Metabolic Syndrome

• Metabolic syndrome, also referred to as syndrome X or insulin resistance syndrome, is a multifactorial disorder characterised by a constellation of interrelated metabolic risk factors.
• First described by Gerald Reaven in 1988, it encompasses central obesity, insulin resistance, dyslipidaemia (elevated triglycerides and reduced HDL cholesterol), hypertension, and impaired glucose metabolism.
• It represents a clustering of risk factors that predispose individuals to cardiovascular disease (CVD), type 2 diabetes mellitus, non-alcoholic fatty liver disease (NAFLD), and certain cancers.
  
  

Multifactorial Pathogenesis

• The precise aetiology of metabolic syndrome remains uncertain. There is no singular initiating abnormality known to account for all its manifestations.
• However, insulin resistance and abdominal obesity consistently emerge as central components across mechanistic studies and epidemiological data.
  
  

Environmental and Lifestyle Contributors

• The rising global prevalence of metabolic syndrome is strongly tied to the “obesity epidemic”, itself driven by:
  • Excess caloric intake
  • High-fat, atherogenic diets
  • Physical inactivity
  • Mechanised transportation and urban sedentary lifestyles
• These external drivers promote adipose tissue accumulation and dysfunction, fostering insulin resistance and metabolic disturbance.
  
  

Adipose Tissue Dysfunction and Inflammation

• Dysfunctional adipocytes contribute to chronic low-grade inflammation and insulin resistance by:
  • Secreting proinflammatory cytokines (e.g., tumour necrosis factor-α, interleukin-6)
  • Promoting macrophage infiltration into adipose tissue
  • Increasing release of free fatty acids, particularly from visceral depots
• Visceral adiposity has a stronger association with metabolic syndrome than subcutaneous fat, possibly due to:
  • Greater resistance to insulin action
  • Direct drainage into the portal circulation, exposing the liver to lipotoxic metabolites
    
    

Insulin Resistance and Cellular Dysregulation

• Insulin resistance is thought to be the primary mediator of metabolic syndrome.
  • It impairs glucose uptake and suppresses hepatic gluconeogenesis less effectively.
  • Abnormalities in insulin receptor signalling, reductions in IRS1/IRS2 activity, and beta-cell dysfunction all contribute.
• Cellular dysfunction is also linked to oxidative stress, glucose toxicity, protein kinase alterations, and mitochondrial dysfunction.
  
  

Genetic and Epigenetic Susceptibility

• A genetic predisposition underlies individual vulnerability, particularly when exposed to obesogenic environments.
• Genes implicated include those encoding:
  • 11β-hydroxysteroid dehydrogenase
  • Adiponectin
  • Beta-3-adrenergic receptor
  • Peroxisome proliferator-activated receptor-α (PPAR-α)
  • Endocannabinoid receptors
• Additionally, epigenetic changes and gene–environment interactions are emerging as key mechanisms.
  
  

Endocrine and Neurohormonal Influences

• Individuals with metabolic syndrome often exhibit subtle hypercortisolism and increased hypothalamic–pituitary–adrenal (HPA) axis activity.
• Hyperandrogenaemia, particularly in women with polycystic ovary syndrome, is associated with insulin resistance and may play a role in syndrome development.
  
  

Gut Microbiota and Circadian Disruption

• Dysbiosis of intestinal microbiota may influence systemic inflammation and insulin sensitivity.
• Disruption of circadian rhythms, including sleep disturbance and altered eating patterns, has been associated with increased metabolic risk.
  
  

Other Contributory Factors

• Advancing age and certain pharmacologic agents (e.g., corticosteroids, second-generation antipsychotics, antidepressants, and HIV protease inhibitors) are recognised risk factors.
• Psychological stressors and traits (such as anger, hostility, and depression) may increase susceptibility to metabolic syndrome, although causality remains uncertain.
  
  

Core Mechanism: Insulin Resistance

• Insulin resistance is the central pathophysiological defect that unifies the components of metabolic syndrome.
• It reflects a reduced responsiveness of peripheral tissues—especially muscle, liver, and adipose tissue—to insulin-mediated glucose uptake and utilisation.
• Affected individuals typically demonstrate impaired glucose metabolism, including elevated fasting glucose and poor clearance of glucose following a load, often in the context of overweight, obesity, or a sedentary lifestyle.
  
  

Adipose Tissue Dysfunction

• Visceral adiposity, rather than subcutaneous fat, is metabolically active and correlates strongly with insulin resistance.
• Insulin-resistant adipose tissue fails to suppress lipolysis, leading to increased circulating free fatty acids (FFAs), which:
  • Impair insulin signalling
  • Inhibit glucose uptake in skeletal muscle
  • Promote hepatic triglyceride synthesis and VLDL secretion
• The resulting lipotoxicity impairs pancreatic beta-cell function, exacerbating insulin resistance.
  
