European Heart Journal (2025) 00, 1–29 SPECIAL ARTICLE

https://doi.org/10.1093/eurheartj/ehaf314 Diabetes and metabolic disorders

Clinical staging to guide management

of metabolic disorders and their sequelae:

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a European Atherosclerosis Society
consensus statement
Stefano Romeo 1,2,3,4,5,*, Antonio Vidal-Puig6,7,8,*, Mansoor Husain9,*,
Rexford Ahima10, Marcello Arca11,12, Deepak L. Bhatt13, Anna Mae Diehl14,
Luigi Fontana 15,16, Roger Foo 17,18, Gema Frühbeck19,20,21,22,
Julia Kozlitina 23,24,25, Eva Lonn26,27, Francois Pattou28, Jogchum Plat29,
Susan E. Quaggin30,31, Paul M. Ridker 32, Mikael Rydén33, Nicola Segata34,35,
Katherine R. Tuttle36,37, Subodh Verma 38, Jeanine Roeters van Lennep 39,
Marianne Benn 40,41, Christoph J. Binder 42, Oveis Jamialahmadi 3,
Rosie Perkins 3, Alberico L. Catapano43,44,†, Lale Tokgözoğlu45,†, and
Kausik K. Ray 46,‡; on behalf of the European Atherosclerosis Society Consensus
1
Department of Medicine, H7 Medicin, Huddinge, H7 Endokrinologi och Diabetes Romeo, Karolinska Institutet, 171 77 Stockholm, Sweden; 2Department of Endocrinology, Karolinska
University Hospital Huddinge, 141 57 Huddinge, Stockholm, Sweden; 3Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy,
University of Gothenburg, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden; 4Department of Cardiology, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden;
5
Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Viale Europa, 88100 Catanzaro, Italy; 6MRC Metabolic Diseases Unit, Institute of Metabolic
Science, University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK; 7Centro de Investigacion Principe Felipe, C/ d’Eduardo Primo Yufera, 3, 46012 Valencia, Spain;
8
Cambridge University Nanjing Centre of Technology and Innovation, No. 23, Rongyue Road, Jiangbei New Area, Nanjing, Jiangsu, China; 9Ted Rogers Centre for Heart Research,
Department of Medicine, University of Toronto, 661 University Avenue, Toronto, ON, Canada M5G 1M1; 10Department of Medicine, Division of Endocrinology, Diabetes and Metabolism,
Johns Hopkins University School of Medicine, Baltimore, MD, USA; 11Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy; 12Unit of Internal
Medicine and Metabolic Diseases, Hospital Policlinico Umberto I, Rome, Italy; 13Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 14Division
of Gastroenterology, Department of Medicine, Duke University, Durham, NC, USA; 15Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW,
Australia; 16Department of Endocrinology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia; 17Cardiovascular Research Institute, Yong Loo Lin School of Medicine, National
University of Singapore, National University Health Systems, Singapore; 18Cardiovascular Metabolic Disease Translational Research Programme, National University Health Systems,
Singapore; 19Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, University of Navarra, Pamplona, Spain; 20Metabolic Research Laboratory, CIBER Fisiopatología de
la Obesidad y Nutrición (CIBEROBN), ISCIII, Pamplona, Spain; 21Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; 22Metabolic
Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain; 23The Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical
Center, Dallas, TX, USA; 24Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; 25Peter O’Donnell Jr. School of Public Health, University of
Texas Southwestern Medical Center, Dallas, TX, USA; 26Department of Medicine, McMaster University, Hamilton, ON, Canada; 27Population Health Research Institute, McMaster
University and Hamilton Health Sciences, Hamilton, ON, Canada; 28Department of Endocrine and Metabolic Surgery, CHU Lille, University of Lille, Inserm, Institut Pasteur Lille, Lille, France;
29
Department of Nutrition and Movement Sciences, NUTRIM School of Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands; 30Department of
Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 31Division of Nephrology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA;
32
Center for Cardiovascular Disease Prevention, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 33Department of Medicine (H7),
Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; 34Department CIBIO, University of Trento, Trento, Italy; 35Department of Experimental Oncology, IEO,
European Institute of Oncology IRCCS, Milan, Italy; 36Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA, USA; 37Providence Medical Research
Center, Providence Inland Northwest Health, Spokane, WA, USA; 38Division of Cardiac Surgery, Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Unity Health Toronto, University
of Toronto, Toronto, ON, Canada; 39Department of Internal Medicine, Cardiovascular Institute, Erasmus Medical Center, Rotterdam, The Netherlands; 40Department of Clinical Biochemistry,
Copenhagen University Hospital-Rigshospitalet, Centre of Diagnostic Investigation, Copenhagen, Denmark; 41Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of
Copenhagen, Copenhagen, Denmark; 42Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria; 43Center for the Study of Atherosclerosis, IRCCS MultiMedica, Sesto
S. Giovanni, Milan, Italy; 44Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; 45Department of Cardiology, Hacettepe University Medical Faculty, Ankara,
Turkey; and 46Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London, UK

* Corresponding author. Tel: +46 768672634, Email: [email protected] (S.R.); Tel: +44 1223762790, Email: [email protected] (A.V.-P.); Tel: +1 4168775914, Email: [email protected]
(M.H.)
†
These authors contributed equally to the study.
‡
For list of other contributors, see Appendix.
© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.
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2 Romeo et al.

Abstract

Obesity rates have surged since 1990 worldwide. This rise is paralleled by increases in pathological processes affecting organs such as the heart, liver,
and kidneys, here termed systemic metabolic disorders (SMDs). For clinical management of SMD, the European Atherosclerosis Society proposes a
pathophysiology-based system comprising three stages: Stage 1, where metabolic abnormalities such as dysfunctional adiposity and dyslipidaemia
occur without detectable organ damage; Stage 2, which involves early organ damage manifested as Type 2 diabetes, asymptomatic diastolic dysfunc­
tion, metabolic-associated steatohepatitis (MASH), and chronic kidney disease (CKD); and Stage 3, characterized by more advanced organ damage

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affecting multiple organs. Various forms of high-risk obesity, driven by maintained positive energy balance, are the most common cause of SMD,
leading to ectopic lipid accumulation and insulin resistance. This progression affects various organs, promoting comorbidities such as hypertension
and atherogenic dyslipidaemia. Genetic factors influence SMD susceptibility, and ethnic disparities in SMD are attributable to genetic and socio­
economic factors. Key SMD features include insulin resistance, inflammation, pre-diabetes, Type 2 diabetes, MASH, hypertension, CKD, atherogenic
dyslipidaemia, and heart failure. Management strategies involve lifestyle changes, pharmacotherapy, and metabolic surgery in severe cases, with
emerging treatments focusing on genetic approaches. The staging system provides a structured approach to understanding and addressing the
multi-faceted nature of SMD, which is crucial for improving health outcomes. Categorization of SMD abnormalities by presence and progression
is aimed to improve awareness of a multi-system trait and encourage a tailored and global approach to treatment, ultimately aiming to reduce
the burden of obesity-related comorbidities.
Graphical Abstract

EAS consensus statement on systemic metabolic disorders

Multi-organ disease Staging Assessment

Stage 1 Stage 2 Stage 3

Prevalence of staging
Prevalence in Prevalence of disorders
UK Biobank (%) in each stage (%)
100
Stage 1 Management
75 Stage 2

50

25
A B C D E F GH I J
0

Prognosis
Cumulative event Public health policy
0.3 Stage 1
Stage 2
0.2 Metabolically
healthy
0.1

0.0 Age,
40 50 60 70 80 years

A: prediabetes; B: overweight; C: liver steatosis; D: hypertension; E: dyslipidaemia; F: type 2 diabetes; G: asymptomatic diastolic dysfunction;
H: metabolic-associated steatohepatitis; I: chronic kidney disease; J: subclinical atherosclerosis

.............................................................................................................................................................................................
Keywords Obesity • Insulin resistance/pre-diabetes • Type 2 diabetes • MASLD • Heart failure • Kidney disease

affect many organs, including the heart, liver, and kidney (and other or­
Introduction gans, such as the brain, but these are beyond the focus of this consen­
Global obesity rates among adults have doubled between 1990 and sus). These systemic abnormalities may progress over time, worsening
2022, and over a billion people worldwide today are living with obesity.1 prognosis and reducing life expectancy.
A large body of evidence indicates that excess adiposity, especially vis­ Although many abnormalities associated with obesity were historic­
ceral obesity, results in several systemic abnormalities. Many of these ally considered and treated separately, it is increasingly being recognized
are early markers of the future trajectory of the disease, which may that the various metabolic risk factors are interconnected, sometimes
Clinical staging to guide management of metabolic disorders 3

with bidirectional relationships affecting disease progression. Earlier ef­ organs’ resilience to inflammatory and associated fibrotic responses
forts to address this topic have focused on the burden and implications, all influence this phenotype. The balance among these factors, whether
which have not translated into actions and better patient care. Recent genetic, epigenetic, or triggered by environmental exposures, can ex­
position papers have started to address this issue by proposing staging plain paradoxical phenotypes, such as people living with lower risk
systems to describe the progression of risk and to guide the manage­ forms of obesity; people with metabolic dysfunction–associated steato­
ment of obesity-related metabolic complications. These include those tic liver disease (MASLD) who are resilient to progression to
from the European Association for the Study of Obesity (EASO)2 metabolic-associated steatohepatitis (MASH); and variability in suscep­
and the Lancet Commission,3 which focus on improving the diagnosis tibility to develop insulin resistance, defective insulin secretion, or dia­
of obesity, and from the American Heart Association,4 which emphasizes betes. Furthermore, the circadian system is tightly coupled with

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the contribution of the kidney. The European Atherosclerosis Society processes controlling sleep and metabolism, and disruption of the cen­
(EAS) Consensus panel convened to develop a clinically intuitive staging tral and peripheral clocks might contribute to the exacerbation of obes­
system based on diverse data related to the cluster of abnormalities asso­ ity, nutritional fluxes, and the development of insulin resistance.10
ciated with excess adiposity (Graphical Abstract), here termed systemic The development of visceral obesity is secondary to the defective ex­
metabolic disorders (SMDs). The staging system, which is based on patho­ pandability and functionality of the subcutaneous adipose tissue.7
physiology, is designed to be easily used by clinicians with actionable man­ This leads to a central redistribution of lipids and lipid-induced insulin
agement for each stage designed to preserve health. resistance, contributing to MASLD, atherogenic dyslipidaemia, endo­
thelial dysfunction, and increased susceptibility to hypertension.11
What is systemic metabolic disorder, and Furthermore, in the obese state, visceral adipose tissue is more suscep­
what causes it? tible to inflammatory and vasoactive cytokines, leading to increased
macrophage infiltration within organs and chronic low-grade systemic
Systemic metabolic disorder comprises a cluster of metabolic abnor­
fibro-inflammation, potentially amplifying the pathogenic process.
malities affecting multiple organs, leading to increased morbidity and
Each of these factors, alone and collectively, is likely to contribute to
mortality from both cardiovascular and non-cardiovascular causes.
an excess risk of atherosclerosis.12
Systemic metabolic disorder has a heterogeneous aetiology with di­
verse, albeit convergent, underlying pathogenic mechanisms. These me­
chanisms progress to create a vicious cycle that obscures the Genetics
identification of the initial pathogenic mechanisms, hindering a more Twin and family studies show that obesity and other cardiometabolic
holistic approach to prevention. Systemic metabolic disorder may be risk factors cluster in families, suggesting that genetic factors play a sig­
initiated by various aetiopathogenic factors determined by an organ’s nificant role in disease susceptibility. Estimates of heritability range be­
genetic-specific signature of vulnerability to an unhealthy diet and a sed­ tween 40% and 70% for obesity and other SMD components.13–16
entary lifestyle. Given the high prevalence of obesity, the most common Although rare gene mutations with large effect sizes cause extreme
determinant of SMD is a maintained positive energy balance, leading to monogenic forms of obesity and dyslipidaemia,15,17 most of the vari­
excessive lipid accumulation and adipose tissue expansion up to an in­ ation in SMD susceptibility in the general population is attributed to
dividual’s predetermined threshold, after which SMD becomes mani­ many common genetic variants with small-size effects.17 Large-scale
fest. However, SMD can also stem from primary defects in skeletal genome-wide association studies (GWASs) have identified hundreds of
muscle, leading to insulin resistance, which, in turn, redistributes fuel common variants contributing to each SMD component and its conse­
to adipose tissue and the liver. Alternatively, initial vulnerability in the quences.18 These studies show that although SMD components are epi­
liver, where lipid homeostasis might be compromised, leads to changes demiologically related, they have unique genetic architectures; while some
in lipid/nutrient metabolic fluxes to other organs. This progressive dis­ genetic risk loci are shared across several SMD components, others con­
ruption of multi-organ metabolic homeostasis sets a trajectory for tribute to specific traits.19,20 This suggests a complex relationship between
SMD, evolving into a relatively dedifferentiated disorder with a progres­ SMD components, with multiple distinct heritable factors contributing, in­
sive accumulation of comorbidities. dependently and in concert, to disease susceptibility.
The identification of genetic underpinnings of SMD and its compo­
High-risk forms of obesity as drivers of nents has also helped to unravel the causal relationships among corre­
systemic metabolic disorder lated metabolic risk factors using Mendelian randomization.21,22 It is
also important to note that modifiable lifestyle factors, such as an un­
Obesity arises from a complex multi-factorial process leading to a main­
healthy diet, lack of physical activity, and other environmental factors,
tained positive energy balance, culminating in the accumulation of lipids
may act as metabolic stressors exacerbating the genetic risk of SMD.23
within adipocytes located beneath the skin (as subcutaneous adipose
Genetic studies lend further support to the notion that visceral adi­
tissue) or around internal organs (as visceral adipose tissue). Efficient
pose tissue is the primary culprit driving metabolic abnormalities in
fat storage in subcutaneous adipose tissue initially serves as a relatively
SMD.24–26 Recent GWASs have shown that local fat depots also
safe mechanism, shielding other organs from excessive nutrient sup­
have a distinct genetic architecture.25,27 Genetic factors increasing vis­
ply.5–8 However, as adiposity increases, the capacity of subcutaneous
ceral adipose tissue are associated with increased risk of hypertension,
adipose tissue to store and mobilize lipids may become insufficient.
Type 2 diabetes, and dyslipidaemia, whereas genetic factors increasing
Consequently, fat may be redistributed to less-efficient lipid stores
gluteofemoral (hip) fat depots are associated with more favourable car­
such as the intra-abdominal depot, liver, skeletal muscles (intra-
diometabolic profiles at the same level of body mass index (BMI).24–31
muscular fat), heart (epicardial and pericardial fat), kidneys, and
beta cells in the pancreas, leading to lipotoxic insults in these ectopic
deposits.7,9 Lipotoxicity initiates a heterogeneous, organ-specific, Ethnicity
fibro-inflammatory response, shaping each person’s unique phenotype. The prevalence and health burden of SMD vary substantially among ra­
The severity of the lipotoxic insult, the extent of cell injury, and the cial and ethnic groups.32–36 This variation can be attributed partly to
4 Romeo et al.

