Global Burden, Attributable Risk Factors, and Future Projections of Lower Extremity Peripheral Arterial Disease Among Postmenopausal Women

Introduction

Lower extremity peripheral arterial disease (LEPAD) is a prevalent cardiovascular disease primarily characterized by atherosclerosis, associated with increased risks of amputation, myocardial infarction, stroke, impaired quality of life, and mortality.^1–3 In 2021, LEPAD affects over 113 million population globally, with incidence increasing progressively with advancing age.^4–6 The global prevalent cases of LEPAD were projected to increase by 220% and reach 360 million population by 2050.⁷ Chronic limb-threatening ischemia, a severe form of LEPAD, is characterized by 1-year amputation rate of 15–20% and 1-year mortality rate of 15–40%. Within a period of 4–5 years, the mortality rate typically exceeds 50%.⁸ High fasting plasma glucose, kidney dysfunction, high body-mass index (BMI), high systolic blood pressure, and smoking were the main attributable risk factors for LEPAD.^5,6

Notably, postmenopausal women constitute a distinct high-risk population for LEPAD, attributable to aging, estrogen decline, and the high prevalence of metabolic syndrome.⁹ Vascular senescence and cellular senescence are key drivers of atherosclerosis, an irreversible process that accumulates with advancing age.^10–12 Estrogen confers protective cardiovascular benefits, and its postmenopausal reduction significantly elevates cardiovascular risk.^13,14 Metabolic syndrome, as a common risk factor for LEPAD, demonstrates higher prevalence among postmenopausal women.^15,16 The combination of aging, menopause, and metabolic syndrome substantially amplifies LEPAD susceptibility in this population. Compared to men, women with LEPAD characteristically exhibit leg symptoms at more advanced ages and disease stages, encounter elevated quality-of-life impairment, and face elevated risks of cardiovascular and cerebrovascular events.^2,17

As early as 2012, the American Heart Association highlighted the need for greater awareness of LEPAD in women.¹⁸ Nevertheless, the condition remains underrecognized and understudied in women, with a substantially underestimated risk and reduced healthcare access compared to men, particularly in socioeconomically disadvantaged regions.^17,19 With global aging accelerating, LEPAD burden is escalating, posing growing challenges to public health systems worldwide. A comprehensive assessment of the epidemiology and burden trends of LEPAD among postmenopausal women is imperative for developing effective prevention strategies, optimizing healthcare resource allocation, and advancing clinical management.

The Global Burden of Disease Study (GBD) 2021 provides updated estimates of health loss across diseases, injuries, and risk factors over time and by sociodemographic groups.^20,21 Although prior studies have examined LEPAD epidemiology and burden, systematic analyses focusing on postmenopausal women remain limited.^22–24 To address this gap, we aim to systematically assess the global burden of LEPAD among postmenopausal women, quantify key modifiable risk factors for LEPAD, and project future burden trends using the GBD 2021 data. Our study is expected to enhance understanding of LEPAD epidemiology among this vulnerable population globally, support evidence-based prevention and intervention strategies for policymakers and clinicians, and ultimately reduce the substantial public health burden imposed by LEPAD.

Materials and Methods

Date Sources

The GBD database provides systematically collated epidemiological data from 204 countries and territories, grouped into 21 predefined GBD regions based on geographic and epidemiological similarity.²⁰ In GBD 2021, LEPAD was defined as an ankle-brachial index (ABI) ≤ 0.90, mapped to ICD-10 codes I70.2–I70.8 and I73–I73.9. Menopause is clinically defined as permanent cessation of ovarian function, diagnosed after 12 consecutive months of amenorrhea, typically occurring between ages 45–55 years.^16,25 Accordingly, we defined postmenopausal status as age ≥ 55 years, consistent with previous epidemiological criteria.^26,27 Using GBD 2021 data, we extracted data on prevalence, deaths, and disability-adjusted life years (DALYs) of LEPAD across nine age groups (55–59, 60–64, 65–69, 70–74, 75–79, 80–84, 85–89, 90–94, and ≥95 years) from 1990 to 2021, along with the corresponding uncertainty intervals (UIs). All the data were retrieved using the GBD Results tool (https://gbd2021.healthdata.org/gbd-results/). This investigation is in accordance with the guidelines for Accurate and Transparent Health Estimates Reporting (GATHER).²⁸ As GBD utilizes de-identified data, the University of Washington Institutional Review Board granted a waiver of informed consent.²²