  

Skeletal Muscle and Liver Involvement

• Accumulation of triglycerides in skeletal muscle interferes with the translocation of GLUT-4 transporters, impairing glucose uptake.
  In the liver, high FFA flux enhances triglyceride synthesis and output of VLDL-cholesterol, contributing to dyslipidaemia.
  
  

Dyslipidaemia Mechanisms

• Increased cholesteryl ester transfer protein (CETP) activity promotes exchange of triglycerides into HDL and LDL particles, producing:
  • Small, dense LDL particles (more atherogenic)
  • Triglyceride-rich HDL particles (more susceptible to degradation by hepatic lipase)
• These alterations lead to low HDL-cholesterol levels and a lipid profile strongly associated with cardiovascular disease.
  
  

Lipoprotein Lipase (LPL) Imbalance

• LPL partitions FFAs from lipoproteins into tissues; in insulin resistance:
  • LPL is overexpressed in skeletal muscle
  • LPL activity is decreased in liver and adipose tissue
• These changes contribute to ectopic fat accumulation and worsen insulin sensitivity.
  
  

Hypertension and Vascular Dysfunction

• Insulin resistance is tightly linked to hypertension via several mechanisms:
  • Enhanced sodium reabsorption in renal tubules
  • Sympathetic nervous system activation
  • Imbalance between vasodilatory and vasoconstrictive actions of insulin
  • Elevated leptin levels and leptin resistance, which modulate hypothalamic circuits and promote sympathetic tone
• Increased levels of resistin and reduced adiponectin also promote vascular inflammation and stiffening.
  
  

Endothelial Dysfunction and Cardiovascular Risk

• Metabolic syndrome contributes to endothelial dysfunction and increased arterial stiffness, both of which are early markers of atherosclerosis.
• It elevates thrombogenicity through:
  • Increased levels of plasminogen activator inhibitor-1 (PAI-1)
  • Enhanced adipokine activity
• These changes raise the risk for coronary heart disease and cerebrovascular events.
  
  

Proinflammatory and Prothrombotic State

• Metabolic syndrome is associated with elevated:
  • C-reactive protein (CRP)
  • Inflammatory cytokines (TNF-α, IL-6, IL-10, IL-18, leptin, resistin)
  • Fibrinogen, homocysteine, and PAI-1
• Adiponectin levels are paradoxically decreased, reducing anti-inflammatory and insulin-sensitising protection.
  
  

Microvascular and Target Organ Injury

• Chronic inflammation and haemodynamic changes in metabolic syndrome induce microvascular dysfunction, perpetuating:
  • Insulin resistance
  • Hypertension
• Target organ damage includes:
  • Left ventricular hypertrophy
  • Peripheral vascular disease
  • Renal dysfunction
• These changes increase susceptibility to heart failure and chronic kidney disease.
  
  

Oxidative Stress and Metabolic Deterioration

• Oxidative stress is both a cause and consequence of insulin resistance, driven by:
  • Excess FFAs
  • Hyperglycaemia
  • Mitochondrial dysfunction
• Reactive oxygen species further impair insulin signalling and promote cellular damage across multiple tissues.
  
  

Prevalence and Diagnostic Criteria

• The prevalence of metabolic syndrome varies depending on the criteria used and the demographics of the population studied.
• The most widely used definitions include:
  • NCEP ATP III (2001/2005 revised)
  • International Diabetes Federation (IDF)
  • AHA/NHLBI criteria
• IDF criteria tend to yield higher prevalence rates than NCEP ATP III. In one comparison, age-adjusted prevalence was 24.5% (NCEP) versus 43.4% (IDF), though vascular event risk was lower in the IDF-defined cohort.

Global and National Trends

• United States:
  • The prevalence has risen in parallel with obesity rates.
  • NHANES data show an increase from 22% (1988–1994) to 34.7% (2011–2016).
  • The prevalence rose from 36.2% (1999–2000) to 47.3% (2017–2018).
  • Trends show a plateau or modest decline since the early 2000s, largely due to improvements in triglyceride and blood pressure control, despite rising obesity and glucose levels.
    
    
• Europe and Latin America:
  • Approximately 25% of adults are estimated to have metabolic syndrome.
    
    
• Asia:
  • Rates vary by region and criteria used. Prevalence ranges:
    • 8–13% in East Asian men
    • 2–18% in East Asian women
  • Urbanisation and dietary transitions contribute to increasing rates.
    
