Metabolic Syndrome: Disease Primers

nature reviews disease primers https://doi.org/10.
1038/s41572-024-00563-5
Primer Check for updates
Metabolic syndrome
Ian J. Neeland1,2, Soo Lim 3,4
, André Tchernof5, Amalia Gastaldelli 6
, Janani Rangaswami7, Chiadi E. Ndumele8,
Tiffany M. Powell-Wiley 9,10
& Jean-Pierre Després 5,11
Abstract Sections
The metabolic syndrome (MetS) is a multiplex modifiable risk factor Introduction
for cardiovascular disease, type 2 diabetes mellitus and other health Epidemiology
outcomes, and is a major challenge to clinical practice and public Mechanisms/pathophysiology
health. The rising global prevalence of MetS, driven by urbanization,
Diagnosis, screening and
sedentary lifestyles and dietary changes, underlines the urgency prevention
of addressing this syndrome. We explore the complex underlying
Management
mechanisms, including genetic predisposition, insulin resistance,
Quality of life
accumulation of dysfunctional adipose tissue and ectopic lipids
in abdominal obesity, systemic inflammation and dyslipidaemia, Outlook
and how they contribute to the clinical manifestations of MetS.

Diagnostic approaches vary but commonly focus on abdominal obesity
(assessed using waist circumference), hyperglycaemia, dyslipidaemia
and hypertension, highlighting the need for population-specific and
phenotype-specific diagnostic strategies. Management of MetS
prioritizes lifestyle modifications, such as healthy dietary patterns,
physical activity and management of excess visceral and ectopic
adiposity, as foundational interventions. We also discuss emerging
therapies, including new pharmacological treatments and surgical
options, providing a forward-looking perspective on MetS research
and care. This Primer aims to inform clinicians, researchers and
policymakers about MetS complexities, advocating for a cohesive,
patient-centred management and prevention strategy. Emphasizing
the multifactorial nature of MetS, this Primer calls for integrated public
health efforts, personalized care and innovative research to address
this escalating health issue.
A full list of affiliations appears at the end of the paper. e-mail: [email protected]; jean-pierre.despres@
criucpq.ulaval.ca
Nature Reviews Disease Primers | (2024) 10:77 1

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Introduction This expanded concept addresses the pathophysiological interrelation-

The metabolic syndrome (MetS) is an established conceptual frame- ship among CVD, chronic kidney disease (CKD) and metabolic disor-
work that links several distinct, albeit interrelated, risk factors for ders. CKM syndrome highlights the convergence of cardiovascular,
cardiovascular diseases (CVDs) to a defined, measurable syndrome kidney and metabolic risk factors contributing to adverse outcomes
associated with increased risk of CVD1–3. The connection between excess in both cardiovascular and renal health.
adiposity, diabetes mellitus and hypertension was first introduced by The aim of this Primer is to familiarize the reader with a broad
the Framingham Heart Study in the 1960s. Yet the late Gerald Reaven overview and update on MetS, covering epidemiology, pathophysiol-
first proposed in 1988, the revolutionary concept that premature CVD ogy, the link to clinical outcomes, diagnosis and screening, prevention
is frequently caused by a cluster of prevalent abnormalities that include and managing patients with MetS. Progress made in linking MetS to
a high triglyceride–low HDL cholesterol state of dyslipidaemia, hyper- clinical outcomes other than CVD is also highlighted. Furthermore,
tension and insulin resistance (IR)4, initially referred to as ‘syndrome gaps in current knowledge and future research perspectives relevant
X’. A major advance underlying this concept was the recognition that to clinical practice and population health strategies are discussed.
this cluster of abnormalities is associated with increased CVD risk even
in the absence of hyperglycaemia or type 2 diabetes mellitus (T2DM). Epidemiology
The public health and clinical implications were obvious: individu- MetS definition
als at increased risk of premature CVD could be detected early and The WHO proposed an initial working definition for IR syndrome in 1998
prescribed preventive interventions, even before the development (ref. 5). Since then, various criteria have been proposed for the clinical
of hyperglycaemia and T2DM. diagnosis of MetS. Among these, the NCEP-ATP III definition has been
As the term syndrome X was used in cardiology to describe another the most widely utilized7. In 2005, the IDF introduced a new, globally
condition, ‘IR syndrome’ became increasingly used as an alternative applicable definition of MetS13, emphasizing abdominal obesity as a cru-
name in the literature. Several high-profile organizations then pro- cial component, which must be assessed using race/ethnicity-specific
posed tools to identify individuals with features of the IR syndrome, and sex-specific cut-off values for WC. Additionally, the American Asso-
such as the WHO in 1998 (ref. 5) and the European Group for the Study ciation of Clinical Endocrinologists14 and the AHA/National Heart, Lung,
of Insulin Resistance in 1999 (ref. 6). However, some of the measure- and Blood Institute (AHA/NHLBI)15 have each proposed their own defi-
ments proposed (for example, serum concentration of insulin) were nitions. In 2009, a collaborative statement from the IDF, AHA/NHLBI,
not always available to many health-care practitioners. the World Heart Federation, the International Atherosclerosis Society
Thus, in 2001, the National Cholesterol Education Program–Third and the International Association for the Study of Obesity introduced
Adult Treatment Panel (NCEP-ATP III) committee proposed simple ‘harmonized’ criteria for MetS10 (Table 1).
clinical markers and cut-off values that could be used in primary care
to identify individuals who are likely to be characterized by the fea- The global prevalence of MetS in adults
tures of the IR syndrome7. Abdominal obesity, particularly visceral Prevalence in the Americas and Europe. In North America, particu-
obesity (excess adipose tissue accumulation inside the abdominal larly in the USA, the National Health and Nutrition Examination Sur-
cavity), was well documented as a frequent comorbid condition of vey (NHANES) from 2011 to 2018 revealed a troubling increase in the
the IR syndrome, if not its most prevalent form by far8. Hence, the prevalence of MetS16. The total prevalence of MetS in the USA using
committee proposed the use of waist circumference (WC) as a crude the NCEP-ATP III definition rose from 37.6% in 2011–2012 to 41.8%
index of abdominal obesity, along with four other simple markers: in 2017–2018. This rise is partly attributable to a population-level
fasting serum levels of triglycerides and HDL cholesterol, blood pres- increase in elevated blood glucose levels, indicative of a growing
sure and fasting glycaemia. As no measurement of insulin or IR was epidemic of T2DM. The trend is more pronounced among participants
used in the NCEP-ATP III diagnosis approach, the term ‘the metabolic with low educational attainment, highlighting the effect of socioeco-
syndrome’ was proposed to describe this constellation of interrelated nomic status on MetS prevalence. The NHANES data underscore the
abnormalities7. On the basis of the relationship with clinical outcomes, need for lifestyle modifications and targeted interventions to manage
the presence of at least three out of the five criteria was suggested to MetS effectively, particularly in socioeconomically disadvantaged
enable the diagnosis of MetS, as all combinations seemed to predict groups.
an increased risk of CVD9. Subsequently, in 2009, specific WC cut-off In Canada, the prevalence of MetS among adults using the harmo-
values for abdominal obesity for various populations were proposed nized definition of 2009 is estimated at 41.9%17. This study found that
by the International Diabetes Federation (IDF) that were dependent the risk of developing MetS was significantly lower among women than
on sex, country or race/ethnicity10. among men. Socioeconomic factors, particularly material deprivation,
Since these landmark publications, more than 150,000 items have also been linked to increased MetS risk. Women were found to be
have been published using ‘the metabolic syndrome’, as found on Web the most socially deprived, indicating the need for sex-specific and
of science. Despite the importance of this constellation of metabolic gender-specific public health strategies in Canada. In Mexico, a study
abnormalities for clinical practice and population health, the concept involving 6,567 adults (mean ± s.d. of age: 37.9 ± 11.4 years for men and
has been the topic of many debates and controversies regarding its 38.2 ± 10.8 years for women), showed that 28.9% of men and 44.4% of
pathophysiology and clinical diagnosis, as well as its questionable use women are affected by MetS (defined using the IDF harmonized defini-
as a risk calculator or binary treatment outcome, not taking severity tion), a notably higher prevalence in women than in men18. Particularly,
into account11. abdominal obesity and low HDL cholesterol components were more
In 2023, the American Heart Association (AHA) expanded the prevalent in women than in men in this study. Contributing factors
concept of MetS into cardiovascular–kidney–metabolic (CKM) syn- included genetic predisposition, consumption of a high carbohydrate
drome, to improve the diagnosis and management of patients through diet, sedentary lifestyle and inadequate public health policies aimed
various stages of metabolic, cardiovascular and kidney dysfunction12. at reducing the effects of MetS. This high prevalence of MetS in these

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Table 1 | Diagnostic criteria proposed for the clinical diagnosis of MetS by professional organizations
Organization MetS Insulin resistance or Adiposity Dyslipidaemia Elevated blood Other

(year) definition hyperglycaemia pressure
WHO (1998)5 Insulin Impaired glucose Waist-to-hip TGs ≥150 mg/dl ≥140/90 mmHg Microalbuminuria (≥20 μg
resistance regulation or diabetes ratio >0.90 in (1.69 mmol/l) and/or per min or albumin-to-
plus any mellitus, or lowered men, waist-to- HDL-C <35 mg/dl creatinine ratio ≥20 mg/g)
other two insulin sensitivity hip ratio >0.85 in (0.91 mmol/l) in men or
criteria women and/or BMI <39 mg/dl (1.01 mmol/l)
>30 kg/m2 in women
EGIR (1999)6 Insulin Plasma insulin >75th WC ≥94 cm in men or TGs ≥150 mg/dl ≥140/90 mmHg or None
resistance percentile, impaired ≥80 cm in women (1.69 mmol/l) and/or on hypertension
plus any glucose tolerance, or HDL-C <39 mg/dl therapy
other two impaired fasting glucose (1.01 mmol/l) in men or
criteria women
ATP III (2001)7 Any three of Fasting plasma glucose WC ≥102 cm in men TGs ≥150 mg/dl ≥130/85 mmHg None
five criteria >110 mg/dl (6.11 mmol/l), or ≥88 cm in women (1.69 mmol/l), HDL-C
which was modified <40 mg/dl (1.03 mmol/l)
in 2004 to >100 mg/dl in men or <50 mg/dl
(5.55 mmol/l), or diabetes (1.29 mmol/l) in women
mellitus
AACE (2003)138 Insulin Impaired glucose BMI ≥25 kg/m2 TGs ≥150 mg/dl ≥130/85 mmHg Other features of insulin
resistance tolerance or impaired (1.69 mmol/l) and resistance including
plus any fasting glucose (but not HDL-C <40 mg/dl family history of diabetes
other two diabetes mellitus) (1.03 mmol/l) in men or mellitus, PCOS or
criteria <50 mg/dl (1.29 mmol/l) sedentary lifestyle
in women
IDF (2005)13 Body weight Fasting plasma glucose Increased WC TGs ≥150 mg/dl ≥130/85 mmHg or None
plus any >100 mg/dl (5.55 mmol/l), (population-specific) (1.69 mmol/l) or on hypertension
other two diabetes mellitus on therapy, HDL-C therapy
criteria <40 mg/dl (1.03 mmol/l)
in men or <50 mg/dl
(1.29 mmol/l) in women
or on lipid-lowering
therapy
AHA/NHLBI Any three of Fasting plasma glucose WC ≥102 cm in men TGs ≥150 mg/dl ≥130/85 mmHg or None
(2005)15 five criteria >100 mg/dl (5.55 mmol/l) or ≥88 cm in women (1.69 mmol/l) or on hypertension
or on antihyperglycaemic on therapy, HDL-C therapy
therapy <40 mg/dl (1.03 mmol/l)
in men or <50 mg/dl
(1.29 mmol/l) in women
or on lipid-lowering
therapy
Joint Scientific Any three of Fasting plasma glucose Population-specific TGs ≥150 mg/dl ≥130/85 mmHg or Recommended that
Statement from five criteria >100 mg/dl (5.55 mmol/l) and country-specific (1.69 mmol/l) or on on hypertension the IDF cut points be
IDF, NHLBI, AHA, or on antihyperglycaemic definitions (see lipid-lowering therapy, therapy used for people who
WHF, IAS and therapy ‘Other’ cell) HDL-C <40 mg/dl are not of European
IASO (2009)10 (1.03 mmol/l) in men or origin and either the
<50 mg/dl (1.29 mmol/l) IDF or AHA/NHLBI cut
in women or on therapy points used for people
of European origin until
more data are available
AACE, American Association of Clinical Endocrinologists; AHA, American Heart Association; ATP III, National Cholesterol Education Program’s Adult Treatment Panel III; EGIR, European Group
for the Study of Insulin Resistance; HDL-C, HDL cholesterol; IAS, International Atherosclerosis Society; IASO, International Association for the Study of Obesity; IDF, International Diabetes
Federation; MetS, the metabolic syndrome; NHLBI, National Heart, Lung, and Blood Institute; PCOS, polycystic ovary syndrome; TGs, triglycerides; WC, waist circumference; WHF, World Heart
Federation; WHO, World Health Organization. Adapted with permission from ref. 11, Elsevier.
regions is alarming and calls for urgent public health strategies to MetS, with a higher proportion being women (53.4%) and a mean age
address the multifactorial components contributing to MetS. of 56.4 years20. Notably, MetS was associated with a 13.6% increased
The MORGAM Project analysed data from 26 European cohorts risk of anxiety over a mean follow-up period of 12.1 years, with certain
and included 69,094 men and women aged 19–78 years, with baseline inflammatory parameters such as C-reactive protein and leukocyte
measurements taken between 1982 and 1997. In this study, the preva- count mediating this relationship20.
lence of MetS was higher using the NCEP-ATP III criteria than using the
IDF criteria: 19.9% versus 9.7% in men and 32.1% versus 29.5% in women19. Prevalence in Asia
Another important European study, the UK Biobank, involved over MetS is a growing problem in Asia. In Japan, a large cohort study focused
308,000 participants and identified 75,486 individuals (24.5%) with on the association between MetS and CVD, emphasizing the importance

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of WC and sex-specific criteria in MetS diagnosis21. The prevalence of in physical activity induced by the excessive use of electronic devices
MetS varied: 11.9% among men and 8.4% among women using the IDF seem to be key factors for the evolving features of MetS in South Korea.
definition and 17.9% among men and 9.2% among women using a modi- In China, MetS is becoming an increasingly important health
fied NCEP-ATP III definition. This study highlights the importance of issue23. Of the 77,639 participants enrolled in the China Multi-Ethnic
specific diagnostic criteria for MetS, as well as the need for sex-specific Cohort (mean age 50.2 ± 11.1 years, 39.0% men), the prevalence of MetS
and race/ethnicity-specific approaches in managing this condition. was 19.4% and varied across demographic subgroups: 31.0% in men,
South Korea has experienced a considerable increase in MetS 17.0% in women; 24.2% in those aged ≥60 years and 18.1% in those aged
prevalence, with age-adjusted prevalence rising from 27.1% in 2001 <60 years. The study of Chinese populations reveals a complex inter-
to 33.2% in 2020 (ref. 22). This increase was driven by increased MetS play of lifestyles, dietary habits and genetic factors, in the prevalence
in men, with a marked difference in MetS prevalence between men and manifestation of MetS.
(25.8% increasing to 40.0%) and women (28.2% decreasing to 26.2%). In a 2003 study involving 475 Indian individuals aged 20–75 years
Key contributors to this trend were high serum levels of glucose and from a population database, the prevalence of MetS was 41.1% using
large WC, which have been increasing steadily over the past 20 years. the NCEP-ATP III criteria with modified WC cut-off values (men ≥90 cm,
The population proportion with a high serum glucose level and large women ≥85 cm)24. In a meta-analysis published in 2020 that included
WC has increased substantially by 17.9% and 12.2% over 20 years, respec- 111 studies, with a total of 133,926 Indian adults, the prevalence of MetS
tively. By contrast, circulating HDL cholesterol levels increased notably, was 30% (95% CI 28–33%) using either the NCEP-ATP III or IDF defini-
resulting in a 20.4% decrease in the proportion of individuals with low tions (WC criteria: men ≥102 cm, women ≥88 cm)25. Region/country and
HDL cholesterol. Notable dietary shifts (for example, decreases in car- ethnicity-specific cut-off points of BMI and WC for defining overweight,
bohydrate intake and increases in fat consumption) and large decreases obesity and abdominal obesity are presented in Table 2.
Prevalence in Africa
Table 2 | Region/country and ethnicity-specific cut-off MetS is also an emerging problem in Africa. In a study from 29 African
values for BMI and WC thresholds for abdominal obesity countries and involving 156,464 participants, the overall prevalence of
MetS in Africa was 32.4% (95% CI 30.2–34.7%) with significant hetero
Country or region BMI (kg/m2) WC (cm) geneity (I2 = 98.9%; P < 0.001)26. In particular, MetS poses consider-
Obesity Overweight Men Women able social and clinical challenges for individuals living with HIV in
Africa27. In a pooled analysis including 24 studies, the prevalence of
Most countries in North 30.0 25.0 102 88
America and Europe221
MetS was found to be 21.01% (95% CI 16.5–25.5%) by the NCEP-ATP III
criteria. Low HDL cholesterol was the highest prevalent component
Asia3
(47.3%), followed by abdominal obesity (38.4%)27. Thus, MetS in this
China222 28.0 24.0 90 85 region presents unique challenges due to the diverse socioeconomic
Malaysia223 27.5 23.0 90 80 and health landscapes across the African continent. Tailored public
health strategies and interventions will be required, which consider
Singapore223 27.5 23.0 90 80
the specific regional and cultural contexts.
Taiwan224 27.0 24.0 90 80
India225 25.0 23.0 90 80 The global prevalence of MetS among children
Japan226 25.0 – 85 90 and adolescents
Notably, no established consensus exists on the definition of MetS in
Republic of Korea227 25.0 23.0 90 85
children and adolescents28. The most widely used definitions are the
Philippines223 25.0 23.0 90 80 IDF definition and the NCEP-ATP III criteria modified for age29,30, both
Sri Lanka223 25.0 23.0 90 80 of which incorporate age-specific and sex-specific WC percentiles for
abdominal obesity and percentiles for height-specific systolic and
Hong Kong, SAR 228
25.0 23.0 90 80
diastolic blood pressure. Several proposed definitions are presented in
Bangladesh223 25.0 23.0 90 80
Supplementary Table 1. The development of a standardized definition
Thailand 223
25.0 23.0 90 80 for MetS in this age group is imperative to ensure accurate diagnosis
Vietnam223 25.0 23.0 90 80 and effective management.
The prevalence of MetS among children and adolescents reveals
Other countries/regions or ethnicities
substantial differences and trends specific to each country. In the USA,
Māori and Pacific 32.0 26.0 102 88 a study utilizing data from NHANES between 2001 and 2020 found the
Islanders229
estimated prevalence of MetS in adolescents to be 2.66%31. The preva-
Tunisia – – 85 85 lence was slightly higher in adolescents from food-insecure households
Iran – – 89 91 (3.39%) compared with those from food-secure households (2.48%).
Hispanic adolescents had the highest prevalence at 3.73%. Over the past
Sub-Saharan Africa – – 94 80
two decades, the prevalence of MetS has remained below 5%, showing
Eastern Mediterranean – – 94 80 no significant time trend31. The study suggested that food-insecure
and Middle East
household status might contribute to the risk of MetS.
Waist circumference (WC) cut-off values that correlate with health risks owing to excess
In South Korea, the prevalence of MetS among adolescents
abdominal adiposity can vary by ethnicity. For example, South Asian individuals tend to
accumulate abdominal adiposity, which is linked to increased health risks such as type 2 increased notably during the COVID-19 pandemic, according to data
diabetes mellitus, at lower WC values compared with other ethnic groups230–232. from the Korean National Health and Nutrition Examination Surveys