Burden Metrics

The primary burden metrics included prevalence, deaths, DALYs, age-standardized prevalence rate (ASPR), age-standardized mortality rate (ASMR), age-standardized DALYs rate (ASDR), and average annual percentage change (AAPC). DALY is a comprehensive metric for evaluating the overall burden of disease, injury, or health condition. The metric is designed to quantify the population’s health status at a given point in time by aggregating the loss of health from both fatal and non-fatal outcomes.

Age-standardized rate (ASR) is defined as the weighted average of age-specific rates and is calculated according to the GBD standard population structure, thus eliminating the confounding effect of differences in age distribution between populations. It is computed by the following formula:

Where a_i represents the age-specific rate in the ith age group, w_i represents the number of individuals in the corresponding age group of the GBD standard population, and N represents its total number of individuals. The standard population structure used in this study was obtained directly from the official Institute for Health Metrics and Evaluation (IHME) GBD resources, which have been previously validated and widely applied.^29,30

AAPC is a summary measure of the trend over a prespecified fixed interval. It is computed as a weighted average of the annual percentage changes from the joinpoint model, with the weights equal to the length of the annual percentage change interval, and is commonly employed to analyze health trends across time periods.³¹ The formula for ASR is:

Where b_i represents the slope coefficient for the ith segment with i indexing the segments in the desired range of years, and w_i represents the length of each segment in the range of years. When the 95% confidence interval (CI) for AAPC is entirely above zero, it is indicative of an overall average annual increase during the study period and vice versa. When the 95% CI contains zero, it is indicative of a stable trend during the study period.

Socio-Demographic Index (SDI)

The SDI is a composite metric of regional development based on its lag-distributed income per capita, mean years of education, and fertility rates among females younger than 25 years. Ranging from 0 to 1, higher values reflect greater socioeconomic development. Studies have shown that SDI correlates with disease burden patterns, supporting its relevance in health disparity research.^32,33 In GBD 2021, all 204 countries and territories are classified into five distinct SDI subgroups (high, high-middle, middle, low-middle, and low SDI quintile) based on the SDI quintile.

Decomposition Analysis

This study performed a decomposition analysis to quantify the drivers of changes in prevalence, deaths, and DALYs of LEPAD among postmenopausal women. This method attributes changes in the absolute burden between two time points to three factors: population growth, aging, and epidemiological changes. The detailed specifications of the decomposition methodology are described in Supplementary Material 1 and have been well established in prior research.^32,34

Risk Factors

GBD 2021 provides comprehensive estimates of exposure levels, relative health risks, and attributable burden for 88 risk factors.²¹ We analyzed the impact of attributable risk factors on the DALYs of LEPAD among postmenopausal women, stratified by SDI to identify disparities. All analyses were based on the GBD comparative risk assessment framework, and employed sophisticated analytical approaches including two Bayesian statistical models (disease model meta-regression and spatiotemporal Gaussian process regression).²¹ Population-attributable fraction (PAF) was used to quantify the contribution of risk factors, which is the proportional change in health risk that would occur if exposure to a risk factor were reduced to the theoretical minimum risk exposure level.

Statistical Analyses and Data Visualizations

Previous studies have explained the methodology of the GBD 2021 in detail.^20,32 In this study, LEPAD burden among postmenopausal women was stratified by age, sex, and SDI. Future burden trends by 2035 were projected using a Bayesian age-period-cohort (BAPC) model, which dynamically integrates age, period, and cohort effects within a traditional generalized linear modeling framework. Supplementary Material 2 provides more information on the fundamental principles and fit process of BPAC. All statistical analyses and data visualizations were performed using R (version 4.4.2) and JD_GBDR (V2.6.2, Jingding Medical Technology Co., Ltd).