    
• Developing countries:
  • Rapid urbanisation has led to increasing prevalence, especially in urban populations.
    
    

Demographic Variation

• Age: 
  • Strong positive association with age.
  • Prevalence increases from 6.7% (ages 20–29) to over 40% in those ≥60 years.
    
    
• Sex:
  • Generally similar prevalence in men and women after adjusting for age.
  • Some studies show higher rates in women, especially African American and Hispanic women.
  • Women of childbearing age show rising prevalence.
    
    
• Ethnicity:
  • Mexican Americans: highest age-adjusted prevalence (~31.9%).
  • African Americans: high rates of obesity, hypertension, and diabetes, though traditional metabolic syndrome definitions may underpredict cardiovascular risk.
  • Asians: experience metabolic abnormalities at lower BMIs than white populations, with suggestions for ethnic-specific criteria (e.g., waist circumference).
    
    
• Socioeconomic and Geographic Factors:
  • Higher rates seen in urban versus rural areas.
  • Lower household income, limited education, and reduced access to health care services are associated with higher risk.
    
    

Childhood and Adolescent Trends

• Increasing prevalence of obesity in children has led to rising rates of metabolic syndrome in paediatric populations.
• IDF has issued criteria for paediatric metabolic syndrome, reflecting the urgency of this trend.
• Obesity tripled in US children since the 1960s; among 12–19-year-olds, obesity rates exceed 20%.

Associated Comorbidities and Risk Factors

• Associated conditions (not required for diagnosis):
  • Polycystic ovary syndrome (PCOS)
  • Hypogonadism
  • Obstructive sleep apnoea
  • Metabolic dysfunction-associated steatotic liver disease (MASLD)
    
    
• Risk factors:
  • Obesity, particularly visceral
  • Sedentary lifestyle and poor diet
  • Smoking and alcohol intake
  • Postmenopausal status
  • Low cardiorespiratory fitness
  • Sugar-sweetened beverage intake
  • Use of certain drugs (e.g., antipsychotics)
  • Parental history and genetic predisposition
    
    
• Racial discrimination and related chronic stressors may contribute via inflammatory and behavioural pathways.
  
  

Genetics and Metabolic Risk in “Normal-Weight” Individuals

• Some individuals with normal BMI display metabolic risk profiles similar to those with obesity—a phenotype termed “metabolically obese normal weight”.
• Genome-wide studies have identified polymorphisms linked to insulin resistance and visceral adiposity, even in individuals with lower BMI.
  
  

Key Diagnostic Indicators to Elicit from History

• Presence of Risk Factors:
  • Lifestyle: sedentary behaviour, diet high in saturated fats or refined carbohydrates, excessive alcohol consumption, smoking.
  • Metabolic and endocrine: insulin resistance, obesity, lipodystrophy, increasing age.
  • Medications: long-term use of glucocorticoids, antipsychotics, antidepressants, and HIV protease inhibitors.
  • Family history: positive family history of metabolic syndrome, type 2 diabetes, hypertension, or dyslipidaemia.
  • Infectious diseases: history of HIV infection, particularly with antiretroviral therapy.
    
    
    
• Symptoms Suggestive of Metabolic Dysregulation:
  • Hyperglycaemia: polyuria, polydipsia, fatigue, blurred vision.
  • Hypertension: often asymptomatic but may present with headaches or visual disturbances.
  • Dyslipidaemia: usually asymptomatic, but history of xanthelasma or corneal arcus may be relevant.
  • Increased BMI/Waist Circumference: self-reported or documented weight gain, especially central obesity.
  • Symptoms of Associated Conditions:
    • Cardiovascular Disease: chest pain (angina), exertional dyspnoea, claudication.
    • Liver Disease: fatigue, right upper quadrant discomfort (MASLD).
    • Hyperuricaemia/Gout: joint pain or history of gout flares.
    • Polycystic Ovary Syndrome (PCOS): irregular menses, hirsutism, acne, infertility.
    • Sleep Apnoea: excessive daytime sleepiness, loud snoring, observed apnoeas.
    • Depression/Anxiety: linked to physical inactivity and poor metabolic control.
      
      
      
• Menstrual and Reproductive History:
  • Important in women of reproductive age; symptoms such as oligo-amenorrhoea or heavy menses may suggest PCOS, which is strongly linked to metabolic syndrome.
  • Features such as hirsutism, acne, or obesity can further support this diagnosis.
    
    
    
• Endocrine History:
  • Signs of hypercortisolism (e.g., weight gain, bruising, muscle weakness) may mimic or exacerbate metabolic syndrome.
  • History of hypogonadism (fatigue, low libido in men) or premature menopause/oestrogen deficiency in women should be elicited due to their association with increased cardiometabolic risk.
    
