FormalPara Key Summary Points

Why carry out this study?

Patients with type 2 diabetes (T2D) and metabolic syndrome have a greater risk of cardiovascular disease than patients with T2D without metabolic syndrome.

A better understanding of the trends in the prevalence of metabolic syndrome in Japanese patients with T2D is needed, but recent data are limited.

This study utilized a nationwide administrative claims database to assess the prevalence of metabolic syndrome among 155,653 adult Japanese patients with T2D and evaluated whether the trends in prevalence differed by body mass index (BMI) or sex.

What was learned from the study?

Approximately 43.0% of patients with T2D in Japan had metabolic syndrome, with a higher prevalence in men and in patients with BMI ≥ 25 kg/m2.

The use of cardiovascular drugs and cardiorenal comorbidities in Japanese patients with T2D and metabolic syndrome increased with higher BMI (BMI ≥ 25 kg/m2), indicating the importance of managing metabolic parameters in addition to glycemic control in this patient population.

Introduction

Metabolic syndrome is the clustering of several metabolic abnormalities, including visceral obesity, hypertension, impaired glucose tolerance, and dyslipidemia, which raises the risk of type 2 diabetes (T2D) and cardiovascular disease [1,2,3]. Patients with both T2D and metabolic syndrome have an increased risk of developing cardiovascular disease compared to patients with T2D without metabolic syndrome [4, 5].

Obesity is a key aspect of metabolic syndrome, with obesity-related pathophysiology frequently postulated to underlie the association of metabolic syndrome and cardiovascular disease [3]. Some clinical features of T2D differ between patients from East Asian countries and those from Western countries [1, 6]. Notably, Japanese and other East Asian patients with T2D have a lower mean body mass index (BMI) but a higher percentage of visceral fat at any given BMI than non-Asian patients [6]. In both Japanese and non-Asian populations, higher BMI and percentage of visceral fat have been associated with higher risks for metabolic syndrome, T2D, and cardiovascular disease [3, 7,8,9,10,11,12,13]; however, Asian patients with T2D have a higher incidence of renal comorbidities and ischemic stroke but a lower incidence of coronary heart disease and peripheral vascular disease compared to non-Asian populations [14]. A better understanding of the trends in the prevalence of metabolic syndrome in Japanese patients with T2D and the impact of BMI on these trends is required to improve metabolic health in this population.

The prevalence of metabolic syndrome in the general population of Japan aged over 40 years has been reported to be 25.9–28.5%, with a prevalence in men (45.7%) thrice that in women (15.8%) [8, 15]. However, recent data on the prevalence of metabolic syndrome in Japanese patients with T2D are limited. This study used a large administrative claims database to evaluate the prevalence of metabolic syndrome in Japanese patients with T2D. The main objective was to assess trends in the prevalence of metabolic syndrome in patients with T2D by sex and BMI. Additionally, we summarized the characteristics, comorbidities, and cardiovascular medication usage of Japanese patients with T2D and metabolic syndrome.

Methods

Data Source

This study was conducted using a Japanese nationwide administrative claims database, maintained by the Japan Medical Data Center Co., Ltd. (JMDC) [10]. The JMDC database contains de-identified inpatient, outpatient, and dispensing claims records and medical examination data pooled from health insurance associations in Japan. The database contains data from mandated annual medical checkups conducted by employers, employee organizations, and local governments, as well as voluntary checkups, and includes records of tests relevant to metabolic parameters. As of April 2023, the JMDC database contained data from approximately 16 million patients, including healthy individuals [16]. A subgroup of the JMDC database containing data of patients with diabetes mellitus (International Classification of Diseases-10th revision [ICD-10] codes E10–E14) was used in this study.

This study was conducted in accordance with the Declaration of Helsinki of 1964 and its later amendments and all applicable laws and regulations in Japan. Since this retrospective observational study used anonymized patient data that were previously collected, informed consent from patients and independent ethical review board approval of the protocol were not required in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects by the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labour and Welfare, Japan. The JMDC database is a commercial database, and the datasets were used through a license with JMDC Inc. (Tokyo, Japan) in accordance with the JMDC Privacy Policy (https://www.jmdc.co.jp/en/personal-info/).

Study Design and Cohort Selection

This was a retrospective, cross-sectional, observational study that comprised 3 years of annual medical checkup data from patients with T2D in Japan. These data were analyzed in three separate cohorts corresponding to the calendar years 2018, 2019, and 2020. Our study design was informed by prior epidemiological studies that used the JMDC database [17, 18]. Patients aged 18 years or over who had at least one annual checkup record between January 2018 and December 2020 with a confirmed diagnosis of T2D (ICD codes E11–E14) and a prescription for a hypoglycemic agent (Anatomical Therapeutic Chemical [ATC] code A10) during the health checkup year (January 1–December 31) were included. If a patient had multiple health checkup records during the health checkup year, only the last visit was considered. Patients with missing waist circumference data were excluded.