socioeconomic disparities, but genetic and other individual susceptibil­ a hepatic triglyceride content >5% and the presence of metabolic dis­
ity factors also play a significant role. For example, Asian Americans ex­ turbances. It encompasses a spectrum of liver diseases progressing
perience cardiometabolic complications at a lower BMI compared with from the accumulation of triglycerides in hepatocytes (isolated stea­
other ethnic groups in the USA, which is likely explained by the preferen­ tosis) to liver inflammation (MASH), fibrosis, and, ultimately, cirrhosis
tial deposition of intra-abdominal fat in this population.37 Moreover, and liver cancer in some people.58 Mendelian randomization studies
South Asian ancestry confers a substantially higher risk of atherosclerotic have shown that liver triglyceride content per se causes hepatic inflam­
cardiovascular disease (ASCVD) compared with other ethnicities, even mation, fibrosis, and cancer.59–61 These studies also suggest that fibrosis
after accounting for social determinants of health.38 Of note, African per se increases insulin resistance and diabetes. Metabolic dysfunction–
Americans have a lower risk of steatotic liver disease compared with associated steatotic liver disease is highly associated with ASCVD and

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European and Hispanic Americans, despite a similar or even higher preva­ Type 2 diabetes in observational studies,62 which is likely explained
lence of obesity and insulin resistance.39 In Latin America, the rising cardi­ by the substantial contribution of MASLD to atherogenic dyslipidaemia.
ometabolic risk is driven by a combination of socioeconomic disparities, However, Mendelian randomization analysis did not identify a causal as­
rapid urbanization, and an increasing prevalence of obesity and diabetes, sociation between genetically determined liver fat content and ischae­
exacerbated by population ageing40 and genetic predisposition.41 mic heart disease.63 On the other hand, secreted factors from the liver
and alterations in lipid metabolism64 might independently promote dia­
stolic heart failure, as supported by a recent study showing that dispro­
Systemic manifestations of portionate levels of liver fat are associated with ventricular functional
systemic metabolic disorder changes associated with heart failure.65 A recent GWAS showed that
liver fat per se is an independent risk factor for Type 2 diabetes but
Systemic metabolic disorder encompasses several critical components not ASCVD and that an association between liver fat and ASCVD is de­
that are commonly present but varying in intensity, especially in the termined by the mechanisms that increase hepatic fat accumulation.66
early stages, before progressing towards a multi-organ systemic meta­ Two further studies have shown the presence of at least two types
bolic failure that compromises global energy homeostasis. Below, we of MASLD with similar hepatic phenotype but diverging pathogenic me­
present the main systemic manifestations of SMD that are included in chanisms and clinical trajectories; one type is systemic and confers in­
our proposed staging system. creased risk for ASCVD, heart, and kidney failure, while a second
type is liver specific and protects against ASCVD.67,68
Insulin resistance, pre-diabetes, and Type Besides the quantity, the composition of hepatic lipids also influences
2 diabetes the risk of progression of MASLD.69 Hepatic levels of saturated, mono­
Systemic insulin resistance emerges due to diminished sensitivity to insulin unsaturated, and, to a lesser extent, polyunsaturated fatty acids are in­
across one or more organs, compensated by increased plasma insulin le­ creased in those with MASLD.70 Among sphingolipids, ceramides are
vels to maintain euglycaemia.42 Insulin resistance usually precedes the on­ present at higher levels in the liver in people with MASH,71 and targeted
set of common forms of Type 2 diabetes, which generally manifest with overexpression of acid ceramidase reduces liver steatosis in mice.72
peripheral and hepatic insulin resistance.43 Hyperglycaemia occurs when Increases in hepatic sphingolipids are associated with increased oxida­
insulin secretion from the pancreatic beta cells becomes insufficient to tive stress and lipid peroxidation,73 potentially important causal media­
overcome insulin resistance.44 Pre-diabetes is an intermediate state be­ tors for MASLD progression. Similarly, diacylglycerols, which are also
tween normal glucose tolerance and Type 2 diabetes. Impaired fasting glu­ elevated in MASLD,70 might contribute to MASLD progression by pro­
cose, defined as a fasting plasma glucose level in the pre-diabetes range, is moting lipotoxicity.74–76 Future studies are needed to determine
primarily associated with hepatic insulin resistance.45 Impaired glucose tol­ whether and how lipid quality is causally related to MASH susceptibility
erance, defined as a plasma glucose level 2 h after an oral glucose toler­ in humans.
ance test (OGTT) in the pre-diabetes range, is primarily associated with
muscle insulin resistance.45
Insulin resistance, even in the absence of dysglycaemia or pre-diabetes,
Hypertension
is predictive of several cardiometabolic traits, such as endothelial dysfunc­ The pathophysiology of hypertension involves several inter-related fac­
tion, hypertension,46 chronic kidney disease (CKD),47 steatotic liver dis­ tors, of which salt intake, obesity, and insulin resistance are the most
ease,48 left ventricular diastolic dysfunction,49 and ASCVD.50,51 Multiple relevant in the context of SMD.77 Visceral adipose tissue produces nu­
causal mechanisms underlie these associations, including dysregulation merous pro-oxidative and pro-inflammatory mediators that reduce in­
of the sympathetic nervous system and the renin–angiotensin–aldoster­ sulin sensitivity predominantly in muscle and liver, thereby contributing
one system (RAAS), maladaptive immune responses, and/or disturbed to compensatory increased circulating insulin levels.78,79 However, at
mitochondrial function, which induce tissue fibro-inflammation and oxida­ the level of the kidney, sensitivity to the tubular sodium-resorptive ac­
tive stress.52,53 These abnormalities are further exacerbated by Type 2 tions of insulin may be preserved. Additionally, insulin resistance results
diabetes, with an increased risk of ASCVD, MASLD-related cirrhosis, in paradoxical hyperactivity of sympathetic nerves within the kidney and
and heart failure.54–56 This phenomenon is driven by various factors, in­ increased levels of angiotensin-II and aldosterone, all of which enhance
cluding the detrimental effects of chronic hyperglycaemia (glucotoxicity) tubular sodium reabsorption in the presence of hyperinsulinaemia.80,81
and lipid-induced toxicity on vascular function and cardiomyocytes.57 As a result, hyperinsulinaemia can contribute to hypertension by sev­
eral mechanisms that promote sodium retention by the kidney.
Obesity is also associated with the activation of RAAS and the sym­
Metabolic dysfunction–associated pathetic nervous system.80–82 The resulting neurohormonal activation
steatotic liver disease is an essential contributor to the elevation of systemic blood pressure.
Metabolic dysfunction–associated steatotic liver disease (also known as Moreover, fat within and around the kidney itself causes organ com­
metabolic dysfunction–associated fatty liver disease) is characterized by pression, which increases blood pressure.83 Once kidney damage
Clinical staging to guide management of metabolic disorders 5

occurs in the context of obesity, these neurohormonal abnormalities, The relationship between lipid abnormalities and insulin resistance is
along with vascular calcification and arterial stiffness, may exacerbate key in atherogenic dyslipidaemia. Insulin resistance causes a marked dys­
hypertension by further augmenting sodium retention and increasing regulation of lipolytic activities, particularly in adipose tissue, resulting in
systemic vascular resistance.84 Additionally, atherosclerosis can affect a net increase in the release of free fatty acids (FFAs).90–92 Elevated
the kidney arteries, which, in association with flow-limiting ischaemia, FFAs, together with hyperglycaemia and hyperinsulinaemia, drive
can lead to resistant hypertension and kidney failure.85,86 Although a VLDL production, raising total cholesterol and triglyceride levels.93,94
direct causal relationship between MASLD and hypertension has not A decrease in LPL activity further contributes to increased triglyceride
been established, some have hypothesized that MASLD contributes levels. Cholesteryl ester transfer protein becomes activated, transfer­
to hypertension via low-grade chronic inflammation and hepatic insulin ring cholesterol from HDL particles to TRLs. This process leads to

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resistance.87 the formation of small, dense HDL particles, which are cleared faster,
lowering HDL levels.95 Increased production of TRLs (both VLDL
and chylomicrons) and impaired lipolysis of TRL remnants contribute
Atherogenic dyslipidaemia to postprandial dyslipidaemia.89 These combined changes exacerbate
Most people with SMD have atherogenic dyslipidaemia, which is char­ atherogenic risk.
acterized by: (i) elevated levels of apolipoprotein B (apoB)–containing Epidemiologic and genetic studies indicate that elevated levels of TRL
very low-density lipoproteins (VLDLs) and chylomicrons [produced remnants and apoB are causally related to the development of athero­
by the liver and intestine, respectively, and collectively termed sclerosis.96 Moreover, a recent study has shown that the per-particle
triglyceride-rich lipoproteins (TRLs)] and TRL remnants, (ii) an in­ atherogenicity of TRLs and TRL remnants appears to be greater than
creased number of small-dense LDL particles, which are more suscep­ that of LDL,97 which may, in part, explain the lipid-related excess risk
tible to oxidation, and (iii) low levels of HDL-cholesterol in plasma. of ASCVD beyond LDL-cholesterol. The atherogenicity of plasma
Atherogenic dyslipidaemia arises from a low hepatic uptake of lipopro­ triglycerides per se is less clear. However, epidemiological studies
teins, increased de novo lipogenesis driven by hyperinsulinaemia in the have shown that moderate elevation of plasma triglycerides [2.3–
context of selective insulin resistance, insufficient fatty acid oxidation, 5.7 mmol/L (200–500 mg/dL)] is a marker of accumulation of TRL
overproduction of VLDL, impaired lipoprotein lipase (LPL)–mediated remnants and may help to identify people at higher risk for ASCVD
lipolysis, and reduced uptake of TRL remnants by the liver88 and all-cause mortality.98,99 A recent study using machine learning iden­
(Figure 1). Increased production of chylomicrons and impaired lipolysis tified plasma triglycerides, but not Type 2 diabetes, as an independent
of chylomicron remnants contribute to postprandial dyslipidaemia.89 predictor of MASLD.100 TRL accumulation is also a causal risk factor for

Figure 1 Overview of the development of atherogenic dyslipidaemia. (A) In the physiological state, the liver produces triglyceride-rich apolipoprotein
B100-containing very low-density lipoprotein (VLDL). Triglycerides in these particles are hydrolyzed by lipoprotein lipase (LPL) to release free fatty
acids (FFA). Both angiopoietin-related protein 3 (ANGPTL3) and apolipoprotein C-III (apoCIII) are endogenous inhibitors of LPL. Delipidation of
VLDL results in the formation of triglyceride-rich lipoprotein (TRL) remnants, which are further delipidated to become LDLs. LDL is taken up by
the liver through the LDL receptor (LDLR) and thereby removed from the circulation. (B) Atherogenic dyslipidaemia is characterized by increased
hepatic de novo lipogenesis (DNL) and secretion of larger, more triglyceride-rich VLDL from the liver, impaired LPL–mediated lipolysis, and reduced
uptake of LDL. All these factors lead to increased accumulation of TRL remnants and LDL. Both LDL and TRL remnants can transverse the endothelium
and contribute to lesion initiation and progression in artery walls
6 Romeo et al.

low-grade inflammation,101 further augmenting the pro-atherogenic antibody targeting IL-1β, provided proof of concept for the inflamma­
processes (see below). tion hypothesis of atherothrombosis.124 Of note, mortality was not re­
Recent studies have highlighted a role for angiopoietin-related pro­ duced in this study, possibly due to the higher incidence of infectious
tein 3 (ANGPTL3) and apolipoprotein C-III (apoCIII) in the develop­ complications.124 Recent data indicate that virtually all auto-
ment of atherogenic dyslipidaemia.102,103 Both proteins inhibit LPL inflammatory disorders, including diverse disorders such as psoriasis,
(Figure 1), but they also have other actions in the liver and adipose tissue rheumatoid arthritis, systemic lupus erythematosus, and inflammatory
that are less understood.104,105 In the ARIC study, both plasma apoCIII bowel disease, are associated with premature atherosclerotic
and ANGPTL3 were positively and significantly correlated with TRL events.125,126 Inflammation is thus well established as a crucial target
remnant-cholesterol and LDL-triglycerides, two biomarkers of dys­ for improved cardiometabolic health. However, it is important to target