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conducted in 2019–2020. The overall prevalence of MetS in adolescents Genetics. Susceptibility to visceral storage of adipose tissue is deter-
rose from 3.79% to 7.79% during this period32. Considerable changes mined in part by genetics, first demonstrated in overfeeding studies of
were observed in components of MetS, such as diastolic blood pressure, monozygotic twins over three decades ago57. Several studies using Men-
serum triglyceride levels and HDL cholesterol levels. The study also delian randomization have since demonstrated associations between
highlighted an increase in severe obesity, which was defined by ≥99th genetic variants that are associated with MetS and its components, and
percentile of BMI for sex and age, and abdominal obesity, particularly adverse health outcomes, such as coronary artery disease58, stroke59,
among boys aged 10–18 years. cancer60 and even psychiatric disorders61. Genetic susceptibility to
In India, a systematic review and meta-analysis of 16 studies involv- MetS has been previously reviewed62 and might be related to sev-
ing 19,044 adolescents showed a pooled prevalence of MetS of 3.4% eral genetic polymorphisms including: LDLR, GBE1, Il1R1, TGFB1, Il6,
using IDF criteria and 5.0% using the NCEP-ATP III criteria33. The study COL5A2, SELE and LIPC (P values range from 0.047 to 0.008)63. Variants
noted a higher prevalence of MetS in urban areas, and found that MetS in seven additional genes show significant gene interaction by sex.
occurrence was linked to factors such as urbanization, sedentary life-
styles and dietary changes. According to the China National Nutrition Sex differences. Sex-based differences in VAT and MetS could also
and Health Surveillance data 2016–2017 (n = 58,712), the prevalence relate to higher circulating levels of oestrogens and lower levels of
of MetS by the revised definition of NCEP-ATP III34 was 5.45% among testosterone in women than in men64,65. An increase in body adipos-
students aged 7–17 years35. Intriguingly, a high level of screen time ity combined with a changed distribution of adipose tissue depots
was significantly associated with MetS in this age group. Thus, the to a more central, abdominal distribution can be observed in post-
prevalence of MetS in children and adolescents is also at a concerning menopausal women, and these effects could be mediated by ovarian
level and might increase rapidly in the future. hormone changes66. Accretion of visceral adiposity in women after
menopause has been postulated as a cause for the increased cardio-
Summary vascular risk seen during this stage of life in women. Furthermore,
These reports detailing the characteristics of MetS across diverse global the notable correlation between the PNPLA3 p.I148M variant and
regions underscore its complex nature, shaped by a confluence of metabolic dysfunction-associated steatotic liver disease (MASLD;
genetic, lifestyle and socioeconomic influences. Robust public health previously called non-alcoholic fatty liver disease) and metabolic
strategies need to be implemented to address the observed increase dysfunction-associated steatohepatitis (MASH) has been shown to be
in MetS prevalence globally. These strategies should focus on promot- stronger in postmenopausal women than in men67, with a stronger cor-
ing healthy lifestyles and enhancing health-care accessibility. Nota- relation with visceral adiposity relative to that in men64. This increased
bly, the prevalence of MetS among adolescents is marked by distinct susceptibility to hepatic accumulation of lipids among postmeno-
variations across different countries, each characterized by unique pausal women was attributed to the deteriorated insulin sensitivity
trends and contributory factors. Collectively, these findings highlight and changes in adiposity that occur with blunted oestrogen secre-
the critical importance of early detection and lifestyle interventions tion, which generate blunted upregulation of hepatic PNPLA3 via the
in the prevention of MetS and its associated complications. oestrogen receptor64,67.
Mechanisms/pathophysiology Ectopic lipid deposition. MetS disease risk tracks closely with VAT and
Visceral adipose tissue and ectopic fat ectopic (for example, cardiac) lipid and adipose tissue accumulation48
Adipose tissue is an endocrine tissue that stores excess lipids and as well as with hepatic steatosis and with MASLD. The risk of disease
expands via two mechanisms: either the existing adipocytes increase does not necessarily reflect the size of the body adipose tissue depots,
in size (hypertrophy) or the number of adipocytes increases (adipo- but the functional ability of adipose tissues to efficiently manage daily
genesis, otherwise known as hyperplasia). One of the predictors and lipid fluxes68.
cardinal indicators of disease in individuals with overweight or obesity Among the ectopic adipose tissue depots, epicardial adipose
is the presence of excess visceral adipose tissue (VAT), defined as an tissue (lipid deposition in the epicardium) has been well studied69.
accumulation of hypertrophic adipose tissue within the abdomen, on Epicardial adipose tissue is associated with clinical and subclinical
abdominal structures such as the greater omentum and mesentery36,37. atherosclerosis70,71, and fatty infiltration in the myocardium resulting
This feature is frequently accompanied by excess ectopic accumulation in abnormal diastolic function72 and elevated risk of arrhythmia73,
of triglycerides in the liver38,39, muscle40,41, pancreas42, renal sinus and/or via the secretion of pro-inflammatory cytokines with paracrine and
perinephric space43, or as intrapericardial44,45 and extrapericardial (that vasocrine effects. Increasing evidence also indicates an association
is, mediastinal) adipose tissue46, or intramyocardial triglycerides47,48. between perinephric adipose tissue, which is located adjacent to
The preferential accumulation of VAT is now recognized as a marker of the kidney in the retroperitoneal area, and increased risk of MetS,
adipose tissue dysfunction in other body sites used for lipid storage, hypertension and adverse cardiovascular and/or kidney outcomes74,75.
including peripheral and more centrally located subcutaneous adipose In addition, adipose tissue dysfunction also leads to spillover of
tissue (SAT) compartments (reviewed in refs. 36,49). non-esterified fatty acids from adipose tissue into the circulation
Adipose tissue dysfunction is now emerging as one of the main during the postprandial phase, reflecting paradoxically impaired
drivers and aetiological factors for MetS. This dysfunction includes triglyceride synthesis76. This condition probably also results from
many features, such as adipocyte hypertrophy, impaired adipogenesis, impaired insulin signalling in adipose tissue, which leads to blunted
resistance to the inhibitory effect of insulin on lipolysis and low free inhibition of lipolysis76,77. Impaired adipose tissue triglyceride synthe-
fatty acid (FFA) uptake, reduced triglyceride synthesis, excess collagen sis and fatty acid spillover contribute to longer transient postprandial
deposition, impaired extracellular matrix remodelling, immune cell rises in serum triglyceride levels, a phenomenon closely linked to
infiltration and inflammatory cytokine secretion, as well as altered IR78 and ectopic lipid accumulation in various tissues and organs
vascular architecture and remodelling36,50–56. (reviewed in ref. 79).

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Adipogenesis or hypertrophy? For a very similar total body adipos- transcription factors such as PPARγ and C/EBPα, which are involved
ity, VAT accumulation can be highly variable, even in the presence of in maintaining the expression of the set of genes involved in mature
normal BMI values (Fig. 1). In the presence of overnutrition and a posi- adipocyte function. Treatment with PPARγ agonists (such as the
tive energy imbalance, adipose tissue expansion takes place through insulin sensitizer thiazolidinedione, which has been used to manage
triglyceride synthesis in existing adipocytes, which leads to cell hyper- blood glucose levels in patients with diabetes mellitus) improves
trophy, as well as the recruitment and adipogenic differentiation of glucose and lipid metabolism through the expansion of SAT (and
precursor cells into new mature, lipid-storing cells (adipogenesis)80. decrease in VAT mass and hepatic steatosis)85. Additional signalling
The ability to generate new adipocytes through adipogenesis is highly pathways are involved in adipogenesis, including WNT and factors
variable. We now know from animal models of impaired adipogenesis or such as VSTM2A and BMP4, which might have a role in early adipogenic
studies in individuals with lipodystrophy (a disorder of complete or par- differentiation86. Reports also show that progenitor cells not undergo-
tial loss, and/or abnormal distribution of adipose tissue) that impaired ing adipogenic differentiation might be senescent87, with lower rates
adipogenesis is a key factor for the development of cardiometabolic of adipogenic d ifferentiation in VAT than in SAT88, which relates to
complications (reviewed in ref. 81) and that this phenomenon quite adipocyte hypertrophy, dyslipidaemia and IR88,89.
logically coincides with hypertrophy of existing adipocytes82.
Excess accumulation of VAT clearly relates to hypertrophy of vis- MASLD
ceral adipocytes (Fig. 1). Such hypertrophy could reflect limited VAT The new criteria for the diagnosis of MASLD are based on the presence
storage capacity as well as low adipogenic capacity in other adipose of steatosis and one or more MetS components, in the absence of other
tissue compartments, including SAT. Limited storage capacity of cer- causes for secondary hepatic lipid accumulation90. Although the new
tain adipose tissue depots could mediate hormonal effects leading to definition does not specifically mention MetS, it recognizes the impor-
sex-specific adipose tissue accumulation patterns, but also adipose tance of individual features of MetS in the development and progression
tissue dysfunction in the case of chronic overnutrition83. Accord- of steatotic liver disease. The prevalence of MASLD is higher in individu-
ingly, in a study where adipogenic capacity was measured in vitro with als with MetS than in those without MetS91 and increases with the number
cell fractions isolated from SAT and VAT biopsy samples obtained from of MetS-defining criteria92. Those with MASLD often show alterations
women, the adipogenic potential of cells from the visceral compartment in their plasma lipid profile, with increased triglycerides due to high
was not related to risk variables of the donors, such as fasting triglyceride secretion of VLDL93, especially in the presence of IR and increased VAT
levels and VLDL triglyceride content. Yet lower adipogenic potential of accumulation94. Moreover, individuals with MASLD have increased
subcutaneous pre-adipocytes was related to increased triglyceride levels VAT accumulation, even when BMI is within the normal range, high adi-
and higher lipid content in VLDLs, and most importantly, to adipocyte pose tissue IR and increased lipolysis39, which trigger a spillover of FFAs
hypertrophy in the VAT compartment of these tissue donors84. to the liver, where they are used for the synthesis of triglycerides and are
Specific mechanisms leading to blunted adipogenesis in adi- associated with elevated gluconeogenesis and hepatic glucose output95,
pocyte precursor cells involve altered cell signalling through thereby increasing the risk of hyperglycaemia and T2DM (Fig. 2).
Patient A Patient B Fig. 1 | Adipose tissue characteristics can differ

• Woman • Woman
between individuals with similar BMI and total
• Body weight: 62.1 kg • Body weight: 64.4 kg
• Height: 159 cm • Height: 161 cm body fat mass. Anthropometric characteristics,
• BMI: 24.6 kg/m2 • BMI: 24.8 kg/m2 CT scans and microscopic adipose tissue images
• Waist circumference: 80 cm • Waist circumference: 94 cm
in two women with similar BMI and total body fat
• Body fat mass: 20.5 kg • Body fat mass: 20.3 kg
mass values, but widely differing visceral adipose
tissue (VAT) accumulation measured by CT. Total
body fat mass was measured by whole-body dual
energy absorptiometry. CT measurement of VAT
was performed at the L4–L5 vertebrae level and
the abdominal cavity was delineated using Image
J software. Adipose tissue samples from patients
A and B were obtained during gynaecological
surgery. A portion of each adipose sample was fixed
in formalin and stained with haematoxylin and
eosin. Slides were visualized under a bright-field
microscope. Representative images are shown
VAT area: 37 cm2 VAT area: 133 cm2
(scale bars 100 µm). The average cell diameter
was measured from 250 mature adipocytes in
suspensions obtained from collagenase digestion of
the remaining portion of each sample. Patient B has
evidence of hypertrophic VAT.
100 µm 100 µm 100 µm 100 µm
Subcutaneous adipocyte Visceral adipocyte Subcutaneous adipocyte Visceral adipocyte

diameter: 87 µm diameter: 69 µm diameter: 87 µm diameter: 92 µm

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↑ Pro-inflammatory Abdominal obesity

↑ Lipolysis
adipokine secretion • Adipose tissue insulin resistance
↑ MCP1 ↓ Anti-inflammatory
↑ IL-6 adipokine secretion
Chronic ↑ TNF
inflammation ↑ TGFβ
↑ Leptin
↑ PAI1 ↓ Adiponectin ↑ FFA
↓ IL-1
↑ Fibrinogen
Liver Muscle Pancreas
↑ Uric acid
↑ CRP
↑ Fetuin A
↓ FGF21 ↑ Hepatokines
• Hepatic and peripheral

insulin resistance
MASLD T2DM
• β-cell dysfunction
Lipotoxicity
↑ Ceramides Glucotoxicity
↑ ITG ↑ AGE
↑ DAG ↑ ROS
↑ LDL Hyperlipidaemia Hyperglycaemia ↑ Oxidative stress
↑ DNL ↑ Gluconeogenesis
↑ ROS ↑ Uric acid
↑ Oxidative stress ↓ Mitochondrial
↓ Mitochondrial function function
↓ HDL
Heart, kidney and blood vessels

CVD • Atherosclerosis CVD
• Endothelial dysfunction
• ↑ Cardiorenal risk
Fig. 2 | Molecular pathways involved in MetS. The visceral adipose tissue insulin resistance results in lipotoxicity and glucotoxicity that increases the
(VAT) that accumulates in abdominal obesity (with associated adipocyte risk of multiorgan dysfunction (type 2 diabetes mellitus (T2DM) and metabolic
hypertrophy and ectopic lipid deposition) is a highly active endocrine organ dysfunction-associated steatotic liver disease (MASLD)), and eventually
that contributes to a cascade of pathophysiological alterations that affect cardiovascular dysfunction and increased risk of cardiovascular disease
several organ systems, thereby leading to multiorgan dysfunction and ultimately (CVD), such as atherosclerosis, heart failure, atrial fibrillation and kidney
cardiovascular–kidney–metabolic syndrome. VAT is highly lipolytic with disease. AGE, advanced glycation end product; CRP, C-reactive protein; DAG,
increased free fatty acid (FFA) deposits in organs such as the liver, skeletal diacylglycerols; DNL, de novo lipogenesis; FGF21, fibroblast growth factor 21;
muscle and pancreas. Imbalance between increased pro-inflammatory ITG, intramyocardial triglyceride; MCP1, monocyte chemoattractant protein 1;
cytokines and reduced anti-inflammatory cytokines leads to a state of chronic MetS, the metabolic syndrome; PAI1, plasminogen activator inhibitor 1; ROS,
inflammation with pro-inflammatory, prothrombotic and pro-insulin resistance reactive oxygen species; TGFβ, transforming growth factor-β; TNF, tumour
consequences. Metabolic dysfunction characterized by hepatic and peripheral necrosis factor.
The liver secretes several hepatokines, such as C-reactive protein and men91. Similar results were confirmed in the Dallas Heart Study
and fetuin A, and in the presence of steatosis and MASLD their synthe- (a multiethnic, population-based study), in which high VAT mass and
sis and secretion are increased, whereas fibroblast growth factor 21 high degree of hepatic steatosis, and high VAT mass and a low degree
(FGF21) is decreased. Fetuin A was the first hepatokine proposed to of hepatic steatosis, were associated with increased risk of T2DM (OR
regulate metabolic homeostasis through inter-organ crosstalk, and is 7.8 and 3.3, respectively)100. Interestingly, in this same study, excess
an independent risk factor for the development of T2DM96. Moreover, hepatic lipid content combined with excess VAT mass was associated
serum levels of fetuin A are positively correlated with the degree of with increased CVD risk, whereas excess hepatic lipid content alone
hepatic lipid content, IR and glucose intolerance97, and increased fetuin was not. In fact, excess VAT mass was associated with increased CVD
A is a risk factor for CVD. Circulating FGF21 is secreted mainly by the risk with or without hepatic steatosis, and individuals with high VAT
liver and exerts metabolic and anti-inflammatory effects on multiple mass but low liver lipid content had the highest incidence of CVD
organs, including adipose tissue, pancreas, heart, kidney and brain, in a events. All these factors could also explain the heterogeneity in the
paracrine or endocrine manner by signalling via several FGF receptors risk of incident CVD in those with MASLD, as shown in various studies
and its co-receptor β-klotho98. including a meta-analysis101 and a Mendelian randomization study102.
The combination of high VAT accumulation and high liver lipid
content is associated with an increase in IR in liver, muscle and adi- Insulin resistance and inflammation
pose tissue99. Individuals with high VAT volume and a high degree of IR is central in the development of MetS and has been recognized
hepatic steatosis also have the highest prevalence of MetS, as shown from the beginning as the major determinant of cardiometabolic risk.
in the Jackson Heart Study, a large cohort of African American women Individuals with IR have impaired insulin action that affects glucose

