Associations of Cardiocerebrovascular Risks and Exercise according to Menopausal Status in Women with Type 2 Diabetes Mellitus: A Nationwide Cohort Study

Article information

Diabetes Metab J. 2026;50(1):101-114

Publication date (electronic) : 2025 August 13

doi : https://doi.org/10.4093/dmj.2024.0487

Ji-Hee Ko ¹^,²^,^*

, Sun Joon Moon ¹^,^*

, Kyung-Do Han ³, Hye-Mi Kwon ¹, Se-Eun Park ¹, Eun-Jung Rhee^,¹

, Won-Young Lee^,¹

¹Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea

²Division of Endocrinology and Metabolism, Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea

³Department of Statistics and Actuarial Science, Soongsil University, Seoul, Korea

Corresponding authors: Eun-Jung Rhee https://orcid.org/0000-0002-6108-7758 Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul 03181, Korea E-mail: hongsiri@hanmail.net

Won-Young Lee https://orcid.org/0000-0002-1082-7592 Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul 03181, Korea E-mail: drlwy@hanmail.net

*Ji-Hee Ko and Sun Joon Moon contributed equally to this study as first authors.

Received 2024 December 11; Accepted 2025 April 8.

Abstract

Background

Menopausal status can increase the risk of cardiocerebrovascular diseases (CCVDs) in women with type 2 diabetes mellitus (T2DM). Regular exercise is well-known to reduce this risk. This study explored the impact of exercise on CCVD and mortality in women with T2DM according to their menopausal status.

Methods

A total of 32,477 premenopausal and 53,690 postmenopausal Korean women with T2DM aged 40 to 60 years from a national health examination cohort (2009 to 2018) were included. We evaluated risks for stroke, myocardial infarction (MI), and mortality based on exercise intensity. Cox proportional hazard regression analyses were performed to obtain the adjusted hazard ratio (aHR) and 95% confidence interval.

Results

Exercise reduced stroke, MI, and mortality risks in women with T2DM, regardless of menopausal status. The highest effects of aHR compared to the sedentary group were 0.68 for stroke, 0.66 for MI, and 0.81 for mortality. Postmenopausal women experienced significant MI risk reductions at most exercise intensities, with the greatest reduction in the ≥1,500 metabolic equivalent of task score group unlike premenopausal women. However, stroke and mortality risk reductions in postmenopausal women were less pronounced compared to premenopausal women.

Conclusion

Exercise reduces CCVD risk in women with T2DM across menopausal status. Postmenopausal women with T2DM had more benefits from exercise on MI but fewer benefits on stroke and mortality than premenopausal women. In premenopausal women with T2DM, exercise was not associated with a lower MI risk.

Keywords: Cardiovascular diseases; Diabetes mellitus, type 2; Exercise; Mortality; Postmenopause

GRAPHICAL ABSTRACT

Highlights

• Exercise effects on CCVD and mortality were assessed by menopausal status in T2DM women.

• Exercise lowered stroke, MI, and mortality risk in both pre- and postmenopausal women.

• Postmenopausal women had greater exercise benefit in reducing MI risk.

• Premenopausal women had stronger exercise benefits in reducing stroke and mortality risk.

• Exercise recommendations should be tailored by menopausal status.

INTRODUCTION

Cardiocerebrovascular diseases (CCVDs) are the leading cause of mortality in patients with type 2 diabetes mellitus (T2DM) [1]. Postmenopausal women with diabetes have two to three times higher cardiovascular mortality risk than non-diabetics [2], due to estrogen loss leading to fat accumulation, insulin resistance, oxidative stress, and inflammation, which increase hypertension and atherosclerosis risks [3,4].

Exercise prevents CCVDs in T2DM patients by improving insulin sensitivity, glycemic control, and lipid profiles [5-7]. A study involving 5,125 women with diabetes reported a 45% reduction in cardiovascular disease (CVD) risk with moderate-to-vigorous activity [8]. A Korean nationwide cohort study of patients with newly diagnosed diabetes revealed a 34% lower CVD risk with sustained physical activity (PA) [9]. The American Diabetes Association recommends at least 150 minutes of moderate-to-vigorous aerobic activity per week for at least 3 days, and the American College of Sports Medicine recommends a minimum cumulative total of 1,000 kcal of PA per week for patients with T2DM [10,11].

Regular PA is also vital in postmenopausal women, helping maintain a healthy lipid profiles and body fat composition [12]. Studies have demonstrated improvements in blood lipid levels after resistance or aerobic exercise [13,14] and a 22% mortality reduction with moderate activity at least once weekly [15]. However, only one-third of Korean women with diabetes regularly engage in walking exercises [16].

Despite extensive evidence on exercise benefits in T2DM and menopause separately, comprehensive research addressing both together for CCVD prevention is lacking. A 15-year study found that postmenopausal women with early menopause and diabetes had higher CCVD rates than those without diabetes, including coronary heart disease (1.15 vs. 1.09), stroke (1.21 vs. 1.10), and atherosclerosis (1.29 vs. 1.10) [17], emphasizing the need to consider menopause and diabetes together in preventing CCVDs and mortality.