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functional triglyceride metabolism.106 Of particular note, this study the immune systems in a way that prevents an increase in infections.
showed that ANGPTL3 levels were predictive of increased risk for
ASCVD events, independent of traditional risk factors. Genetic studies Heart failure
provide further support for the role of these proteins in atherogenic
Insulin resistance, Type 2 diabetes, hypertension, atherogenic dyslipidae­
dyslipidaemia. People with loss-of-function mutations in genes encoding
mia, and inflammation, all associated with obesity as noted above, increase
ANGPTL3 or apoCIII experience accelerated removal of TRLs and TRL
the risk of heart failure by promoting atherosclerosis, leading to epicardial
remnants during the postprandial phase.107,108
coronary artery disease and myocardial infarction. Ischaemic myocardial
Other members of the ANGPTL family are also involved in lipoprotein
injury is followed by left ventricular remodelling and dilatation, promoting
metabolism and insulin resistance. These include ANGPTL4, which is se­
a decline in left ventricular ejection fraction and, subsequently, heart failure
creted mainly in the adipose tissue and acts as a local inhibitor of LPL, and
with reduced ejection fraction (HFrEF) or heart failure with mildly re­
ANGPTL8, which is secreted by the liver and adipose tissue and forms a
duced ejection fraction (HFmrEF).
complex with ANGPTL3 that inhibits LPL.109 Mice overexpressing
More recently, a unique and potent direct association between obes­
ANGPTL4 in adipose tissue show a predisposition to liver steatosis110
ity and heart failure with preserved ejection fraction (HFpEF) has been
and ANGPTL8 levels were found to be elevated in humans with
identified, common in people without a history of myocardial infarction
MASLD.111 Furthermore, levels of ANGPTL4, but not ANGPTL3, are re­
or flow-limiting epicardial coronary artery disease. Epidemiological
duced by Roux-en-Y gastric bypass, possibly due to the loss of fat mass.112
studies have identified a robust independent relationship between in­
Taken together, these findings indicate that apoCIII and ANGPTLs con­
creased BMI and HFpEF but not between BMI and HFrEF.127–130
tribute to the lipid and metabolic phenotypes associated with atherogenic
Over 80% of people with HFpEF are overweight or living with obesity,
dyslipidaemia, but their precise role remains to be determined.
and HFpEF is projected to become the dominant form of heart failure in
the near future.131,132
Inflammation In contrast to atherosclerotic vascular diseases, the link between
obesity and HFpEF is not explainable by traditional cardiovascular risk
People with visceral adiposity and insulin resistance often have an
factors alone. Obesity contributes to HFpEF via a range of mechanisms,
underlying pro-inflammatory phenotype that contributes to an ele­
including harmful effects on myocardial structure and function, haemo­
vated risk of ASCVD.113,114 Systemic inflammation is triggered by: (i) in­
dynamic changes, neurohormonal activation, and inflammation, leading
creased levels of pro-inflammatory lipid species in adipose tissue, which
to increased left ventricular filling pressures, and through obesity-
promote cellular stress and Toll-like receptor signalling in adipocytes
associated comorbidities such as type 2 diabetes, hypertension, coron­
and local macrophages, further promoting the recruitment of inflam­
ary artery disease, and sleep apnoea (see Box 1).131–134
matory macrophages115,116; (ii) tissue hypoxia, cell death, and mechan­
While all people with HFpEF share haemodynamic abnormalities of
ical stress; and (iii) gut inflammation and leakage leading to the release of
increased filling pressures and resultant tissue congestion, the initiating
bacterial metabolites into the circulation.117 Activation of the canonical
mechanism leading to HFpEF differs. Multiple lines of evidence suggest
NOD, LRR, and pyrin domain–containing protein 3 (NLRP3) in inflam­
that HFpEF results from a combination of pathophysiological pheno­
matory macrophages and adipocytes drives the production of
types that converge to produce the common haemodynamic signature
pro-inflammatory cytokines such as tumour necrosis factor-α and
of elevated left ventricular filling pressure at rest or with exercise (see
interleukin (IL)-1, which in turn increases IL-6 production thereby pro­
Supplementary data online, Table S1).131
moting systemic inflammation.118 Similarly, excess lipid accumulation in
Heart failure with preserved ejection fraction is more prevalent in wo­
the liver is sensed by Kupffer cells (resident macrophages) and recruited
men than in men, and compared with men, women with HFpEF tend to
macrophages that acquire a pro-inflammatory phenotype and propa­
be more symptomatic, with more severe dyspnoea and worse overall
gate hepatic inflammation, thereby contributing to metabolic rewiring
health status. However, men with HFpEF have a higher risk of mortality
of lipid metabolism.119 In addition, chronic lipotoxic stress promotes
and hospitalization. Some diagnostic parameters for HFpEF also differ
senescence in hepatocytes; MASLD severity increases in parallel with
by sex, with more frequent concentric left ventricular remodelling,
the accumulation of senescent hepatocytes, and reducing the burden of
more impaired left ventricular relaxation, and higher diastolic stiffness in
senescent hepatocytes has been shown to suppress fibro-inflammatory
women than men. Women also tend to have a smaller left ventricular
liver damage in mice.120
chamber size and a higher left ventricular ejection fraction. Therefore,
Studies from nearly 30 years ago showed that low-grade systemic in­
using sex-independent definitions of ‘normal’ ejection fraction results in
flammation, detected either by IL-6 or the downstream biomarker
an underestimation of left ventricular dysfunction in women.132
high-sensitivity C-reactive protein (hsCRP), predicts incident Type 2
diabetes.121,122 Mendelian randomization studies provided support
for a causal role of IL-6 receptor signalling in the development of cor­ Kidney disease
onary heart disease.123 Moreover, CANTOS, a placebo-controlled, The CKD phenotype associated with SMD is characterized by a high
randomized trial to test canakinumab, a therapeutic monoclonal urine albumin-to-creatinine ratio (UACR) and/or a low estimated
Clinical staging to guide management of metabolic disorders 7

glomerular filtration rate (eGFR). Excess adiposity promotes kidney bidirectional association between dysfunction of the heart and the kid­
damage through both direct and indirect effects.84,135–137 Mendelian neys is well established.143 Excess and dysfunctional adipose tissue,
randomization analyses provide evidence for a causal link between leading to inflammation and metabolic abnormalities as described in
obesity and kidney disease.138 Histological studies show that the earlier sections, greatly increases the risk for developing both cardiovas­
most common forms of CKD in people with obesity reflect overlapping cular disease and CKD,144 and these abnormalities have foundational
pathologies associated with diabetes, hypertension, and focal segmental pathophysiologic roles in bidirectional cardiovascular–kidney interac­
glomerulosclerosis.136 The latter lesion may be directly obesity related, tions. Notably, kidney dysfunction is a major driver of both ASCVD
driven by intra-glomerular hypertension leading to enlarged hyper- and heart failure.145,146 Hence, the American Heart Association has
filtrating glomeruli. These glomerular haemodynamic disturbances are placed particular emphasis on the role of the kidney in the cardiovascu­

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exacerbated indirectly by diabetes and hypertension, common shared lar–kidney–metabolic syndrome and has introduced a staging sys­
risk factors for CKD and ASCVD.139 Additionally, excess adiposity dys­ tem4,142 that includes designations of moderate, high, and very
regulates the production of adipokines (e.g. leptin, resistin, and adipo­ high-risk CKD, as defined by the Kidney Disease Improving Global
nectin) and pro-inflammatory mediators (e.g. tumour necrosis Outcomes (KDIGO) heat map.147
factor-α, IL-6, angiotensinogen, and aldosterone) that incite injury in
the vasculature and kidney.140,141
The American Heart Association has introduced the concept of a Systemic metabolic disorder
cardiovascular–kidney–metabolic syndrome to describe the complex
pathophysiologic interactions among obesity, CKD, and total cardiovas­
staging, prevalence of systemic
cular risk, including both ASCVD and heart failure.4,142 The metabolic disorder, and risk
conferred by systemic metabolic
disorder
Box 1 Mechanisms and conditions As indicated above, the individual SMD components do not appear in iso­
through which obesity contributes to lation, and there are many bidirectional associations between them. Given
heart failure with preserved ejection that a person with SMD will likely have more than one comorbidity, it is,
fraction therefore, essential to take a holistic approach to clinical management. To
facilitate this process, we propose a staging system for SMD, as shown in
• Myocardial stiffness and increased chamber stiffness due to struc­ Box 2, that we use to guide actionable management of SMD as it pro­
tural myocardial change, which may or may not be associated gresses. Stage 1 is characterized by metabolic abnormalities before organ
with hypertension damage, Stage 2 is characterized by early organ damage, and Stage 3 is
• A pro-inflammatory state associated with visceral adiposity with characterized by more advanced organ damage. The defining criteria
resultant coronary microvascular endothelial dysfunction and in­ for each SMD stage are described in more detail in the next section.
creased oxidative stress, which can lead to cardiomyocyte hyper­
trophy and fibrosis and to interstitial fibrosis To investigate the burden of SMD in the general population, we used
• Increased blood volume resulting in greater cardiac filling our proposed staging system to calculate the prevalence of SMD Stages
pressures 1 and 2 in European participants of the UK Biobank (aged 40–69 years).
• Increased cardiac output, stroke volume, stroke work, and hyper­ We did not calculate the prevalence of SMD Stage 3 as the UK Biobank
tension, which can lead to left ventricular hypertrophy or remod­ is a prospective cohort more suited to estimate the risk of future dis­
elling, including both concentric and eccentric left ventricular ease and did not include many participants with organ damage at base­
hypertrophy/remodelling
line. Systemic metabolic disorder Stage 1 was observed in 58% of the
• Right ventricular dilatation and dysfunction
• Increased epicardial fat causing right ventricular dysfunction population (Figure 2); the most common SMD features were over­
• Increased pericardial restraint and ventricular interdependence weight and dyslipidaemia (present in 96% and 91%, respectively, of
(mechanical factors) those with Stage 1) followed by liver steatosis (52%) and hypertension
• Left atrial remodelling (left atrial myopathy) and atrial fibrillation (48%). Only 18% with Stage 1 SMD had pre-diabetes; the percentage
• Increased myocardial work and decreased efficiency with increas­ with insulin resistance would likely be higher but proxies of this compo­
ing BMI and insulin resistance, possibly related to greater myocar­ nent are not available in the UK Biobank. When comparing
dial reliance on fat metabolism versus glucose oxidation
• Decreased exercise capacity (reduced peak oxygen consump­
tion) related to decreased myocardial and skeletal muscle meta­
bolic efficiency and increased filling pressures with exercise Box 2 Definition of each stage of
• Impaired venous capacitance with resultant increased stressed
blood volume resulting in increased filling pressures systemic metabolic disorder
• Sympathetic activation with blood volume redistribution from • Stage 1 is defined as the presence of (i) insulin resistance/pre-
the splanchnic to the intravascular space diabetes alone or (ii) overweight/dysfunctional adiposity and at least
• Autonomic dysfunction leading to chronotropic incompetence one of the following traits: isolated liver steatosis, hypertension, or
• Activation of RAAS and direct action on the adrenal gland result­ atherogenic dyslipidaemia
ing in increased release of aldosterone • Stage 2 is defined as Type 2 diabetes, asymptomatic diastolic dys­
• Diabetic cardiomyopathy function, MASH/fibrosis, albuminuria or CKD Categories 1–2, or
• Sleep apnoea, which increases risk of hypertension and atrial sub-clinical atherosclerosis with no history of events
fibrillation • Stage 3 is defined as symptomatic HFpEF, cirrhosis/liver failure, re­
• Epicardial coronary artery disease with minor or no ischaemic duced kidney function/failure and CKD Categories 3–5, or clinical
myocardial damag manifestation of ASCVD
8 Romeo et al.

A B

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Figure 2 Prevalence of systemic metabolic disorder Stages 1 and 2 among Europeans from the UK Biobank. (A) Stage 1 was defined as individuals with
pre-diabetes alone (HbA1c 39 to ≤47 mmol/mol; fasting insulin measurements were not available) or overweight (either body mass index ≥25 or waist
circumference ≥88/102 cm female/male) with at least one of the following conditions: liver steatosis (fatty liver index ≥60), hypertension (systolic blood
pressure >140 or diastolic blood pressure >90 mmHg), and dyslipidaemia [non-fasting circulating triglycerides ≥2.0 mmol/L (177 mg/dL) or non–
HDL-cholesterol ≥3.4 mmol/L (131 mg/dL) or apolipoprotein B ≥3.9 µmol/L (100 mg/dL)]. Individuals taking anti-hyperglycaemic medications or
with self-reported diabetes at baseline were excluded from Stage 1. Stage 2 was defined as individuals with at least one of the following conditions:
Type 2 diabetes (HbA1c ≥48 mmol/mol), asymptomatic diastolic dysfunction (B-type natriuretic peptide or N-terminal-pro-B-type natriuretic peptide
plasma Normalized Protein eXpression levels ≥95th percentile), metabolic-associated steatohepatitis/fibrosis (Fibrotic NASH Index score >0.33), al­
buminuria and chronic kidney disease Categories 1–2 (estimated glomerular filtration rate ≥60 mL/min per 1.73 m2 and urine albumin-to-creatinine
ratio 3–29 mg/mmol), or atherosclerosis with no history of events (5 ≤ Systematic Coronary Risk Evaluation < 10% using the coefficients corresponding
to low-risk individuals). Individuals who met the criteria for both stages were excluded from Stage 1. (B) Prevalence of each condition within individuals
with either systemic metabolic disorder Stage 1 or 2. T2D, Type 2 diabetes; ADD, asymptomatic diastolic dysfunction; MASH, metabolic-associated stea­
tohepatitis; CKD, chronic kidney disease.

