Metabolic Syndrome

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).

Renl 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 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

Risk Calculators

• 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

Weight Loss

• 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.

Dietary Recommendations

• 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.

Physical Activity

• 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.

Smoking Cessation

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

Pharmacological and Surgical Interventions for Weight Loss

Medications

• 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.

Bariatric Surgery

• 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

Insulin Resistance and Hyperglycaemia

• 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.

Dyslipidaemia

• 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.

Hypertension

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

Management of Associated Comorbidities

Hypogonadism

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

Polycystic Ovary Syndrome (PCOS)

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

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

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

Obstructive Sleep Apnoea (OSA)

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

Chronic Kidney Disease (CKD)

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

Cardiovascular Risk Reduction

Aspirin

• 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)

• Frequently coexistent and may exacerbate insulin resistance and metabolic abnormalities.
• Mechanisms include intermittent hypoxia and sleep fragmentation.

Psoriasis

• Shows a strong epidemiological association with metabolic syndrome.
• Likely driven by shared inflammatory pathways, including TNF-α and IL-6 signalling.

Mental illness

• Increases cardiometabolic risk through a combination of socioeconomic disadvantage, unhealthy behaviours, and medication side effects.
• Psychotropic drugs such as atypical antipsychotics contribute to weight gain and dyslipidaemia.

Bone health

• Some studies suggest a paradoxical association with lower fracture risk.
• Findings remain controversial and may be influenced by measurement bias or confounding variables; 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, especially when coexistent with type 2 diabetes mellitus.
• A meta-analysis of over 170,000 individuals showed a 78% increased relative risk of cardiovascular events and death, with greater impact in women.
• Subclinical vascular changes (e.g., increased carotid intima-media thickness) are seen even in adolescents, suggesting early vascular involvement.

Type 2 Diabetes Mellitus

• Metabolic syndrome increases the risk of developing T2DM by up to fivefold.
• Coexisting insulin resistance magnifies this risk to six- to sevenfold.
• Early identification and glycaemic intervention are critical to prevent progression.

Hepatic Complications

• MASLD (formerly NAFLD) is considered the hepatic manifestation of metabolic syndrome.
• It includes a spectrum: steatosis → steatohepatitis → fibrosis → cirrhosis → hepatocellular carcinoma.
• Metabolic syndrome increases MASLD risk 4–11 times.
• MASLD independently raises cardiovascular risk, even after adjusting for confounders.

Chronic Kidney Disease

• Metabolic syndrome is linked to both onset and progression of CKD.
• Contributing factors include central obesity, lipid-mediated nephrotoxicity, hypertension, and insulin resistance.
• Managing metabolic components is key to preserving renal function.

Cardiovascular–Kidney–Metabolic (CKM) Syndrome

• Reflects the overlap of CVD, CKD, and metabolic dysfunction.
• Recently formalised by the American Heart Association.
• Emphasises holistic and multidisciplinary management.
• Social determinants of health are critical to address.

Reproductive and Endocrine Effects

• Hypogonadism is common and worsens insulin resistance and visceral adiposity.
• In men: testosterone deficiency correlates with impaired glucose metabolism.
• In women: oestrogen deficiency post-menopause contributes to adverse metabolic changes.
• Hormone therapy may improve outcomes in selected individuals.

Osteoarthritis

• Central obesity increases joint load, especially on knees, promoting osteoarthritis.
• Inflammatory mediators from visceral fat further degrade cartilage.

Gout

• Hyperuricaemia is common in metabolic syndrome due to impaired renal uric acid clearance.
• Increases risk of monosodium urate deposition and gouty arthritis.

Cancer Risk

• Associated malignancies include colorectal, breast, prostate, and liver cancers.
• Mechanisms involve hyperinsulinaemia, inflammation, adipokine imbalance, and hormonal dysregulation.
• Obesity contributes to cancer incidence and mortality.

Cognitive Dysfunction

• Higher risk of dementia and cognitive decline is observed.
• Mediated by cerebrovascular disease, insulin resistance, and chronic inflammation.