Cardiovascular profiles differ between pre- and postmenopausal women. Young women’s atherosclerotic plaques contain more fatty deposits with less calcium and less dense fibrous tissue, making them more susceptible to rupture [18]. Premenopausal women have fewer collateral vessels, which increases the risk of coronary complications such as spasms, plaque erosion, and rupture [19]. These differences suggest that PA’s cardiovascular effects may vary by menopausal status due to underlying pathophysiological mechanisms.

Few studies compare pre- and postmenopausal women with diabetes to establish specific exercise recommendations for CCVD risk reduction. A systematic review of 14 randomized controlled trials (RCTs) found only one addressing PA’s differential cardiovascular benefits by menopausal status [20]. Therefore, we evaluated exercise’s influence on CCVD and mortality rates in women with T2DM by menopausal status using nationwide real-world data.

METHODS

National Health Insurance Service data

The Korean National Health Insurance Service (NHIS), a government agency that implements a medical insurance system for all Koreans, manages a database containing individual medical records, including hospital visits, disease diagnoses, tests performed, and medication prescriptions. In addition to these data, records of regular health examinations for adults aged >40 years and workers aged >20 years were merged. These health screening databases include anthropometric measurements and personalized questionnaires, such as past medical history, information on drinking, smoking, and PA, and laboratory findings. The NHIS has processed and distributed all these databases for use in cohort studies [21]. This study was approved by the Institutional Review Board of Kangbuk Samsung Hospital (No. KBSMC 2021-04-049). Written informed consent was obtained from all patients.

Study population

This study identified Korean women aged >40 years who underwent general health checkups and cancer screening examinations at the NHIS in 2009 (n=3,109,491). T2DM diagnosis was defined as meeting one of the following criteria: (1) International Classification of Diseases, 10th revision, Clinical Modification (ICD-10-CM) codes E11–E14 and prescribed with at least one of the glucose-lowering agents, including oral hypoglycemic agents or insulin, or (2) fasting glucose level of ≥126 mg/dL [22].

Among the initial participants, those who underwent hysterectomy (n=286,649), had missing data (n=598,108), or did not have T2DM (n=2,004,025) were excluded, resulting in a cohort of 220,709 patients with T2DM. Individuals previously diagnosed with any cancer except thyroid cancer (n=4,894), those with a history of stroke (n=28,766), myocardial infarction (MI) (n=6,099), those with a 1-year lag following stroke, MI, or death (n=1,986), and those aged >60 years (n=92,797) were also excluded. Finally, 32,477 premenopausal and 53,690 postmenopausal Korean women with T2DM were included in the study and followed up until 2018 (Fig. 1). Information on menopause status was obtained using a self-administered questionnaire.

Fig. 1.

Enrollment of study participants. CVD, cardiovascular disease; MI, myocardial infarction.

Definition of physical activity stages

PA was assessed using a self-administered questionnaire that inquired about the intensity, frequency, and duration of their PA. PA levels were evaluated using a self-administered NHIS questionnaire, a modified version of the International PA Questionnaire (IPAQ) developed by the World Health Organization (WHO) that consists of questions on PA frequency and intensity per week [23].

Regular PA was defined as performing at least 30 minutes of moderate PA at least five times a week or at least 20 minutes of strenuous PA at least three times a week. Each participant was asked to report their weekly PA levels according to the following categories: vigorous PA (≥20 min/day, e.g., running, aerobics, or fast cycling at least thrice a week); moderate PA (≥30 min/day, e.g., brisk walking, bicycling at a usual speed, or gardening at least five times a week); and walking, defined as usual-pace walking for at least 10 minutes at a time (≥30 min/day at least five times a week) [24]. This self-administered PA questionnaire has been validated and found to be reliable [24,25]. For quantitative estimation, we calculated each participant’s weekly PA volume as the metabolic equivalent of tasks (METs), expressed as MET-min/week. We assigned eight, five, and three METs for vigorous PA, moderate PA, and walking, respectively, according to the 2011 Compendium of Physical Activities [26]. Using the minimum time consumed for each PA category, we calculated the overall volume of weekly PA (MET-min/week) as follows: (8 METs×20 min×a)+(5 METs×30 min×b)+(3 METs×30 min×c), where a, b, and c represent the frequencies of vigorous PA, moderate PA, and walking, respectively. Subsequently, MET-min/week was stratified into five groups: 0, 1–499, 500–999, 1,000–1,499, and ≥1,500 MET-min/week.

Definition of outcome

The incidence of each disease was provided by the NHIS, and mortality data were supplied by the Korean National Statistical Office for the period analyzed from the date of the health examination from 2009 to 2018 or until the date of death. Data were analyzed in the NHIS database using ICD-10-CM codes. The study outcomes were defined as the composite occurrence of MI, stroke, and mortality. MI was defined as at least one hospitalization with ICD-10-CM codes I21 or I22. Stroke was defined as at least one hospitalization with ICD-10-CM codes I63 or I64 accompanied by a claim for brain imaging (computed tomography or magnetic resonance imaging).