combinations of SMD features, most people with Stage 1 SMD had 14.9 years in the UK Biobank. Stage 1 conferred a 6% prospective in­
both overweight and dyslipidaemia, followed by those with overweight, crease, while Stage 2 conferred a 49% increase in mortality after adjust­
dyslipidaemia and liver steatosis, and overweight, dyslipidaemia, liver ment for sex and age (Figure 3).
steatosis, and hypertension (see Supplementary data online, Figure S1).
Systemic metabolic disorder Stage 2 was observed in 19% of the
European UK Biobank population; the most common SMD feature was Defining criteria for each stage of
sub-clinical atherosclerosis (present in 59% of those with Stage 2), which
parallels the high prevalence of atherogenic dyslipidaemia observed in
systemic metabolic disorder
Stage 1 and is not unexpected given that ASCVD is the leading cause of The defining criteria for each SMD stage and the clinical variables that
death in the population, followed by CKD (present in 42% of those should be measured in a person with SMD are summarized in Figures
with Stage 2) (Figure 2). Metabolic-associated steatohepatitis and asymp­ 4–6. Below, we describe the diagnostic tools and/or biomarkers that
tomatic diastolic dysfunction were present in 30% and 29%, respectively, can be used to assess each SMD component.
whereas Type 2 diabetes was only present in 18% of those with Stage 2
(Figure 2). Our observation that CKD is more prevalent than Type 2 dia­
betes in this population is consistent with obesity acting as a major driver Insulin resistance, pre-diabetes, and Type
of CKD. Interestingly, most early signs of organ damage were present only 2 diabetes
in one organ (see Supplementary data online, Figure S1), which is likely due The gold standard for evaluating insulin resistance, namely the
to an individual predisposition to develop disease in a particular organ. The hyperinsulinaemic-euglycaemic clamp technique,148 is impractical for
most common combination was Type 2 diabetes and MASH. regular large-scale clinical practice. Hence, surrogate markers for insulin
Stage 1 is likely dependent on metabolic insults that are potentially resistance have been proposed, the best known of which is the
reversible by lifestyle interventions; in addition, functioning allostatic/ Homeostasis Model Assessment of Insulin Resistance (HOMA-IR),149
homeostatic responses help to contain progression. Stage 2 likely re­ calculated using the formula: [fasting plasma insulin (mU/L) × plasma
presents increased inflammation and failure of allostatic/homeostatic fasting glucose (mmol/L)]/22.5. A value of 2.5 or higher is considered
mechanisms, leading to failure of the cells and resultant cellular injury, to indicate insulin resistance.150 Additional surrogate markers include
thus initiating fibro-inflammatory changes with some organs preferen­ the triglyceride-glucose index151 and triglyceride to HDL-cholesterol
tially affected based on their genetic/epigenetic vulnerability.9 ratio,152 both of which are associated with risk of cardiovascular disease
To validate the clinical relevance and discriminative capacity of the independent of LDL-cholesterol.153
SMD staging, we examined the prospective association between Pre-diabetes and Type 2 diabetes can be diagnosed by measuring (i)
Stages 1 and 2 and all-cause mortality over a median follow-up of glycated haemoglobin (HbA1c), (ii) fasting plasma glucose, or (iii) plasma
Clinical staging to guide management of metabolic disorders 9

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Figure 3 Kaplan–Meier estimates of cumulative events for all-cause mortality among Europeans in the UK Biobank with or without systemic meta­
bolic disorder Stages 1 or 2. The defining criteria used here for Stages 1 and 2 are described in the legend in Figure 2. Individuals who met the criteria for
both stages were excluded from Stage 1. All-cause mortality was defined using the date of death from record linkage to Hospital Episode Statistics
(England and Wales) and Scottish Morbidity Records. Follow-up began at the date of baseline assessment visit and ended at the date of death, loss
to follow-up, or censoring date (31 October 2022, https://biobank.ctsu.ox.ac.uk/crystal/exinfo.cgi?src=Data_providers_and_dates), whichever hap­
pened first. The median follow-up period was 14.95 years (interquartile range 14.94–14.95). Hazard ratios with 95% confidence intervals were calcu­
lated using Cox proportional hazard models for Stages 1 (grey) and 2 (orange) vs metabolically healthy (green), adjusted for age and sex. aHR, adjusted
hazard ratio; CI, confidence interval.

glucose 2 h after an OGTT (Figures 4 and 5). The OGTT consists of fat distribution.156,157 An analysis of pooled data from over 650 000
a fasting glucose blood test followed by the consumption of a 75 g white adults in 2014 showed that waist circumference was positively
glucose drink and a diagnostic glucose blood test at 120 min. This associated with mortality at all BMI levels from 20–50 kg/m2, leading
test provides information about the pancreatic reserve to compensate to the conclusion that waist circumference should be assessed in com­
for insulin resistance. bination with BMI to assess the risk of obesity-related premature
In the context of obesity, pre-diabetes is an easily measurable clinical mortality.158
manifestation of insulin resistance. However, it is important to note Given the heterogeneity of obesity and the wide variability in health
that insulin resistance can exist in the absence of dysglycaemia,51 and outcomes for any given BMI, the Lancet Commission and the EASO re­
therefore, some individuals at an early stage of SMD will not be identi­ cently proposed new frameworks for the diagnosis and staging of obes­
fied when using pre-diabetes as a proxy for insulin resistance. ity that better align with current evidence.2,3 Both initiatives focus on
Therefore, we recommend using HOMA-IR in addition to HbA1c to obesity as an adiposity-based chronic disease and emphasize its clinical
determine whether an individual is at an early stage of SMD. consequences. Moreover, both recognize that dysfunctional subcutane­
ous adipose tissue releases FFA, leading to visceral obesity and fat
deposition in other ectopic depots and associated sequelae as de­
Overweight/obesity scribed above.7 In line with this, the EASO framework states that the
Excess adiposity is most commonly assessed using the BMI (weight diagnosis of obesity should be based on the recognition of abnormal
in kilograms divided by height in metres squared). The World and/or excessive fat accumulation (anthropometric component) and
Health Organization defines overweight and obesity as BMI ≥25 and the analysis of its present and potential effects on health (clinical com­
≥30 kg/m2, respectively.154 However, given the increased risk of Type ponent).2 The framework recommends using waist-to-height ratio as
2 diabetes and ASCVD in Asian people even at a BMI ≤25 kg/m2, the the anthropometric component instead of waist circumference (in
American Diabetes Association guidelines in 2022 recommended combination with BMI) as it has shown superiority as a cardiometabolic
that a BMI ≥23 kg/m2 defines overweight in Asian people.155 A limita­ disease risk marker and is not dependent on sex-specific or ethnic dif­
tion of BMI is that it does not consider the body fat distribution or the ferences.159 The Lancet Commission used the term ‘clinical obesity’ to
amount of free fat mass, while several anthropometric (e.g. waist cir­ describe a situation in which symptoms and signs of excess adiposity are
cumference) and imaging measurements can be used to assess body present and ‘pre-clinical obesity’ as a state of excess adiposity with
10 Romeo et al.

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Figure 4 Defining criteria and potential management strategies for systemic metabolic disorder Stage 1. Conventional units: a101–124 mg/dL; b141 to
≤198 mg/dL; c150 mg/dL; d131 mg/dL: e100 mg/dL. *Non-fasting P-triglycerides ≥2.0 mmol/L (177 mg/dL). †Values shown for individuals at moderate
risk of atherosclerotic cardiovascular disease. For those at high risk of atherosclerotic cardiovascular disease, lower thresholds apply: non–
HDL-cholesterol ≥2.6 mmol/L (100 mg/dL); apolipoprotein B ≥1.5 µmol/L (≥80 mg/dL). P, plasma; WC, waist circumference; WtHR, waist-to-height
ratio; EASO, European Association for the Study of Obesity; FLI, fatty liver index; CAP, controlled attenuation parameter; MRI, magnetic resonance
imaging; BP, blood pressure; C, cholesterol; ACE, angiotensin-converting enzyme; ARB, angiotensin-II receptor blocker

preserved function of other tissues and organs but with increased risk Liver function and damage can be screened using traditional bio­
of developing clinical obesity.3 The commissioners agreed that clinical chemical markers. Several tests for liver fibrosis using combinations
assessment of obesity should include measures of adiposity in addition of non-invasive markers now exist. One example is the Fibrotic
to BMI (such as other anthropometric measures) to determine NASH Index (FNI; https://fniscore.github.io/), which has been shown
whether an individual has excess adiposity.3 to accurately identify those with MASH and MASH regression after
Some advantages and disadvantages of the different methods to as­ weight loss.161,162
sess adiposity are presented in Supplementary data online, Table S2. Liver fibrosis can be assessed by transient elastography, magnetic res­
We recommend measuring BMI combined with at least one other an­ onance elastography, or liver biopsy followed by histological evaluation
thropometric component, preferably the waist-to-height ratio, to diag­ by a pathologist. Although liver biopsy remains the gold standard to
nose excess adiposity, and cut-off points will depend on ethnicity. measure liver inflammation and fibrosis, this procedure is invasive,
not easily standardized, and occasionally associated with complications
such as bleeding.
Isolated liver steatosis and
metabolic-associated steatohepatitis Hypertension
Ultrasound can determine the presence of liver steatosis. Although Hypertension is diagnosed using widely accepted methods.163 The
widely available and easy to use, this imaging method is only qualitative 2024 European Society of Cardiology (ESC) guidelines define hyperten­
and has poor accuracy. The fatty liver index (FLI), which uses variables sion (as before) as systolic blood pressure (SBP) ≥140 mmHg or dia­
that are routinely measured in clinical practice (BMI, waist circumfer­ stolic blood pressure (DBP) ≥90 mmHg and introduce a new term:
ence, triglycerides, and gamma-glutamyl transferase), can be used to se­ elevated blood pressure, defined as SBP 120–139 mmHg or DBP 70–
lect individuals who should be referred for ultrasound.160 Liver fat 89 mmHg.164 This addition recognizes that the risk associated with
content can be quantitatively measured by controlled attenuation par­ high blood pressure is continuous and should be considered together
ameter, an ultrasound-based technique that is becoming more com­ with other risk factors to estimate cardiovascular risk.164 Other guide­
monly available. Magnetic resonance imaging can be used to measure lines state that cardiovascular risk is present in individuals with SBP
liver triglyceride content precisely. However, this is available only in 130–139 or DBP 85–89 mmHg if they have three or more other risk
specialized centres and does not measure qualitative changes in lipids. factors.163,165
Clinical staging to guide management of metabolic disorders 11

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Figure 5 Defining criteria and potential management strategies for systemic metabolic disorder Stage 2. Conventional units: a126 mg/dL; b200 mg/dL.
*Presence of plaques by coronary computed tomography angiography or peripheral atherosclerosis by ultrasound or angiography. P, plasma; CVD,
cardiovascular disease; DPP4i, dipeptidylpeptidase-4 inhibitor; SU, sulfonylureas; TZD, thiazolidinediones; CAC, coronary artery calcium; CKD, chronic
kidney disease; FNI, Fibrotic NASH Index; MRE, magnetic resonance elastography; FDA, US Food and Drug Administration; EMA, European Medicines
Agency

Atherogenic dyslipidaemia, helping to reclassify individuals into higher or lower risk categories
than predicted by conventional factors alone. Non-invasive techniques
atherosclerosis, and atherosclerotic to detect atherosclerosis include documentation of plaques by ultra­
cardiovascular disease sonography or coronary computed tomography (CT) angiography.173
Atherogenic dyslipidaemia is diagnosed as indicated in Figure 4. People Coronary artery calcium (CAC), which is a relatively late occurrence
can have atherogenic dyslipidaemia even when LDL-cholesterol levels in atherosclerosis, can be detected using a CT scan without contrast.
are normal. A recent study using data from the UK Biobank showed A CAC score >100 is associated with >7.5% 10-year risk of
that apoB, as a marker of the total number of atherogenic particles, ASCVD.174 Peripheral atherosclerosis can be diagnosed by ultrasound
is a more accurate marker of cardiovascular risk than is or angiography. The clinical manifestation of ASCVD is defined accord­
LDL-cholesterol or non–HDL-cholesterol.166 Although apoB is not ing to the criteria listed in Figure 6.
routinely measured in clinical practice, a growing body of evidence sup­
ports its use as a valuable tool for assessing atherogenic dyslipidaemia
and the total atherogenic lipid burden,167 which is of particular rele­ Asymptomatic diastolic dysfunction and
vance for SMD. Furthermore, given that it does not require fasting
and is relatively low cost, we strongly recommend measuring apoB heart failure with preserved ejection
and using the apoB thresholds stated in the 2019 ESC/EAS guidelines fraction
to guide clinical management.168 Asymptomatic left ventricular diastolic dysfunction is generally diag­
Sub-clinical atherosclerosis is prevalent in apparently healthy people nosed based on specific findings on echocardiography (see
in middle age due to cumulative exposure to risk factors. Risk models Supplementary data online, Table S1).
have been developed that combine information on conventional car­ The diagnosis of HFpEF is challenging. It requires the presence of
diovascular risk factors and estimate the 10-year risk of, for example: signs and symptoms of heart failure, documented left ventricular ejec­
(i) death from cardiovascular disease [Systematic Coronary Risk tion fraction ≥50% and objective evidence of cardiac structural and/or
Evaluation (SCORE)]169 and (ii) fatal and non-fatal cardiovascular functional abnormalities consistent with the presence of left ventricular
events (SCORE2).170 Imaging studies have shown that half of men diastolic dysfunction and raised left ventricular filling pressures, derived
above age 40 have sub-clinical atherosclerosis,171,172 and thus many in­ from echocardiographic measures, and elevated plasma levels of B-type
dividuals are likely at higher risk than indicated by risk models. Measures natriuretic peptide (BNP) and its N-terminal fragment (NT-proBNP)
of sub-clinical atherosclerosis may aid clinical decision-making by (see Supplementary data online, Table S1).131,132,175–180
12 Romeo et al.