Outcomes

Patient characteristics including demographics (age on the annual checkup date and sex), BMI, waist circumference, vital signs (blood pressure), and laboratory tests (fasting blood glucose, glycated hemoglobin [HbA1c], and lipid profile) on the date of checkup were described (Supplementary Materials Table S1). Comorbidities (congestive heart failure, ischemic and hemorrhagic stroke, myocardial infarction, atrial fibrillation, and chronic kidney disease) and use of cardiovascular drugs (antihypertensive drugs, lipid-lowering drugs, and aspirin) during the applied checkup year (January–December) were identified using ICD-10 codes and ATC codes, respectively [19]. For chronic kidney disease, health checkup data on estimated glomerular filtration rate (< 60 ml/min/1.73 m2) were used in combination with ICD-10 codes (Supplementary Materials Table S1) [20].

Statistical Analysis

Patient characteristics were expressed as mean ± standard deviation for continuous variables and as frequencies (percentages) for categorical variables. Missing data were not imputed and are summarized by frequency count.

To estimate the prevalence of metabolic syndrome in patients with T2D, the Japanese Committee for the Diagnostic Criteria of Metabolic Syndrome (2005) was used [21, 22]. Metabolic syndrome was defined as the presence of visceral obesity (waist circumference at the umbilical level of ≥ 85 cm in men and ≥ 90 cm in women is considered equivalent to visceral fat ≥ 100 cm2) plus two or more of the following: (1) elevated triglycerides (≥ 150 mg/dL) and/or low levels of high-density lipoprotein cholesterol (< 40 mg/dL); (2) elevated systolic blood pressure (≥ 130 mmHg) and/or elevated diastolic blood pressure (≥ 85 mmHg); and (3) elevated fasting blood glucose (≥ 110 mg/dL) (Fig. 1a). Patients with T2D were only considered to have metabolic syndrome if they met the full criteria (i.e., visceral obesity plus two or more additional components of the syndrome). Trends in the prevalence of metabolic syndrome were assessed by sex and BMI subgroups (< 25, 25 to < 30, and ≥ 30 kg/m2). Sensitivity analyses were conducted using a modified definition of metabolic syndrome which included the Japanese 2005 criteria for metabolic syndrome and/or a prescription of antihypertensive agent (ATC code C02–04, C07, and C08) or a lipid-lowering drug (ATC code C10) during the health checkup year (Fig. 1b).

Fig. 1
figure 1

Definitions of metabolic syndrome. Metabolic syndrome was assessed on the basis of a the Japanese Committee for the Diagnostic Criteria of Metabolic Syndrome (2005) [21, 22] for the main analysis; and b the standard definition in a and/or a prescription of antihypertensive agent or lipid-lowering drug for the sensitivity analysis. DBP diastolic blood pressure, HDL-C high-density lipoprotein cholesterol, Rx prescription, SBP systolic blood pressure, TG triglyceride

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Statistical analyses were conducted using SAS 9.4. (SAS Institute Inc., Cary, NC, USA).

Results

Patient Characteristics

Of the three separate cohorts examined in this study, the results presented focus on the 2020 study cohort as the most recent data. Of 168,995 patients with T2D who had a health checkup in 2020, 157,547 were prescribed a hypoglycemic drug during 2020. Following the exclusion criteria, a total of 155,653 patients were included in the 2020 study cohort (Fig. 2).

Fig. 2
figure 2

Patient selection for the 2020 study cohort. Diagnosis of T2D was based on ICD-10 codes E11 (type 2 diabetes mellitus), E12 (malnutrition-related diabetes mellitus), E13 (other specified diabetes mellitus), and E14 (unspecified diabetes mellitus). ATC Anatomical Therapeutic Chemical, ICD-10 International Classification of Diseases-10th revision, T2D type 2 diabetes

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Overall, the majority of patients were men (81.6%; Supplementary Materials Fig. S1) with a mean age of 54.6 ± 8.5 years (Table 1). Patient characteristics were largely similar across the study cohorts (Supplementary Materials Table S2), including the relative proportions of men and women (Supplementary Materials Fig. S1). The mean BMI of the cohort was 26.9 ± 4.9 kg/m2, with 38.1%, 39.4%, and 22.5% of patients in the BMI < 25 kg/m2, 25 to < 30 kg/m2, and ≥ 30 kg/m2 subgroups, respectively. Mean waist circumference of the cohort was 92.4 ± 11.9 cm (men 92.8 cm; women 90.5 cm). Patients with metabolic syndrome had a higher mean BMI and waist circumference (BMI 29.1 ± 4.5 kg/m2; waist circumference 98.3 ± 10.0 cm) compared with patients without metabolic syndrome (BMI 25.2 ± 4.5 kg/m2; waist circumference 87.9 ± 11.2 cm), as well as higher blood pressure, low-density lipoprotein cholesterol and triglyceride levels, fasting blood glucose levels, and HbA1c (Table 1).