Results

Global Burden of LEPAD Among Postmenopausal Women in 2021

In 2021, there were 66,392,811 prevalent cases, 33,854 deaths, and 777,299 DALYs of LEPAD among postmenopausal women globally, accounting for 58.39%, 49.97%, and 49.88% of the total individuals, respectively (Table 1). At the GBD regional level, East Asia recorded the highest prevalence cases (18,415,727), and Western Europe recorded the highest deaths (9493) and DALYs (154 908) (Table 1).

Table 1 Number and Age-Standardized Rate (ASR) of Prevalence, Deaths, and Disability-Adjusted Life years (DALYs) for Lower Extremity Peripheral Arterial Disease Among Postmenopausal Women in 1990/2021, and Their Average Annual Percentage Change (AAPC) From 1990 to 2021

Following age standardization, the global ASPR, ASMR, and ASDR were 8441.89, 4.30, and 98.83 per 100,000 population, respectively (Table 1). At the GBD regional level, the region with the highest ASPR was High-income North America (13,693.70 per 100,000population). Meanwhile, Central Europe recorded both the highest ASMR (16.75 per 100,000 population) and ASDR (252.81 per 100,000 population) (Table 1).

Burden Trends of LEPAD Among Postmenopausal Women From 1990 to 2021

From 1990 to 2021, the global prevalent cases, deaths, and DALYs of LEPAD among postmenopausal women demonstrated a marked increasing trend, with increases of 99.84%, 72.93%, and 73.06%, respectively (Table 1 and Figure 1). In contrast, the global ASPR, ASMR, and ASDR showed an overall declining trend, with declines of 8.54% (AAPC: −0.29), 20.96% (AAPC: −0.77), and 20.8% (AAPC: −0.78), respectively (Table 1 and Figure 1).

Figure 1 Number and age-standardized rate of prevalence, deaths, and disability-adjusted life years (DALYs) for lower extremity peripheral arterial disease among postmenopausal women globally by year and sex (A–C), and by age group and sex in 2021 (D–F).

At the GBD regional level, the most significant increases in ASPR, ASMR, and ASDR were observed in North Africa and Middle East (AAPC: 0.61), High-income Asia Pacific (AAPC: 3.36), and Central Europe (AAPC: 1.50), respectively, while the most substantial declines occurred in Australasia (AAPC: −0.83), Eastern Europe (AAPC: −1.29), and Australasia (AAPC: −1.51), respectively (Table 1).

Comparative Analysis Between Postmenopausal Women and Age-Matched Men

From 1990 to 2021, postmenopausal women consistently demonstrated greater prevalence cases and ASPR of LEPAD than age-matched men. Despite maintaining lower ASMR and ASDR than age-matched men, postmenopausal women exhibited greater absolute deaths and DALYs (Figure 1 and Supplementary Table 1).

Analysis stratified by age revealed that ASPR, ASMR, and ASDR showed a consistent upward trend with advancing age in both sexes. Postmenopausal women exhibited higher prevalence cases and ASPR across all age groups. Regarding deaths and DALYs, postmenopausal women progressively surpassed age-matched men with advancing age (Figure 1 and Supplementary Table 2).

Decomposition Analysis of LEPAD Burden Among Postmenopausal Women

At the global level, population growth constituted the primary driver of increased prevalent cases, deaths, and DALYs of LEPAD among postmenopausal women from 1990 to 2021, followed by aging. However, epidemiological changes partially offset these increases. At the regional level, the proportional contribution of these factors varied across SDI quintiles, though population growth remained the dominant driver. Aging demonstrated its most substantial absolute contribution in the high SDI quintile. Notably, epidemiological changes had a protective effect in the high and high-middle SDI quintiles, whereas a detrimental effect was observed in the low and low-middle SDI quintiles (Figure 2 and Supplementary Table 3).

Figure 2 Changes in prevalent cases (A), deaths (B), and disability-adjusted life years (DALYs) (C) of lower extremity peripheral arterial disease among postmenopausal women according to population growth, aging, and epidemiological change from 1990 to 2021 at 5 socio-demographic Index (SDI) quintiles and globally.

Burden of LEPAD Among Postmenopausal Women by SDI

In 2021, the highest prevalent cases, deaths, and DALYs of LEPAD among postmenopausal women were observed in the high SDI quintile, while the lowest were observed in the low SDI quintile. Following age standardization, the high SDI quintile maintained the highest ASPR, ASMR, and ASDR. The low SDI quintile recorded the lowest ASPR, while the low-middle SDI quintile recorded the lowest ASMR and ASDR (Table 1).