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Figure 6 Defining criteria and potential management strategies for systemic metabolic disorder Stage 3

The presence of echocardiographic and natriuretic peptide indica­ fatigue, and physical limitations even in the absence of heart failure.
tors of congestion is useful to confirm the diagnosis of HFpEF. Moreover, in people living with obesity, echocardiography is often tech­
However, their absence does not exclude HFpEF due to challenges as­ nically challenging, and BNP levels are typically lower and often normal
sociated with these tests, such as technical difficulties and imprecision even in those with HFpEF.
of echocardiographic measures, especially in the presence of atrial fib­
rillation. More than 30% of people with HFpEF have normal natriuretic
peptide values, and this is a particular issue in people living with obes­
Albuminuria, estimated glomerular
ity.178,181,182 In addition, several common conditions, including older filtration rate, and chronic kidney disease
age and CKD, can cause elevated BNP or NT-proBNP in the absence Current clinical practice guidelines, consensus statements, and advi­
of heart failure. Moreover, approximately one-third of patients with sories on CKD from KDIGO, the American Diabetes Association,
HFpEF have normal left ventricular filling pressures at rest. and the American Heart Association, respectively, recommend testing
Therefore, invasive haemodynamic testing and exercise testing are of­ for UACR and eGFR at least annually and more often, e.g. three to four
ten necessary to determine whether or not an individual has HFpEF times per year, at higher KDIGO risk categories.4,142,183,184 UACR and
(see Supplementary data online, Table S1).131,132,175–180 eGFR are essential to the ongoing reassessment of heart and kidney dis­
It is also important to exclude non-cardiovascular entities that may ease risks because risk-modifying therapies are to be initiated or ad­
mimic HFpEF, such as kidney failure or nephrotic syndrome, liver fail­ justed based on risk status.
ure, lung disease and primary pulmonary hypertension and specific car­
diac diseases with similar presentation but different pathophysiology
and different disease-specific therapies, such as infiltrative cardiomyop­ Management of systemic metabolic
athies (especially cardiac amyloidosis), hypertrophic cardiomyopathy,
pericardial disease, valvular heart disease, and high output heart
disorder
failure.131,132 The primary goal of clinical management of SMD is to prevent progres­
Establishing the diagnosis of HFpEF is particularly difficult in the pres­ sion and reduce the risk of end-organ damage. Successful management
ence of obesity, which is often associated with symptoms of dyspnoea, requires an individually tailored approach where the importance of
Clinical staging to guide management of metabolic disorders 13

lifestyle changes cannot be overestimated. Our prevalence data show A recent meta-analysis reveals that short-term carbohydrate restric­
that over half of the UK Biobank population has Stage 1 SMD and thus clin­ tion significantly improves cardiometabolic outcomes at the 6-month
ical management should focus on: (i) reducing the number of individuals follow-up; however, these effects are not sustained beyond 12 months.203
who reach this stage and (ii) preventing the transition to Stage 2 and be­ Furthermore, total cholesterol and LDL-cholesterol have been shown to
yond. Below we describe the latest evidence supporting the use of lifestyle increase when carbohydrate intake falls below 40%.203,204 Diets with
changes and metabolic surgery to manage this complex multi-system con­ equal carbohydrate amounts but different glycaemic indexes may exert
dition and the currently recommended pharmacotherapy. Management varying effects on cardiometabolic risk factors,205 with low glycaemic in­
strategies for each SMD stage are summarized in Figures 4–6. dex diets promoting small yet significant improvements in people with
diabetes.206

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Engaging in regular physical activity enhances metabolic health by ac­
Lifestyle changes tivating key metabolic pathways, such as glycogen synthase and LPL ac­
Lifestyle changes to improve diet quality while reducing caloric intake tivity, and GLUT4 expression, independent of weight loss.207 Aerobic
and increasing energy expenditure should be considered the corner­ exercise in particular is effective at improving glucose tolerance and in­
stone of treatment for all stages of SMD. Healthy dietary patterns sulin sensitivity, making it a crucial component of any weight loss pro­
linked to lower cardiometabolic risk prioritize vegetables, minimally gramme.208 It helps to prevent reductions in serum levels of the
processed whole grains, healthy protein sources (primarily plant-based, thyroid hormone triiodothyronine (T3) and resting metabolic rate,
fish, seafood, and low-fat or fat-free dairy), liquid plant oils, and fruit.185 which are key to avoiding weight regain209 and countering skeletal
These patterns are low in added sugars, salt and sugary beverages. and bone mass loss.210 A 1-year clinical trial demonstrated that regular
A recent umbrella review of epidemiological meta-analyses showed high-volume endurance training alone (1 h/day, 6 days a week at 71% of
that greater exposure to nutrient-poor, ultra-processed food (with maximal heart rate) led to a substantial (∼40%) reduction in visceral fat
high levels of sugar, salt and saturated fat and low levels of dietary fibre) and marked improvements in glucose, lipid and insulin metabolism in
is associated with adverse health outcomes, including an increased risk middle-aged people.192,208 Aerobic exercise combined with resistance
of cardiovascular disease-related mortality, overweight/obesity, and exercise also helps to prevent the loss of skeletal muscle and bone
Type 2 diabetes.186 These findings highlight the need for a major trans­ mass.210 Reducing sedentary behaviour, i.e. reducing the awake time
formation of our entire economic system, starting with support for spent in seated, reclined or lying posture, is also essential.211–214
public health policies that discourage or de-incentivize consumption The circadian system is tightly coupled with processes controlling
of ultra-processed food. Such policies would reduce the development sleep and metabolism, and disruption of the central and peripheral
and progression of SMD with substantial benefits for population health. clocks might contribute to the exacerbation of obesity, nutritional
Evidence from the PREDIMED-Plus and CALERIE trials shows that fluxes and the development of insulin resistance.10
calorie restriction with optimal nutritional composition can lead to re­
ductions in body weight, visceral adiposity, inflammation, oxidative
stress, and blood pressure and improvements in insulin sensitivity, glu­ Metabolic surgery
cose tolerance, and lipid metabolism in people living with both normal Metabolic/bariatric surgery exerts positive effects on cardiovascular
weight and overweight.187–194 Diet-induced weight loss can lead to health by ameliorating obesity-related cardiovascular risk factors, in­
dose-dependent remission of Type 2 diabetes,195 improvements in cluding lowered blood pressure, improved lipid profiles, and enhanced
multiple cardiometabolic and CKD risk factors,191 and marked reduc­ glycaemic control, and can be considered in individuals living with severe
tions in liver steatosis and fibrosis.196 Intermittent fasting has increased obesity.
in popularity in recent years. However, a recent meta-analysis did not STAMPEDE was the first randomized controlled trial (RCT) in peo­
identify any advantage of intermittent restriction diets (combined re­ ple with Type 2 diabetes to show that metabolic surgery has durable
sults from time-restricted eating, alternate-day fasting, and the 5:2 effects on glycaemic control.215–217 A meta-analysis of RCTs comparing
diet) compared with continuous energy restriction diets.197 surgery and (pre-incretin) medical therapy after 3 years showed better
Accumulating evidence suggests that the quality of diet (i.e. beyond glucose control and a higher rate of diabetes remission after surgery.218
the quantity of calories) influences the metabolic response to caloric re­ These superior outcomes were confirmed 10 years after surgery in one
duction. Consuming a high-protein diet during weight loss therapy RCT.219 In a meta-analysis using patient-level survival data recon­
seems to eliminate the favourable effects of weight loss on insulin resist­ structed from prospective controlled trials and high-quality matched
ance.198 By contrast, consuming a diverse range of foods rich in vege­ cohort studies, surgery was associated with a 9.3-year increase in me­
table fibre, vitamins, polyunsaturated fats, phytosterols, and dian life expectancy for individuals with diabetes.220
polyphenols while maintaining low levels of salt and saturated fatty One RCT demonstrated that surgery is an effective strategy for
acids—characteristic of the Mediterranean or the Nordic diet—con­ blood pressure control in those with hypertension.221 In people with
veys additional cardiometabolic benefits.199,200 The 2021 ESC guide­ MASLD, surgery resulted in the complete resolution of steatohepatitis
lines recommend a healthy, more plant-based Mediterranean diet as in 84% after 1 year and the resolution of advanced liver fibrosis in 68%
a cornerstone of cardiovascular disease prevention in all individuals, ir­ after 5 years.222 In a retrospective study, surgery was associated with a
respective of risk level.173 LDL-cholesterol lowering is a primary goal in reduction of the 10-year adjusted risk of incident major adverse liver
dietary interventions, and relatively small reductions [in the range of and cardiovascular outcomes of 12.4% and 13.9%, respectively.223 An
0.15–0.50 mmol/L (5.8–19 mg/dL) with and without blood pressure RCT recently showed 3.5 times higher resolution of steatohepatitis
lowering] that are within reach of dietary interventions have shown with no worsening of fibrosis 1 year after surgery.224
substantial ‘dose-dependent’ cardiovascular risk reductions.201 The In a prospective controlled study, metabolic surgery reduced the risk
portfolio diet, a plant-based diet including nuts, plant protein, viscous of developing CKD and lowered albuminuria.225 In an RCT in people
fibre, and plant sterols, is another example of an effective strategy to with type 2 diabetes and early-stage CKD, remission of albuminuria
lower LDL-cholesterol.202 and CKD was more frequent after Roux-en-Y gastric bypass than after
14 Romeo et al.

medical treatment (82% vs 55% and 82% vs 48%, respectively).226 In a

Table 1 Dosing schedules for the currently prescribed
prospective cohort study, the postoperative stabilization of eGFR was
glucagon-like peptide-1 and glucagon-like peptide-1/
linked to the reduction of insulin resistance and hyperinsulinism, with glucose-dependent insulinotropic polypeptide receptor
the largest effect being in a subgroup of participants with severe insulin- agonists
resistant diabetes.227
In a recent meta-analysis including 39 observational cohort studies, Dosing schedule for Type 2
metabolic surgery was associated with a beneficial effect on cardiovas­ diabetes (and obesity)a
....................................................................................
cular mortality [hazard ratio (HR) 0.59].228 Metabolic surgery was also GLP-1 receptor agonist
associated with a reduced incidence of heart failure (HR 0.50), myocar­

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Dulaglutide 0.75–4.5 mg once weekly
dial infarction (HR 0.58), and stroke (HR 0.64). Mechanisms underlying
these cardiovascular improvements are being elucidated. Beyond mere Exenatide 5–10 µg twice daily
weight loss, metabolic adaptations contribute to enhanced insulin sen­ Exenatide 2 mg once weekly
sitivity, modulation of adipokines, and anti-inflammatory effects. (extended-release)
Metabolic surgery also improves lipid abnormalities beyond low HDL
and high triglycerides, including effects on oxidized lipoproteins, pro­ Liraglutide 0.6–1.8 mg once daily (3.0 mg/day for
obesity)
protein convertase subtilisin/kexin type 9 (PCSK9), and HDL particle
functionality.229 The ongoing BRAVE study (NCT04226664), a large Lixisenatide 10–20 µg once daily
multicentre international RCT, aims to confirm the role of surgery in Semaglutide 0.25–1.0 mg once weekly (2.4 mg/week
the secondary prevention of major adverse cardiovascular events in in­ subcutaneous for obesity)
dividuals with obesity.
Semaglutide tablet 3–14 mg once daily (50 mg/day for
obesity)
Pharmacotherapy Dual GLP-1/GIP receptor
Glucagon-like peptide-1 receptor agonists and dual agonist
and triple peptide agonists
Tirzepatide 2.5–15 mg once weekly (same for
Glucagon-like peptide-1 (GLP-1) receptor agonists are today recog­ obesity)
nized as a class of drugs with wide-ranging therapeutic potential beyond
a
Type 2 diabetes and obesity. Evidence supporting their benefits across a All are administered subcutaneously, with the exception of semaglutide tablet. All
range of SMDs, including ASCVD, HFpEF, MASH, and CKD, is de­ drugs are initiated at the lowest dose, which is then increased over several weeks to
attenuate possible gastrointestinal side effects.
scribed in detail below. The multi-organ protective effects of these
therapies appear to go beyond the ‘downstream’ measures of efficacy
for which they were developed, namely glycaemia and weight loss.230
The first-in-class GLP-1 receptor agonist, exenatide, was exendin- may limit the use of this formulation to treat obesity. A recent develop­
based and gained Food and Drug Administration (FDA) approval in ment of relevance is the orally available non-peptide GLP-1 receptor
2005 for Type 2 diabetes. The more recent GLP-1 receptor agonists agonist orforglipron, which produced dose-dependent weight reduc­
are human-based, the first being liraglutide (daily dosing) and later du­ tions of up to 14.7% in a Phase 2 trial.237 In this rapidly evolving field,
laglutide and semaglutide (weekly dosing). It is now well established that therapies under investigation also include the so-called ‘triple G’ recep­
GLP-1 receptor agonists not only reduce glycaemia but also promote tor agonists (GLP-1, GIP, and glucagon)238 and amylin agonists alone or
weight loss, albeit at higher doses. Of these, semaglutide is the most po­ combined with other gut hormone analogues,239 with the potential for
tent.231 The dual GLP-1 and glucose-dependent insulinotropic polypep­ even greater reductions in weight.
tide (GIP) receptor agonist tirzepatide has been shown to promote Definitive proof that GLP-1 receptor agonists offer cardiovascular
even greater weight loss232 and HbA1c lowering233 than semaglutide benefits beyond glucose lowering came first from trials in populations
in individuals who are overweight or obese with Type 2 diabetes. with Type 2 diabetes for liraglutide (subcutaneous 1.8 mg once
Topline results from a head-to-head trial (NCT05822830) show an daily),240 semaglutide (subcutaneous 0.5 and 1 mg once weekly),241
average weight loss of 20.2% for tirzepatide vs 13.7% for semaglutide and dulaglutide (subcutaneous 1.5 mg once weekly).242 The beneficial
in adults who are overweight or obese but without type 2 diabetes.234 effects of these therapies to reduce cardiovascular events in individuals
Liraglutide, semaglutide, and tirzepatide were approved by the FDA for who are overweight or obese and with pre-existing cardiovascular dis­
the treatment of obesity in 2014, 2021, and 2023, respectively. ease but without diabetes were proven in the landmark SELECT trial
Dosing schedules for the currently prescribed GLP-1/GIP receptor for semaglutide (subcutaneous 2.4 mg once weekly vs placebo).243
agonists for Type 2 diabetes and obesity are shown in Table 1. These Results from this trial led to the first approval by the FDA, in 2024,
drugs are mainly administered subcutaneously due to poor oral bio­ for an agent (semaglutide) for secondary prevention of cardiovascular
availability, but an oral daily formulation of semaglutide is available. A re­ disease in adults who are either overweight or obese. The dual agonist
cent trial showed that oral semaglutide 50 mg per day promotes similar tirzepatide is currently being assessed in two cardiovascular outcome
weight reductions to those observed with subcutaneous semaglutide trials. The first, SURPASS-CVOT, compares once weekly subcutaneous
2.4 mg once weekly.235 In a 68-week trial, oral semaglutide at 25 and injection of either tirzepatide up to 15 mg or dulaglutide 1.5 mg in indi­
50 mg per day was shown to be safe and more effective in terms of viduals who are overweight or obese and have diabetes and established
both HbA1c lowering and weight loss compared with the usual cardiovascular disease.244 This active comparator design, i.e. against
14 mg per day diabetes dose in individuals who were overweight and a treatment proven to reduce cardiovascular disease rather than
with diabetes.236 However, given the global shortage and cost of placebo, will provide novel insights into the role of greater weight
GLP-1 receptor agonists, the high dose required for oral administration loss and HbA1c reduction in this high-risk group.244 The second,
Clinical staging to guide management of metabolic disorders 15