    
    
• Lifestyle and Behavioural Factors:
  • Diet: high intake of saturated fats, refined carbohydrates, processed foods; low intake of fibre, fruit, and vegetables.
  • Exercise: low physical activity, sedentary work or lifestyle.
  • Alcohol: heavy drinking, especially binge patterns, contributes to dyslipidaemia and liver dysfunction.
  • Sleep: duration, quality, and timing—both short and long sleep durations, insomnia, and circadian misalignment increase risk.
  • Substance Use: smoking history is independently associated with increased risk.
    
    
    
• Family and Genetic History:
  • Strong hereditary component; a positive family history increases the probability of metabolic syndrome.
  • Genetic susceptibility interacts with environmental factors, and may be particularly relevant in certain ethnic groups (e.g., South Asians, Hispanics).
    
    
    
• Psychosocial and Socioeconomic Context:
  • Socioeconomic disadvantage, psychological stress, and experience of racial discrimination may increase the risk via behavioural and inflammatory pathways.
    
    
    
    

Essential Clinical Measurements for Diagnosis

• Blood Pressure:
  • Hypertension is one of the core diagnostic features.
  • Consistently elevated readings ≥130/85 mmHg or documented hypertension support the diagnosis.
  • Accurate, standardised measurement is essential at each clinical encounter.
    
    
    
• Waist Circumference:
  • Reflects central (visceral) obesity, a key component of metabolic syndrome.
  • Thresholds vary by ethnicity and definition (e.g., NCEP ATP III vs. IDF criteria).
  • Waist-to-hip ratio may be additionally informative.
  • Documented increases in waist circumference correlate strongly with insulin resistance and adverse metabolic markers.
    
    
    
• Body Mass Index (BMI):
  • Assessed through height and weight calculation.
  • Obesity (BMI ≥30 kg/m²) and overweight (BMI 25–29.9 kg/m²) are strongly associated with metabolic abnormalities, particularly when adiposity is central.
    
    

Additional Physical Findings Suggestive of Metabolic Dysregulation

• Acanthosis Nigricans:
  • Velvety, hyperpigmented plaques, commonly in the axilla, groin, or nape of the neck.
  • Reflects chronic severe insulin resistance; often present in obesity, type 2 diabetes mellitus, and PCOS.
    
    
• Hirsutism and Acne:
  • May indicate hyperandrogenism, frequently seen in women with PCOS.
  • PCOS is a common comorbidity in metabolic syndrome and contributes to insulin resistance and cardiovascular risk.
    
    
• Xanthelasma and Corneal Arcus:
  • Lipid-rich deposits seen around the eyelids or as arcus in the cornea.
  • Associated with longstanding hyperlipidaemia, especially elevated LDL cholesterol.
    
    
• Hepatomegaly:
  • May suggest metabolic dysfunction-associated steatotic liver disease (MASLD).
  • Liver enlargement can be appreciated on palpation or percussion; usually non-tender.
    
    
• Arterial Bruits:
  • May be detected over the carotid, abdominal aorta, or femoral arteries.
  • Suggest underlying atherosclerotic disease, common in patients with metabolic syndrome.
    
    
• Peripheral Neuropathy and Retinopathy:
  • Seen in patients with type 2 diabetes mellitus.
  • Signs may include decreased vibration sense, impaired proprioception, and retinal microaneurysms.
    
    
• Signs of Cardiovascular Disease:
  • Displaced apex beat, murmurs, or gallop rhythms may indicate left ventricular hypertrophy or diastolic dysfunction.
  • Peripheral pulses should be assessed for amplitude and symmetry; diminished pulses may suggest peripheral vascular disease.
    
    
    
    

First-Line Diagnostic Tests

• Fasting Blood Glucose
  • Essential for metabolic syndrome diagnosis.
  • Normal: <5.5 mmol/L (<100 mg/dL).
  • Diabetes: ≥6.9 mmol/L (≥126 mg/dL) on two occasions.
  • Borderline (5.6–6.9 mmol/L): further testing with HbA1c or OGTT.
    
    
• Fasting Lipid Profile
  • Requires 12-hour fast.
  • Triglycerides: <1.7 mmol/L (<150 mg/dL) is normal.
  • HDL-Cholesterol:
    • Men: >1.04 mmol/L (>40 mg/dL)
    • Women: >1.3 mmol/L (>50 mg/dL)
  • LDL-Cholesterol: threshold varies with cardiovascular risk.
    Total Cholesterol: evaluated in context of overall risk.
    
    
    

Second-Line and Supportive Investigations

• HbA1c
  • Recommended when fasting glucose is 5.6–6.9 mmol/L.
  • Diabetes: ≥6.5% (≥48 mmol/mol).
    