Spearman correlation analysis revealed significant positive associations between both ASPR (R = 0.78, P < 0.001) and ASDR (R = 0.56, P < 0.001) with SDI, while significant negative correlations were observed between their AAPC and SDI (R = −0.25, P < 0.001) and ASDR (R = −0.26, P < 0.001) (Figure 3). High SDI regions generally demonstrated elevated ASPR and ASDR compared to low SDI regions. Notably, most high SDI regions demonstrated significant declining trends over time, while most low SDI regions showed divergent increasing trends (Figure 3).

Figure 3 Age-standardized prevalence rate (ASPR) (A) and age-standardized disability-adjusted life years rate (ASDR) (B) of lower extremity peripheral arterial disease among postmenopausal women at the global and regional levels by socio-demographic Index (SDI) from 1990 to 2021, and their average annual percentage change (AAPC) (C and D) at the national levels by socio-demographic Index (SDI) in 2021. The blue line and shaded area represent the expected value and 95% CI based on the SDI, disease rates, and AAPC across all locations.

Risk Factors of LEPAD Burden Among Postmenopausal Women

In GBD 2021, high fasting plasma glucose, high systolic blood pressure, high body-mass index, kidney dysfunction, smoking, and low physical activity were identified as major attributable risk factors for LEPAD. Globally, high fasting plasma glucose was the leading attributable risk factor for DALYs of LEPAD among postmenopausal women (contributing 35.39%), followed by kidney dysfunction (contributing 29.83%), high body-mass index (contributing 20.26%), and high systolic blood pressure (contributing 13.21%). Smoking and low physical activity demonstrated minor contributions (12.31% and 2.91%). Similar patterns were observed across all SDI quintiles. Notably, smoking showed a greater attributable burden in the high SDI quintile (contributing 16.55%) (Figure 4).

Figure 4 Population-attributable fraction of disability-adjusted life years (DALYs) (A) for lower extremity peripheral arterial disease among postmenopausal women in 2021, and their trends (B) from 1990 to 2021 at 5 socio-demographic Index (SDI) quintiles and globally.

From 1990 to 2021, high fasting plasma glucose and high body-mass index exhibited a significantly increasing contribution. In contrast, the burden attributable to smoking demonstrated a decline, particularly in the high SDI quintile (Figure 4).

Projections of LEPAD Burden Among Postmenopausal Women

The BAPC model indicates that the absolute prevalence cases, deaths, and DALYs of LEPAD among postmenopausal women will continue to increase. In 2035, there will be 91,669,132 prevalent cases, 41,370 deaths, and 1,011,323 DALYs, with increases of 38.07%, 22.2%, and 30.11%, respectively, compared to 2021. Conversely, the ASPR, ASMR, and ASDR are projected to maintain a continued decline, reaching 8289.05, 3.74, and 91.45 per 100,000 population in 2035, with a decline of 1.81%, 13.02%, and 7.47% compared to 2021, respectively (Figure 5).

Figure 5 The future trends in global prevalent cases (A), deaths (B), disability-adjusted life years (DALYs) (C), age-standardized prevalence rate (ASPR) (D), age-standardized mortality rate (ASMR) (E), and age-standardized DALYs rate (ASDR) (F) of lower extremity peripheral arterial disease among postmenopausal women are predicted by the Bayesian age-period-cohort (BAPC) model.

Discussion

LEPAD poses a significant clinical and public health challenge. Our study focuses on postmenopausal women and provides a comprehensive analysis of the global burden and attributable risk factors of LEPAD in this particular population from 1990 to 2021, which simultaneously accounts for demographic characteristics, regional disparities, risk factor profiles, and aging dynamics. Additionally, we project their future trends by 2035.