SURMOUNT-MMO (NCT05556512), is in individuals who are over­ Sodium–glucose co-transporter 2 inhibitors

weight or obese; as approximately two-thirds have cardiovascular As a class, these drugs are effective agents for glycaemic control. They
risk factors without established cardiovascular disease, results from have also been shown to reduce hospitalization and cardiovascular
this trial could help to clarify the benefits of obesity management deaths across a range of left ventricular ejection fractions in individuals
with these types of therapies in a primary prevention population. with or without diabetes.256 Most heart failure data are available for da­
Direct evidence of organ protection for GLP-1 receptor agonists has pagliflozin, empagliflozin, and sotagliflozin.257–261 Earlier initiation of so­
recently emerged. In individuals with HFpEF and obesity, semaglutide dium–glucose co-transporter 2 (SGLT2) inhibitors is warranted in
reduced heart failure symptoms and improved exercise capacity in par­ individuals with heart failure, including those in hospital who have
allel with substantial weight loss (STEP-HFpEF trial), supporting a direct been stabilized.260

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role of obesity in the development of HFpEF.245 However, the symp­ Sodium–glucose co-transporter 2 inhibitors have also been shown to
tomatic benefits started to appear before maximal weight loss was have protective effects on major kidney and cardiovascular events, es­
achieved, suggesting direct effects of GLP-1 on cardiometabolic path­ pecially heart failure, in persons with CKD, with or without dia­
ways. In a similar population, tirzepatide improved symptoms of heart betes.260,262,263 Sotagliflozin has also been shown to reduce both
failure and the composite of death or heart failure hospitalization myocardial infarction and stroke in individuals with diabetes, CKD,
(SUMMIT trial).246 and cardiovascular risk factors.264 Current treatment recommenda­
Given that loss of visceral adipose tissue is accompanied by loss of tions consistently advise initiation of SGLT2 inhibitors in persons
liver fat, the logical next step was to evaluate GLP-1 receptor agonists with CKD and an eGFR as low as 20 mL/min/1.73 m2, irrespective of
as a treatment for MASLD/MASH. A Phase 2 trial showed that semaglu­ diabetes status.4,142,183,184
tide promotes the resolution of MASH but not regression of fibrosis.247
A Phase 3 trial is currently ongoing.248 In Phase 2 trials, tirzepatide249
and survodutide,250 a dual GLP-1 and glucagon receptor agonist, Other anti-hyperglycaemic drugs
were shown to be superior to placebo in terms of resolution of In addition to GLP-1 receptor agonists and SGLT2 inhibitors, Type 2
MASH without worsening fibrosis. Promising clinical safety and diabetes can be treated with metformin, sulfonylureas, meglitinides
proof-of-concept data have also been reported for HEC88473, a (repaglinide), acarbose, thiazolidinediones (pioglitazone), and
dual agonist for GLP-1 and fibroblast growth factor 21 (FGF21) recep­ dipeptidylpeptidase-4 inhibitors.54,265 Pioglitazone and metformin are
tors, in a Phase 1b/2a trial in individuals with MASLD and Type 2 dia­ insulin sensitizers and may ameliorate the adverse effects of insulin re­
betes.251 Taken together, these data are in keeping with our clinical sistance on the vessel wall directly or indirectly.
staging whereby early intervention with residual healing capacity may Except for pioglitazone, all drugs can be combined with subcutane­
be augmented or enhanced by GLP-1/GIP receptor agonists. At the ous insulin treatment. While evidence supports heart and kidney pro­
more advanced end of the spectrum with fibrosis, reversal is unlikely tection only for GLP-1 receptor agonists and SGLT2 inhibitors, safety
at present with current approaches. trials spanning the past decades indicate that other anti-hyperglycaemic
Semaglutide has also been shown to reduce the risk of major kidney drugs appear safe from a cardiovascular perspective.
and ASCVD events, including cardiovascular death and death from any
cause in individuals with Type 2 diabetes and CKD (FLOW trial).252 A
recent report showed that oral semaglutide was associated with a low­ Lipid-lowering medications
er risk of major adverse cardiovascular events in individuals with Type 2 The primary objective of lipid-lowering medications is to lower
diabetes and ASCVD, CKD, or both (SOUL trial).253 Consistent with LDL-cholesterol. However, even if the LDL-cholesterol is at goal,
obesity being a major driver of CKD, the SELECT trial showed that se­ individuals with atherogenic dyslipidaemia will still have residual cardio­
maglutide prevented CKD onset and progression in people without vascular risk due to elevated TRLs, and the ESC/EAS guidelines recom­
diabetes but with overweight or obesity and cardiovascular disease.254 mend that non–HDL-cholesterol and apoB should be secondary
In early 2025, semaglutide gained European Medicines Agency (EMA) targets of treatment.168
and FDA approval to prevent kidney function loss, kidney failure, major High-intensity statins are the first-line therapy for achieving reduc­
ASCVD events, and cardiovascular death in adults with Type 2 diabetes tions in LDL-cholesterol, apoB, and non–HDL-cholesterol, as they
and CKD. The EMA label update for semaglutide additionally includes have demonstrated robust benefits in numerous large-scale trials.168
prevention of all-cause mortality. Contemporary approaches call for combination therapy with ezeti­
One consequence of the rapid weight loss induced by GLP-1 re­ mibe, a selective inhibitor of intestinal cholesterol absorption, followed
ceptor agonists is loss of muscle mass, but the extent and implications by bempedoic acid,266 an oral agent that specifically inhibits ATP citrate
of this loss are unclear. Reductions in lean mass lost (as a percentage lyase and thereby reduces cholesterol synthesis in the liver, or therapies
of total weight lost) reported in clinical trials of GLP-1 receptor ago­ targeting PCSK9. Proprotein convertase subtilisin/kexin type 9 inhibitors
nists range from below 15% up to 60%.255 Although the associated include monoclonal antibodies, such as alirocumab or evolocumab,267,268
improvement in insulin sensitivity and lower infiltration of fat into and inclisiran,269 which relies on RNA interference mechanisms to silence
muscles may compensate partly for the loss in strength and function, hepatic PCSK9 expression. Inclisiran has been shown to promote reduc­
older adults with sarcopenia or those with CKD may be at higher risk tions of LDL-cholesterol in the range of 50%–60% and similar reductions
of adverse effects from muscle loss.255 The loss of muscle mass em­ in apoB and non–HDL-cholesterol.270 Inevitably, the choice will depend
phasizes the notion that these drugs should be accompanied by a upon drug availability and reimbursement in different parts of the world.
physical activity/exercise programme. Strength training and increased A recent open-label study in people with coronary artery disease but
protein intake can help to reduce the potential detrimental effects of not diabetes showed that metformin in combination with statins re­
muscle loss in individuals on GLP-1 receptor agonists. Thus, despite duces both the statin-induced increase in PCSK9 levels and
the benefits of these therapies they must always be accompanied by LDL-cholesterol levels.271 Although statins have been shown to confer
lifestyle changes. a slightly increased risk of new-onset diabetes, a recent meta-analysis
16 Romeo et al.

indicates that the overall benefit of statin therapy in reducing cardiovas­ antibodies targeting apoCIII and ANGPTL3; these proteins inhibit
cular events greatly outweighs the small increase in glycaemia.272 LPL (Figure 1) but likely have additional actions. Whilst these ap­
Fibrates are agonists of peroxisome proliferator-activated proaches reduce triglycerides dramatically in individuals with se­
receptor-α (PPAR-α) and regulate steps in lipid and lipoprotein metab­ vere hypertriglyceridaemia (Table 2), further studies are needed
olism. Although they are effective at lowering plasma levels of triglycer­ to establish whether targeting these pathways will result in reducing
ides and TRLs, their benefits in reducing cardiovascular risk have not the residual cardiovascular risk in individuals with SMD-related
been proven. The only agent documented to lower cardiovascular dyslipidaemia.
risk in statin-treated individuals with elevated triglycerides is high-dose In people with severe hypertriglyceridaemia, it is important to lower
icosapent ethyl (2–4 g/day).273–275 Its benefits appear independent of triglycerides to reduce the risk of pancreatitis. Fenofibrate and omega-3

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triglyceride-lowering, but the mechanisms involved remain unclear.276 fatty acids, as monotherapy or in combination, can be prescribed to
Furthermore, the recent PROMINENT study showed that pemafi­ lower triglycerides in individuals with severe hypertriglyceridaemia
brate, a new selective PPAR-α agonist that is effective at reducing [>11.4 mmol/L (1009 mg/dL)].285 Fenofibrate may be considered for
TRLs and non–HDL-cholesterol, did not reduce either apoB levels or its beneficial macro- and microvascular effects in individuals with
cardiovascular events.277 Thus, altering the composition of TRLs to SMD without ASCVD but elevated triglycerides [2.3–5.6 mmol/L
lower triglyceride levels without enhancing the clearance of (204–496 mg/dL)] despite LDL-lowering therapy.286
apoB-containing TRLs is unlikely to provide cardiovascular benefits. Finally, lipoprotein(a) is an independent risk factor for ASCVD, and it
Future therapies to treat hypertriglyceridaemia include anti­ should be taken into account when estimating cardiovascular risk and
sense oligonucleotides, siRNA-based therapies, and monoclonal treatment goals.287

Table 2 Emerging therapies for hypertriglyceridaemia

Drug Dose Mechanism of action Comments

......................................................................................................................................................................................
Volanesorsen Subcutaneous injection of ASO inhibiting apoCIII A randomized, placebo-controlled trial in 15 adults with Type 2 diabetes
300 mg once a week mRNA production (HbA1c >7.5%) and hypertriglyceridaemia [2.26–5.65 mmol/L (200–
500 mg/dL)]; volanesorsen reduced triglyceride levels by 69% after 91
days.278 Volanesorsen has been approved in EU and UK to treat familial
chylomicronaemia syndrome, and it has been shown to reduce the risk of
acute pancreatitis279
Olezarsen Subcutaneous injection of 50 GalNAc-conjugated ASO Bridge-TIMI 73a, a randomized, placebo-controlled Phase 2b trial in 154
or 80 mg every 4 weeks inhibiting apoCIII adults either with moderate hypertriglyceridaemia [1.69–5.63 mmol/L
mRNA production (150–499 mg/dL)] and elevated cardiovascular risk or with severe
hypertriglyceridaemia [≥5.65 mmol/L (500 mg/dL)]; olezarsen reduced
triglyceride levels by 53% at the highest dose and reduced the risk of acute
pancreatitis280
Plozasiran Subcutaneous injection of 10, siRNA inhibiting apoCIII SHASTA-2, a placebo-controlled, double-blind, dose-ranging, Phase 2b
25, or 50 mg on Day 1 and mRNA production randomized trial in 229 adults with severe hypertriglyceridaemia [5.65–
at Week 12 (follow-up 45.2 mmol/L (500–4000 mg/dL)]; plozasiran reduced triglyceride levels by
through Week 48) 57% at the highest dose281
A Phase 2b, double-blind, randomized, placebo-controlled trial in 353
adults with mixed hyperlipidaemia [triglycerides 1.69–5.63 mmol/L (150–
499 mg/dL) and either LDL-cholesterol ≥1.8 mmol/L (70 mg/dL) or non–
HDL-cholesterol ≥2.6 mmol/L (100 mg/dL)]; plozasiran reduced
triglyceride levels by 62% at the highest dose282
Evinacumab Intravenous injection of Monoclonal antibody A randomized, placebo-controlled Phase 2 trial; evinacumab reduced
15 mg/kg every 4 weeks targeting circulating triglyceride levels by 62% and 82% after 12 weeks in patients with
ANGPTL3 protein multi-factorial chylomicronaemia syndrome (MCS) with heterozygous
loss-of-function LPL pathway mutations [n = 15; triglycerides 11.3–
26.0 mmol/L (1000–2300 mg/dL)] and MCS without LPL pathway
mutations [n = 19, triglycerides 13.5–29.3 mmol/L (1200–2600 mg/dL)],
respectively283
Zodasiran Subcutaneous injection of 50, siRNA inhibiting ARCHES-2, a placebo-controlled, dose-ranging Phase 2b trial in 204 adults
100, or 200 mg on Day 1 ANGPTL3 mRNA with mixed hyperlipidaemia [triglycerides 1.69–5.63 mmol/L (150–
and Week 12 (follow-up production 499 mg/dL) and either LDL-cholesterol ≥1.8 mmol/L (70 mg/dL) or non–
through Week 36) HDL-cholesterol ≥2.6 mmol/L (100 mg/dL)]; zodasiran reduced
triglyceride levels by 74% after 24 weeks at the highest dose284

ASO, anti-sense oligonucleotide.