    
• Oral Glucose Tolerance Test (OGTT)
  • 2-hour post-load glucose test following 75 g glucose.
  • Diabetes: ≥11.1 mmol/L (≥200 mg/dL).
  • Impaired tolerance: 7.8–11.0 mmol/L (140–199 mg/dL).
    
    
• Renal Function Tests
  • Urea and Creatinine: may be elevated with nephropathy.
  • Urine Albumin-Creatinine Ratio: screens for early diabetic or hypertensive nephropathy.
    
    
• Liver Function Tests
  • ALT/AST: often mildly elevated in metabolic dysfunction-associated steatotic liver disease (MASLD).
  • Consider abdominal ultrasound if aminotransferases are elevated—may show increased hepatic echotexture and vascular blurring.
    
    
• Thyroid Function Tests
  • TSH and Free T4: screen for hypothyroidism, which is associated with dyslipidaemia and weight gain.
    
    

Hormonal Assessment for Related Comorbidities

• In Women with Suspected PCOS:
  • Total and Free Testosterone
  • Dehydroepiandrosterone Sulphate (DHEAS)
  • Androstenedione
  • Sex Hormone-Binding Globulin (SHBG)
  • Luteinising Hormone (LH) and Follicle-Stimulating Hormone (FSH)
  • Prolactin
  • Ovarian Ultrasound
    • Findings may include increased ovarian volume and multiple small follicles.
      
      
• In Men with Suspected Hypogonadism:
  • Total and Free Testosterone
  • SHBG
  • Reduced levels may suggest testosterone deficiency, a common finding in males with metabolic syndrome.
    
    
• Serum Oestradiol
  • To evaluate for oestrogen deficiency in women with early menopause or ovarian insufficiency.
    
    
    

Additional Investigations

• Serum Uric Acid
  • Often elevated; reflects oxidative stress and systemic inflammation.
  • Although not diagnostic, it is an independent predictor of metabolic risk.
    
    
• Electrocardiogram (ECG)
  • May show signs of silent ischaemia, previous infarction (Q waves), LV hypertrophy, or arrhythmias.
    
    
• Polysomnography
  • Consider in patients with snoring, daytime somnolence, or obesity—helps identify obstructive sleep apnoea, which is frequently comorbid.
    
    
• Advanced Lipid and Inflammatory Markers (optional based on risk profile):
  • Lipoprotein(a)
  • Apolipoprotein B-100
  • High-sensitivity C-reactive protein (hs-CRP)
  • Homocysteine
  • Fractionated LDL-C
    
    

Cardiovascular Risk Assessment

• For adults aged 20–79 years without clinical ASCVD, use the AHA/ACC risk calculator to estimate 10-year and lifetime risk of:
  • Myocardial infarction
  • Stroke
  • Coronary heart disease death
    
    
• Assess every 4–6 years; communicate risk and manage per guidelines on diet, cholesterol, obesity, and physical activity.
  
  
  

Imaging Studies for Cardiovascular or Liver Complications

• Consider based on clinical signs:
  • Stress ECG or Echocardiography (rest or stress)
  • Cardiac PET or SPECT
  • Carotid ultrasound or ankle-brachial index for vascular assessment
  • Liver ultrasound for suspected steatotic liver disease
    
    

Chronic Liver Disease

• Clinical Clues:
  • Spider angiomas, palmar erythema, jaundice, hepatosplenomegaly, ascites, and abdominal wall collateral vessels.
• Distinguishing Features:
  • Disruption in hepatic metabolism may alter glucose, lipid, and protein regulation, mimicking features of metabolic syndrome.
• Investigations:
  • Elevated ALT, AST, and gamma-glutamyl transferase.
  • Hypoalbuminaemia, hyponatraemia, prolonged prothrombin time.
  • Thrombocytopaenia and elevated bilirubin in advanced disease.
    
    

Cushing’s Syndrome

• Clinical Clues:
  • Central obesity, moon face, buffalo hump, purple striae, acne, glucose intolerance, and hypertension.
• Distinguishing Features:
  • Endogenous or exogenous glucocorticoid excess causes insulin resistance and dyslipidaemia.
• Investigations:
  • Elevated serum cortisol (especially midnight levels), loss of diurnal cortisol rhythm.
  • Non-suppressed cortisol after dexamethasone suppression test.
  • Raised 24-hour urinary free cortisol or late-night salivary cortisol.
    
    

Congenital Adrenal Hyperplasia (CAH)

• Clinical Clues:
  • Signs of androgen excess (e.g., ambiguous genitalia in females, early puberty in males), obesity, hypertension.
    