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metabolism in the muscle and liver, as well as FFA release from adipose fibrosis)122,123. Adipose tissue pericellular fibrosis is closely related to
tissue through reduced lipolysis inhibition. These effects are linked to the number of macrophages infiltrated in adipose tissue, particularly
high release or postprandial spillover of FFAs that are then taken up by in VAT, and is also associated with features of MetS51.
peripheral tissues where, when in excess, they alter insulin signalling
and action103,104. Vascular inflammation. The mechanisms underlying the presence of
FFAs induce IR and decrease muscle ATP synthesis105 and stimulate hypertension in MetS are complex and probably involve the presence
nitric oxide production as well as endothelial nitric oxide synthase106. of ectopic adipose tissue depots, such as perivascular adipose tissue124
Furthermore, IR impairs insulin-stimulated activation of PI3K, pyruvate and perirenal adipose tissue125. Perivascular adipose tissue is located
dehydrogenase kinase, isozyme 1 and RACα serine–threonine protein around coronary arteries and strong evidence indicates a bidirectional
kinase106. Reduced insulin sensitivity in muscle, adipose tissue and paracrine and vasocrine interaction between this depot and events in
liver leads to high hepatic glucose production through activation of the vascular wall involving vascular inflammation126. Perirenal adipose
gluconeogenesis107. Both excessive glucose and FFA release are associ- tissue also has a crucial role by increasing physical renal compression,
ated with increased oxidative stress, uncoupled oxidative phospho- renal sympathetic nerve activity, and angiotensin II and aldosterone
rylation, production of reactive oxygen species (ROS), formation of secretion, as well as inducing a deficiency of natriuretic hormones
advanced glycated end-products, accumulation of toxic lipids such and causing glucolipotoxicity through inflammation and substrate
as diacylglycerols (DAG), ceramides and long-chain fatty acyl-CoA, excess (reviewed in ref. 127). Perivascular adipose tissue might also
which have been shown to promote inflammation and impair cellular modulate plaque vulnerability through its effects on the vascular wall,
metabolism108. Moreover, certain lipids, such as ceramides and DAGs, but many of its biological features could in turn be affected by events in
are linked to IR in muscle and liver109–114 and when found in excess in the the vascular wall126,128. Vulnerable plaques can progress to thrombosis
circulation, they are a marker of increased risk of CVD115. in the milieu created by MetS, the most frequent causes being plaque
Inflammation is closely linked to IR and adipose tissue dysfunc- rupture and erosion (reviewed in ref. 128).
tion through several mechanisms and is an important contributor to
the pathophysiology of MetS. Activation of the NLRP3 inflammasome Summary and the CKM syndrome concept
in adipose tissue stimulates the secretion of pro-inflammatory adipo Collectively, adipose tissue dysfunction has a critical role in the aetiol-
kines, such as monocyte chemoattractant protein 1 (MCP1), tumour ogy of MetS, which manifests through reduced adipogenesis, adipocyte
necrosis factor (TNF), transforming growth factor-β (TGFβ), plasmino- hypertrophy, reduced triglyceride synthesis, poor inhibition of lipolysis
gen activator inhibitor 1 (PAI1) and IL-6 (ref. 116). By contrast, the release by insulin, immune cell infiltration, inflammatory cytokine secretion
of anti-inflammatory adipokines, such as adiponectin, is reduced by and altered adipose tissue extracellular matrix. Such a dysfunctional
activation of the inflammasome. Accumulation of lipotoxic lipids (such state reflects but also drives the accumulation of ectopic adipose tissue,
as ceramides) in liver, muscle, pancreatic islets or cardiomyocytes a major determinant of systemic and hepatic IR and the related meta-
is also associated with metabolic alterations. Studies in mice have bolic alterations which affect both lipid and glucose metabolism (Fig. 2).
shown that overexpression of adipose tissue or hepatic adiponectin Obesity and IR in MetS have harmful effects on the vascular system,
receptors decreases intrahepatic ceramides, but also induces IR in liver thereby predisposing people to endothelial dysfunction, arterial stiff-
and muscle117, probably through the increase in ceramidase activity118. ness and vascular resistance, leading to hypertension129, which results in
However, as a marker of abdominal obesity, a large WC is commonly the development of atherosclerosis and plaque formation130,131. Athero
associated with elevated serum levels of inflammatory markers. There- genic dyslipidaemia, inflammatory cytokines, ROS and immune cells
fore, measuring WC in clinical practice might be sufficient to capture are also involved in formation of atheromatous plaques132–135.
a key driver of inflammation in MetS. This concept was highlighted in 2023 in the AHA’s Presidential
Infiltration of adipose tissues by immune cells and the result- Advisory136 and Scientific Statement12 on CKM syndrome, emphasizing
ing pro-inflammatory cytokine secretory profile are also well-known the importance of a holistic approach to managing the interrelated risk
aspects of adipose tissue dysfunction and IR, but a detailed descrip- factors of MetS, diabetes mellitus, CKD and CVD due to excess and/or
tion is beyond the scope of this Primer. In a 2020 study that utilized dysfunctional adiposity. The interplay among MetS, diabetes mellitus
single-cell RNA sequencing of VAT and SAT biopsy samples obtained and excess and/or dysfunctional adiposity is central to the newly devel-
from individuals with severe obesity, 17 different adipose-resident oped construct of CKM syndrome, which is characterized by the central
immune cell types were identified119. These adipose infiltrating cells milieu of inflammation, endothelial dysfunction, oxidative stress and
relate to, and might actually contribute to IR, although most stud- IR136. Further potentiated by the development of MASLD as described
ies addressing causality were performed in animal models. Yet this above, these key mechanisms exacerbate pathophysiological processes
chronic, low-grade inflammatory state has been shown to alter many involved in direct vascular, myocardial and kidney injury12. Additional
aspects of adipose tissue function, including adipogenesis, matrix multi-organ crosstalk (such as cardiorenal interactions), with concomi-
remodelling and adipose tissue metabolism, which is supported by tant perturbations across haemodynamic and neurohormonal axes
this single-cell analysis119. (such as the sympathetic nervous system and the renin–angiotensin–
aldosterone system (RAAS)) are also a hallmark of CKM syndrome137.
Adipose tissue remodelling. Altered extracellular matrix remodelling Ultimately, the multidirectional interactions in CKM syndrome that
in adipose tissue is an important feature of adipose tissue dysfunc- largely occur downstream from excess and/or dysfunctional adiposity
tion that also has a potential effect on adipose tissue expandability result in excess morbidity and mortality, which is predominantly driven
(reviewed in refs. 120,121). Excess collagen deposition causes adipose by CVD, the burden of which exceeds the simple sum of its components.
tissue fibrosis, which can be examined through the presence of large This risk is further amplified by adverse social determinants of health,
areas of collagen fibre located in certain areas of the tissue, or around which are influenced by the interconnectedness of genetic, biological,
individual adipocytes in strands of varying thickness (pericellular environmental and social risk.

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Diagnosis, screening and prevention Clinical manifestations

Definition and diagnostic criteria All five clinical criteria used to diagnose MetS (WC, blood pressure,
A clear definition of MetS is crucially important to enable prompt serum levels of HDL cholesterol and triglycerides, and fasting levels of
identification of affected patients (including with population-based blood glucose) (Table 1) can be easily and reproducibly measured in clin-
tools such as electronic medical record screening), assessment of both ical practice. A comprehensive but simple framework has been devel-
biological and social determinants of MetS and classification into a oped that can be used to identify the clinical manifestations of MetS and
MetS staging rubric with guideline-directed, actionable recommen- its consequences on target organs in order to apply evidence-based,
dations for comprehensive care. The past three decades have seen targeted therapeutic interventions (Fig. 3). This framework starts by
great debate over what term most precisely defines MetS, to articulate recognizing individuals who are at risk of MetS, but without any of
its adverse cardiovascular and metabolic effects (Table 1). Terms for the five criteria required to meet a MetS diagnosis (stage A). Thera-
MetS have continued to evolve, each focused around varying aspects peutic interventions can be implemented to address specific health
of its pathophysiology, and have included syndrome X4, the dysmeta- behaviours or markers of susceptibility to prevent progression (pri-
bolic syndrome138, IR syndrome138 and cardiometabolic syndrome. mary prevention). The model then moves towards increasingly severe
Another position, such as that adopted by the International Chair on stages of MetS (stages B–D) on the basis of established risk factors and
Cardiometabolic Risk, has been to emphasize that excess VAT and/or diagnostic criteria, and residual risk markers. Each of these stages pro-
ectopic adipose tissue underpins most forms of MetS139. In 2009, several poses more intensive therapeutic strategies to treat MetS and its risk
major organizations released a statement harmonizing the criteria for factors. Of note, the risk of adverse outcomes generally increases with
MetS, which is currently used today10 and the International Classifica- each subsequent stage; however, the absolute risk of developing MetS
tion of Diseases (ICD) 10 coding terminology has adopted the current consequences varies substantially within populations. Thus, treatment
terminology of metabolic syndrome (E88.81). decisions must be incorporated within the context of absolute risk.
These definitions are organized around the concepts that: first, A concept essential to this framework is that people with MetS
MetS is a chronic and progressive pathophysiological state; sec- have or are at risk of end-organ damage to multiple organs. This
ond, MetS represents a clustering of risk factors that form a complex damage includes, but is not limited to, cardiovascular (athero-
syndrome defined by a unifying pathophysiology; and third, MetS is sclerosis and non-atherosclerosis types), metabolic (for example,
associated with increased risk of CVD, T2DM and other related dis- T2DM, dyslipidaemia and MASLD), hormonal (for example, polycys-
orders. Importantly, MetS is not just a repackaging of its individual tic ovarian syndrome), sleep disordered breathing, certain malig-
risk components, but is rather a clinical entity associated with an nancies (for example, gastrointestinal malignancy), psychological
increased risk of CVD or death, even after controlling for its compo- distress (for example, depression), CKD and orthopaedic and/or
nent risk factors, as seen in at least one analysis (relative risk 1.54, 95% joint diseases90. The substantial variability seen in end-organ conse-
CI 1.32–1.79)140. Furthermore, MetS incorporates so-called residual risk quences emphasizes a need to identify subtypes of MetS on the basis
markers that are associated with CVD and metabolic disease risk, but of their underlying pathophysiology and predisposition to adverse
are not universally agreed upon as criteria for MetS diagnosis; these consequences. Different subtypes can then be targeted for specific
include elevated serum levels of apolipoprotein B and small, dense preventive and therapeutic management strategies11.
LDL particles; a prothrombotic and pro-inflammatory state signified Emerging methods that use a personalized medicine approach to
by high levels of circulating inflammatory markers (such as C-reactive identify clinical manifestations of MetS in their early stages include: the
protein and fibrinogen); and microalbuminuria15. Recognizing this con- use of novel imaging techniques to quantify the amount and quality of
struct is important, as it provides an opportunity to identify and treat VAT and ectopic adipose tissue139,141; and the use of genetic risk scores
residual risk markers beyond the standard management of established for screening and prognostication of MetS. However, in one study142,
risk factors for CVD. a polygenic risk score developed from a genome-wide association study
Fig. 3 | Stages in the evolution of MetS and

Stage A Stage B Stage C Stage D
recommended therapy by stage. This staging
system highlights the progressive nature of the
At risk for MetS, At risk for MetS, MetS without MetS with
no criteria met ≥1 criterion end-organ damage end-organ damage metabolic syndrome (MetS), with suggested criteria
and recommended therapy for each stage. All
Patients with Patients with Patients with Patients with: therapeutic decisions should be made within the
• Overweight (1 or 2 criteria): (3-5 criteria): • CVD context of absolute risk for end-organ damage. BP,
• Ectopic fat • WC • WC • Diabetes
• Susceptibility • BP • BP • CKD blood pressure; CKD, chronic kidney disease; CVD,
conferred by race • Glucose • Glucose • OSA cardiovascular disease; HDL-C, HDL cholesterol;
and/or ethnicity • TGs • TGs • PCOS MASLD, metabolic dysfunction-associated steatotic
• Low level of • HDL-C • HDL-C • MASLD
physical activity • Alternative risk • Alternative risk • Other liver disease; OSA, obstructive sleep apnoea; PCOS,
• Parental MetS factors factors polycystic ovarian syndrome; TGs, triglycerides;
WC, waist circumference. Reprinted with permission
from ref. 11, Elsevier.
Therapy Therapy Therapy Therapy
• Physical activity • All measures under • All measures under • All measures under
• Nutrition stage A stage B stage C
• Obesity prevention • Medical therapy • Adiposity reduction • Disease-specific
and risk factor surgery therapies
modification

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in MetS predicted only 5.9% of the variance in MetS. Furthermore, 53 physical activity is associated with a substantially decreased risk of
(22.5%) of the MetS-associated loci overlapped with loci that were asso- CVD148. The proposed mechanisms include beneficial effects on blood
ciated with two or more MetS components. These findings indicate that pressure and serum levels of lipids, which are key components of MetS.
MetS is a very complex, heterogeneous disorder and a single dominant Appropriate nutritional choices can also modify the risk of car-
genetic factor for predicting MetS might not exist. diometabolic disease. The Strong Heart Study, an epidemiological
study of CVD in American Indian individuals identified specific die-
Screening tary patterns associated with improved health outcomes149. Several
Screening for MetS components is suggested across the life course to dietary patterns, such as the dietary approaches to stop hypertension
enhance approaches to prevention and management in both youth (known as DASH) and Mediterranean diets, which focus on whole
and adults, with the frequency and intensity of the suggested screen- grains, low-fat dairy products, legumes, nuts and olive oil, can reduce
ing linked to the MetS stage (Fig. 3). In adults, at a minimum, screening blood pressure, improve the blood lipid profile, reduce inflammation
should include measurement of BMI and WC at least annually, with and reduce the risk of CVD150. Emphasis should be placed on dietary
screening for MetS components (elevated blood pressure, elevated patterns, rather than specific macronutrients, given inconclusive evi-
serum levels of triglycerides, low levels of HDL cholesterol and hyper- dence to date for an independent effect of macronutrient composition
glycaemia) annually in those with existing risk factors to ensure targets on outcomes151. Emerging from these data is the belief that focused
are met, every 2–3 years in those living with overweight or obesity but research and improved education on lifestyle interventions should be
without other risk factors, and every 3–5 years in individuals without prioritized for MetS prevention and treatment.
any risk factors136. This approach to screening facilitates the identifi-
cation of individuals at different levels of syndromic severity, thereby Management
providing windows for preventive action to halt or reverse disease pro- Given the growing prevalence of MetS and its high likelihood of being
gression. A novel screening approach in development is to use artificial present in most adults with obesity, the optimal management of MetS
intelligence (AI) to find patterns in large datasets to identify individuals is an important clinical and public health priority. A key paradigm in
as at risk of or with MetS. Several studies have demonstrated feasibility the management of MetS is the importance of addressing both the
in using AI to screen for MetS in both adults143 and adolescents144 using diagnostic components of MetS and its additional pathophysiologi-
a variety of AI techniques. cal features. Several systemic abnormalities that contribute to risk of
end-organ damage in MetS, such as inflammation, endothelial dysfunc-
Race/ethnicity tion, a prothrombotic state and an excess of circulating small, dense
As discussed, the primary driver of MetS is accumulation of lipids and LDL particles as well as abdominal obesity and hepatic steatosis, are not
adipose tissue in the abdominal cavity in the form of VAT and other routinely measured in clinical practice, nor are they directly targeted
organs which are not physiological storage compartments for lipids by existing pharmacological therapies152. Therefore, fully addressing
(ectopic fat). Several factors, both modifiable and non-modifiable, are risk related to MetS involves lifestyle modification to address its root
associated with excess VAT and MetS. causes, including sedentary lifestyle and a lack of physical activity,
Race/ethnicity-based differences in VAT are well known and have excess calorie intake and an energy-dense diet of overall poor quality,
important clinical implications for classification and risk assess- and excess or dysfunctional adipose tissue, in addition to targeted
ment of obesity and MetS. For example, Asian American individuals, pharmacotherapy to ensure optimal control of major modifiable risk
in particular South Asian people, have been observed to manifest factors (Fig. 4).
T2DM at lower BMI levels compared with white individuals145. This
finding could be explained in part by race/ethnicity-associated differ- The importance of addressing excess or
ences in visceral adiposity even when adjusted for differences in body dysfunctional adiposity
composition. These observations have led the IDF to recommend The concept of MetS has been quite useful to better discriminate the
race/ethnicity-specific cut-off values for WC in the diagnosis of MetS heterogeneity of health risk among individuals with obesity. For exam-
(Table 2). However, WC data for many populations are either unavail- ple, patients with obesity without MetS have been consistently reported
able or not appropriately assessed, which has led to a knowledge gap to be at lower risk of various cardiovascular and other health outcomes
as to what specific WC cut-off values should be used to meet criteria than patients with obesity with MetS. The Lancet Commission on the
for MetS in these populations. In a North American cohort, Black indi- Definition and Diagnosis of Clinical Obesity153 and The European Asso-
viduals were less likely to have visceral obesity and more likely to have ciation for the Study of Obesity154 have produced statements related
increased lipolytic activity and show more efficient clearance of dietary to the diagnosis, staging and management of obesity in adults, which
triglycerides compared with white individuals146. Nevertheless, the both recognize the remarkable heterogeneity of obesity. In that con-
relationships between visceral adiposity and adverse cardiometabolic text, a clinical diagnosis of MetS is certainly relevant to discriminate
traits persist in Black individuals. risk early in asymptomatic individuals with obesity.
Prevention through lifestyle patterns Weight reduction. Addressing obesity, particularly visceral adiposity,
Lifestyle, referring to physical activity and nutrition, is a modifiable is one of the most important therapeutic options for MetS. Weight loss
factor that interacts with genetic susceptibility, and a healthy lifestyle from lifestyle modification, pharmacotherapy and bariatric surgery
is crucial to prevent and treat MetS and its consequences. Many obser- (also known as metabolic surgery) have each been shown to improve
vational studies of study populations across the world have shown an the diagnostic components of MetS, as well as related pathophysi-
association between increased levels of physical activity and decreased ological features, in a weight-loss dependent manner155–157. In particular,
rates of chronic diseases and increased longevity147. Even in the presence both observational studies and clinical trials have shown metabolic
of MetS, findings from a Europe-wide study indicated that increased surgery to result in sustained weight loss (20–30%), T2DM remission