Table 1 Characteristics of adult Japanese patients with T2D in the 2020 study cohort
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Patients with T2D had similar rates of comorbidities regardless of whether they also had metabolic syndrome; however, those with metabolic syndrome had higher rates of antihypertensive drug use (42.1% versus 31.5%, respectively) and lipid-lowering drug use (55.9% versus 52.9%, respectively) compared with patients without metabolic syndrome (Table 1).

Trends in Prevalence of Metabolic Syndrome

Overall, the prevalence of metabolic syndrome was 43.0% (95% confidence interval [CI] 42.7, 43.2) in Japanese patients with T2D, which remained largely unchanged between 2018 and 2020 (Supplementary Materials Fig. S2). The prevalence of metabolic syndrome was 17.3% in the BMI < 25 kg/m2 subgroup, increasing to 54.6%, and 66.1%, respectively, in the BMI 25 to < 30 kg/m2 and BMI ≥ 30 kg/m2 subgroups (Fig. 3). In each BMI subgroup, men had a higher prevalence of metabolic syndrome compared to women (overall prevalence 46.6% versus 27.0%), with prevalence increased in both men and women subgroups at higher BMI (men versus women: BMI < 25 kg/m2, 20.6% versus 3.4%; BMI 25 to < 30 kg/m2, 58.8% versus 32.6%; BMI ≥ 30 kg/m2, 68.6% versus 56.3%; Fig. 3).

Fig. 3
figure 3

Trends in the prevalence of metabolic syndrome by sex and BMI subgroups in the 2020 study cohort. BMI body mass index

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Sensitivity Analysis

The sensitivity analysis using a modified definition of metabolic syndrome (Fig. 1b) showed a prevalence of 57.2% (95% CI 57.0, 57.5) in Japanese patients with T2D, with trends similar to the main analysis when examined by sex (men versus women 61.5% versus 38.5%; Supplementary Materials Fig. S3).

Comorbidities and Use of Cardiovascular Medications in Patients with T2D and Metabolic Syndrome

In the higher BMI subgroups, patients with T2D and metabolic syndrome had higher rates of comorbidity compared to those in the lowest BMI (< 25 kg/m2) subgroup (Fig. 4). The most common comorbidities in all BMI subgroups were congestive heart failure (BMI < 25 kg/m2, 1.4%; BMI 25 to < 30 kg/m2, 4.8%; BMI ≥ 30 kg/m2, 6.8%) and chronic kidney disease (BMI < 25 kg/m2, 2.0%; BMI 25 to < 30 kg/m2, 6.2%; BMI ≥ 30 kg/m2, 6.5%). Similarly, the proportion of patients with T2D and metabolic syndrome who were prescribed cardiovascular medications was higher in patients with BMI ≥ 25 kg/m2 compared to those with BMI < 25 kg/m2 (Fig. 5), including antihypertensive drugs (BMI < 25 kg/m2, 6.4%; BMI 25 to < 30 kg/m2, 22.1%; BMI ≥ 30 kg/m2, 30.8%), lipid-lowering drugs (BMI < 25 kg/m2, 9.0%; BMI 25 to < 30 kg/m2, 31.1%; BMI ≥ 30 kg/m2, 37.0%), and aspirin (BMI < 25 kg/m2, 1.3%; BMI 25 to < 30 kg/m2, 3.8%; BMI ≥ 30 kg/m2, 3.5%).