    
• Distinguishing Features:
  • Associated with insulin resistance and hyperandrogenism.
    
    
• Investigations:
  • Elevated 17-hydroxyprogesterone levels.
  • Electrolyte abnormalities in salt-wasting forms (e.g., hyponatraemia, hyperkalemia).
    
    

Polycystic Ovary Syndrome (PCOS)

• Clinical Clues:
  • Irregular menses, hirsutism, acne, infertility.
• Distinguishing Features:
  • Strongly associated with insulin resistance and increased prevalence of metabolic syndrome.
• Investigations:
  • Elevated androgens (testosterone, androstenedione), LH/FSH ratio.
  • Polycystic ovaries on ultrasound.
    
    

Obstructive Sleep Apnoea (OSA)

• Clinical Clues:
  • Loud snoring, witnessed apnoeas, excessive daytime sleepiness.
• Distinguishing Features:
  • Recurrent hypoxia and arousals contribute to insulin resistance, hypertension, and dyslipidaemia.
• Investigations:
  • Confirmed by polysomnography.
    
    

Steatotic Liver Disease (Metabolic Dysfunction-Associated Steatotic Liver Disease)

• Clinical Clues:
  • Often asymptomatic; may present with hepatomegaly or elevated liver enzymes.
• Distinguishing Features:
  • Closely linked to central obesity, dyslipidaemia, and insulin resistance.
• Investigations:
  • Elevated ALT/AST, hepatic steatosis on ultrasound.
    
    
    

Hyperthyroidism

• Clinical Clues:
  • Weight loss despite increased appetite, tremor, tachycardia, heat intolerance.
• Distinguishing Features:
  • Increases basal metabolic rate and may mimic or mask elements of metabolic syndrome.
• Investigations:
  • Suppressed TSH, elevated free T4/T3.
    
    

Malignancy (e.g., lung or pancreatic cancer)

• Clinical Clues:
  • Unintentional weight loss, cachexia, systemic symptoms.
• Distinguishing Features:
  • Hypermetabolism in malignancy may affect lipid and glucose metabolism.
• Investigations:
  • Disease-specific imaging and tumour markers.
    
    
    

Medication-Induced Metabolic Disturbances

• Relevant Drugs:
  • Atypical antipsychotics (e.g., olanzapine, clozapine), corticosteroids, some antidepressants, and HIV protease inhibitors.
• Distinguishing Features:
  • Drug-related weight gain, insulin resistance, and lipid abnormalities.
• Management:
  • Consider medication review and risk–benefit reassessment.
    
    

Lifestyle Modification

• Primary goal: ≥10% reduction in body weight; secondary goal: achieving BMI <25 kg/m².
• Achieved through caloric restriction, dietary change, and physical activity.
• Associated with improved insulin sensitivity, blood pressure (BP), triglyceride levels, HDL-cholesterol, and glucose metabolism.
  
  

• High in complex carbohydrates and dietary fibre (10–25 g/day), low in added sugars and sodium.
• Carbohydrates: 40–65% of total energy; favour low-glycaemic load over refined sugars.
• Fat intake: 20–35% of total energy; saturated fat <7%, trans fats <1%, cholesterol <200 mg/day.
• Emphasise monounsaturated (e.g., olive oil) and n-3 polyunsaturated fats (e.g., oily fish).
• Mediterranean diet and low-glycaemic load diets are particularly beneficial.
• Avoidance of sugar-sweetened beverages and excessive alcohol is advised.
  
  

• Minimum: 30 minutes of moderate to vigorous activity daily (e.g., brisk walking).
• Additional benefits include visceral fat reduction and improved lipid and glucose metabolism.
• Supervised or telemonitored exercise programmes improve adherence and outcomes.
  
  

• Mandatory due to synergistic effects with other metabolic syndrome components on CVD risk.
  
  

Pharmacological and Surgical Interventions for Weight Loss

• Indicated in BMI ≥30 kg/m² or ≥27 kg/m² with comorbidities.
• Options include:
  • Semaglutide: GLP-1 receptor agonist with significant weight loss and cardiometabolic benefit.
  • Phentermine/topiramate: Effective but limited by sympathomimetic effects and abuse potential.
  • Orlistat: Lipase inhibitor that reduces fat absorption; favourable lipid effects.
  • Liraglutide, bupropion/naltrexone: Additional agents with central appetite-regulating effects.
    
    
    

• Considered for BMI ≥40 kg/m² or ≥35 kg/m² with comorbidities.
• Procedures (e.g., gastric bypass, sleeve gastrectomy) improve all metabolic syndrome components and reduce mortality.
• Most effective long-term strategy in morbid obesity for T2DM and CVD prevention.
  