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Stages 1-3:
Patient with CKM syndrome at risk for CVD
Promotion of cardiovascular health with an emphasis on Life’s Essential 8 framework: eat better, be more active,
quit tobacco, get healthy sleep, manage weight, control cholesterol, manage blood sugar, manage blood pressure
Systematic screening for SDOH using validated tools; incorporation of community health workers and
care navigators into the care team; leveraging existing community resources and community programmes
Interdisciplinary care — Use of CKM coordinator and interdisciplinary team;

targeted referrals of high-risk patients with CKM to subspecialists
Stage 1: Stage 2: Stage 3:

Excess or dysfunctional Established CKM risk factors Subclinical CVD in CKM syndrome
adiposity
Presence of metabolic syndrome triggers intensive lifestyle Subclinical Subclinical
Discuss weight loss using intervention targeting multifactorial risk control atherosclerosis heart failure
STOP obesity alliance toolkit Pharmacotherapy for comprehensive control of residually uncontrolled MetS CAC >0 • EF <40% →
components • Favours statin use ACEi/ARB,
Can consider weight loss in intermediate risk β-blocker
support via integrated team Hypertriglyceridaemia Hypertension Moderate-risk to high-risk CAC >100 • In diabetes
to facilitate lifestyle change/ • Lifestyle modification • Lifestyle modification CKDª • Favours aspirin use → SGLT2ib
navigate weight loss options • Maximize statin therapy • Follow established • With albuminuria if low bleeding risk
(obesity medicine, metabolic in intermediate or hypertension (UACR >30 mg/g) → • Favours considering
surgery, dietician, pharmacy, higher ASCVD risk guidelines to achieve ACEi/ARB other agents for
mental health, CHW/care • TGs ≥500 mg/dl → BP <130/80 mmHg • CKD (with or without ASCVD risk reduction
manager): fibrates • In those with diabetes diabetes) → SGLT2ib (e.g. PCSK9i, GLP1RA,
• Intensive lifestyle • TGs: 135–499 mg/dl + and albuminuria → • DKD with residual icosapent ethyl) based
intervention diabetes + additional prioritize ACEi/ARB albuminuria (>30 mg/g) on CKM profile
• Pharmacotherapies risk factors → consider • In those with CKD → on ACEi/ARB →
(BMI ≥30 kg/m2 eicosapentaenoic acid prioritize ACEi/ARB finerenonec (can be used
(EPA) on background SGLT2i) CVD risk equivalents for stage 3 CKM
without comorbidities)
• Very high-risk CKDa
• Bariatric surgery
• High predicted CVD risk per
(BMI ≥40 kg/m2 Diabetes
risk calculator
without comorbidities) • Lifestyle modification
• Moderate-to-high intensity statin
If persistent/progressive IGT • Ezetimibe for high risk
despite intensive lifestyle Comorbidity-based approach to antihyperglycaemic pharmacotherapy:
modification → consider • BMI ≥35 kg/m2 → GLP1RA
metformin • HbA1c ≥9% or high insulin dose → GLP1RA
• CKD → SGLT2ib
Considerations for metformin co-utilization
HbA1c ≥7.5% or on insulin HbA1c <7.5%

→ Co-utilization of metformind and → Cardioprotective antihyperglycaemics
cardioprotective antihyperglycaemics without metformin initiation (continue
metformind if already using)
Fig. 4 | Algorithm for the management of patients with CKM syndrome replacement therapies. ACEi, angiotensin-converting enzyme inhibitor; ARB,
stages 1–3. The American Heart Association illustrates the progressive risk of angiotensin II receptor blocker; ASCVD, atherosclerotic cardiovascular disease;
adverse cardiovascular events with advancing cardiovascular–kidney–metabolic BP, blood pressure; CAC, coronary artery calcium; CHW, community health
(CKM) syndrome136. In stage 0, individuals have normal weight, blood glucose worker; DKD, diabetic kidney disease; EF, ejection fraction; GLP1RA, glucagon-
levels, blood pressure, lipid profiles and kidney function, and no cardiovascular like peptide 1 receptor agonist; HbA1c, haemoglobin A1c; IGT, impaired glucose
disease (CVD); therefore the focus is on prevention. Stage 1 includes individuals tolerance; MetS, metabolic syndrome; PCSK9i, proprotein convertase subtilisin/
with excess or dysfunctional adiposity, such as abdominal obesity or impaired kexin type 9 inhibitor; SDOH, social determinants of health; SGLT2i, sodium–
glucose tolerance. Stage 2 includes individuals with metabolic risk factors (for glucose transport protein 2 inhibitors; STOP, Strategies to Overcome and
example, hypertension, type 2 diabetes mellitus), moderate-to-high risk chronic Prevent; TGs, triglycerides; UACR, urine albumin–creatinine ratio. aPer Kidney
kidney disease (CKD), or both. Stage 3 includes individuals with subclinical CVD Disease Improving Global Outcomes heat map. bSGLT2i can be safely initiated in
alongside CKM syndrome risk factors (such as excess and/or dysfunctional patients with estimated glomerular filtration rate (eGFR) ≥20 ml/min per 1.73 m2.
c
adiposity, metabolic risk factors or CKD), or those with very high-risk CKD or Finerenone can be initiated on background SGLT2i in those with eGFR >25 ml/
high predicted cardiovascular risk using the AHA PREVENT risk calculator216. min per 1.73 m2 and potassium <5 mEq/l. dMetformin can also be used in patients
Stage 4 includes individuals with clinical CVD (for example, coronary heart with eGFR ≥30 ml/min per 1.73 m2. Reprinted with permission from ref. 136,
disease or heart failure), further stratified by kidney failure and the need for American Heart Association.
rates ranging from 23% to 60%, improvements in cardiovascular risk 15–20% weight loss and improvements in multiple CVD risk factors,
factors, such as hypertension and dyslipidaemia, and reductions in as well as reductions in major cardiovascular events and cardiovas-
incident and recurrent cardiovascular events and mortality. Addition- cular mortality158. Metabolic surgery can also be cost-effective and
ally, clinical trials of novel anti-obesity medications (AOMs) have shown is fairly safe, with perioperative risks and mortality similar to those

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of low-risk procedures such as cholecystectomy, hysterectomy and also have a favourable effect on the likelihood of engaging in healthy
appendectomy159,160. lifestyle behaviours, and should be advised for patients with MetS.
Health-care professionals should adopt a non-judgemental Given the increased risk of atherothrombosis in MetS, smoking cessa-
approach when initiating weight loss discussions, as this strategy tion in this patient population is particularly key to emphasize, as a key
is associated with the greatest likelihood of successful weight loss aspect of healthy lifestyle practices. In addition to lifestyle modifica-
attempts. A toolkit provided by the STOP Obesity Alliance, pro- tion, moderation of alcohol use should be advised to lessen the risk of
vides a helpful framework for approaching weight loss discussions, hepatic complications.
with emphasis on the ‘six As’: ask, assess, advise, agree, assist and
arrange161. Given the availability of multiple modalities to facilitate Targeted pharmacotherapy
weight loss, integrated weight management teams can help support In the management of MetS, lifestyle modification should be accom-
a patient-centred approach to addressing overweight and obesity. panied by targeted pharmacotherapy for optimal cardiovascular
According to the CKM syndrome health guidance, the use of such a risk reduction (Table 3 and Fig. 4). In the STENO-2 randomized trial
team should be prioritized for individuals with existing CVD or at high in 160 patients with overweight or obesity, T2DM and albuminuria,
risk of CVD owing to multiple comorbid conditions136. standard care was compared with a multifactorial intervention includ-
ing lifestyle modification, glycaemic control, RAAS inhibition, aspirin
Lifestyle interventions and lipid-lowering therapy170. Over a mean 5 years of follow-up, those
Lifestyle modification in MetS is focused on behaviour change to sup- individuals who received the multifactorial intervention had a 46%
port sustained beneficial lifestyle practices, such as improving overall lower risk of death, a 57% lower risk of cardiovascular death, and a
dietary patterns (DASH or Mediterranean-type diets), moderate calorie 59% lower risk of cardiovascular events. These findings highlight the
restriction and regular physical activity162. Lifestyle modification is clinical benefit of combining lifestyle change with pharmacothera-
best achieved through structured, multidisciplinary programmes with pies known to control risk factors and reduce cardiovascular risk in
ongoing support to facilitate sustained behaviour change163. individuals with MetS. Also of relevance is that heterogeneity exists
among individuals with MetS, with individuals having IR-dominant,
Diet. From a dietary standpoint, key elements include a balanced lipid-dominant and vascular-dominant phenotypes11. Pharmacotherapy
diet with limited intake of simple carbohydrates and saturated fat, should therefore be targeted towards addressing these overt risk fac-
and increased intake of lean proteins, whole-grains, fruits, vegeta- tor abnormalities to customize approaches for cardiovascular risk
bles and ω-3 fatty acids164. The Mediterranean diet, the DASH diet and reduction.
high-fibre diets each improve multiple aspects of MetS. The Medi-
terranean diet demonstrates particularly potent anti-inflammatory T2DM. MetS confers up to a fivefold higher risk of developing T2DM
effects and the DASH diet has a notable effect on reducing blood pres- and the majority of individuals with T2DM have concurrent MetS171.
sure. In those with excess adiposity, moderate calorie restriction of MetS traits also increase the risk of major adverse liver outcomes in
500–1,000 kcal per day can promote reductions in weight and adipose patients with T2DM172. The Diabetes Prevention Program trial dem-
tissue mass165. However, even in the absence of weight and adipose tissue onstrated that lifestyle modification is a highly effective strategy for
mass loss, dietary interventions can have substantial benefits in reduc- preventing the development of diabetes mellitus173. Metformin is
ing the risk of CVD. The PREDIMED trial, which tested the Mediter- also effective for T2DM prevention, although less so than lifestyle
ranean diet in patients with MetS with and without diabetes mellitus, modification, and can be considered for those with progressive
was aimed at improving overall diet quality rather than weight loss hyperglycaemia despite lifestyle changes. If T2DM develops, life-
and showed a 28–31% relative risk reduction in the composite CVD style modification should be accompanied by moderate-intensity to
end point150. high-intensity statin therapy for LDL cholesterol lowering, and gly-
caemic control with haemoglobin A1c of <7% to prevent microvascular
Physical activity. Physical activity has a substantial positive effect complications. Established anti-hyperglycaemic medications that
on MetS. In randomized trials of heterogeneous populations, aerobic have shown benefit in MetS include insulin sensitizers (metformin
physical activity improved each of the diagnostic components of MetS and thiazolidinediones, such as pioglitazone). Additionally, modern
and additional pathophysiological features, such as inflammation and anti-diabetic agents such as glucagon-like peptide 1 (GLP1) receptor
endothelial dysfunction166. Furthermore, the addition of resistance agonists (Box 1) and sodium–glucose cotransporter 2 (SGLT2) inhibi-
training to aerobic activity is linked to further improvements in MetS tors (Fig. 5) improve cardiovascular outcomes in several subgroups of
components and is therefore advised as part of the exercise regimen167. patients at high cardiovascular risk with and without T2DM174–177. Novel
In general, moderate to vigorous physical activity on most days of dual GLP1–glucose-dependent insulinotropic polypeptide (GIP) recep-
the week is recommended, with a goal of 150 min or more of physical tor agonists and triple (GLP1–GIP–glucagon) receptor agonists have
activity per week168. While weight loss with lifestyle modification is also been proven to have cardiometabolic benefits among individu-
desirable, patients and health-care professionals must recognize that als with overweight or obesity and diabetes mellitus178–181. Common
improved dietary patterns and regular physical activity improve MetS adverse effects with SGLT2 inhibitors include genital mycotic infec-
independent of weight loss155. tion and volume depletion, and those with GLP1 and related receptor
agonists include gastrointestinal issues, such as nausea, vomiting and
Other aspects of lifestyle modifications. One important part of constipation.
the approach to lifestyle modification is to screen for adverse social
determinants of health that affect lifestyle behaviours, and to provide Hypertension. Hypertension is a diagnostic component of MetS, and
social support where needed through community health workers, care blood pressure reduction confers marked reduction in cardiovascular
navigators or social workers169. Adequate sleep and stress management risk in individuals with or at risk of CVD182. Major societies have agreed

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Table 3 | Candidate therapeutic agents for metabolic syndrome and its components
Therapy MetS component Other factors Strengths Limitations or Medications

caveats
Abdominal Glucose TGs HDL-C BP Inflammation Hepatic
obesity or IR (CRP) steatosis
GLP1RA ↓↓ ↓↓ ↓↓ ↑ ↓ ↓ ↓↓ CV benefits mainly GI adverse Liraglutide, exenatide,

or GLP1- in ASCVD; kidney events lixicenatide, dulaglutide,
based benefits efpeglenitide, semaglutide,
therapy tirzepatide, orforgliprona,
survodutidea, retatrutidea,
cafraglutidea
SGLT2i ↓ ↓ ↓ ↑ ↓ ↓ ↓ CV benefits mainly ↑ Genital tract Dapagliflozin, empagliflozin,
in HF; kidney infection; canagliflozin, ipragliflozin,
benefits volume enavogliflozin
depletion;
ketosis
DPP4i – ↓ ↓ – – ↓ – Albuminuria ↑ HF risk in Sitagliptin, vildagliptin,
reduction saxagliptin linagliptin, alogliptin,
saxagliptin, teneligliptin,
gemigliptin, anagliptin,
evogliptin
TZD ↑b ↓↓ ↓↓ ↑ – ↓ ↓↓ CV benefits, mainly ↑ HF risk; ↑ Pioglitazone, rosiglitazone,
in stroke osteoporosis lobeglitazone
risk
Statins – Slightly ↑ ↓ – – ↓ – CV benefits Muscle-related Atorvastatin, rosuvastatin,
side effects; simvastatin, fluvastatin,
glucose pravastatin, lovastatin,
dysregulation; pitavastatin
↑ LFT
Fibrates – Slightly ↓ ↓↓ ↑ – ↓ – ↓ Diabetic Transient ↓ Fenofibrate, gemfibrozil
microvascular eGFR
complications
EPA – Slightly ↓ ↓↓ ↑ – ↓ ↓ CV benefits Atrial Icosapent ethyl
fibrillation at
high dose; GI
adverse events
ARB or – Slightly ↓ – – ↓↓ ↓ – CV benefits; kidney Cough with Losartan, candesartan,
ACEi benefits ACEi telmisartan, irbesartan,
eprosartan, fimasartan,
olmesartan, azilsartan
ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ASCVD, atherosclerotic cardiovascular disease; BP, blood pressure; CRP, C-reactive protein; CV,
cardiovascular; DPP4i, dipeptidyl peptidase 4 inhibitor; eGFR, estimated glomerular filtration rate; EPA, eicosapentaenoic acid; GI, gastrointestinal; GLP1, glucagon-like peptide 1; GLP1RA, GLP1
receptor agonist; HDL-C, HDL cholesterol; HF, heart failure; IR, insulin resistance; LFT, liver function test; MetS, the metabolic syndrome; SGLT2i, sodium–glucose cotransporter 2 inhibitors;
TGs, triglycerides; TZD, thiazolidinedione. aNot yet approved for obesity or diabetes management by the FDA or EMA, or in other countries. bMainly subcutaneous adipose tissue.
that a blood pressure goal of <130/80 mmHg should be targeted with MetS. Genetic studies have demonstrated a causal relationship between
lifestyle modifications, a low sodium diet and pharmacological therapy elevated triglycerides and CVD, in contrast to low HDL cholesterol,
for individuals who are at increased risk183. From a dietary standpoint, which is now appreciated as a marker of metabolic dysregulation. In the
the DASH diet is associated with notable lowering of blood pressure. absence of secondary causes for elevated triglycerides, lifestyle modifi-
From a pharmacological standpoint, the use of diuretics, calcium cation is the first-line therapy for hypertriglyceridaemia in the context
channel blockers or RAAS inhibitors as pharmacological agents to of MetS. In those with CVD or intermediate-to-high predicted risk,
reduce blood pressure confer similar cardiovascular benefits in most statin therapy is indicated and has a moderate triglyceride-lowering
patients with MetS. However, RAAS inhibitors should be prioritized effect. Icosapent ethyl can be considered to further reduce CVD risk
in patients with CKD, diabetes mellitus with albuminuria and existing in those with elevated triglycerides concomitant with CVD or with
CVD (particularly heart failure), to confer additional risk reduction diabetes mellitus in addition to other risk factors184.
against adverse kidney and cardiovascular events12. High potency statins might slightly increase the risk of incident
T2DM in those with prediabetes. The number needed to be treated
Dyslipidaemia. Atherogenic dyslipidaemia, characterized by the inter- to harm one individual is ~100, so individuals with a predicted CVD
related lipid phenotypes of elevated blood levels of triglycerides, low risk exceeding 2.5% over 10 years derive more benefit than poten-
HDL cholesterol, elevated apolipoprotein B (or non-HDL cholesterol) tial harm from statin use. Aspirin should be used infrequently in the
and an increased proportion of small, dense LDL particles, is closely routine primary prevention of CVD related to MetS owing to a lack
related to IR, and is therefore commonly encountered in patients with of net benefit185–187. Current guidelines from the American College of