Statistical analysis

We analyzed exercise effects on disease risks in premenopausal and postmenopausal groups using a Cox proportional hazards model with a 95% confidence interval (CI). The sedentary group (0 MET-min/week) served as reference for calculating hazard ratios (HRs) across exercise volume groups. We also analyzed risk differences by exercise frequency (0, 1–3, 4–5, ≥6 days/week).

Multivariable-adjusted analysis included potential confounders: age, body mass index (BMI), menstruation, smoking, drinking, low income, comorbidities (hypertension, hyperlipidemia, end stage renal disease), clinical parameters (blood pressure, fasting glucose level, estimated glomerular filtration rate, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol), medications (insulin, metformin, sulfonylurea, meglitinide), diabetes duration, creatinine clearance, hormone replacement therapy (HRT), and oral contraceptives (OC). HRT and OC use was assessed through self-reported questionnaires from the National Cancer Screening Program. HRT was categorized by duration of use (never, <2, 2–5, ≥5 years) and defined as current/past hormone therapy for menopausal symptoms. OC use was similarly categorized by duration (never, <1, ≥1 year, and unknown).

Subgroup analyses were based on the PA relative to WHO recommendations (at least 150 to 300 minutes moderate or 75 to 150 minutes vigorous aerobic activity weekly). We converted these to MET values: four METs for moderate, eight METs for vigorous activities. Total weekly MET-minutes were calculated by multiplying each activity’s MET intensity by duration and summing across all activities. We divided participants into tertiles: <600, 600–1,200, and >1,200 MET-min/week. While initially using five METs for moderate activity, we adopted four METs to align with WHO guidelines, which we found to be methodologically acceptable based on a previous study [27]. Additional analyses were conducted based on the presence of early menopause (before age 45), BMI and HRT use. Statistical analyses used SAS version 9.3 (SAS Institute, Cary, NC, USA), with statistical significance at P<0.05 using t-tests for continuous variables and chi-square for categorical variables.

RESULTS

Baseline characteristics of the study population

Of the 3,109,491 women aged 40 years and older who underwent general health checkups and cancer screening examinations in 2009, 32,477 were premenopausal, and 53,690 were postmenopausal. The baseline characteristics of the study population are presented in Table 1.

Table 1.

Baseline characteristics of study participants according to menopausal state

The average age was 46 years for premenopausal and 56 years for postmenopausal women (Table 1). Both groups had similar BMI and proportions of individuals with past or current smoking history. The baseline fasting blood glucose level was 150.2±49.2 mg/dL in premenopausal and 142.3±46.1 mg/dL in postmenopausal women. Diabetes duration was longer in postmenopausal women (2.2±1.9 years) than in premenopausal women (1.7±2.1 years). Hypertension and hyperlipidemia were more prevalent in postmenopausal women. The MET score for postmenopausal women (524.6±567.8) was slightly higher than that of premenopausal women (495.1±520.6).

Effects of exercise on stroke, MI, and mortality in the total study population

In the total study population, the incidence rates (per 1,000 person-years) for sedentary participants (MET score of 0) were 3.15, 2.56, and 3.01 for stroke, MI, and mortality, respectively, in women with T2DM during a mean follow-up of 8.2 years (Table 2). In the unadjusted model, the participants who exercised had a significantly lower risk of stroke, MI, and mortality than those in the sedentary group. In the model adjusted for potential confounding factors, the HRs for incident stroke, MI, and mortality showed attenuated associations yet did not alter the overall trend. For stroke, there was a graded decrease in adjusted hazard ratios (aHRs) according to exercise intensity, except for ≥1,500 MET score (aHR, 0.93 [95% CI, 0.83 to 1.05]; aHR, 0.81 [95% CI, 0.71 to 0.91]; and aHR, 0.68 [95% CI, 0.57 to 0.81] for 1–499, 500–999, and 1,000–1,499 MET score, respectively). For MI, all grades of exercise demonstrated risk reductions (aHR, 0.83 [95% CI, 0.73 to 1.95]; aHR, 0.72 [95% CI, 0.63 to 0.82]; aHR, 0.66 [95% CI, 0.55 to 0.80]; and aHR, 0.67 [95% CI, 0.53 to 0.85] for 1–499, 500–999, 1,000–1,499, and ≥1,500 MET score, respectively). For mortality, a gradual risk reduction trend was observed, with statistical significance noted only in the 1,000 to 1,499 MET group (aHR, 0.83; 95% CI, 0.71 to 0.98).

Table 2.

The incidence rates and the risk for a stroke, MI, and mortality according to intensity of physical activity in women with T2DM

Effects of exercise on stroke, MI, and mortality according to menopausal status

We evaluated the outcomes according to menopausal status (Tables 3 and 4). Postmenopausal women exhibited higher rates of stroke, MI, and mortality than premenopausal women. Compared to premenopausal participants, postmenopausal women displayed unadjusted HRs for stroke, MI, and death of 1.76 (95% CI, 1.58 to 1.95), 1.92 (95% CI, 1.67 to 2.16), and 1.84 (95% CI, 1.66 to 2.04), respectively. When adjusted for covariates, the significance diminished for stroke (aHR, 0.96; 95% CI, 0.82 to 1.12). However, postmenopausal women still faced a significantly higher risk of MI and death, aHRs of 1.21 (95% CI, 1.01 to 1.45) and 1.18 (95% CI, 1.01 to 1.38), respectively.

