Clinical staging to guide management of metabolic disorders and their sequelae: a European Atherosclerosis Society consensus statement

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 dysfunction, metabolic-associated steatohepatitis (MASH), and chronic kidney disease (CKD); and Stage 3, characterized by more advanced organ damage 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 socioeconomic 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.

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

Graphical Abstract

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

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), albuminuria 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 steatohepatitis; CKD, chronic kidney disease.

Figure 3

Kaplan–Meier estimates of cumulative events for all-cause mortality among Europeans in the UK Biobank with or without systemic metabolic 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 happened first. The median follow-up period was 14.95 years (interquartile range 14.94–14.95). Hazard ratios with 95% confidence intervals were calculated 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.

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

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

Figure 6

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