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Cardiology–AHA recommend that low-dose aspirin (75–100 mg orally Semaglutide on Chronic Kidney Disease in Type 2 Diabetes (FLOW)
daily) be considered for the primary prevention of CVD among selected trial is the first kidney outcomes trial of GLP1 receptor agonists that
adults aged 40 to 70 years who are at increased risk of CVD but not at demonstrated significant reductions in the rates of adverse kidney
increased risk of bleeding (class IIb recommendation)183. events and death from cardiovascular causes in individuals with T2DM
and CKD with semaglutide compared with placebo (HR 0.76, 95% CI
Chronic kidney disease. CKD is a frequent consequence of MetS, 0.66–0.88)193. The FLOW trial also notably showed a 20% reduction
reflecting the adverse effects of obesity, inflammation, IR, T2DM and in rates of death from all causes in this high-risk patient population.
elevated blood pressure. In individuals with MetS, the health guid-
ance for CKM syndrome emphasizes the measurement of the urine Management in children and adolescents
albumin-to-creatinine ratio and estimated glomerular filtration rate MetS in children and adolescents is a frequently discussed topic in
to fully characterize CKD-related risk136. Therapies to prevent kidney the literature, yet uniform guidelines on its definition and treatment
function decline should be prioritized in individuals with CKD. RAAS are still lacking28. As in adults, IR, central obesity, dyslipidaemia and
inhibitors are proven to reduce adverse kidney events in individu- hypertension are commonly considered as the main components of
als with CKD with albuminuria188. Furthermore, SGLT2 inhibitors are MetS in children and adolescents. The first recommended approach
now known to reduce adverse kidney events in most individuals with to all these pathological conditions in these groups is lifestyle inter-
CKD, even in the absence of diabetes mellitus or albuminuria189,190. vention (that is, weight management, diet and physical activity)193,194.
In addition, the non-steroidal mineralocorticoid receptor antagonist However, in selected patients at very high risk, a pharmacological or
finerenone reduces adverse kidney events in individuals with diabetic surgical treatment might prove useful for the prevention of metabolic
CKD191. In patients with CKD and T2DM, treatment with the GLP1 recep- and cardiovascular complications193,194.
tor agonist semaglutide improved kidney outcomes192. Importantly,
these kidney-protective agents also have favourable effects on car- Quality of life
diovascular outcomes (especially heart failure), which are mediated MetS has considerable potential to affect multiple domains of a patient’s
in part by protection against kidney function decline. The Effects of health-related quality of life (HRQOL): psychosocial, emotional and
physical195,196. This issue is particularly relevant, as self-perceived HRQOL
is suggested to be an important predictor of chronic disease develop-
Box 1 | The potential role of GLP1RA or ment and premature mortality197. For example, in several cross-sectional
studies, MetS was found to be associated with increased prevalence of
GLP1–GIP dual agonists in glucose and depressive symptoms and adverse mental health QOL, particularly in
lipid metabolism and cardiorenal systems women198,199 and those from lower socioeconomic backgrounds198. In an
8-year prospective cohort study that followed middle-aged adults (aged
Glucose and lipid metabolism 35–55 years) in Taiwan, after adjusting for physical activity, MetS was a
• ↓ Insulin resistance strong risk factor for negative psychological well-being, particularly in
• ↓ Glucose and glycated haemoglobin relation to vitality and overall mental health196. The syndrome also pre-
• ↓ Body weight and WC disposes individuals to bodily pain and can limit physical activity197,200,
• ↓ Visceral adipose tissue which might impede the ability to lose excess body weight and can
• ↓ Hepatic steatosis and MASLD further compound the negative effects on HRQOL200.
• ↓ Pericardial adipose tissue As MetS encompasses a cluster of cardiometabolic risk factors,
• ↓ Triglycerides and VLDL it is implicated in increased rates of morbidity and mortality across
• ↓ LDL cholesterol and sdLDL the lifespan198,201. These increases are due in part to associations with
• ↑ HDL cholesterol cognitive and functional decline and poor perception of health, as well
as to increased rates of cerebrovascular disease and CVD198,199. In a study
Cardiorenal systems including populations historically under-represented in research in the
• ↓ Blood pressure USA, MetS was linked to reduced HRQOL among non-Hispanic white
• ↑ Endothelial function individuals, non-Hispanic Black individuals and Mexican Americans201.
• ↑ Cardiac function Notably, the findings were variable across studies, as some showed no
• ↓ Cardiac ischaemia differences in HRQOL domains (such as depressive symptoms) between
• ↓ Atherosclerosis those with and without MetS202. Future studies including patients
• ↓ Albuminuria from diverse backgrounds196, of all age groups and with standardized
measurements for HRQOL and MetS200, are needed to better elucidate
Shared pathways the independent effect of MetS on HRQOL.
• ↓ Inflammation Primary treatment recommendations typically involve life-
• ↓ Oxidative stress style modifications, including exercise203, yoga204, nutrition health
• ↑ Adiponectin education205 and health behaviour changes206. In a randomized con-
trolled trial exploring the effects of lifestyle changes on MetS man-
GIP, glucose-dependent insulinotropic polypeptide; GLP1, glucagon-like agement, lifestyle modification significantly improved the physical
peptide 1; GLP1RA, GLP1 receptor agonist; MASLD, metabolic dysfunction- health domain of HRQOL at 3 months (P = 0.02)203. These findings were
associated steatotic liver disease; sdLDL, small dense LDL; WC, waist bolstered in a meta-analysis of such interventions, which highlighted
circumference.
the value of healthy lifestyle modifications on all HRQOL domains203–206.
In addition, one unique population comprises patients who develop

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SGLT2 inhibitor Confirmed

in human study
Not confirmed
Glycosuria Natriuresis yet in human study
Haemodynamic effect
↓ Blood ↑ TubuloglomeruIar ↓ Plasma

↑ Uricosuria ↓ Blood glucose Negative caloric balance pressure feedback
concentration volume
↓ Uric acid ↓ Glucose ↓ Total body ↑ Fasting Lipolysis ↓ Arterial Afferent

toxicity fat mass mimicking stiffness arteriole ↓ Myocardial ↑ O2
response constriction stretch delivery
by hct
↑ Coronary
flow
↓ Pericardial ↓ Visceral
adipose adipose ↑ Mitochondrial ↑ Ketones
tissue tissue function
↑ Ejection fraction Activation of
Effective ATP ↑ Cardiac
ACE2 and
production contractility
Ang1 and/or
↓ Inflammation ↓ Hepatic steatosis Ang7
↓ Fibrosis ↓ Interglomerular
pressure
↓ Inflammasome
↓ Proteinuria
↓ Atherosclerosis
Cardiorenal and metabolic benefits
Fig. 5 | The potential mechanisms of SGLT2 inhibitors leading to cardiorenal haemodynamic effects, including natriuresis, reduced blood pressure
and metabolic benefits. Sodium–glucose cotransporter 2 (SGLT2) inhibitors and plasma volume, contribute to improved renal function by decreasing
exert cardiorenal and metabolic benefits through multifaceted mechanisms. tubuloglomerular feedback and interglomerular pressure. Enhanced coronary
SGLT2 inhibitors promote glycosuria, leading to a reduction in blood glucose flow, reduced arterial stiffness and improved myocardial oxygen delivery further
levels and a negative caloric balance. These effects contribute to decreased support cardiac function, evidenced by increased ejection fraction and cardiac
uric acid levels, reduced glucose toxicity and decreased total body fat contractility. Together, these mechanisms underscore the systemic benefits of
mass, particularly visceral and pericardial adipose tissue, while enhancing SGLT2 inhibitors in managing cardio–renal–metabolic disorders. Solid lines:
mitochondrial function and increasing ketone production. These metabolic confirmed in human study. Dashed line: not confirmed yet in human study. ACE2,
changes are associated with decreased inflammation and fibrosis, reduced angiotensin-converting enzyme 2; Ang1, angiotensin 1; Ang7, angiotensin 7; hct,
hepatic steatosis and overall cardiovascular protection. Additionally, the haematocrit.
cancer treatment-induced MetS, thereby emphasizing a need to inte- to recognize the need to assess and target abdominal obesity and its
grate surveillance for MetS in patients with cancer, especially as part clinical consequences as early as possible. Abdominal obesity is char-
of routine survivorship health care to potentially improve HRQOL207. acterized by dysfunctional and hypertrophic SAT (which is not able
Thus, additional investigation into the relationship between MetS and to expand and act as a metabolic sink) accompanied by excess VAT
HRQOL is warranted to better understand the multifaceted effects of and ectopic lipid accumulation. Health-care professionals need to be
MetS on all domains of well-being. aware that the current tool used in clinical practice to assess obesity
(that is, BMI) cannot adequately assess the quality of SAT and the size of
Outlook adipose tissue depots associated with features of MetS (such as visceral
Gaps between scientific evidence and implementation adiposity and hepatic steatosis). A diagnosis of MetS enables patients
Considerable evidence indicates that a clinical diagnosis of MetS can with overweight or obesity who are at increased risk to be identified and
predict an increased risk of developing T2DM and CVD, as well as other targeted for early intervention to prevent the development of various
clinical outcomes. Yet, several gaps exist between the science under- clinical outcomes. In addition, a MetS diagnosis should be incorporated
lying MetS and implementation of MetS diagnosis and intervention into a proper individualized health risk assessment that considers
in clinical practice. Importantly, health-care professionals often fail the severity of the MetS, as well as many genetic and environmental

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Population-based solutions the importance of addressing upstream drivers of the CKM syndrome
with a holistic approach. Whereas clinicians familiar with the concept
Environment
• Urban
will ‘code’ MetS for these patients, too many of them still see MetS cri-
• School teria such as hypertension, impaired fasting glucose and high serum
• Workplace levels of triglycerides, in isolation from each other and treat these risk
Targeting
• Policies
health-challenged factors in silos. Therefore, appropriately using the MetS concept for
• Laws
environment
• Disparities (education, social support) optimal assessment and management of health risk remains a challenge
• Consumerism, food desert
• Access to healthy food in clinical practice.
• Proximity to fast food This situation could be partly attributed to the fact that some
groups of experts have even debated about the added value of the
Clinical approaches
MetS concept. MetS is not a risk calculator, and clinicians have diffi-
culties with incorporating a MetS diagnosis into the risk assessments
Behaviours
• Nutritional quality Targeting
of their patients for various health outcomes. We propose that just
• Sedentary and sitting time behaviours assessing the metabolic and/or haemodynamic features of MetS in
• Lack of physical activity or exercise themselves does not make sense, until attention is paid to the key
driver: dysfunctional SAT that leads to excess VAT and ectopic lipid
Obesities
• Visceral adipose tissue and/or ectopic Targeting new accumulation. Thus, if a consensus can be achieved around visceral
fat (hypertriglyceridaemic waist) adiposity and/or obesity with excess ectopic lipid accumulation being the most com-
• Cardiorespiratory fitness fitness outcomes
• Severe obesity mon form of MetS, approaches will need to be developed so that
health professionals can diagnose visceral obesity at any BMI value.
WC has been proposed as a simple marker of abdominal obesity.
However, the widely used single sex-specific WC cut-off values (88 cm
• CVD
• Diabetes mellitus in women and 102 cm in men) to diagnose abdominal obesity are not
• Other clinical outcomes sufficient because both BMI and WC are strongly correlated (Fig. 7).
Rather, sex-specific and BMI category-specific WC values have been
Fig. 6 | Clinical approaches and public health solutions to tackle obesities. proposed210 but these recommendations have failed to be widely
As high-risk forms of obesity result from the complex interactions of biological, implemented. Further work in this area and additional consensus
behavioural, psychosocial and environmental factors, the current obesity activities are clearly needed.
epidemic will not be curbed until an integrated set of population-based solutions
and clinical approaches are put in place, going beyond body weight and weight Body adiposity imaging and cardiometabolic risk assessment
loss as the single assessment or management outcome. CVD, cardiovascular Another area of uncertainty is the role of body adiposity imaging
disease. Reprinted with permission from ref. 208, Elsevier. in assessing cardiometabolic risk and the distinct contribution of
excess visceral adiposity versus those of ectopic lipid depots (such
as in the liver, muscle or pancreas) and the epicardial, pericardial
or lifestyle factors. AI approaches have tremendous potential to help and perirenal adipose tissue depots to various clinical outcomes.
address these challenges. Advanced body adiposity imaging using CT or MRI (the gold stand-
Clinicians also need to recognize that features of MetS result ard) is not available in most centres and the cost-effectiveness of an
from the interaction between genetic susceptibility, family history imaging-based screening approach has not been evaluated. Dual
and lifestyle factors (including, among others, overall dietary pat- energy X-ray absorptiometry scanning is more widely available but
terns, physical activity and sedentary time, and quality of sleep). provides limited information. In the absence of direct, imaging-based
These factors are also related to socioeconomic issues that often tools such as CT and MRI for clinical use, a combination of anthro-
cannot be addressed by classic health-care models, as clinical treat- pometry and laboratory markers could aid in the differentiation of
ments that target the individual and public health approaches high-risk adiposity phenotypes208.
that target populations are often in their separate silos208 (Fig. 6). Whereas hepatic steatosis has an important role in the develop-
In that regard, the AHA CKM syndrome screening and staging con- ment of T2DM, its contribution to CVD outcomes is uncertain100,211.
cept published by the AHA12 (Fig. 4) is an important conceptual step However, MASLD or MASH, rather than isolated hepatic steatosis,
forward. This approach puts an emphasis on targeting stage 1 (high is associated with increased CVD risk. A meta-analysis investigated
risk obesity and/or prediabetes) with specific recommendations the association between MASLD (diagnosed by liver imaging, ICD
around screening and intervention to prevent stage 2 (essentially codes or liver histology) in ~5.8 million middle-aged individuals
MetS). Furthermore, this AHA presidential advisory paper12 empha- from different countries with nearly 100,000 fatal and non-fatal
sizes the need to develop integrated models to fill the gap between CVD events over a median follow-up of 6.9 years, and found a hazard
clinical approaches and strategies to address social determinants ratio of 1.45, but this risk markedly increased across the severity of
of health, such as patient-centred, team-based approaches like the MASLD, especially with the stage of fibrosis (pooled random effects
CINEMA programme209. HR 2.50)212. Moreover, in Sweden from 1998 to 2021, the risk of major
adverse liver outcomes increased with the number of MetS traits in
Recognition of MetS as a distinct clinical entity individuals with T2DM without a history of liver disease identified
The concept of MetS was introduced >20 years ago; however, primary from national registers173. In addition, in a 2024 Korean nationwide
care providers (and many specialists) still consider the component risk analysis, patients with MASLD (assessed as a fatty liver index (FLI) of
factors in isolation and do not appreciate their interconnectedness nor ≥30) and T2DM (and even those with mild MASLD (FLI 30 to <60)) had

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a higher risk of CVD and all-cause death than those without MASLD and equitable clinical and public health approaches to manage a highly
(FLI <30)213. In a 2023 study that used the NHANES data from 1999 to prevalent condition. Public health approaches to increase physical
2018, assessment of MASLD led to identification a greater propor- activity and improve overall nutritional quality will be the most suc-
tion of the population with metabolic risk214. Moreover, although cessful when we can translate them into improvements in defining the
epicardial and pericardial adipose tissue are related to CVD outcomes, features of MetS and related risk. Thus, from a public policy standpoint,
their specific contribution to clinical outcomes after controlling monitoring changes in the features of MetS and its severity could help
for VAT remains debated. For instance, in a recent analysis of 44,475 track and measure improvements in risk factors conferred by lifestyle
participants from the UK Biobank, although epicardial and pericar- modification.
dial adiposity was associated with incident CVD, the association was Finally, with the availability of costly drugs (including AOMs)
largely explained by a metabolically unhealthy adiposity phenotype and surgical procedures, a remaining challenge will be to identify
characterized by excess VAT215. the best therapeutic option for the right patient. In this regard, the
In summary, the relative contribution of various ectopic adipose recently published statement on the CKM syndrome is an important
tissue depots to MetS could depend upon the clinical outcome consid- step forward to better assess, manage and even prevent this important
ered. As multiple forms of ectopic adipose phenotypes are observed condition136. Taking this prevention mindset even further, the field
in the population, machine learning systems and AI will be helpful to should add focus to not just managing MetS but rather emphasizing
categorize these adiposity phenotypes and their associated risk. the promotion of ‘metabolic health’ to prevent the development
and complications of MetS in the first place. Prevention efforts will
The role of MetS in risk stratification and
personalized medicine
Another limitation of the definition of MetS is that it is an ‘all or none’ a b
diagnosis (presence versus absence on the basis of meeting three out
of the five clinical criteria or not). New models of CKM syndrome risk
have attempted to address this issue by developing approaches to
integrate lifestyle indices with biological risk factors12. These include
the PREVENT risk calculator published by a working group with the
AHA, which is a set of novel risk prediction equations that incorporate
predictors and outcomes relevant to the CKM syndrome context216.
This risk prediction tool includes an assessment of social determinants
of health, which are key upstream drivers of CVD, to more equitably
estimate and address risk216. Further work is certainly needed to prop-
erly evaluate how the severity of MetS features can be considered in
overall risk assessment tools. No international consensus exists around
this question.
The utilization of MetS as a risk stratification tool to target inten-
sive interventions towards those at highest risk of adverse outcomes
should be a research priority in the next 5–10 years. For example,
an opportunity exists to ensure the appropriate utilization of AOMs
using screening and diagnosis of MetS to focus treatment on the high-
est risk individuals. The prescribing of AOMs should be approached in
the context of cardiometabolic risk management (atherosclerotic CVD,
heart failure and T2DM) and not for weight loss alone. In particular,
GLP1-based agents are effective in decreasing both abdominal VAT and
hepatic steatosis176,217–219. An accurate assessment of MetS can assist with
identifying those at highest risk and likely to derive greatest benefit
from these costly agents.
Metabolic surgery is another area in which the screening and
identification of MetS can help further refine risk stratification and the
application of resources to target those who will benefit the most. Fig. 7 | Two individuals with identical waist circumference values but
Severe obesity is the fastest growing obesity category in the USA220. markedly different body composition and adipose tissue distribution. The
Progress has been made in the development of less-invasive and safer individual in panel a (individual a) has a waist circumference of 102 cm and a BMI
of 26 kg/m2. The individual in panel b (individual b) also has a waist circumference of
approaches (for example, laparoscopic and endoscopic procedures),
102 cm but a BMI of 32 kg/m2. Assessing health risk only on the basis of the BMI
making metabolic surgery a more acceptable, viable option for many
would imply that individual b is at higher risk than individual a, which would be
patients.
incorrect. However, simultaneous measurement and interpretation of both waist
In summary, the concept of MetS and simple diagnostic tools have circumference and BMI values would reveal that individual a has sarcopenia and
been helpful to identify the subgroup of individuals with overweight or visceral obesity and should be assessed for metabolic dysfunction-associated
obesity who are at highest risk of developing various adverse clinical steatotic liver disease. Individual a is therefore at high risk of cardiometabolic
outcomes. Dysfunctional adipose tissue in the presence of a permissive outcomes. Individual b has higher levels of subcutaneous adipose tissue and a
lifestyle and environmental or socioeconomic factors drive the devel- greater muscle mass than individual a. Thus, despite having a higher BMI than
opment of MetS; therefore, the challenge will be to develop integrated individual a, individual b is at lower risk of cardiometabolic outcomes.