Table 3.

The incidence rates and the risk for a stroke, MI, and mortality according to intensity of physical activity in premenopausal women with T2DM

Table 4.

The incidence rates and the risk for a stroke, MI, and mortality according to intensity of physical activity in postmenopausal women with T2DM

Among premenopausal women with T2DM, exercise significantly reduced the risk of stroke and mortality, with gradual trends evident across the different levels of exercise (Table 3, Fig. 2). The highest effects among these exercise levels were observed with aHRs of 0.60 (95% CI, 0.42 to 0.86) for stroke at a 1,000–1,499 MET score, and 0.62 (95% CI, 0.39 to 0.98) for mortality at a ≥1,500 MET. However, MI was not influenced by exercise in premenopausal participants.

Fig. 2.

Multivariable-adjusted hazard ratios (95% confidence interval) for (A) stroke, (B) myocardial infarction (MI), (C) mortality, according to the amount of exercise (metabolic equivalent of task [MET]-min/wk) in premenopausal (PRE MP) women with diabetes mellitus (DM).

The data presented a different scenario for postmenopausal participants (Table 4, Fig. 3). The degree of exercise effect on reducing stroke risk was significantly lower, with the most substantial reduction observed at an aHR of 0.72 (95% CI, 0.59 to 0.88) for a 1,000–1,499 MET score. Mortality showed no significant association with exercise intensity (P=0.582), despite a trend toward lower risk at higher exercise levels. Conversely, MI risks were significantly impacted across all exercise levels, with the most pronounced effect observed at an aHR of as much as 0.57 (95% CI, 0.43 to 0.76) for a MET score of ≥1,500.

Fig. 3.

Multivariable-adjusted hazard ratios (95% confidence interval) for (A) stroke, (B) myocardial infarction (MI), (C) mortality, according to the amount of exercise (metabolic equivalent of task [MET]-min/wk) in postmenopausal (POST MP) women. DM, diabetes mellitus.

Subgroup analyses according to exercise levels above and below WHO recommendations

A subgroup analysis was performed based on exercise levels (<600, 600–1,199, ≥1,200 MET/week) in relation to WHO recommendations (Supplementary Table 1). In premenopausal women, insufficient exercise (<600 MET-min/week) was associated with significantly higher risks of stroke (aHR, 1.28; 95% CI, 1.03 to 1.59; P=0.023) and mortality (aHR, 1.26; 95% CI, 1.01 to 1.56; P=0.030), with no significant differences observed in MI risk.

In postmenopausal women, insufficient exercise (<600 MET-min/week) was associated with higher risks of both stroke (aHR, 1.27; 95% CI, 1.11 to 1.44; P=0.001) and MI (aHR, 1.29; 95% CI, 1.12 to 1.49; P<0.00). High-intensity exercise (>1,200 MET-min/week) demonstrated a trend toward lower MI risk (aHR, 0.82; 95% CI, 0.65 to 1.03), while no significant association was found between exercise intensity and mortality risk in postmenopausal women.

Subgroup analyses according to exercise levels based on the presence of early menopause

Among postmenopausal women with early menopause, the incidence rates (per 1,000 person-years) were 4.31, 4.46, and 3.92 for stroke, MI, and mortality, respectively (Supplementary Table 2). Women with early menopause had a significantly higher risk of MI (aHR, 1.68; 95% CI, 1.15 to 2.45; P=0.007), while showing no statistical significance with stroke (aHR, 1.34; 95% CI, 0.92 to 1.96; P=0.133) or mortality (aHR, 1.20; 95% CI, 0.81 to 1.78; P=0.370).

In women without early menopause, exercise significantly reduced the risk of stroke at 1,000 to 1,499 MET-min/week (aHR, 0.70; 95% CI, 0.57 to 0.85) and progressively reduced the risk of MI, with maximum benefit observed at ≥1,500 MET-min/week (aHR, 0.56; 95% CI, 0.42 to 0.75). However, no significant association was found with mortality. In women with early menopause (n=768), exercise intensity showed no statistically significant associations with cardiovascular outcomes, including stroke (P=0.373), MI (P=0.573), and mortality (P=0.571) (Supplementary Table 3).

Subgroup analyses according to BMI and hormone replacement therapy

We conducted subgroup analyses based on BMI (<25 and ≥25 kg/m²) and HRT or OC treatment status, as detailed in Supplementary Tables 4 and 5. For premenopausal participants, significant risk reductions in mortality associated with exercise intensity were noted exclusively in individuals in those not undergoing HRT or OC treatment (P=0.004). However, the P value for the interaction indicated no significant differences across subgroups (Supplementary Table 4). Similarly, among postmenopausal women, no significant differences were observed in outcome risk reduction across the subgroups analyzed, with all P values for interactions >0.05 (Supplementary Table 5).