Clinical staging to guide management of metabolic disorders 17

Anti-hypertensive medications Ongoing trials are investigating the effects of IL-6 inhibition in the set­
This Consensus statement recommends anti-hypertensive therapy in line tings of CKD, dialysis, HFpEF, and acute coronary ischaemia.298
with international guidelines. The 2024 ESC guidelines recommend a tar­ Proprotein convertase subtilisin/kexin type 9 inhibitors do not have
get of <130/80 mmHg provided the treatment is well tolerated; these substantive effects on hsCRP; however, they may have local anti-
guidelines list some important exceptions and recommend the use of inflammatory benefits as they have been shown to reduce lipid content
risk stratification.164 The US guidelines also recommend treating to a tar­ in the arterial wall and macrophage content within atherosclerotic
get of <130/80 mmHg,165 but the European Society of Hypertension plaques.299,300
(ESH) guidelines recommend a target of at least <140/90 mmHg.163 In usual outpatient practice, hsCRP values <1 mg/L, 1–3 mg/L, and
First-line therapy for hypertension includes thiazide diuretics, calcium >3 mg/L reflect lower, moderate, and higher cardiovascular risk in

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channel blockers, and angiotensin-converting enzyme (ACE) inhibitors the context of other traditional risk markers. Among statin-treated in­
or angiotensin-II receptor blockers (ARBs).165,288,289 For those with dividuals, residual inflammatory risk (defined as hsCRP >2 mg/mL)
blood pressure >140/90 mmHg or more than 20/10 mmHg above the could trigger the initiation of long-term low-dose colchicine, and several
blood pressure target, two first-line classes of anti-hypertensive agents ongoing trials of novel anti-inflammatory agents are using hsCRP
are recommended. Specific high-risk groups may require a more stringent >2 mg/L as a core enrolment criterion.
target. For example, for adults with hypertension and ASCVD or a
10-year ASCVD risk of ≥10%, a target of <130/80 mmHg is recom­ Pharmacotherapy for metabolic dysfunction–
mended.165 In persons with CKD, a lower target of <120/70 mmHg is re­ associated steatotic liver disease
commended if it can be achieved safely.288 However, this lower target is Resmetirom, a beta-selective thyroid hormone receptor agonist, re­
not recommended by all scientific societies; the ESH guidelines, for ex­ cently received a fast-track FDA approval as the first specific treatment
ample, recommend a less stringent target.163 for MASLD. In a Phase 3 study, resmetirom 80 mg was shown to re­
Angiotensin-converting enzyme inhibitors or ARBs (but not com­ duce liver fibrosis at least one stage, promote resolution of MASH,
bined) are indicated if albuminuria or heart failure is present. and reduce levels of LDL-cholesterol levels by 14%, triglycerides by
Mineralocorticoid receptor antagonists are particularly effective for 20% and lipoprotein(a) by 30%.301 However, evaluation of clinical event
resistant hypertension, and beta-blockers may be preferentially outcomes (e.g. decompensated cirrhosis, liver transplant, cardiovascu­
used in those with HFrEF. Alpha-1 blockers are considered second- lar disease, and mortality) is still lacking, and resmetirom is not yet ap­
or third-line therapies that may be helpful in men with prostatism. proved for MASLD in Europe.
The 2024 ESC guidelines also recommend the use of renal denerv­ The FGF21 analogue pegozafermin is currently in development for
ation to treat resistant hypertension in people with uncontrolled the treatment of severe hypertriglyceridaemia and MASLD.302 In a
blood pressure, despite the use of three or more blood pressure- Phase 2b trial, it has been shown to improve fibrosis in individuals
lowering drugs.164 with biopsy-conformed MASH and moderate or severe fibrosis.303

Anti-inflammatory drugs Convergent recommendations

Statin therapy lowers both atherogenic LDL-cholesterol and hsCRP,
the primary biomarker for low-grade systemic inflammation.290
with other position statements
However, residual inflammatory risk after initiation of statin therapy Given the recent dramatic rise in obesity and related health risks to­
is underappreciated and undertreated. In a recent analysis of 31 245 gether with the recognition of metabolic heterogeneity, improved clas­
adults with atherosclerosis receiving guideline-directed medical care, in­ sification and management strategies for SMD are required. In our EAS
cluding high-intensity statins, residual inflammatory risk (as detected by consensus statement, we provide a clinically actionable framework,
on-treatment hsCRP) was strongly associated with recurrent cardio­ namely a three-stage system, based on the underlying pathophysiology
vascular events, cardiovascular death and all-cause mortality.291 of SMD. We define criteria and management strategies for each of the
Until recently, the only recommendations to lower inflammation three stages, centred on the progression of disease across multiple or­
were to increase exercise and improve diet. However, based on results gans and the importance of early treatment and of treating more than
from the CANTOS,124 LoDoCo2,292 and COLCOT293 trials,294 the US one pathology. We used our staging system to calculate the prevalence
FDA approved low-dose colchicine as an anti-inflammatory therapy to of SMD Stages 1 and 2 in European participants of the UK Biobank.
lower cardiovascular risk. The 2021 ESC guidelines on cardiovascular As noted earlier, other recent position papers (including those
disease prevention, the 2023 ESC guidelines for the management of from EASO,2 the Lancet Commission,3 and the American Heart
acute coronary syndromes and the 2024 ESC guidelines for the man­ Association4) have proposed staging systems to describe the progres­
agement of chronic coronary syndromes now recommend low-dose sion of risk and to guide clinical management. The EASO presents a new
colchicine (0.5 mg orally once daily) for secondary prevention in se­ framework for the diagnosis, staging and management of obesity,2 and
lected high-risk individuals with suboptimal control of risk fac­ the Lancet Commission has introduced a two-stage system to differen­
tors.173,295,296 The benefit of anti-inflammatory therapies in primary tiate between clinical and pre-clinical obesity.3 The American Heart
prevention remains to be established from outcome trials. Even in sec­ Association has placed emphasis on the kidney by introducing the con­
ondary prevention, it should be noted that daily treatment with colchi­ cept of the cardiovascular–kidney–metabolic syndrome; the authors
cine started soon after myocardial infarction and continued for a present a four-stage system that aims to identify individuals at early
median of 3 years did not reduce the incidence of major adverse cardio­ stages of this syndrome and prevent progression to cardiovascular
vascular events in the recent CLEAR SYNERGY trial,297 suggesting that disease.4
it does not have a role in routine treatment following a myocardial in­ Below we indicate how recommendations for diagnosis and manage­
farction. It could, however, be considered in more stable secondary ment of SMD described in our EAS consensus statement align and con­
prevention settings. verge with those from these recent position statements.
18 Romeo et al.

Redefining diagnosis of obesity markers in the myocardium (including left ventricular fibrosis) may
Body mass index alone does not provide information about the health add a new actionable dimension to the prevention of heart failure.
status of an individual. Body mass index measurement should be com­
bined with at least one other anthropometric component (e.g. waist Polygenic risk scores
circumference), and cut-off points should be appropriate for ethnicity. The identification of the genetic basis of SMD components through
large GWAS led to the development of polygenic risk scores
Comprehensive and inter-disciplinary (PRS)—the weighted sums of disease-associated variants that quantify
evaluation of other metabolic risk factors the overall burden of risk due to multiple risk variants across the gen­

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ome inherited by each individual.17 Increasingly large GWAS over the
Dysfunctional subcutaneous adipose tissue releases FFA, leading to vis­
past decade have resulted in the development of PRS for SMD compo­
ceral obesity and fat deposition in other ectopic depots. Central to this
nents and disease outcomes, including obesity,306 Type 2 diabetes,307
process is insulin resistance and accompanying atherogenic dyslipidae­
hypercholesterolaemia,17 coronary artery disease,17,307–310
mia, increased blood pressure, and low-grade chronic inflammation. 311,312 61,67,313
CKD, , MASLD, and cirrhosis. These PRS have been
Collective assessment of inter-related risk factors is essential to enab­
shown to associate with large increases in the odds of metabolic abnor­
ling a whole-body approach to prevention. Therefore, individuals with
malities and to identify individuals at an increased risk of disease, com­
excess adiposity should be screened before disease progression for
parable to those in carriers of monogenic variants.309,310,314–317
multiple metabolic risk factors.
Furthermore, PRS have been shown to improve risk stratification inde­
pendently of other risk factors, both genetic and non-genetic. For ex­
Recognition and management of systemic ample, PRS were shown to identify individuals with increased risk of
metabolic disorder as a progressive cardiovascular disease even among carriers of monogenic rare variants
pathophysiology causing familial hypercholesterolaemia.309 Similarly, it has been shown
The progressive pathophysiology of obesity-related metabolic compli­ that PRS provide independent information and can improve risk predic­
cations leads to a stepwise increase in the risk of organ damage asso­ tion compared to the use of clinical and lifestyle risk factors.17,23,308 A
ciated with later stages. The staging systems help clinicians decide PRS for MASLD-related fibrosis has been shown to refine risk stratifi­
how to manage SMD at the different stages, recognize that other or­ cation and prediction calculated by non-invasive tests.313
gans might be involved, and indicate when treatment should be inten­ In addition, studies indicate that PRS can predict the absolute and
sified. Lifestyle changes, focusing on improvements in the quality of relative benefits of pharmacological therapies and lifestyle
diet and increased physical activity, are recognized as the cornerstone changes.23,314,318 For example, in one study individuals with a high
of obesity management at all stages. Multiple risk factors should be as­ PRS for coronary artery disease (above the 90th percentile) experi­
sessed at each stage and treated appropriately. enced a greater risk reduction in major adverse cardiovascular events
and mortality when treated with a PCSK9 inhibitor.319 Similarly, a
PRS for Type 2 diabetes was predictive of treatment responsiveness
Future perspectives to sulfonylureas.320 Finally, since the genotype does not change
throughout a lifetime, PRS, unlike clinical risk factors, can be ascertained
Estimating the risk of systemic metabolic early in life (even at birth) and can be used to identify individuals at high
disorder progression risk of SMD, even before overt clinical symptoms are present. Thus,
Clinical risk scores PRS can potentially identify at-risk individuals at an early stage of
SMD, allowing high-risk individuals to benefit from early lifestyle inter­
The development of future risk scores to predict the likelihood of SMD
ventions and preventive treatments.
progression may aid clinical decision-making and offer personalized ap­
Although PRS are poised to improve risk prediction and outcomes
proaches. Several factors should be considered. First, lifestyle variables
via personalized treatment strategies, several challenges remain before
offer the potential to identify dynamic and personalized modifiable risk
they can be readily used in the clinic. Early PRS were developed in pre­
factors. Second, consideration of lifetime risk and exposure will move
dominantly European populations and had diminished predictive accur­
practice towards prevention rather than treating disease. Third, a cost-
acy in populations of other ancestries.321 More recently, PRS developed
effective selection of new molecular markers such as metabolites, cyto­
in ancestrally diverse populations have been shown to have improved
kines, microRNA, or exosomes could refine the risk of sub-clinical dis­
risk prediction accuracy.308 Moreover, PRS are usually generated by
ease. In the coming decades, big data and artificial intelligence will
pooling together variants based on their effect on a single trait.
generate prediction tools based on pattern recognition, relying on
However, the effect of variants may be discordant on outcomes, there­
billion-point databases across multiple different ethnicities, offering a
fore nullifying the predictive value of the PRS. Partitioned PRS con­
better way to include genes, environmental exposures, and time.
structed by combining genetic variants based on physiological
These are essential if the global challenges from an increase in cardio­
pathways will strengthen the predictive value.
metabolic traits are to be addressed.
The framework started by the Multi-Ethnic Study of Atherosclerosis
(MESA) 20 years ago established that sub-clinical disease markers of Microbiome-based treatments
atherosclerosis add prognostic value above traditional risk factors There is increasing evidence of a link between the human microbiome
and are actionable.304 Today, in conjunction with risk scores, non- (particularly the gut microbiome) and host metabolism, partly mediated
invasive vascular imaging (e.g. plaque burden and CAC) can be used by diet.322–324 Of relevance to SMD, biomarkers of obesity, dyslipidae­
to refine and personalize risk assessment.173 While widely validated mia, insulin resistance, and diabetes have been shown to be associated
for sub-clinical coronary artery disease, the same does not yet exist with specific taxonomic and functional characteristics of the gut micro­
for asymptomatic diastolic dysfunction.305 Assessing sub-clinical biome.325–327 Disentangling the extent to which these links are due to
Clinical staging to guide management of metabolic disorders 19

nutritional differences rather than metabolism and the precise causal We also summarize the management strategy for each stage.
mechanisms remain open research areas.322 However, increasingly Lifestyle changes are effective at reducing metabolic risk factors at all
large sample sizes and longitudinal intervention studies will help to an­ stages and should be encouraged in addition to pharmacological treat­
swer some of the many questions in this field. ment and metabolic surgery in those with severe obesity. Many of these
The microbiome offers potential as a therapeutic target for the approaches target more than one of the systemic manifestations. Due
prevention and treatment of SMD. Next-generation therapeutics, to the complex interplay of factors contributing to the development
as well as pre-biotics, post-biotics, and a combination of these (sym­ and progression of SMD, an individually tailored and multi-faceted strat­
biotics), are all currently being explored in pre-clinical and clinical egy is required for effective intervention.
settings.328,329 Specific dietary regimes—ideally personalized to an

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individual’s genetics and microbiome characteristics—may be able
to modulate the gut microbiome to favour metabolically healthy mi­ Acknowledgements
crobial configurations.330 Microbiome re-programming can be max­ We acknowledge AstraZeneca and Novo Nordisk for their support
imized by more direct medical devices such as faecal microbiota through unrestricted educational grants.
transfer, which is under active scrutiny for metabolic disorders.331
Altogether, while there are multiple promising microbiome-based
potential therapeutics for metabolic diseases, all these approaches Supplementary data
need to be further developed, standardized and validated before Supplementary data are available at European Heart Journal online.
they are deemed clinically relevant.