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require individual, regional and societal efforts towards change that 24. Ramachandran, A., Snehalatha, C., Satyavani, K., Sivasankari, S. & Vijay, V. Metabolic
syndrome in urban Asian Indian adults – a population study using modified ATP III
can set a new trajectory towards optimal metabolic health for the criteria. Diabetes Res. Clin. Pract. 60, 199–204 (2003).
next generation. 25. Krishnamoorthy, Y. et al. Prevalence of metabolic syndrome among adult population
in India: a systematic review and meta-analysis. PLoS ONE 15, e0240971 (2020).
26. Bowo-Ngandji, A. et al. Prevalence of the metabolic syndrome in African populations:
Published online: xx xx xxxx a systematic review and meta-analysis. PLoS ONE 18, e0289155 (2023).
27. Asgedom, Y. S. et al. Prevalence of metabolic syndrome among people living with human
References immunodeficiency virus in sub-Saharan Africa: a systematic review and meta-analysis.
1. Reaven, G. M. Why syndrome X? From Harold Himsworth to the insulin resistance Sci. Rep. 14, 11709 (2024).
syndrome. Cell Metab. 1, 9–14 (2005). 28. Tagi, V. M., Samvelyan, S. & Chiarelli, F. Treatment of metabolic syndrome in children.
2. Despres, J. P. & Lemieux, I. Abdominal obesity and metabolic syndrome. Nature 444, Horm. Res. Paediatr. 93, 215–225 (2020).
881–887 (2006). 29. Reisinger, C., Nkeh-Chungag, B. N., Fredriksen, P. M. & Goswami, N. The prevalence of
A paper outlining that the most prevalent form of the metabolic syndrome is found pediatric metabolic syndrome – a critical look on the discrepancies between definitions
among individuals with excess visceral adipose tissue and ectopic fat. and its clinical importance. Int. J. Obes. 45, 12–24 (2021).
3. Despres, J. P. et al. Abdominal obesity and the metabolic syndrome: contribution to A critical discussion of issues relevant to the metabolic sydrome in the paediatric
global cardiometabolic risk. Arterioscler. Thromb. Vasc. Biol. 28, 1039–1049 (2008). population.
4. Reaven, G. M. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 30. Noubiap, J. J. et al. Global, regional, and country estimates of metabolic syndrome
37, 1595–1607 (1988). burden in children and adolescents in 2020: a systematic review and modelling analysis.
5. Alberti, K. G. & Zimmet, P. Z. Definition, diagnosis and classification of diabetes mellitus Lancet Child. Adolesc. Health 6, 158–170 (2022).
and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional 31. Messiah, S. E. et al. Prevalence of the metabolic syndrome by household food insecurity
report of a WHO consultation. Diabet. Med. 15, 539–553 (1998). status in the United States adolescent population, 2001-2020: a cross-sectional study.
6. Balkau, B. & Charles, M. A. Comment on the provisional report from the WHO consultation. Am. J. Clin. Nutr. 119, 354–361 (2023).
European Group for the Study of Insulin Resistance (EGIR). Diabet. Med. 16, 442–443 32. Choi, J. E. et al. Increase of prevalence of obesity and metabolic syndrome in children
(1999). and adolescents in Korea during the COVID-19 pandemic: a cross-sectional study using
7. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in the KNHANES. Children 10, 1105 (2023).
Adults. Executive summary of the third report of the National Cholesterol Education 33. Varhlunchungi, V. et al. Metabolic syndrome among adolescents aged 10–19 years in
Program (NCEP) expert panel on detection, evaluation, and treatment of high blood India: a systematic review and meta-analysis. Cureus 15, e48636 (2023).
cholesterol in adults (Adult Treatment Panel III). JAMA 285, 2486–2497 (2001). 34. Cook, S., Weitzman, M., Auinger, P., Nguyen, M. & Dietz, W. H. Prevalence of a metabolic
8. Hagberg, C. E. & Spalding, K. L. White adipocyte dysfunction and obesity-associated syndrome phenotype in adolescents: findings from the third National Health and Nutrition
pathologies in humans. Nat. Rev. Mol. Cell Biol. 25, 270–289 (2024). Examination Survey, 1988-1994. Arch. Pediatr. Adolesc. Med. 157, 821–827 (2003).
An update on the function and roles of white adipocytes in human diseases. 35. Cheng, X. et al. Association between sedentary behavior, screen time and metabolic
9. Grundy, S. M. et al. Definition of metabolic syndrome: report of the National Heart, Lung, syndrome among Chinese children and adolescents. BMC Public. Health 24, 1715 (2024).
and Blood Institute/American Heart Association conference on scientific issues related 36. Tchernof, A. & Despres, J. P. Pathophysiology of human visceral obesity: an update.
to definition. Circulation 109, 433–438 (2004). Physiol. Rev. 93, 359–404 (2013).
10. Alberti, K. G. et al. Harmonizing the metabolic syndrome: a joint interim statement of the A comprehensive review of the role of excess visceral adiposity as a key driver of
International Diabetes Federation Task Force on Epidemiology and Prevention; National cardiometabolic risk.
Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; 37. Neeland, I. J. et al. Associations of visceral and abdominal subcutaneous adipose tissue
International Atherosclerosis Society; and International Association for the Study of with markers of cardiac and metabolic risk in obese adults. Obesity 21, E439–E447 (2012).
Obesity. Circulation 120, 1640–1645 (2009). 38. Yaskolka Meir, A. et al. Intrahepatic fat, abdominal adipose tissues, and metabolic state:
The most contemporary definition of the metabolic syndrome and rationale for the magnetic resonance imaging study. Diabetes Metab. Res. Rev. 33, e2888 (2017).
definition. 39. Saponaro, C. et al. Adipose tissue dysfunction and visceral fat are associated with
11. Sperling, L. S. et al. The Cardiometabolic Health Alliance: working toward a new care hepatic insulin resistance and severity of NASH even in lean individuals. Liver Int. 42,
model for the metabolic syndrome. J. Am. Coll. Cardiol. 66, 1050–1067 (2015). 2418–2427 (2022).
A discussion of the strategy and intervention for the metabolic syndrome from a joint A paper showing that individuals with non-alcoholic steatohepatitis have increased
cardiovascular and endocrinological perspective. VAT that is associated with insulin resistance in liver, muscle and adipose tissue,
12. Ndumele, C. E. et al. A synopsis of the evidence for the science and clinical management increased lipolysis and decreased adiponectin levels.
of cardiovascular-kidney-metabolic (CKM) syndrome: a scientific statement from the 40. Gepner, Y. et al. Intramyocellular triacylglycerol accumulation across weight loss
American Heart Association. Circulation 148, 1636–1664 (2023). strategies; sub-study of the CENTRAL trial. PLoS ONE 12, e0188431 (2017).
13. Alberti, K. G., Zimmet, P. & Shaw, J. The metabolic syndrome – a new worldwide 41. Choe, H. J., Chang, W., Bluher, M., Heymsfield, S. B. & Lim, S. Independent association
definition. Lancet 366, 1059–1062 (2005). of thigh muscle fat density with vascular events in Korean adults. Cardiovasc. Diabetol.
14. Bloomgarden, Z. T. American Association of Clinical Endocrinologists (AACE) consensus 23, 44 (2024).
conference on the insulin resistance syndrome: 25-26 August 2002, Washington, DC. 42. Roh, E. et al. Comparison of pancreatic volume and fat amount linked with glucose
Diabetes Care 26, 1297–1303 (2003). homeostasis between healthy Caucasians and Koreans. Diabetes Obes. Metab. 20,
15. Grundy, S. M. et al. Diagnosis and management of the metabolic syndrome: an American 2642–2652 (2018).
Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. 43. Zelicha, H. et al. Changes of renal sinus fat and renal parenchymal fat during an 18-month
Circulation 112, 2735–2752 (2005). randomized weight loss trial. Clin. Nutr. 37, 1145–1153 (2018).
16. Liang, X., Or, B., Tsoi, M. F., Cheung, C. L. & Cheung, B. M. Y. Prevalence of metabolic 44. Kim, T. H. et al. Pericardial fat amount is an independent risk factor of coronary
syndrome in the United States National Health and Nutrition Examination Survey 2011-18. artery stenosis assessed by multidetector-row computed tomography: the Korean
Postgrad. Med. J. 99, 985–992 (2023). Atherosclerosis Study 2. Obesity 19, 1028–1034 (2011).
17. Dev, R. et al. Impact of sex and gender on metabolic syndrome in adults: a retrospective 45. Chin, J. F. et al. Association between epicardial adipose tissue and cardiac dysfunction
cohort study from the Canadian Primary Care Sentinel Surveillance Network. in subjects with severe obesity. Eur. J. Heart Fail. 25, 1936–1943 (2023).
Can. J. Diabetes 99, 36–43.e2 (2023). 46. Chen, O. et al. Correlation between pericardial, mediastinal, and intrathoracic fat
18. Perez-Castro, E., Godinez-Jaimes, F., Vazquez-Medina, M. U., Ocharan-Hernandez, M. E. volumes with the presence and severity of coronary artery disease, metabolic syndrome,
& Vargas-De-Leon, C. Derivation and validation of sex-specific continuous metabolic and cardiac risk factors. Eur. Heart J. Cardiovasc. Imaging 16, 37–46 (2015).
syndrome scores for the Mexican adult population. Sci. Rep. 12, 9659 (2022). 47. Tsaban, G. et al. Dynamics of intrapericardial and extrapericardial fat tissues during
19. Vishram, J. K. et al. Impact of age and gender on the prevalence and prognostic long-term, dietary-induced, moderate weight loss. Am. J. Clin. Nutr. 106, 984–995 (2017).
importance of the metabolic syndrome and its components in Europeans. The MORGAM 48. Sironi, A. M. et al. Impact of increased visceral and cardiac fat on cardiometabolic risk
Prospective Cohort Project. PLoS ONE 9, e107294 (2014). and disease. Diabet. Med. 29, 622–627 (2012).
20. Cen, M. et al. Associations between metabolic syndrome and anxiety, and the 49. Piche, M. E., Tchernof, A. & Despres, J. P. Obesity phenotypes, diabetes, and
mediating role of inflammation: findings from the UK Biobank. Brain Behav. Immun. 116, cardiovascular diseases. Circ. Res. 126, 1477–1500 (2020).
1–9 (2023). A proposal to move discussions from obesity as a single disorder to obesities (that is,
21. Yamazaki, Y. et al. Usefulness of new criteria for metabolic syndrome optimized for obesity phenotypes).
prediction of cardiovascular diseases in Japanese. J. Atheroscler. Thromb. 31, 382–395 50. Bilson, J. et al. Markers of adipose tissue fibrogenesis associate with clinically significant
(2024). liver fibrosis and are unchanged by synbiotic treatment in patients with NAFLD.
22. Park, D. et al. 20-year trends in metabolic syndrome among Korean adults from 2001 to Metabolism 151, 155759 (2023).
2020. JACC Asia 3, 491–502 (2023). 51. Michaud, A. et al. Relevance of omental pericellular adipose tissue collagen in the
23. Yang, S. et al. Development and validation of an age-sex-ethnicity-specific metabolic pathophysiology of human abdominal obesity and related cardiometabolic risk.
syndrome score in the Chinese adults. Nat. Commun. 14, 6988 (2023). Int. J. Obes. 40, 1823–1831 (2016).

0123456789();:
Primer
52. Laforest, S., Labrecque, J., Michaud, A., Cianflone, K. & Tchernof, A. Adipocyte size as 83. Iacobini, C., Vitale, M., Haxhi, J., Menini, S. & Pugliese, G. Impaired remodeling of white
a determinant of metabolic disease and adipose tissue dysfunction. Crit. Rev. Clin. Lab. Sci. adipose tissue in obesity and aging: from defective adipogenesis to adipose organ
52, 301–313 (2015). dysfunction. Cells 13, 763 (2024).
53. Michaud, A., Drolet, R., Noel, S., Paris, G. & Tchernof, A. Visceral fat accumulation is an 84. Lessard, J. et al. Low abdominal subcutaneous preadipocyte adipogenesis is associated
indicator of adipose tissue macrophage infiltration in women. Metabolism 61, 689–698 with visceral obesity, visceral adipocyte hypertrophy, and a dysmetabolic state.
(2012). Adipocyte 3, 197–205 (2014).
54. Harman-Boehm, I. et al. Macrophage infiltration into omental versus subcutaneous 85. Gastaldelli, A. et al. PPAR-γ-induced changes in visceral fat and adiponectin levels are
fat across different populations: effect of regional adiposity and the comorbidities of associated with improvement of steatohepatitis in patients with NASH. Liver Int. 41,
obesity. J. Clin. Endocrinol. Metab. 92, 2240–2247 (2007). 2659–2670 (2021).
55. Rosendo-Silva, D. et al. Clinical and molecular profiling of human visceral adipose tissue 86. Hammarstedt, A., Gogg, S., Hedjazifar, S., Nerstedt, A. & Smith, U. Impaired adipogenesis
reveals impairment of vascular architecture and remodeling as an early hallmark of and dysfunctional adipose tissue in human hypertrophic obesity. Physiol. Rev. 98,
dysfunction. Metabolism 153, 155788 (2024). 1911–1941 (2018).
56. Rosso, C. et al. Crosstalk between adipose tissue insulin resistance and liver A comprehensive review of the role of impaired adipogenesis as a primary defect
macrophages in non-alcoholic fatty liver disease. J. Hepatol. 71, 1012–1021 (2019). leading to increased cardiometabolic risk.
Altered adipose tissue metabolism is associated with macrophage activity in MASLD, 87. Gustafson, B., Nerstedt, A. & Smith, U. Reduced subcutaneous adipogenesis in human
independent of obesity and diabetes mellitus, probably due to FFA spillover from hypertrophic obesity is linked to senescent precursor cells. Nat. Commun. 10, 2757 (2019).
adipose tissue. 88. Rouault, C. et al. Senescence-associated β-galactosidase in subcutaneous adipose
57. Bouchard, C. et al. The response to long-term overfeeding in identical twins. N. Engl. J. Med. tissue associates with altered glycaemic status and truncal fat in severe obesity.
322, 1477–1482 (1990). Diabetologia 64, 240–254 (2021).
A seminal intervention study documenting that susceptibility to visceral versus 89. Smith, U., Li, Q., Ryden, M. & Spalding, K. L. Cellular senescence and its role in white
subcutaneous adipose tissue deposition has a genetic basis. adipose tissue. Int. J. Obes. 45, 934–943 (2021).
58. Thomas, D. G., Wei, Y. & Tall, A. R. Lipid and metabolic syndrome traits in coronary artery 90. Rinella, M. E. et al. A multisociety Delphi consensus statement on new fatty liver disease
disease: a Mendelian randomization study. J. Lipid Res. 62, 100044 (2021). nomenclature. J. Hepatol. 79, 1542–1556 (2023).
59. He, Q. et al. Genetic insights into the risk of metabolic syndrome and its components on The new definition of MASLD, which now includes steatosis plus at least one feature
stroke and its subtypes: bidirectional Mendelian randomization. J. Cereb. Blood Flow. of the metabolic syndrome, especially steatosis with increased waist circumference.
Metab. 43, 126–137 (2023). 91. Liu, J. et al. Fatty liver, abdominal visceral fat, and cardiometabolic risk factors: the
60. Xia, L. et al. A Mendelian randomization study between metabolic syndrome and its Jackson Heart Study. Arterioscler. Thromb. Vasc. Biol. 31, 2715–2722 (2011).
components with prostate cancer. Sci. Rep. 14, 14338 (2024). 92. Chen, Y.-l et al. Prevalence of and risk factors for metabolic associated fatty liver
61. Gao, X. et al. Genetic evidence for the causal relations between metabolic syndrome disease in an urban population in China: a cross-sectional comparative study.
and psychiatric disorders: a Mendelian randomization study. Transl. Psychiatry 14, 46 BMC Gastroenterol. 21, 212 (2021).
(2024). 93. Adiels, M. et al. Overproduction of large VLDL particles is driven by increased liver fat
62. Marc, J. Genetic succeptibility to metabolic syndrome. EJIFCC 18, 7–14 (2007). content in man. Diabetologia 49, 755–765 (2006).
63. McCarthy, J. J. et al. Evidence for substantial effect modification by gender in a 94. Hodson, L. et al. The contribution of splanchnic fat to VLDL triglyceride is greater in
large-scale genetic association study of the metabolic syndrome among coronary heart insulin-resistant than insulin-sensitive men and women: studies in the postprandial state.
disease patients. Hum. Genet. 114, 87–98 (2003). Diabetes 56, 2433–2441 (2007).
64. Xiao, Z. & Liu, H. The estrogen receptor and metabolism. Womens Health 20, 95. Boden, G., Chen, X., Capulong, E. & Mozzoli, M. Effects of free fatty acids on
17455057241227362 (2024). gluconeogenesis and autoregulation of glucose production in type 2 diabetes. Diabetes
65. Tchernof, A. et al. Androgens and the regulation of adiposity and body fat distribution in 50, 810–816 (2001).
humans. Compr. Physiol. 8, 1253–1290 (2018). 96. Stefan, N. et al. Plasma fetuin-A levels and the risk of type 2 diabetes. Diabetes 57,
66. Starcke, S. & Vollmer, G. Is there an estrogenic component in the metabolic syndrome. 2762–2767 (2008).
Genes. Nutr. 1, 177–188 (2006). 97. Peter, A. et al. The hepatokines fetuin-A and fetuin-B are upregulated in the state of
67. Cherubini, A. et al. Interaction between estrogen receptor-α and PNPLA3 p.I148M variant hepatic steatosis and may differently impact on glucose homeostasis in humans.
drives fatty liver disease susceptibility in women. Nat. Med. 29, 2643–2655 (2023). Am. J. Physiol. Endocrinol. Metab. 314, E266–E273 (2018).
68. White, U. & Ravussin, E. Dynamics of adipose tissue turnover in human metabolic health 98. Mindur, J. E. & Swirski, F. K. Growth factors as immunotherapeutic targets in
and disease. Diabetologia 62, 17–23 (2019). cardiovascular disease. Arterioscler. Thromb. Vasc. Biol. 39, 1275–1287 (2019).
69. Lim, S. & Meigs, J. B. Links between ectopic fat and vascular disease in humans. 99. Gaggini, M. et al. Non-alcoholic fatty liver disease (NAFLD) and its connection with
Arterioscler. Thromb. Vasc. Biol. 34, 1820–1826 (2014). insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease. Nutrients 5,
70. Rosito, G. A. et al. Pericardial fat, visceral abdominal fat, cardiovascular disease risk 1544–1560 (2013).
factors, and vascular calcification in a community-based sample: the Framingham Heart 100. Tejani, S. et al. Cardiometabolic health outcomes associated with discordant visceral
Study. Circulation 117, 605–613 (2008). and liver fat phenotypes: insights from the Dallas Heart Study and UK Biobank.
71. Ding, J. et al. Association between non-subcutaneous adiposity and calcified coronary Mayo Clin. Proc. 97, 225–237 (2022).
plaque: a substudy of the Multi-Ethnic Study of Atherosclerosis. Am. J. Clin. Nutr. 88, 101. Targher, G., Byrne, C. D., Lonardo, A., Zoppini, G. & Barbui, C. Non-alcoholic fatty liver
645–650 (2008). disease and risk of incident cardiovascular disease: a meta-analysis. J. Hepatol. 65,
72. Wu, Y., Zhang, A., Hamilton, D. J. & Deng, T. Epicardial fat in the maintenance of 589–600 (2016).
cardiovascular health. Methodist. Debakey Cardiovasc. J. 13, 20–24 (2017). 102. Lauridsen, B. K. et al. Liver fat content, non-alcoholic fatty liver disease, and ischaemic
73. Thanassoulis, G. et al. Pericardial fat is associated with prevalent atrial fibrillation: heart disease: Mendelian randomization and meta-analysis of 279 013 individuals.
the Framingham Heart Study. Circ. Arrhythm. Electrophysiol. 3, 345–350 (2010). Eur. Heart J. 39, 385–393 (2018).
74. Lamacchia, O. et al. Para- and perirenal fat thickness is an independent predictor of 103. Klein, S., Gastaldelli, A., Yki-Jarvinen, H. & Scherer, P. E. Why does obesity cause diabetes?
chronic kidney disease, increased renal resistance index and hyperuricaemia in type-2 Cell Metab. 34, 11–20 (2022).
diabetic patients. Nephrol. Dial. Transpl. 26, 892–898 (2011). This review discusses the complex cellular and physiological mechanisms responsible
75. Guo, X. L., Wang, J. W., Tu, M. & Wang, W. Perirenal fat thickness as a superior for the link between obesity and T2DM, which involve adiposity-induced alterations in
obesity-related marker of subclinical carotid atherosclerosis in type 2 diabetes mellitus. β-cell function, adipose tissue biology and multi-organ insulin resistance.
Front. Endocrinol. 14, 1276789 (2023). 104. DeFronzo, R. A. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the
76. Bosy-Westphal, A., Braun, W., Albrecht, V. & Muller, M. J. Determinants of ectopic liver fat missing links. The Claude Bernard Lecture 2009. Diabetologia 53, 1270–1287 (2010).
in metabolic disease. Eur. J. Clin. Nutr. 73, 209–214 (2019). 105. Brehm, A. et al. Increased lipid availability impairs insulin-stimulated ATP synthesis in
77. Montastier, E. et al. Increased postprandial nonesterified fatty acid efflux from adipose human skeletal muscle. Diabetes 55, 136–140 (2006).
tissue in prediabetes is offset by enhanced dietary fatty acid adipose trapping. 106. Belfort, R. et al. Dose-response effect of elevated plasma free fatty acid on insulin
Am. J. Physiol. Endocrinol. Metab. 320, E1093–E1106 (2021). signaling. Diabetes 54, 1640–1648 (2005).
78. Couillard, C. et al. Postprandial triglyceride response in visceral obesity in men. Diabetes 107. Gastaldelli, A. et al. Relationship between hepatic/visceral fat and hepatic insulin
47, 953–960 (1998). resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology 133, 496–506
79. Carpentier, A. C., Labbé, S. M., Grenier-Larouche, T. & Noll, C. Abnormal dietary fatty (2007).
acid metabolic partitioning in insulin resistance and type 2 diabetes. Clin. Lipidol. 6, 108. Masoodi, M. et al. Metabolomics and lipidomics in NAFLD: biomarkers and non-invasive
703–716 (2013). diagnostic tests. Nat. Rev. Gastroenterol. Hepatol. 18, 835–856 (2021).
80. Spalding, K. L. et al. Dynamics of fat cell turnover in humans. Nature 453, 783–787 109. Magkos, F. et al. Intrahepatic diacylglycerol content is associated with hepatic insulin
(2008). resistance in obese subjects. Gastroenterology 142, 1444–1446.e2 (2012).
81. Virtue, S. & Vidal-Puig, A. Adipose tissue expandability, lipotoxicity and the metabolic 110. Luukkonen, P. K. et al. Hepatic ceramides dissociate steatosis and insulin resistance
syndrome – an allostatic perspective. Biochim. Biophys. Acta 1801, 338–349 (2010). in patients with non-alcoholic fatty liver disease. J. Hepatol. 64, 1167–1175 (2016).
82. Arner, E. et al. Adipocyte turnover: relevance to human adipose tissue morphology. 111. Samuel, V. T. & Shulman, G. I. The pathogenesis of insulin resistance: integrating
Diabetes 59, 105–109 (2010). signaling pathways and substrate flux. J. Clin. Invest. 126, 12–22 (2016).