DISCUSSION

This nationwide cohort study, including over 86,000 perimenopausal women with T2DM, investigated the impact of PA intensity on the risk of stroke, MI, and mortality. The findings revealed that postmenopausal women with T2DM have higher risks of MI and mortality than premenopausal women with mixed results for stroke risk. PA was associated with reduced risks of stroke, MI, and mortality in perimenopausal women with T2DM. However, the effects of exercise varied between pre and postmenopausal women. Exercise significantly reduced MI risk in postmenopausal women, a benefit not observed in premenopausal women. Conversely, premenopausal women showed more significant improvements in stroke risk and mortality than postmenopausal women. Our study suggests that physiological responses differ according to menopausal status, indicating the need for higher exercise levels in postmenopausal women to achieve the stroke and mortality benefits observed in premenopausal women.

CCVD is the leading cause of death in people with diabetes [28]. Current guidelines recommend regular PA to prevent cardiocerebrovascular comorbidities [29]. Exercise improves insulin sensitivity and glucose control, while also enhancing blood flow, endothelial function, and reducing oxidative stress and diabetic complication risks [30,31]. One study showed that high-intensity training reduced fat mass and improved glycosylated hemoglobin and lipid profiles [32]. However, large-scale studies comparing exercise effects by menopausal status have been limited. To our knowledge, this is the first nationwide cohort study to assess stroke, MI, and mortality risks in women with diabetes based on PA intensity and menopausal status to recommend proper exercise intensity.

We found that PA reduced the risk of stroke, MI, and mortality, regardless of menopausal status, with greater benefits at higher intensities, though stroke risk plateaued at ≥1,500 MET-min/week. These results align with a previous meta-analysis showing that PA reduces CVD and all-cause mortality in a dose-response manner in patients with diabetes [33]. Specifically, an increase of 1 MET-hr/day in PA was linked to a reduction of 7.9% in CVD risk and 9.5% in all-cause mortality [33]. However, the smaller reduction in stroke risk at the highest activity levels warrants further investigation.

Among postmenopausal women, MI risk decreased significantly with PA >500 MET-min/week, with the largest decrease of 43% at >1,500 MET-min/week. Menopause increases CVD risk in patients with diabetes through loss of estrogen’s cardioprotective effects, insulin resistance, hyperglycemia, inflammation, and reduced endothelial function [34]. Exercise strengthens the heart muscles, improves blood pressure and cholesterol profiles, and reduces atherosclerosis risk [35]. Postmenopausal women, who develop MI primarily through atherosclerosis from estrogen deficiency, benefit significantly from PA, compared to sedentary counterparts [36,37].

In contrast, premenopausal women did not show a significant MI risk reduction with PA. Premenopausal women benefit from the cardioprotective effects of estrogen [38]. Recent data show increasing ischemic heart disease mortality in young women, with non-obstructive coronary artery MI more common at younger ages [39]. Young women’s MI often results from coronary spasm, plaque microrupture, and microthrombosis rather than obstructive atherosclerosis [40]. Additional risk factors more common in younger patients include autoimmune diseases, pregnancy complications, OC use, and polycystic ovary syndrome [41]. High-intensity exercise might potentially exacerbate coronary artery stress, causing spontaneous coronary artery dissection in young MI [42-44]. These different pathophysiological mechanisms may explain the lack of exercise benefits for MI in premenopausal women [45].

Exercise provides greater stroke risk reduction benefits in premenopausal women than postmenopausal women at equivalent PA levels. The 1,000 to 1,499 MET-min/week group showed 40% and 24% stroke risk reductions in pre- and postmenopausal women, respectively. Premenopausal women achieved a significant 23% stroke risk reduction starting at 500 to 999 MET-min/week, while postmenopausal women needed >1,000 MET-min/week for comparable benefits. Mortality rates improved with minimal exercise in premenopausal women but showed no significant improvements in postmenopausal women.

Hormonal transition affects stroke risk through physiological mechanisms, with differences in risk reduction between pre- and postmenopausal women due to cardiovascular changes from estrogen decline [46]. Estrogen deficiency causes endothelial dysfunction and arterial stiffness [47], creating a challenging vascular protection environment. Aerobic exercise improves early-stage endothelial dysfunction in both groups, but late-stage improvements occur only in premenopausal women [48]. Research shows moderate-intensity exercise improved endothelial function in postmenopausal women on estradiol therapy [49]. This hormonal-vascular relationship suggests postmenopausal women need higher exercise intensities for comparable cardiovascular benefits.

While moderate exercise (500 to 1,499 MET-min/week) reduced stroke risk in postmenopausal women, highest intensity exercise (≥1,500 MET-min/week) showed no significant reduction. This may be due to reduced vascular adaptability in postmenopausal women limiting their ability to respond effectively to very high-intensity exercise [50]. Pierce et al. [51] found no difference in brachial artery flow-mediated dilatation between sedentary and highly-trained postmenopausal women, suggesting reduced vascular adaptability. Lower exercise capacity after menopause from increased fat mass, decreased skeletal mass, and reduced estrogen receptor stimulation suggests that tailored exercise regimens based on menopausal status are crucial [50].

