities to more lenient thresholds for lipids, blood pressure, or insulin sensitivity[3,7,19]. This inconsistency may lead to misclassification of individuals at risk. Some definitions overlook subclinical impairments such as low-grade inflammation or endothelial dysfunction[1,3]. Adoption of empirically derived criteria may enhance risk prediction and clinical utility[19]. A unified, consensus-based definition is urgently needed to guide both research and clinical practice.

CONCLUSION

The presence of obesity may confer elevated clinical risk irrespective of the absence of striking metabolic dysregulation. Although the term MHO suggests a benign profile, it masks the cardiovascular vulnerabilities that remain, especially among postmenopausal women who face a multi-level unfavorable metabolic change due to estrogen deficiency. MHO should be viewed not as a quiescent state but as a dynamic and potentially unstable phenotype, particularly among older female populations.