0123456789();:
Primer
112. Stratford, S., Hoehn, K. L., Liu, F. & Summers, S. A. Regulation of insulin action by 144. Benmohammed, K., Valensi, P., Omri, N., Al Masry, Z. & Zerhouni, N. Metabolic
ceramide: dual mechanisms linking ceramide accumulation to the inhibition of syndrome screening in adolescents: new scores AI_METS based on artificial intelligence
Akt/protein kinase B. J. Biol. Chem. 279, 36608–36615 (2004). techniques. Nutr. Metab. Cardiovasc. Dis. 32, 2890–2899 (2022).
113. Powell, D. J., Hajduch, E., Kular, G. & Hundal, H. S. Ceramide disables 3-phosphoinositide 145. Neeland, I. J., Poirier, P. & Despres, J. P. Cardiovascular and metabolic heterogeneity
binding to the pleckstrin homology domain of protein kinase B (PKB)/Akt by a of obesity: clinical challenges and implications for management. Circulation 137,
PKCζ-dependent mechanism. Mol. Cell Biol. 23, 7794–7808 (2003). 1391–1406 (2018).
114. Lyu, K. et al. A membrane-bound diacylglycerol species induces PKCε-mediated hepatic A review article describing the heterogeneous manifestations and health
insulin resistance. Cell Metab. 32, 654–664.e5 (2020). complications related to obesity.
115. Hilvo, M. et al. Development and validation of a ceramide- and phospholipid-based 146. Despres, J. P. et al. Race, visceral adipose tissue, plasma lipids, and lipoprotein lipase
cardiovascular risk estimation score for coronary artery disease patients. Eur. Heart J. 41, activity in men and women: the Health, Risk Factors, Exercise Training, and Genetics
371–380 (2020). (HERITAGE) family study. Arterioscler. Thromb. Vasc. Biol. 20, 1932–1938 (2000).
116. Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced 147. Warburton, D. E., Charlesworth, S., Ivey, A., Nettlefold, L. & Bredin, S. S. A systematic
inflammation and insulin resistance. Nat. Med. 17, 179–188 (2011). review of the evidence for Canada’s Physical Activity Guidelines for Adults. Int. J. Behav.
117. Holland, W. L. et al. Receptor-mediated activation of ceramidase activity initiates the Nutr. Phys. Act. 7, 39 (2010).
pleiotropic actions of adiponectin. Nat. Med. 17, 55–63 (2011). 148. Broekhuizen, L. N. et al. Physical activity, metabolic syndrome, and coronary risk: the
118. Holland, W. L. et al. Inducible overexpression of adiponectin receptors highlight the EPIC-Norfolk prospective population study. Eur. J. Cardiovasc. Prev. Rehabil. 18, 209–217
roles of adiponectin-induced ceramidase signaling in lipid and glucose homeostasis. (2011).
Mol. Metab. 6, 267–275 (2017). 149. Eilat-Adar, S. et al. Dietary patterns and their association with cardiovascular risk factors
119. Vijay, J. et al. Single-cell analysis of human adipose tissue identifies depot and disease in a population undergoing lifestyle changes: the Strong Heart Study. Nutr. Metab.
specific cell types. Nat. Metab. 2, 97–109 (2020). Cardiovasc. Dis. 23, 528–535 (2013).
120. Lin, D., Chun, T. H. & Kang, L. Adipose extracellular matrix remodelling in obesity and 150. Estruch, R. et al. Primary prevention of cardiovascular disease with a Mediterranean diet.
insulin resistance. Biochem. Pharmacol. 119, 8–16 (2016). N. Engl. J. Med. 368, 1279–1290 (2013).
121. Ruiz-Ojeda, F. J., Mendez-Gutierrez, A., Aguilera, C. M. & Plaza-Diaz, J. Extracellular matrix 151. Mozaffarian, D., Appel, L. J. & Van Horn, L. Components of a cardioprotective diet: new
remodeling of adipose tissue in obesity and metabolic diseases. Int. J. Mol. Sci. 20, 4888 insights. Circulation 123, 2870–2891 (2011).
(2019). 152. Alexander, C. M. et al. NCEP-defined metabolic syndrome, diabetes, and prevalence of
122. Divoux, A. et al. Fibrosis in human adipose tissue: composition, distribution, and link with coronary heart disease among NHANES III participants age 50 years and older. Diabetes
lipid metabolism and fat mass loss. Diabetes 59, 2817–2825 (2010). 52, 1210–1214 (2003).
123. Divoux, A. & Clement, K. Architecture and the extracellular matrix: the still unappreciated 153. Rubino, F. et al. Lancet Diabetes & Endocrinology Commission on the definition and
components of the adipose tissue. Obes. Rev. 12, e494–e503 (2011). diagnosis of clinical obesity. Lancet Diabetes Endocrinol. 11, 226–228 (2023).
124. Antoniades, C. et al. Perivascular adipose tissue as a source of therapeutic targets and 154. Busetto, L. et al. A new framework for the diagnosis, staging and management of obesity
clinical biomarkers. Eur. Heart J. 44, 3827–3844 (2023). in adults. Nat. Med. 20, 2395–2399 (2024).
125. Sun, J. Y., Su, Z., Yang, J., Sun, W. & Kong, X. The potential mechanisms underlying the 155. Rao, S. et al. Effect of exercise and pharmacological interventions on visceral adiposity:
modulating effect of perirenal adipose tissue on hypertension: physical compression, a systematic review and meta-analysis of long-term randomized controlled trials.
paracrine, and neurogenic regulation. Life Sci. 342, 122511 (2024). Mayo Clin. Proc. 94, 211–224 (2019).
126. Antoniades, C., Antonopoulos, A. S. & Deanfield, J. Imaging residual inflammatory 156. Neeland, I. J. et al. Effects of liraglutide on visceral and ectopic fat in adults with
cardiovascular risk. Eur. Heart J. 41, 748–758 (2020). overweight and obesity at high cardiovascular risk: a randomised, double-blind,
127. Hall, J. E. et al. Obesity, kidney dysfunction, and inflammation: interactions in placebo-controlled, clinical trial. Lancet Diabetes Endocrinol. 9, 595–605 (2021).
hypertension. Cardiovasc. Res. 117, 1859–1876 (2021). The first randomized clinical trial to describe the effects of GLP1 receptor agonists
128. Gaba, P., Gersh, B. J., Muller, J., Narula, J. & Stone, G. W. Evolving concepts of the on VAT and ectopic fat in individuals without diabetes mellitus.
vulnerable atherosclerotic plaque and the vulnerable patient: implications for patient 157. Meyer-Gerspach, A. C. et al. Quantification of liver, subcutaneous, and visceral
care and future research. Nat. Rev. Cardiol. 20, 181–196 (2023). adipose tissues by MRI before and after bariatric surgery. Obes. Surg. 29, 2795–2805
129. Cuspidi, C. et al. Nondipping pattern and carotid atherosclerosis: a systematic review (2019).
and meta-analysis. J. Hypertens. 34, 385–391 (2016). 158. Hanipah, Z. N. & Schauer, P. R. Bariatric surgery as a long-term treatment for type 2
130. Li, M. et al. The pathophysiological associations between obesity, NAFLD, and diabetes/metabolic syndrome. Annu. Rev. Med. 71, 1–15 (2020).
atherosclerotic cardiovascular diseases. Horm. Metab. Res. https://doi.org/10.1055/ 159. Picot, J. et al. The clinical effectiveness and cost-effectiveness of bariatric (weight loss)
a-2266-1503 (2024). surgery for obesity: a systematic review and economic evaluation. Health Technol.
131. Gallo, G. & Savoia, C. New insights into endothelial dysfunction in cardiometabolic Assess. https://doi.org/10.3310/hta13410 (2009).
diseases: potential mechanisms and clinical implications. Int. J. Mol. Sci. 25, 2973 (2024). 160. Yu, W., Chen, J., Fan, L., Yan, C. & Zhu, L. Cost-effectiveness of laparoscopic sleeve
132. Luciani, L., Pedrelli, M. & Parini, P. Modification of lipoprotein metabolism and function gastrectomy for Chinese patients. Obes. Surg. 34, 2828–2834 (2024).
driving atherogenesis in diabetes. Atherosclerosis 394, 117545 (2024). 161. Gallagher, C., Corl, A. & Dietz, W. H. Weight can’t wait: a guide to discussing obesity and
133. Moriyama, K. The association between the triglyceride to high-density lipoprotein organizing treatment in the primary care setting. Obesity 29, 821–824 (2021).
cholesterol ratio and low-density lipoprotein subclasses. Intern. Med. 59, 2661–2669 162. Wadden, T. A., Tronieri, J. S. & Butryn, M. L. Lifestyle modification approaches for the
(2020). treatment of obesity in adults. Am. Psychol. 75, 235–251 (2020).
134. Silveira Rossi, J. L. et al. Metabolic syndrome and cardiovascular diseases: going beyond 163. Alamuddin, N. & Wadden, T. A. Behavioral treatment of the patient with obesity.
traditional risk factors. Diabetes Metab. Res. Rev. 38, e3502 (2022). Endocrinol. Metab. Clin. North. Am. 45, 565–580 (2016).
135. Masenga, S. K., Kabwe, L. S., Chakulya, M. & Kirabo, A. Mechanisms of oxidative stress in 164. Lichtenstein, A. H. et al. 2021 dietary guidance to improve cardiovascular health:
metabolic syndrome. Int. J. Mol. Sci. 24, 7898 (2023). a scientific statement from the American Heart Association. Circulation 144, e472–e487
136. Ndumele, C. E. et al. Cardiovascular-kidney-metabolic health: a presidential advisory (2021).
from the American Heart Association. Circulation 148, 1606–1635 (2023). 165. Jensen, M. D. et al. 2013 AHA/ACC/TOS guideline for the management of overweight
137. Rangaswami, J. et al. Cardiorenal syndrome: classification, pathophysiology, diagnosis, and obesity in adults: a report of the American College of Cardiology/American Heart
and treatment strategies: a scientific statement from the American Heart Association. Association Task Force on Practice Guidelines and The Obesity Society. Circulation 129,
Circulation 139, e840–e878 (2019). S102–S138 (2014).
138. Einhorn, D. et al. American College of Endocrinology position statement on the insulin 166. Wewege, M. A., Thom, J. M., Rye, K. A. & Parmenter, B. J. Aerobic, resistance or combined
resistance syndrome. Endocr. Pract. 9, 237–252 (2003). training: a systematic review and meta-analysis of exercise to reduce cardiovascular risk
139. Neeland, I. J. et al. Visceral and ectopic fat, atherosclerosis, and cardiometabolic in adults with metabolic syndrome. Atherosclerosis 274, 162–171 (2018).
disease: a position statement. Lancet Diabetes Endocrinol. 7, 715–725 (2019). 167. Chomiuk, T., Niezgoda, N., Mamcarz, A. & Sliz, D. Physical activity in metabolic syndrome.
A key position statement describing the link between visceral adipose tissue and Front. Physiol. 15, 1365761 (2024).
ectopic fat, and cardiometabolic disease. 168. Barone Gibbs, B. et al. Physical activity as a critical component of first-line treatment
140. Gami, A. S. et al. Metabolic syndrome and risk of incident cardiovascular events and for elevated blood pressure or cholesterol: who, what, and how?: A scientific statement
death: a systematic review and meta-analysis of longitudinal studies. J. Am. Coll. Cardiol. from the American Heart Association. Hypertension 78, e26–e37 (2021).
49, 403–414 (2007). 169. Powell-Wiley, T. M. et al. Social determinants of cardiovascular disease. Circ. Res. 130,
141. Neeland, I. J., Yokoo, T., Leinhard, O. D. & Lavie, C. J. 21st century advances in multimodality 782–799 (2022).
imaging of obesity for care of the cardiovascular patient. JACC Cardiovasc. Imaging 14, 170. Gaede, P., Lund-Andersen, H., Parving, H. H. & Pedersen, O. Effect of a multifactorial
482–494 (2021). intervention on mortality in type 2 diabetes. N. Engl. J. Med. 358, 580–591 (2008).
142. van Walree, E. S. et al. Disentangling genetic risks for metabolic syndrome. Diabetes 71, 171. Cornier, M. A. et al. The metabolic syndrome. Endocr. Rev. 29, 777–822 (2008).
2447–2457 (2022). 172. Shang, Y. et al. Metabolic syndrome traits increase the risk of major adverse liver
143. Hsu, N. W. et al. Building a model for predicting metabolic syndrome using artificial outcomes in type 2 diabetes. Diabetes Care 47, 978–985 (2024).
intelligence based on an investigation of whole-genome sequencing. J. Transl. Med. 20, 173. Knowler, W. C. et al. Reduction in the incidence of type 2 diabetes with lifestyle
190 (2022). intervention or metformin. N. Engl. J. Med. 346, 393–403 (2002).