WHO recommends at least 150 to 300 minutes of moderate or 75 to 150 minutes of vigorous weekly activity. In our analysis, exercise at recommended levels (600 to 1,200 MET-min/week) reduced cardiovascular event risks in premenopausal women with diabetes. Insufficient exercise (<600 METs/week) increased stroke and mortality risks in premenopausal women, without affecting MI risks, while increasing stroke and MI risks in postmenopausal women. High-intensity exercise (>1,200 MET-min/week) showed a trend toward reduced MI risk in postmenopausal women, though not statistically significant. These findings align with WHO recommendations and highlight the need for menopausal-stage-specific exercise prescriptions.

Given limited research on optimal exercise intensity for women with diabetes by menopausal status, our study suggests the following recommendations. For premenopausal women, exercise of at least 500 MET-min/week can be beneficial for lowering cardiovascular risk, with 1,000 to 1,499 MET-min/week maximizing stroke reduction and mortality benefits. For postmenopausal women, exercise of at least 1,000 MET-min/week is needed for cardiovascular benefits comparable to premenopausal women, with ≥1,500 MET-min/week providing maximum MI risk reduction.

Early menopause is characterized by estrogen decline, increasing cardiovascular risks. Regular aerobic exercise during early menopause can improve vascular health through enhanced nitric oxide production, vascular remodeling, and reduced inflammation, potentially lowering stroke and MI risks [52]. In our study, women with early menopause had significantly higher MI risk, but exercise showed no significant impact on cardiovascular outcomes. This could be due to the small sample size (27 stroke, 23 MI, and 25 mortality events) limiting reliability, necessitating larger-scale research. Also, ‘exercise timing hypothesis’ suggests exercise initiated soon after menopause may better preserve vascular function due to higher estrogen-related receptor bioavailability [53]. The nature of early menopause suggests that exercise initiation might be delayed compared to typical menopause populations, potentially influencing cardiovascular benefits.

Our subgroup analysis found no significant interaction between HRT and exercise benefits in postmenopausal women. Previous studies have consistently demonstrated that HRT is associated with reduced CVD risk in postmenopausal women [54-56]. RCTs have demonstrated cardiovascular health benefits when initiating combined estrogen-progestin therapy in women recently entering menopause who have an intact uterus [54,55]. However, our study was limited by the lack of comprehensive data on HRT parameters (dose, type, duration, and timing relative to menopause onset). The inclusion of current/past OC users with varied estrogen-progesterone dose combinations could potentially introduce bias in cardiovascular outcome interpretations [57-59]. Few studies have examined whether exercise and HRT combined consistently improve cardiovascular health, warranting further research [60,61].

Our study has several limitations. First, it used a non-randomized design. However, we attempted to account for potential bias by adjusting for as many confounding factors as possible. Second, exercise intensity was calculated based on participants’ self-reported questionnaires and memories. This reliance may introduce inaccuracies in recalling precise exercise intensities, potentially resulting in time bias. Third, our study addressed all-cause mortality rates. Analyzing the primary contributing factors is challenging, and our study lacks a detailed physiological explanation for the changes in mortality in relation to PA intensity. Notably, our study did not assess the impact of muscle strengthening activity on CVD risk. Considering that combining resistance and aerobic exercise can reduce diabetes risk and CVD mortality [62-64], future cohort studies should incorporate comprehensive assessments of both aerobic and resistance training to provide a more understanding of exercise’s cardiovascular protective effects. Furthermore, racial factors may have influenced the results, as the participants were restricted to Korean women. Finally, there was a discrepancy in the number of participants between the subgroups, making the analysis challenging.

However, this study has several strengths. This is the first nationwide cohort study to demonstrate the relationship between PA intensity, CCVD, and mortality in both premenopausal and postmenopausal women with diabetes. These results can help individualize recommendations for PA according to menopausal status. Second, this cohort study had a large sample size, which included only perimenopausal women with diabetes. Third, our study considered various factors that may influence the incidence of diabetic complications, including medical history, personal medications, and numerous other laboratory findings.

In conclusion, PA can reduce the likelihood of major diabetic complications, including stroke, MI, and mortality in women with T2DM. Postmenopausal women showed more benefits from exercise on MI but fewer on stroke and mortality than premenopausal women. However, in premenopausal women, despite the substantial benefits for stroke and mortality, exercise was not associated with a lower MI risk.

SUPPLEMENTARY MATERIALS

Supplementary materials related to this article can be found online at https://doi.org/10.4093/dmj.2024.0487

Supplementary Table 1.

Incidence rates and risk of stroke, MI, and mortality based on exercise levels above and below WHO recommendations

dmj-2024-0487-Supplementary-Table-1.pdf

Supplementary Table 2.

Incidence rates and the risk for stroke, MI, and mortality based on the presence of early menopause among postmenopausal women

dmj-2024-0487-Supplementary-Table-2.pdf

Supplementary Table 3.

The incidence rates and the risk for a stroke, MI, and mortality based on the presence of early menopause according to exercise intensity

dmj-2024-0487-Supplementary-Table-3.pdf

Supplementary Table 4.

Incidence rates and the risk for stroke, MI, and mortality based on body mass index and hormone replacement therapy in premenopausal women

dmj-2024-0487-Supplementary-Table-4.pdf

Supplementary Table 5.

Incidence rates and the risk for stroke, MI, and mortality based on body mass index and hormone replacement therapy in postmenopausal women

dmj-2024-0487-Supplementary-Table-5.pdf

Notes

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS

Conception or design: E.J.R.