1. Alberti KGMM, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome. Circulation. 2009;120(16):1640–1645.
2. Alberti KGMM, Zimmet P, Shaw J. The metabolic syndrome—a new worldwide definition. Lancet. 2005;366(9491):1059–1062.
3. Anand SS, Yusuf S, Vuksan V, et al. Differences in risk factors, atherosclerosis, and cardiovascular disease between ethnic groups in Canada. Lancet. 2000;356(9226):279–284.
4. Athyros VG, Bouloukos VI, Pehlivanidis AN, et al. Prevalence of metabolic syndrome in the working population. Am Heart J. 2005;149(1):152–159.
5. Bhasin S, Coviello AD, Xu X, et al. Relationship between sex hormones and metabolic syndrome in men. J Clin Endocrinol Metab. 2005;90(7):3650–3657.
6. Bjorntorp P. Metabolic implications of body fat distribution. Diabetes Care. 1991;14(12):1132–1143.
7. Cameron AJ, Shaw JE, Zimmet PZ. The metabolic syndrome: prevalence in worldwide populations. Endocrinol Metab Clin North Am. 2004;33(2):351–375.
8. Cornier MA, Dabelea D, Hernandez TL, et al. The metabolic syndrome. Endocr Rev. 2008;29(7):777–822.
9. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes. Diabetes Care. 2018;41(12):2669–2701.
10. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365(9468):1415–1428.
11. Esser N, Legrand-Poels S, Piette J, Scheen AJ, Paquot N. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract. 2014;105(2):141–150.
12. Ford ES, Giles WH, Mokdad AH. Increasing prevalence of the metabolic syndrome among US adults. Diabetes Care. 2004;27(10):2444–2449.
13. Galassi A, Reynolds K, He J. Metabolic syndrome and risk of cardiovascular disease: A meta-analysis. Am J Med. 2006;119(10):812–819.
14. Grundy SM. Metabolic syndrome pandemic. Arterioscler Thromb Vasc Biol. 2008;28(4):629–636.
15. Grundy SM. Metabolic syndrome: connecting and reconciling cardiovascular and diabetes worlds. J Am Coll Cardiol. 2006;47(6):1093–1100.
16. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome. Circulation. 2005;112(17):2735–2752.
17. Huang PL. A comprehensive definition for metabolic syndrome. Dis Model Mech. 2009;2(5-6):231–237.
18. Huxley R, Barzi F, Lee CMY, et al. Ethnic comparisons of the cross-sectional relationships between diabetes and obesity: the Asia Pacific perspective. Diabetologia. 2008;51(5):843–852.
19. International Diabetes Federation. The IDF consensus worldwide definition of the metabolic syndrome. IDF. 2006.
20. Kassi E, Pervanidou P, Kaltsas G, Chrousos G. Metabolic syndrome: definitions and controversies. BMC Med. 2011;9:48.
21. Kim JA, Montagnani M, Koh KK, Quon MJ. Reciprocal relationships between insulin resistance and endothelial dysfunction. Circulation. 2006;113(15):1888–1904.
22. Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002;288(21):2709–2716.
23. Lin DS, Fulgoni VL, Welch V, et al. The role of low-glycemic index/load diets in the management of insulin resistance. Nutrients. 2021;13(4):1205.
24. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J. 2020;41(1):111–188.
25. Meigs JB. Metabolic syndrome: an emerging clinical challenge. N Engl J Med. 2003;349(11):1047–1049.
26. Misra A, Khurana L. Obesity and the metabolic syndrome in developing countries. J Clin Endocrinol Metab. 2008;93(11 Suppl 1):S9–S30.
27. Moore JX, Chaudhary N, Akinyemiju T. Metabolic syndrome prevalence by race/ethnicity and sex in the United States, NHANES 2011–2016. Prev Chronic Dis. 2017;14:E24.
28. Mottillo S, Després JP. Metabolic syndrome and cognitive decline. Curr Opin Lipidol. 2013;24(1):56–62.
29. Mottillo S, Filion KB, Genest J, et al. The metabolic syndrome and cardiovascular risk: a systematic review and meta-analysis. J Am Coll Cardiol. 2010;56(14):1113–1132.
30. Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists in the treatment of type 2 diabetes. Diabetes Obes Metab. 2021;23(S1):30–44.
31. Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing’s syndrome. Lancet. 2006;367(9522):1605–1617.
32. Pi-Sunyer X. The Look AHEAD Trial: a review and discussion. Obesity. 2014;22(S2):S5–S13.
33. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37(12):1595–1607.
34. Ryan DH, Yockey SR. Weight loss and improvement in comorbidity. Am J Med. 2017;130(1):S17–S24.
35. Samuel VT, Shulman GI. The pathogenesis of insulin resistance: integrating signalling pathways and substrate flux. J Clin Invest. 2016;126(1):12–22.
36. Vgontzas AN, Bixler EO, Chrousos GP. Metabolic disturbances in obesity versus sleep apnoea: the importance of visceral obesity and insulin resistance. J Intern Med. 2003;254(1):32–44.
37. Vgontzas AN, Bixler EO, Chrousos GP. Obesity-related sleepiness and fatigue: the role of the stress system and cytokines. Ann N Y Acad Sci. 2006;1083:329–344.
38. Vgontzas AN, Fernandez-Mendoza J, Bixler EO. Insomnia with short sleep duration: risk for metabolic syndrome and other chronic conditions. Sleep. 2013;36(4):343–352.
39. Yki-Järvinen H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol. 2014;2(11):901–910.
40. Zimmet P, Alberti KGMM, Kaufman F, et al. The metabolic syndrome in children and adolescents. Lancet. 2007;369(9579):2059–2061.
41. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–2128.