  
  

Management of Metabolic Components

• Metformin: Improves insulin sensitivity and reduces T2DM incidence in high-risk individuals.
• Thiazolidinediones: Improve insulin sensitivity; pioglitazone favoured over rosiglitazone due to cardiovascular risk concerns.
  
  
  

• Statins: First-line agents for LDL-cholesterol reduction; pleiotropic benefits include anti-inflammatory effects.
• Other agents:
  • Ezetimibe, bile acid sequestrants, PCSK9 inhibitors, fibrates, omega-3 fatty acids, and niacin.
• Lipid targets are stratified based on cardiovascular risk (see ESC/EAS and AHA/ACC guidelines).
• Monitor liver enzymes and creatine kinase during therapy.
  
  

• BP goal: <130/80 mmHg.
• ACE inhibitors or ARBs are preferred, especially with T2DM or CKD, for renal protection.
  
  
  

Management of Associated Comorbidities

• Men: Testosterone replacement may improve metabolic control.
• Women: HRT may favourably influence insulin sensitivity and adiposity, especially when initiated early post-menopause.
  
  

• Treat shared components (e.g., insulin resistance, dyslipidaemia).
• Consider referral to a gynaecologist or endocrinologist for hormonal management.
  
  

• Lifestyle modification is first-line.
• Pioglitazone and vitamin E may be considered; no approved pharmacotherapy exists.
• Liver transplantation in end-stage cases.
  
  

• Associated with increased insulin resistance.
• Continuous positive airway pressure (CPAP) may benefit metabolic parameters.
  
  

• Optimise metabolic syndrome components to slow CKD progression.
• ACE inhibitors or ARBs preferred for hypertension management.
• Multidisciplinary input is essential.
  
  

Cardiovascular Risk Reduction

• Low-dose aspirin may be considered in patients aged 40–59 years with ≥10% 10-year CVD risk, balancing bleeding risk.
  
  
  
  

Impact on Cardiovascular and Metabolic Health

• Cardiovascular complications are the most significant contributors to poor prognosis in metabolic syndrome. These include:
  • Coronary heart disease
  • Atrial fibrillation
  • Heart failure
  • Aortic stenosis
  • Ischaemic stroke
  • Venous thromboembolism
• Each component of the syndrome (e.g., hypertension, dyslipidaemia, insulin resistance) independently contributes to elevated CVD risk.
• Activation of the renin–angiotensin–aldosterone system and abnormalities in glucose and lipid metabolism may lead to pulmonary arterial hypertension and right-sided heart failure.
• Type 2 diabetes mellitus (T2DM) frequently coexists with or follows metabolic syndrome. The combination of insulin resistance and central obesity accelerates pancreatic beta-cell dysfunction and glucose dysregulation.
  
  

Neurological and Cognitive Sequelae

• Metabolic syndrome is associated with an increased risk of ischaemic stroke, beyond the sum of its individual components.
• Systemic inflammation, endothelial dysfunction, and insulin resistance may also contribute to peripheral neuropathy and cognitive decline, even in the absence of overt diabetes.
• There is emerging evidence that metabolic syndrome accelerates cognitive ageing and is linked to impaired neurocognitive performance.
  
  

Hepatic Manifestations

• Metabolic dysfunction-associated steatotic liver disease (MASLD)—previously known as non-alcoholic fatty liver disease—is both a consequence and a contributor to metabolic syndrome.
• Hepatic steatosis correlates with insulin resistance and dyslipidaemia and increases the risk of hepatic fibrosis, cirrhosis, and hepatocellular carcinoma in the long term.
  
  
  

Oncological Associations

• Epidemiological data suggest increased incidence of several malignancies in individuals with metabolic syndrome:
  • Breast cancer, particularly in postmenopausal women, possibly through dysregulation of the plasminogen activator inhibitor-1 (PAI-1) pathway.
  • Cancers of the colon, gallbladder, kidney, and potentially prostate gland.
• The mechanisms may include chronic low-grade inflammation, hyperinsulinaemia, altered adipokine profiles, and oxidative stress.
  
  

Reproductive and Obstetric Implications

• In women with previous preeclampsia, the development of metabolic syndrome between pregnancies significantly increases the risk of recurrent preeclampsia.
• The likelihood of recurrence appears to be proportional to the number of metabolic syndrome components present in the interpregnancy interval.
  