Acquisition, analysis, or interpretation of data: K.D.H.

Drafting the work or revising: J.H.K., S.J.M., H.M.K., S.E.P., E.J.R., W.Y.L.

Final approval of the manuscript: E.J.R., W.Y.L.

FUNDING

None

ACKNOWLEDGMENTS

The authors thank the National Health Insurance Service and the Korean National Statistical Office for their cooperation.

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Characteristic	Total (n=86,167)	Premenopausal (n=32,477)	Postmenopausal (n=53,690)	P value
Age, yr	52.2±5.9	46.3±4.2	55.7±3.4	<0.001
Body mass index, kg/m²	25.3±3.6	25.3±3.8	25.2±3.5	<0.001
Waist circumference, cm	81.9±8.8	80.9±9.1	82.5±8.5	<0.001
Systolic blood pressure, mm Hg	125.8±15.8	124.2±15.6	126.8±15.8	<0.001
Diastolic blood pressure, mm Hg	77.5±10.1	77.3±10.3	77.7±10.0	<0.001
Fasting blood glucose, mg/dL	145.3±47.5	150.2±49.2	142.3±46.1	<0.001
Total cholesterol, mg/dL	205.0±43.3	202.2±41.3	206.7±44.4	<0.001
HDL cholesterol, mg/dL	55.5±30.2	55.9±30.2	55.3±30.2	0.007
LDL cholesterol, mg/dL	119.6±41.2	117.5±40.6	121.0±42.2	<0.001
TG, mg/dL	132.6 (132.1–133.1)	127.4 (126.6–128.2)	135.7 (135.1–136.4)	<0.001
eGFR, mL/min/m²	86.7±29.2	90.0±29.8	84.7±28.7	<0.001
AST, IU/L	24.2 (24.2–24.3)	22.8 (22.7–25.3)	25.1 (25.0–25.2)	<0.001
ALT, IU/L	24.5 (24.4–24.6)	22.8 (22.7–23.0)	25.2 (25.5–25.7)	<0.001
rGTP, IU/L	26.2 (26.1–26.3)	25.1 (24.9–25.3)	26.9 (26.8–27.0)	<0.001
Smoker				<0.001
Ex	1,177 (1.4)	515 (1.6)	656 (1.2)
Current	3,603 (4.2)	1,509 (4.7)	2,094 (3.9)
Drinker^a				<0.001
Non	70,691 (82.0)	24,580 (75.7)	46,111 (85.9)
Mild	14,437 (16.8)	7,359 (22.7)	7,078 (13.2)
Heavy	1,039 (1.2)	538 (1.7)	501 (0.9)
Hypertension on medication	33,657 (39.1)	8,649 (26.6)	26,008 (46.6)	<0.001
Hyperlipidemia	37,438 (43.5)	11,881 (36.6)	29,361 (54.7)	<0.001
ESRD on hemodialysis	226 (0.3)	58 (0.2)	168 (0.3)	<0.001
Household income ≤20%	21,431 (24.9)	8,521 (26.2)	12,910 (24.1)	<0.001
Hormone replacement therapy	9,006 (10.5)	0	9,006 (16.8)	<0.001
Oral contraceptives	13,834 (16.1)	4,678 (14.4)	9,156 (17.1)	<0.001
Oral antidiabetic drugs ≥3	13,527 (15.7)	4,301 (13.2)	9,226 (17.2)	<0.001
Use of insulin	5,960 (6.9)	2,560 (7.8)	4,066 (7.6)	<0.001
MET score	513.5±550.7	495.1±520.6	524.6±567.8	<0.001
MET score by grade				<0.001
0	24,077 (27.9)	8,604 (26.5)	15,473 (28.8)
1–499	24,913 (28.9)	10,240 (31.5)	14,673 (27.3)
500–999	22,359 (26.0)	8,455 (26.0)	13,904 (25.9)
1,000–1,499	9,373 (10.9)	3,444 (10.6)	5,929 (11.0)
≥1,500	5,445 (6.3)	1,734 (5.3)	3,711 (6.9)