Declarations
Consensus key points
Disclosure of Interest
• Systemic metabolic disorder is complex and multi-factorial, resulting A.L.C. received honoraria as a consultant and speaker and/or research
from metabolic abnormalities that affect multiple organs. It often grants or support from: Amarin, Amgen, AstraZeneca, Daiichi Sankyo,
arises due to dysfunctional excess adiposity, particularly visceral Eli Lilly, Esperion, Ionis Pharmaceuticals, Medscape, Menarini, MSD,
obesity, driven by an imbalance between caloric intake and energy ex­ New Amsterdam Pharma, Novartis, Novo Nordisk, Regeneron,
penditure. Systemic metabolic disorder progresses through various Sanofi, Ultragenyx, and Viatris. A.M.D. received consultancy fees and/
stages, with the initial phase driven by genetic predispositions and life­ or research grants from Boehringer Ingelheim, HeptaBio, and Tune
style factors, eventually leading to multi-organ dysfunction and in­ Therapeutics and participated in clinical trials (as a professional) for
creased morbidity and mortality. Madrigal, Hanmi, Intercept, Inventiva, and Novo Nordisk. A.M.D. has
• Visceral obesity is a central driver of SMD, contributing to insulin resist­ a leadership role in AASLD and the International Society for Cells of
ance, MASLD, atherogenic dyslipidaemia, hypertension, and inflamma­ the Hepatic Sinusoid and is an Associate Editor for Journal of
tion. The accumulation of lipids in ectopic tissues such as the liver, Hepatology. She has published articles with non-academic co-authors
muscles, and pancreas triggers organ-specific fibro-inflammatory re­ (Boehringer Ingelheim). A.V.-P. declares consultancy with Altimmune.
sponses, leading to diverse metabolic dysfunctions that increase the C.J.B. declares equity interests from Novartis and Novo Nordisk, is a
risk of cardiovascular and non-cardiovascular diseases. board member of Technoclone Gmbh, and has received honoraria as
• Genetic factors contribute to the susceptibility to SMD, with herit­ a consultant or speaker and/or grants for travel and research from
ability estimates ranging between 40% and 70% for different compo­ Amgen, Biotest AG, Daiichi Sankyo, Boehringer Ingelheim, Novartis,
nents. Genetic predispositions, such as those favouring visceral fat Oxitope, and SOBI. D.L.B. is on the advisory board for Angiowave,
accumulation, are associated with higher risks of conditions such as Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier
hypertension, Type 2 diabetes, and dyslipidaemia, particularly among Practice Update Cardiology, E-Star Biotech, High Enroll, Janssen,
certain ethnic groups. However, lifestyle factors can exacerbate the Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia,
genetic risk of developing SMD. NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Stasys, and
• Lifestyle changes are the cornerstone of treatment for all stages and Tourmaline Bio; is on the Board of Directors for American Heart
should be combined with pharmacological treatment and, in extreme Association New York City, Angiowave (stock options), Bristol
cases, metabolic surgery. Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock);
is a consultant for Broadview Ventures, Corcept Therapeutics,
GlaxoSmithKline, Hims, SFJ, Summa Therapeutics, and Youngene; is
Conclusions on the Data Monitoring Committees for Acesion Pharma, Assistance
In this Consensus article, we describe the manifestations of SMD, focus­ Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (for­
ing on metabolic abnormalities affecting the liver, heart, and kidney. To merly Harvard Clinical Research Institute, for the PORTICO trial,
combine the individual components and facilitate a holistic approach to funded by St. Jude Medical, now Abbott), Boston Scientific (Chair,
clinical management, we propose a staging system for SMD that is based PEITHO trial), Cleveland Clinic, Contego Medical (Chair,
on pathophysiology and emphasizes the progression from metabolic PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic,
abnormalities before organ damage (Stage 1) to early organ damage Mount Sinai School of Medicine (for the ENVISAGE trial, funded by
(Stage 2) and further to moderately advanced organ damage Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept
(Stage 3). We report that 58% of the European participants of the Medical; and for ALLAY-HF, funded by Alleviant Medical), Novartis,
UK Biobank have Stage 1 SMD, which confers a 6% increase in all-cause Population Health Research Institute, and Rutgers University (for the
mortality. In addition, a further 19% of this cohort have Stage 2 SMD, NIH-funded MINT Trial); has received honoraria from the American
which confers a 49% increase in all-cause mortality. College of Cardiology (Senior Associate Editor, Clinical Trials and
20 Romeo et al.

News, ACC.org; Chair, ACC Accreditation Oversight Committee), Scribe Therapeutics, and Pemi31. He served as a consultant and/or par­
Arnold and Porter law firm (work related to Sanofi/Bristol Myers ticipated in clinical trials for Abbott Laboratories, Amarin, AstraZeneca,
Squibb clopidogrel litigation), Baim Institute for Clinical Research (for­ Bayer, Beren Therapeutics, Cleerly, Crispr, Daiichi Sankyo, Eli Lilly,
merly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial Emendobio, Esperion, GSK, Kowa, MSD, New Amsterdam Pharma,
steering committee funded by Boehringer Ingelheim; AEGIS-II execu­ Novartis, Nodthera, Novo Nordisk, Sanofi, SCRIBE, Silence
tive committee funded by CSL Behring), Belvoir Publications (Editor Therapeutics, Ultragenyx, and Vaxxinity. He received honoraria as a
in Chief, Harvard Heart Letter), Canadian Medical and Surgical speaker from Amarin, Amgen, Algorithm, Astra Zeneca, Boehringer
Knowledge Translation Research Group (clinical trial steering commit­ Ingelheim, Daiichi Sankyo, Esperion, Dr Reddys, Mankind, Novartis,
tees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Novo Nordisk, Sanofi, Tecnofarma, Viatris, and Macleod Pharma for

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Research Institute (clinical trial steering committees, including for the symposia at international meetings and received research grants from
PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Amgen, Daiichi Sankyo, Regeneron, Sanofi, and Ultragenix to Imperial
Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the College London. K.R.T. received honoraria as a consultant and/or
American College of Cardiology (Guest Editor; Associate Editor), K2P speaker, participated in clinical trials and/or received research grants
(Co-Chair, inter-disciplinary curriculum), Level Ex, Medtelligence/ from Lilly, Boehringer Ingelheim, AstraZeneca, Bayer, Novo Nordisk,
ReachMD (CME steering committees), MJH Life Sciences, Oakstone ProKidney, and Travere. She is a chair of the Diabetic Kidney Disease
CME (Course Director, Comprehensive Review of Interventional Collaborative, American Society of Nephrology Council on the
Cardiology), Piper Sandler, Population Health Research Institute (for Kidney, and American Heart Association. L.T. received honoraria as a
the COMPASS operations committee, publications committee, steer­ consultant and/or speaker from Abbott, Amgen, AstraZeneca, Bayer,
ing committee, and US national co-leader, funded by Bayer), WebMD Daiichi Sankyo, Lilly, MSD, Pfizer, Novartis, Novo Nordisk, Sanofi,
(CME steering committees), Wiley (steering committee), and other: Ultragenyx, and Zentiva and participated in clinical trials for Amgen,
Clinical Cardiology (Deputy Editor); named on a patent for sotagliflozin Novo Nordisk, Novartis, MSD, and Ionis. She is the past president of
assigned to Brigham and Women’s Hospital who assigned to Lexicon the EAS and past president of the Turkish Society of Cardiology.
(neither he nor Brigham and Women’s Hospital receive any income M.A. received honoraria as a consultant and/or speaker, participated
from this patent); has received research funding from Abbott, in clinical trials, and/or received travel or research grants from
Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Alfasigma, Amarin, Amgen, Amryt, Daiichi Sankyo, Ionis/Akcea, Lilly,
Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Novartis, Pfizer, Regeneron, Sanofi, Soby, Viatris, and Ultragenyx.
Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno M.H. received research grants from AstraZeneca, Merck, and Novo
Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Faraday Nordisk; consultancy fees for participation in advisory board meetings
Pharmaceuticals, Ferring Pharmaceuticals, Fractyl, Garmin, HLS from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo
Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Nordisk, and Roche; speaker fees from AstraZeneca, Boehringer
Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Ingelheim, Janssen, Merck, and Novo Nordisk; and holds two patents
Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, relating to glucagon-like peptides. M.R. received honoraria as a consult­
Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, ant and/or speaker from Novo Nordisk, Lilly, AstraZeneca, Boehringer
Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; Ingelheim, Sanofi, Sigrid Therapeutics, and Atrogi. He has also received
Royalties: Elsevier (Editor, Braunwald’s Heart Disease); an is a site co- research funding from Novo Nordisk for a project revolving around no­
investigator for Cleerly. E.L. received honoraria as a consultant and vel targets in adipocytes without any links to the present EAS consensus
speaker and/or received research grants from Amgen, Canadian statement and is a member of the EASD Committee on Clinical Affairs.
Institutes of Health Research, HLS Therapeutics, Lib Therapeutics, N.S. declares equity interests in PreBiomics (cofounder, shareholder,
Novartis, and Novo Nordisk and participated in clinical trials (as a pro­ and consultant) and ZOE Ltd (consultant and stock option grantee)
fessional) for Amgen and Boehringer Ingelheim. F.P. received consult­ and received honoraria as a consultant for ZOE Ltd, PreBiomics,
ancy fees from Eli Lilly, Ethicon, Medtronic, and Novo Nordisk. Roche, Ysopia, Alia Theraputics, INRAE Transfert, and Freya
G.F. received honoraria as a consultant and/or speaker from Lilly, Biosciences and as a speaker for Illumina and Tillotts Pharma. O.J. re­
Novo Nordisk, and Regeneron and is a co-chair (unpaid) of the ceived honoraria as a consultant from Ribocure. P.M.R. has received in­
Scientific Advisory Board of the European Association for the Study stitutional research grant support from Kowa, Novartis, Amarin, Pfizer,
of Obesity (EASO). J.P. received research funding from the Dutch Esperion, Novo Nordisk, and the NHLBI; during the past 3 years has
Research Council (NWO), The Netherlands Organization for Health served as a consultant to Novartis, Agepha, Ardelyx, Arrowhead,
Research and Development (ZonMW), Applied and Engineering AstraZeneca, CSL Behring, Janssen, Civi Biopharm, Glaxo Smith
Sciences (STW), The Dutch Topsector for Life Sciences and Health Kline, SOCAR, Novo Nordisk, Eli Lilly, New Amsterdam, Boehringer
(TKI-LSH), The Californian Almond Foundation, EzCol, Newtricious, Ingelheim, Cytokinetics, Nodthera, Tourmaline Bio, and Cardio
BASF, RAISIO, Upfield, and Unilever; has received reimbursement for Therapeutics; has minority shareholder equity positions in Uppton,
travel and/or speaking from Unilever, Raisio, BASF, and Upfield; and Bitteroot Bio, and Angiowave; and has received compensation for ser­
is secretary of the Board from the foundation Nutrition in Transition vice on the Peter Munk Advisory Board (University of Toronto), the
(NIT) and is chair of the Department Nutrition and Movement Leducq Foundation, Paris, France, and the Baim Institute (Boston,
Sciences of the Maastricht University. J.R.v.L. received a research grant MA, USA). R.A. is a member of the board of directors for the
from Novartis and is a member of the scientific advisory board of the Endocrine Society. R.F. receives research grants from the National
Dutch Heart Foundation, a board member of Durch Society Gender Medical Research Council (NMRC) Singapore and the Biomedical
& Health and chair of the Dyslipidemia Working Group of the Dutch Research Council (BMRC) Singapore and is President of the
Society of Internists Vascular Medicine. K.K.R. declares stock options International Society of Heart Research, South East Asia Section (cur­
as part of consultancy agreement from New Amsterdam Pharma, rently being incorporated). S.E.Q. is on the board of directors for
Clinical staging to guide management of metabolic disorders 21

Abbvie; received consultancy fees from Roche, Genentech, Society of Lipid and Atherosclerosis, Jaetaek Kim; Kyrgyzstan: Kyrgyz
AstraZeneca, Pfizer, Janssen and Novartis; and is a councillor of AAP. Atherosclerosis Society, Erkin Mirrakhimov; Mexico: Sociedad
S.R. declares equity from Heptabio and a patent with US Provisional Mexicana de Nutricion y Endocrinologia (SMNE), Juan Eduardo
Application No. 62/908 041; received honoraria as a consultant and/ Garcia Garcia; Mexico: Mexican Society of Atherosclerosis—AMPAC,
or speaker from Ultragenyx, Amgen, Sanofi, Ribocure, Wave Life Juan José Parcero Valdés; Romania: Atherosclerosis Working Group
Sciences, AstraZeneca, Chiesi, and Novartis; received research grants of the Romanian Society of Cardiology, Dan Gaita; Romania:
from AstraZeneca; and has published articles with non-academic co- Atherosclerosis & Atherothrombosis Working Group within
authors (AstraZeneca, related to treatments for liver disease). S.V. Romanian Society of Cardiology, Roxana Rimbas; Russia: Russian
holds a Tier 1 Canada Research Chair in Cardiovascular Surgery and re­ National Atherosclerosis Society, Marat Ezhov; Spain: Spanish Society

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ports receiving grants and/or research support and/or speaking honor­ of Arteriosclerosis, Carlos Guijarro Herráiz; Tunisia: Tunisian Heart
aria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Foundation, Habib Gamra; UK: British Atherosclerosis Society,
Canadian Medical and Surgical Knowledge Translation Research Tomasz Guzik; and Ukraine: Ukrainian Atherosclerosis Society, Olena
Group, Eli Lilly, HLS Therapeutics, Humber River Health, Janssen, Mitchenko.
Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, S & L Solutions
Event Management Inc, Sanofi, and Sun Pharmaceuticals. He is the
President of the Canadian Medical and Surgical Knowledge References
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