Our findings indicate that the global ASPR, ASMR, and ASDR of LEPAD among postmenopausal women generally exhibited a fluctuating decline from 1990 to 2021, reflecting improvements in disease prevention and medical technology. However, there was a significant increase in the absolute prevalence cases, deaths, and DALYs globally. This persistent absolute burden aligns with trends observed in the general population but is notably higher among postmenopausal women,^4,35,36 mainly due to the decline in estrogen levels. The effects of estrogen on cardiovascular function are mediated by nuclear and membrane estrogen receptors (ERs), including estrogen receptor alpha, beta and G protein-coupled ER.³⁷ Estrogen exerts vascular protective effects by regulating oxidative stress, anti-inflammation, and inhibiting leukocyte and platelet adhesion, which can reduce the incidence of atherosclerosis in young women.^38,39

Consistent with previous reports, significant age and sex disparities were observed in our study.^4,35 Among postmenopausal women, age-standardized rates of prevalence, deaths, and DALYs progressively increased with advancing age, with the burden being particularly pronounced in the elderly population. Postmenopausal women had a higher absolute burden than age-matched men, and the age-standardized rates of deaths and DALYs of women surpassed those of age-matched men with advancing age, likely due to women’s longevity and the cumulative impact of metabolic disorders.^15,16 These disparities suggest the need for population-specific interventions tailored to demographic characteristics, with particular emphasis on enhancing early screening and health management for elderly women.

Significant disparities in LEPAD burden were observed across SDI regions. This highlights the significant impact of socioeconomic factors on cardiovascular health. Overall, high SDI regions generally exhibited a greater LEPAD burden, potentially due to pronounced population growth and aging, as well as a higher metabolic syndrome prevalence.^40,41 Nevertheless, most high SDI regions demonstrated declining trends from 1990 to 2021, likely attributable to robust healthcare systems and advanced medical technology. In contrast, the increasing burden in low SDI regions may stem from limited healthcare access and insufficient medical resources. Socioeconomic disparities in LEPAD burden have been well documented.^2,42 These findings highlight systemic health inequities and call for region-specific responses: high SDI regions should enhance metabolic risk management, while low SDI regions require strengthened basic health infrastructure and improved service availability.

Our study identified high fasting plasma glucose, kidney dysfunction, high BMI, high systolic blood pressure, smoking, and low physical activity as the primary risk factors for LEPAD among postmenopausal women, aligning with previous studies.^43–47 Compared with the general population, postmenopausal women exhibited a similar pattern of risk factor contributions, with the exception of smoking.⁴⁸ The global burden attributable to smoking among postmenopausal women was significantly lower than that observed in the general population (12.31% vs 24.17%). Meanwhile, the smoking-attributable burden gradually declined from 1990 to 2021, particularly in the high SDI quintile, likely benefiting from smoking management. Notably, the continuously rising attributable burden of high fasting plasma glucose and high body-mass index may be associated with an unhealthy lifestyle and higher metabolic syndrome prevalence. Kidney dysfunction has continued to have a significant impact on LEPAD globally over the past three decades. This shifting risk profile underscores the importance of promoting healthy lifestyles and prioritizing metabolic health in current prevention frameworks.

Although global age-standardized rates of LEPAD burden among postmenopausal women declined over the past three decades, the absolute burden continued to increase, driven predominantly by population growth and aging. Epidemiological changes partially offset this increase in high SDI regions, illustrating the impact of strong health systems. Given the accelerating population aging and the rising metabolic syndrome prevalence, the absolute burden of LEPAD is projected to continue increasing, necessitating targeted strategies that address both metabolic risk management and demographic change.

It is important to acknowledge the potential limitations of this study. First, GBD data are derived from compiled national reports and publications, which raises concerns about their accuracy and completeness. Second, unreliable epidemiological data in some low-income countries may lead to underreporting or misclassification, which could result in an underestimation of the true burden. Third, mathematical modeling was required for countries with poor-quality data, which introduces possible estimation biases. Despite these limitations, our findings align with prior epidemiological evidence, which affirms the validity and robustness of our conclusions.

Conclusions

This study reveals a substantial and persistently increasing LEPAD burden globally, characterized by significant demographic and regional disparities. Given the accelerated aging and the rising metabolic syndrome prevalence, the absolute burden is projected to continue increasing. Our findings provide valuable insights and a global perspective for policymakers and clinicians. They emphasize the necessity of developing targeted strategies that account for demographic characteristics, regional disparities, and attributable risk factors to effectively reduce LEPAD burden among postmenopausal women and promote healthier aging.