Fig. 4
figure 4

Trends of comorbidities in patients with T2D and metabolic syndrome by BMI subgroups in the 2020 study cohort. Proportion of patients in each BMI subgroup with a congestive heart failure; b stroke (ischemic and hemorrhagic); c CKD; d myocardial infarction; and e atrial fibrillation. BMI body mass index, CKD chronic kidney disease, T2D type 2 diabetes

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Fig. 5
figure 5

Use of cardiovascular medications in patients with T2D and metabolic syndrome by BMI subgroups in the 2020 study cohort. Proportion of patients prescribed a lipid-lowering drugs; b antihypertensive drugs; and c aspirin. BMI body mass index, T2D type 2 diabetes

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Discussion

This study provides data on the prevalence of metabolic syndrome among patients with T2D using a large administrative claims database in Japan. Approximately 43.0% of Japanese patients with T2D met the full criteria for metabolic syndrome, with differences observed between sex and BMI subgroups. While the BMI ≥ 30 kg/m2 subgroup had the highest prevalence of metabolic syndrome at 66.1%, the BMI 25 to < 30 kg/m2 subgroup also had a high prevalence, with a rate more than triple that of the BMI < 25 kg/m2 subgroup (54.6% versus 17.3%). Although recent data on the prevalence of metabolic syndrome in Japanese patients with T2D are lacking, the current findings are in general agreement with estimates from other countries in the Asia–Pacific region, where higher rates of metabolic syndrome among patients with T2D have been observed [23, 24].

In the current study, the prevalence of metabolic syndrome in men (46.6%) was nearly double that of women (27.0%). This difference between the sexes was observed in each BMI subgroup but was less pronounced in the highest BMI subgroup, in which prevalence rose to 68.6% in men and 56.3% in women. These data are in accordance with a previous assessment of metabolic disease trends using data collected in the Japanese National Health and Nutrition Survey, which showed steady increases in BMI and HbA1c levels and the prevalence of T2D and obesity/overweight between 1995 and 2019. These increases were much more prominent in men than women [25]. The findings of the sensitivity analysis showed similar trends to the main analysis. The higher estimates of prevalence in the sensitivity analyses (57.2% overall; 61.5% men; 38.5% women) are in keeping with the use of broader criteria for the definition of metabolic syndrome (i.e., the incorporation of the prescription of antihypertensive and lipid-lowering drugs) compared to the main analysis. The higher prevalence in the sensitivity analysis also suggests that the main analysis may have underestimated the prevalence of metabolic syndrome as a result of the resolution of individual components of the definition, such as hypertension or abnormal lipid profiles, by medical treatment.

The higher prevalence of metabolic syndrome in patients with a BMI > 25 kg/m2 was not unexpected, as the Japanese clinical guidelines define obesity as BMI ≥ 25 kg/m2 [26], and obesity is associated with higher risks of T2D and cardiovascular diseases in Japanese patients [3, 27]. In addition, visceral fat accumulation in Japanese patients has been shown to increase the risk of metabolic abnormalities (elevated blood pressure, dyslipidemia, and elevated blood glucose levels) and metabolic syndrome, even in the normal-weight BMI range (18.5–22.9 kg/m2) [12].

In patients with T2D and metabolic syndrome, the rates of cardiovascular and renal comorbidities and cardiovascular drug usage increased in the higher BMI (BMI ≥ 25 kg/m2) subgroups compared to the BMI < 25 kg/m2 subgroup. These findings are in keeping with prior literature indicating that cardiovascular and renal diseases are common in patients with metabolic syndrome and T2D [1]. These data highlight the need to better manage metabolic syndrome in addition to glycemic control in Japanese patients with T2D, for example, via lifestyle interventions such as diet and physical activity to reduce BMI and/or visceral adiposity and to counter hypertension and dyslipidemia. Reduction of waist circumference via improvement in lifestyle factors has been suggested as a key treatment target to improve metabolic health and reduce adverse outcomes [28, 29]; however, additional study is required to establish optimal waist circumference cutoffs for risk management by age, sex, and ethnicity [29].

The JMDC database provided a large, real-world sample population for this study, an important consideration for the analysis of disease prevalence; however, this study had limitations. Since the data were sourced mainly from healthcare insurance associations for company employees and their dependents, patients aged over 75 years are under-represented. Additionally, fewer women than men were included in the study cohort, which is aligned with the reported lower T2D prevalence in women compared to men in Japan [25]; however, the smaller sample size for women should be taken into consideration when interpreting the data. Finally, some metabolic parameters had missing data, and the potential impact of this on the current estimates of prevalence should also be considered.

Conclusions

Approximately two in five Japanese patients with T2D had metabolic syndrome, accounting for 43.0% of the study cohort, with a higher prevalence in patients with a BMI ≥ 25 kg/m2. In patients with T2D and metabolic syndrome, cardiovascular and renal comorbidities and cardiovascular medication usage were increased in the higher BMI subgroups, underscoring the importance of managing metabolic parameters in addition to glycemic control in Japanese patients with T2D, particularly in those with a BMI ≥ 25 kg/m2. These results also suggest that body weight management in Japanese patients with T2D is important to achieve improved clinical outcomes.