Amount of exercise	No. of participants	No. of event	Duration, yr	IR, /1,000 person-yr	Unadjusted model		Adjusted model
Amount of exercise	No. of participants	No. of event	Duration, yr	IR, /1,000 person-yr	HR (95% CI)	P value	Adjusted HR (95% CI)	P value
Stroke
0	24,077	624	198,072	3.15	1 (Reference)	<0.001	1 (Reference)	<0.001
1–499	24,913	565	204,860	2.76	0.88 (0.78–0.98)		0.93 (0.83–1.05)
500–999	22,359	455	184,390	2.47	0.79 (0.70–0.89)		0.81 (0.71–0.91)
1,000–1,499	9,373	162	77,460	2.09	0.67 (0.56–0.79)		0.68 (0.57–0.81)
≥1,500	5,445	125	45,098	2.77	0.88 (0.73–1.07)		0.87 (0.72–1.06)
MI
0	24,007	525	198,598	2.64	1 (Reference)	<0.001	1 (Reference)	<0.001
1–499	24,913	428	205,622	2.08	0.79 (0.70–0.90)		0.83 (0.73–1.95)
500–999	22,359	342	184,889	1.85	0.70 (0.61–0.80)		0.72 (0.63–0.82)
1,000–1,499	9,373	133	77,618	1.71	0.65 (0.54–0.79)		0.66 (0.55–0.80)
≥1,500	5,445	82	45,269	1.81	0.68 (0.54–0.89)		0.67 (0.53–0.85)
Death
0	24,077	602	200,271	3.01	1 (Reference)	0.03	1 (Reference)	0.099
1–499	24,913	536	206,943	2.59	0.86 (0.77–0.97)		0.91 (0.81–1.02)
500–999	22,359	500	185,851	2.69	0.90 (0.780–1.01)		0.92 (0.82–1.04)
1,000–1,499	9,373	190	78,023	2.44	0.81 (0.69–0.96)		0.83 (0.71–0.98)
≥1,500	5,445	112	45,535	2.46	0.82 (0.67–1.00)		0.81 (0.66–1.00)

Amount of exercise	No. of participants	No. of event	Duration, yr	IR, /1,000 person-yr	Unadjusted model		Adjusted model
Amount of exercise	No. of participants	No. of event	Duration, yr	IR, /1,000 person-yr	HR (95% CI)	P value	HR (95% CI)	P value
Stroke
0	8,604	163	70,827	2.30	1 (Reference)	0.005	1 (Reference)	0.017
1–499	10,240	156	84,249	1.85	0.81 (0.65–0.93)		0.85 (0.68–1.06)
500–999	8,455	118	69,877	1.69	0.58 (0.41–0.83)		0.77 (0.61–0.98)
1,000–1,499	3,444	38	28,510	1.33	0.60 (0.41–0.83)		0.60 (0.42–0.86)
≥1,500	1,734	19	14,407	1.32	0.57 (0.36–0.92)		0.61 (0.38–0.98)
MI
0	8,604	114	71,034	1.60	1 (Reference)	0.100	1 (Reference)	0.192
1–499	10,240	100	84,515	1.18	0.74 (0.57–0.93)		0.77 (0.59–1.01)
500–999	8,455	84	70,039	1.20	0.75 (0.56–1.10)		0.77 (0.58–1.02)
1,000–1,499	3,444	37	28,544	1.30	0.81 (0.56–1.17)		0.82 (0.57–1.12)
≥1,500	1,734	25	14,386	1.74	1.09 (0.70–1.67)		1.09 (0.71–1.68)
Death
0	8,604	160	71,369	2.24	1 (Reference)	0.010	1 (Reference)	0.012
1–499	10,240	145	84,801	1.71	0.77 (0.61–0.96)		0.78 (0.62–0.97)
500–999	8,455	108	70,247	1.54	0.67 (0.54–0.87)		0.69 (0.54–0.88)
1,000–1,499	3,444	44	28,655	1.54	0.68 (0.49–0.96)		0.68 (0.49–0.95)
≥1,500	1,734	20	14,469	1.38	0.62 (0.39–0.98)		0.62 (0.39–0.98)

Amount of exercise	No. of participants	No. of event	Duration, yr	IR, /1,000 person-yr	Unadjusted model		Adjusted model
Amount of exercise	No. of participants	No. of event	Duration, yr	IR, /1,000 person-yr	HR (95% CI)	P value	HR (95% CI)	P value
Stroke
0	15,502	461	127,408	3.62	1 (Reference)	0.002	1 (Reference)	0.027
1–499	14,683	400	120,761	3.31	0.92 (0.80–1.05)		0.95 (0.83–1.09)
500–999	13,876	334	114,270	2.92	0.81 (0.70–0.93)		0.85 (0.74–0.98)
1,000–1,499	5,835	123	48,155	2.55	0.71 (0.58–0.86)		0.76 (0.62–0.93)
≥1,500	3,611	102	29,902	3.41	0.94 (0.76–1.17)		0.99 (0.80–1.22)
MI
0	15,502	389	127,851	3.04	1 (Reference)	<0.001	1 (Reference)	<0.001
1–499	14,683	324	121,201	2.67	0.88 (0.76–1.02)		0.89 (0.77–1.04)
500–999	13,876	263	114,669	2.29	0.76 (0.65–0.88)		0.78 (0.67–0.91)
1,000–1,499	5,835	94	48,286	1.95	0.64 (0.51–0.80)		0.67 (0.53–0.84)
≥1,500	3,611	47	30,127	1.56	0.51 (0.38–0.69)		0.52 (0.39–0.71)
Death
0	15,502	446	129,126	3.45	1 (Reference)	0.199	1 (Reference)	0.301
1–499	14,683	398	122,207	3.26	0.94 (0.83–1.08)		0.97 (0.85–1.11)
500–999	13,876	385	115,441	3.34	0.97 (0.84–1.11)		1.00 (0.87–1.14)
1,000–1,499	5,835	147	48,571	3.03	0.88 (0.73–1.06)		0.92 (0.76–1.11)
≥1,500	3,611	80	30,264	2.64	0.76 (0.60–0.97)		0.78 (0.62–0.99)