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174. Jang, H. et al. Outcomes of various classes of oral antidiabetic drugs on nonalcoholic 207. Emery, J. et al. Management of common clinical problems experienced by survivors of
fatty liver disease. JAMA Intern. Med. 184, 375–383 (2024). cancer. Lancet 399, 1537–1550 (2022).
175. Ahmad, E., Lim, S., Lamptey, R., Webb, D. R. & Davies, M. J. Type 2 diabetes. Lancet 400, 208. Despres, J. P., Carpentier, A. C., Tchernof, A., Neeland, I. J. & Poirier, P. Management of
1803–1820 (2022). obesity in cardiovascular practice: JACC focus seminar. J. Am. Coll. Cardiol. 78, 513–531
176. Moon, J. S. et al. SGLT-2 inhibitors and GLP-1 receptor agonists in metabolic (2021).
dysfunction-associated fatty liver disease. Trends Endocrinol. Metab. 33, 424–442 (2022). 209. Neeland, I. J. et al. Second-year results from CINEMA: a novel, patient-centered,
177. Nuffield Department of Population Health Renal Studies Group; SGLT2 inhibitor team-based intervention for patients with type 2 diabetes or prediabetes at high
Meta-Analysis Cardio-Renal Trialists’ Consortium. Impact of diabetes on the effects cardiovascular risk. Am. J. Prev. Cardiol. 17, 100630 (2024).
of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative 210. Ross, R. et al. Waist circumference as a vital sign in clinical practice: a consensus
meta-analysis of large placebo-controlled trials. Lancet 400, 1788–1801 (2022). statement from the IAS and ICCR working group on visceral obesity. Nat. Rev. Endocrinol.
178. Jastreboff, A. M. et al. Tirzepatide once weekly for the treatment of obesity. N. Engl. J. Med. 16, 177–189 (2020).
387, 205–216 (2022). 211. Gastaldelli, A. & Cusi, K. From NASH to diabetes and from diabetes to NASH:
179. Campbell, J. E. et al. GIPR/GLP-1R dual agonist therapies for diabetes and weight mechanisms and treatment options. JHEP Rep. 1, 312–328 (2019).
loss-chemistry, physiology, and clinical applications. Cell Metab. 35, 1519–1529 (2023). 212. Mantovani, A. et al. Non-alcoholic fatty liver disease and risk of fatal and non-fatal
180. Rosenstock, J. et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist cardiovascular events: an updated systematic review and meta-analysis.
tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, Lancet Gastroenterol. Hepatol. 6, 903–913 (2021).
phase 3 trial. Lancet 398, 143–155 (2021). 213. Kim, K. S., Hong, S., Han, K. & Park, C. Y. Association of non-alcoholic fatty liver disease
181. Jastreboff, A. M. et al. Triple-hormone-receptor agonist retatrutide for obesity – a phase 2 with cardiovascular disease and all cause death in patients with type 2 diabetes mellitus:
trial. N. Engl. J. Med. 389, 514–526 (2023). nationwide population based study. BMJ 384, e076388 (2024).
182. Wright, J. T. Jr et al. A randomized trial of intensive versus standard blood-pressure 214. Fu, C. E. et al. The prognostic value of including non-alcoholic fatty liver disease in the
control. N. Engl. J. Med. 373, 2103–2116 (2015). definition of metabolic syndrome. Aliment. Pharmacol. Ther. 57, 979–987 (2023).
183. Arnett, D. K. et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular 215. Ramo, J. T. et al. Cardiovascular significance and genetics of epicardial and pericardial
disease. Circulation 140, e596–e646 (2019). adiposity. JAMA Cardiol. 9, 418–427 (2024).
184. Bhatt, D. L. et al. Cardiovascular risk reduction with icosapent ethyl for 216. Khan, S. S. et al. Novel prediction equations for absolute risk assessment of total
hypertriglyceridemia. N. Engl. J. Med. 380, 11–22 (2019). cardiovascular disease incorporating cardiovascular-kidney-metabolic health:
185. Gaziano, J. M. et al. Use of aspirin to reduce risk of initial vascular events in patients a scientific statement from the American Heart Association. Circulation 148, 1982–2004
at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, (2023).
placebo-controlled trial. Lancet 392, 1036–1046 (2018). This AHA scientific statement describes the rationale behind the development of
186. McNeil, J. J. et al. Effect of aspirin on cardiovascular events and bleeding in the healthy the new AHA PREVENT equation for predicting total cardiovascular disease risk in
elderly. N. Engl. J. Med. 379, 1509–1518 (2018). individuals with CKM syndrome.
187. Bowman, L. et al. Effects of aspirin for primary prevention in persons with diabetes 217. Liao, C., Liang, X., Zhang, X. & Li, Y. The effects of GLP-1 receptor agonists on visceral fat
mellitus. N. Engl. J. Med. 379, 1529–1539 (2018). and liver ectopic fat in an adult population with or without diabetes and nonalcoholic
188. Lewis, E. J., Hunsicker, L. G., Bain, R. P. & Rohde, R. D. The effect of fatty liver disease: a systematic review and meta-analysis. PLoS ONE 18, e0289616
angiotensin-converting-enzyme inhibition on diabetic nephropathy. Collaborative Study (2023).
Group. N. Engl. J. Med. 329, 1456–1462 (1993). 218. Gastaldelli, A. et al. Effect of tirzepatide versus insulin degludec on liver fat content
189. Herrington, W. G. et al. Empagliflozin in patients with chronic kidney disease. N. Engl. J. Med. and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI):
388, 117–127 (2023). a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial.
190. Heerspink, H. J. L. et al. Dapagliflozin in patients with chronic kidney disease. N. Engl. J. Med. Lancet Diabetes Endocrinol. 10, 393–406 (2022).
383, 1436–1446 (2020). Clinical trial documenting the effects of dual GIP and GLP1 agonists on visceral
191. Bakris, G. L. et al. Effect of finerenone on chronic kidney disease outcomes in type 2 adiposity and liver fat content.
diabetes. N. Engl. J. Med. 383, 2219–2229 (2020). 219. Kadowaki, T. et al. Semaglutide once a week in adults with overweight or obesity, with or
192. Perkovic, V. et al. Effects of semaglutide on chronic kidney disease in patients with type 2 without type 2 diabetes in an east Asian population (STEP 6): a randomised, double-blind,
diabetes. N. Engl. J. Med. 391, 109–121 (2024). double-dummy, placebo-controlled, phase 3a trial. Lancet Diabetes Endocrinol. 10,
193. Weihe, P. & Weihrauch-Bluher, S. Metabolic syndrome in children and adolescents: 193–206 (2022).
diagnostic criteria, therapeutic options and perspectives. Curr. Obes. Rep. 8, 472–479 220. Ward, Z. J. et al. Projected U.S. state-level prevalence of adult obesity and severe obesity.
(2019). N. Engl. J. Med. 381, 2440–2450 (2019).
194. DeBoer, M D. Assessing and managing the metabolic syndrome in children and 221. WHO Consultation on Obesity. Obesity: preventing and managing the global epidemic:
adolescents. Nutrients 11, 1788 (2019). report of a WHO consultation. WHO Technical Report Series 894 (WHO, 2000).
195. Ford, E. S. & Li, C. Metabolic syndrome and health-related quality of life among U.S. 222. Zhou, B. F., Cooperative Meta-Analysis Group of the Working Group on Obesity in China.
adults. Ann. Epidemiol. 18, 165–171 (2008). Predictive values of body mass index and waist circumference for risk factors of certain
196. Lin, Y. H. et al. Changes in metabolic syndrome affect the health-related quality of life of related diseases in Chinese adults – study on optimal cut-off points of body mass index
community-dwelling adults. Sci. Rep. 11, 20267 (2021). and waist circumference in Chinese adults. Biomed. Env. Sci. 15, 83–96 (2002).
197. Tsai, A. G. et al. Metabolic syndrome and health-related quality of life in obese individuals 223. Tham, K. W. et al. Obesity in South and Southeast Asia – a new consensus on care and
seeking weight reduction. Obesity 16, 59–63 (2008). management. Obes. Rev. 24, e13520 (2023).
198. Chen, M. Z., Wong, M. W. K., Lim, J. Y. & Merchant, R. A. Frailty and quality of life in older 224. Health Promotion Administration, Ministry of Health and Welfare. 2016 Annual Report
adults with metabolic syndrome – findings from the Healthy Older People Everyday of Health Administration. Health Promotion Administration https://www.hpa.gov.tw/
(HOPE) study. J. Nutr. Health Aging 25, 637–644 (2021). Pages/ashx/File.ashx?FilePath=~/File/Attach/7085/File_6404.pdf (2016).
199. Limon, V. M., Lee, M., Gonzalez, B., Choh, A. C. & Czerwinski, S. A. The impact of 225. Misra, A. et al. Consensus statement for diagnosis of obesity, abdominal obesity and
metabolic syndrome on mental health-related quality of life and depressive symptoms. the metabolic syndrome for Asian Indians and recommendations for physical activity,
Qual. Life Res. 29, 2063–2072 (2020). medical and surgical management. J. Assoc. Physicians India 57, 163–170 (2009).
200. Marcos-Delgado, A. et al. Health-related quality of life in individuals with metabolic 226. Examination Committee of Criteria for ‘Obesity Disease’ in Japan; Japan Society for the
syndrome: a cross-sectional study. Semergen 46, 524–537 (2020). Study of, Obesity. New criteria for ‘obesity disease’ in Japan. Circ. J. 66, 987–992 (2002).
201. Okosun, I. S., Annor, F., Esuneh, F. & Okoegwale, E. E. Metabolic syndrome and impaired 227. Yang, Y. S. et al. Obesity fact sheet in Korea, 2021: trends in obesity prevalence
health-related quality of life and in non-Hispanic White, non-Hispanic Blacks and and obesity-related comorbidity incidence stratified by age from 2009 to 2019.
Mexican-American Adults. Diabetes Metab. Syndr. 7, 154–160 (2013). J. Obes. Metab. Syndr. 31, 169–177 (2022).
202. Vetter, M. L. et al. Relation of health-related quality of life to metabolic syndrome, 228. Centre for Health Protection. Body mass index chart. Centre for Health Protection
obesity, depression and comorbid illnesses. Int. J. Obes. 35, 1087–1094 (2011). https://www.chp.gov.hk/en/resources/e_health_topics/pdfwav_11012.html (2019).
203. Wang, Q., Chair, S. Y. & Wong, E. M. The effects of a lifestyle intervention program on 229. Tobias, M., Paul, S. & Turley, M. Tracking the obesity epidemic: New Zealand
physical outcomes, depression, and quality of life in adults with metabolic syndrome: 1977–2003. Ministry of Health https://www.health.govt.nz/system/files/2011-11/
a randomized clinical trial. Int. J. Cardiol. 230, 461–467 (2017). trackingtheobesityepidemic.pdf (2004).
204. Yadav, R., Yadav, R. K., Pandey, R. M. & Upadhyay, A. D. Predictors of health-related quality 230. Ntuk, U. E., Gill, J. M., Mackay, D. F., Sattar, N. & Pell, J. P. Ethnic-specific obesity cutoffs for
of life in Indians with metabolic syndrome undergoing randomized controlled trial of diabetes risk: cross-sectional study of 490,288 UK biobank participants. Diabetes Care
yoga-based lifestyle intervention vs dietary intervention. Behav. Med. 47, 151–160 (2021). 37, 2500–2507 (2014).
205. Jeon, J. S. et al. Temporal changes of metabolic indicators and quality of life by a two-day 231. Misra, A., Wasir, J. S. & Vikram, N. K. Waist circumference criteria for the diagnosis of
patient education program for metabolic syndrome patients. Int. J. Environ. Res. Public abdominal obesity are not applicable uniformly to all populations and ethnic groups.
Health 19, 3351 (2022). Nutrition 21, 969–976 (2005).
206. Marcos-Delgado, A., Hernandez-Segura, N., Fernandez-Villa, T., Molina, A. J. & Martin, V. 232. Haam, J. H. et al. Diagnosis of obesity: 2022 update of clinical practice guidelines for
The effect of lifestyle intervention on health-related quality of life in adults with obesity by the Korean Society for the Study of Obesity. J. Obes. Metab. Syndr. 32, 121–129
metabolic syndrome: a meta-analysis. Int. J. Environ. Res. Public Health 18, 887 (2021). (2023).

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Author contributions Boehringer Ingelheim and acts as a consultant (advisory boards) for Boehringer Ingelheim,
Introduction (all authors); Epidemiology (J.-P.D. and S.L.); Mechanisms/pathophysiology Edwards LifeSciences, Procyrion Inc. and AstraZeneca. T.M.P.-W. is paid by the American Heart
(J.-P.D., I.J.N., A.T., S.L. and A.G.); Diagnosis, screening and prevention (J.-P.D., I.J.N., A.T., A.G., Association as an Associate Editor for JAHA. C.E.N. and J.-P.D. declare no competing interests.
J.R. and C.E.N.); Management (J.-P.D., I.J.N., A.T., S.L., J.R., C.E.N. and T.M.P.-W.); Quality of life
(T.M.P.-W.); Outlook (J.-P.D., I.J.N., S.L., A.G., J.R. and T.M.P.-W.); revisions/editing of the whole Additional information
manuscript (all authors). Supplementary information The online version contains supplementary material available at
https://doi.org/10.1038/s41572-024-00563-5.
Competing interests
I.J.N. has received honoraria, consulting and speaker’s bureau fees from Boehringer Peer review information Nature Reviews Disease Primers thanks E. Rinkuniene,
Ingelheim/Lilly Alliance, consulting and speakers’ bureau fees from Bayer Pharmaceuticals, E. Stener-Victorin, D. Tousoulis, G. Watts and the other, anonymous, reviewer(s) for
and has participated in scientific advisory boards for Lilly, Boehringer Ingelheim, Novo their contribution to the peer review of this work.
Nordisk and AMRA Medical. S.L. has been a member on advisory boards or has consulted
with Novo Nordisk, and has also served on the speakers’ bureau of AstraZeneca, Boehringer Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in
Ingelheim, Abbott, LG Chem., Daewoong Pharmaceutical, Chong Kun Dang Pharmaceutical published maps and institutional affiliations.
and Novo Nordisk. A.T. receives research funding from Johnson & Johnson, Medtronics,
GI Windows and Biotwin for studies on obesity and bariatric surgery, and has acted as a Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this
consultant for Bausch Health, Novo Nordisk and Biotwin. A.G. has served as a consultant article under a publishing agreement with the author(s) or other rightsholder(s); author
for Boehringer Ingelheim, Eli Lilly and Company, Metadeq Diagnostics; has participated on self-archiving of the accepted manuscript version of this article is solely governed by the
advisory boards for Boehringer Ingelheim, Merck Sharp & Dohme, Novo Nordisk, Metadeq terms of such publishing agreement and applicable law.
Diagnostics and Pfizer; and has received speaker’s honoraria and other fees from Eli Lilly and
Company, Merck Sharp & Dohme, Novo Nordisk and Pfizer. J.R. is on the speakers’ bureau of © Springer Nature Limited 2024
1
Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA. 2Division of Cardiovascular Medicine, University
Hospitals Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA. 3Department of Internal Medicine,
Seoul National University College of Medicine, Seoul, South Korea. 4Department of Internal Medicine, Seoul National University Bundang Hospital,
Seongnam, South Korea. 5Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Québec, Québec, Canada. 6Institute
of Clinical Physiology, National Research Council, Pisa, Italy. 7Division of Nephrology, George Washington University School of Medicine and Health
Sciences, Washington, DC, USA. 8Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
9
Cardiovascular Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
10
Intramural Research Program, National Institute on Minority Health and Health Disparities, National Institutes of Health, Bethesda, MD, USA. 11VITAM –
Centre de recherche en santé durable, Centre intégré universitaire de santé et de services sociaux de la Capitale-Nationale, Québec, Québec, Canada.

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nature reviews disease primers https://doi.org/10.

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The metabolic syndrome (MetS) is a multiplex modifiable risk factor Introduction

and how they contribute to the clinical manifestations of MetS.

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Introduction This expanded concept addresses the pathophysiological interrelation-

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Organization MetS Insulin resistance or Adiposity Dyslipidaemia Elevated blood Other

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Patient A Patient B Fig. 1 | Adipose tissue characteristics can differ

100 µm 100 µm 100 µm 100 µm

Subcutaneous adipocyte Visceral adipocyte Subcutaneous adipocyte Visceral adipocyte

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↑ Pro-inflammatory Abdominal obesity

• Hepatic and peripheral

Heart, kidney and blood vessels

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Diagnosis, screening and prevention Clinical manifestations

Fig. 3 | Stages in the evolution of MetS and

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Interdisciplinary care — Use of CKM coordinator and interdisciplinary team;

Stage 1: Stage 2: Stage 3:

HbA1c ≥7.5% or on insulin HbA1c <7.5%

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Therapy MetS component Other factors Strengths Limitations or Medications

GLP1RA ↓↓ ↓↓ ↓↓ ↑ ↓ ↓ ↓↓ CV benefits mainly GI adverse Liraglutide, exenatide,

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SGLT2 inhibitor Confirmed

↓ Blood ↑ TubuloglomeruIar ↓ Plasma

↓ Uric acid ↓ Glucose ↓ Total body ↑ Fasting Lipolysis ↓ Arterial Afferent

Cardiorenal and metabolic benefits

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