  
  

Other Associations

• Obstructive sleep apnoea (OSA) is frequently coexistent and may exacerbate insulin resistance and metabolic abnormalities via intermittent hypoxia and sleep fragmentation.
• Psoriasis has shown a strong epidemiological association with metabolic syndrome, likely due to shared inflammatory pathways.
• Mental illness increases cardiometabolic risk, often mediated by socioeconomic disadvantage, suboptimal health behaviours, and side effects of psychotropic medications.
• Bone health: Paradoxically, some studies suggest that metabolic syndrome may confer a lower risk of bone fractures, although this finding remains controversial and further research is needed.
  
  
  

Effect of Intervention on Prognosis

• Multifactorial interventions, including:
  • Weight reduction
  • Dietary optimisation
  • Increased physical activity
  • Pharmacological treatment of hyperglycaemia, hypertension, and dyslipidaemia
• These approaches significantly reduce the risk of cardiovascular events and delay or prevent the onset of T2DM.
• Evidence shows a ~40% reduction in metabolic syndrome prevalence following lifestyle modification, supporting the effectiveness of early and aggressive intervention.

Cardiovascular Disease

• Individuals with metabolic syndrome face a markedly increased risk of cardiovascular disease (CVD), including myocardial infarction, stroke, and peripheral vascular disease.
• Data indicate a 2–3-fold rise in cardiovascular mortality among those affected, with risk being amplified when metabolic syndrome coexists with type 2 diabetes mellitus.
• A meta-analysis involving over 170,000 individuals found a 78% increased relative risk of cardiovascular events and death, with the impact being greater in women.
• Subclinical vascular changes, such as increased carotid intima-media thickness, have also been observed in adolescents with metabolic syndrome, indicating early vascular involvement.
  
  

Type 2 Diabetes Mellitus

• Metabolic syndrome is one of the strongest predictors of future type 2 diabetes mellitus (T2DM), increasing risk by up to five times.
• When insulin resistance is present alongside metabolic syndrome, the risk is magnified further, with a 6- to 7-fold increase.
• Early detection and intervention targeting glucose metabolism are essential to mitigate this progression.
  
  
  

Hepatic Complications

• Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly termed non-alcoholic fatty liver disease (NAFLD), is now recognised as the hepatic manifestation of metabolic syndrome.
• The condition encompasses a spectrum from hepatic steatosis to steatohepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma.
• Those with metabolic syndrome are between four and eleven times more likely to develop MASLD.
• Even after adjusting for traditional risk factors, MASLD independently raises the risk of cardiovascular complications.
  
  

Chronic Kidney Disease

• The renal impact of metabolic syndrome is substantial, with a clear link to the onset and progression of chronic kidney disease (CKD).
• Mechanisms include both direct injury from lipid deposition and mechanical effects of central obesity, as well as indirect damage from hypertension and insulin resistance.
• Effective management of metabolic syndrome components is vital to slow renal deterioration.
  
  

Cardiovascular–Kidney–Metabolic (CKM) Syndrome

• The interconnected nature of cardiovascular, renal, and metabolic diseases is reflected in the concept of CKM syndrome, recently outlined by the American Heart Association.
• This umbrella diagnosis includes individuals at risk of, or already living with, multiple overlapping conditions such as CVD, CKD, and metabolic abnormalities.
• Multidisciplinary management and attention to social determinants of health are key to optimising outcomes.
  
  

Reproductive and Endocrine Effects

• Hypogonadism in both sexes is frequently associated with metabolic syndrome and contributes to its progression.
• In men, testosterone deficiency is linked with increased visceral adiposity, insulin resistance, and impaired glucose tolerance. In women, oestrogen deficiency—particularly after early menopause—has similar adverse effects.
• Hormonal therapy may improve metabolic parameters and reproductive health in selected patients.
  
  

Osteoarthritis

• Central obesity, a hallmark of metabolic syndrome, increases the mechanical load on weight-bearing joints, predisposing individuals to osteoarthritis, particularly in the knees.
• Inflammatory mediators released by visceral fat may also contribute to cartilage degeneration.
  
  

Gout

• Elevated serum uric acid, frequently seen in individuals with metabolic syndrome, can lead to gout.
• Obesity and insulin resistance impair uric acid clearance, enhancing the risk of monosodium urate crystal deposition.
  
  

Cancer Risk

• Epidemiological data suggest associations between metabolic syndrome and several malignancies, including colorectal, breast (especially recurrence), prostate, and liver cancers.
• Contributing mechanisms include hyperinsulinaemia, systemic inflammation, altered adipokine levels, and hormonal dysregulation.
• Obesity alone has been associated with increased cancer-related mortality across multiple cancer types.
  
  
  

Cognitive Dysfunction

• Cognitive decline and dementia risk appear to be increased in individuals with metabolic syndrome.
• Proposed mechanisms include cerebrovascular injury, insulin resistance affecting neuronal metabolism, and chronic systemic inflammation.
  
  
  
  

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