Metabolic syndrome

Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL).

Metabolic syndrome
Other names	Dysmetabolic syndrome X
A man with marked central obesity, a hallmark of metabolic syndrome. His weight is 182 kg (400 lbs), height 185 cm (6 ft 1 in), and body mass index (BMI) 53 (normal 18.5 to 24.9).
Specialty	Endocrinology
Symptoms	Obesity
Differential diagnosis	Acanthosis nigricans, erectile dysfunction, hyperuricemia, insulin resistance, nonalcoholic fatty liver disease, obesity, polycystic ovarian syndrome, prediabetes

Metabolic syndrome is associated with the risk of developing cardiovascular disease and type 2 diabetes.^[1] In the U.S., about 25% of the adult population has metabolic syndrome, a proportion increasing with age, particularly among racial and ethnic minorities.^[2][3]

Insulin resistance, metabolic syndrome, and prediabetes are closely related to one another and have overlapping aspects. The syndrome is thought to be caused by an underlying disorder of energy utilization and storage, but the cause of the syndrome is an area of ongoing medical research. Researchers debate whether a diagnosis of metabolic syndrome implies differential treatment or increases risk of cardiovascular disease beyond what is suggested by the sum of its individual components.^[4]

Signs and symptoms

The key sign of metabolic syndrome is central obesity, also known as visceral, male-pattern or apple-shaped adiposity. It is characterized by adipose tissue accumulation predominantly around the waist and trunk.^[5] Other signs of metabolic syndrome include high blood pressure, decreased fasting serum HDL cholesterol, elevated fasting serum triglyceride level, impaired fasting glucose, insulin resistance, or prediabetes. Associated conditions include hyperuricemia; fatty liver (especially in concurrent obesity) progressing to nonalcoholic fatty liver disease; polycystic ovarian syndrome in women and erectile dysfunction in men; and acanthosis nigricans.^[6]

Neck circumference

Neck circumference has been used as a simple surrogate index of upper-body subcutaneous fat. Values >40.25 cm (15.85 in) (men) and >35.75 cm (14.07 in) (women) are considered high risk for metabolic syndrome, and large neck circumference more than doubles risk.^[7] In adults with overweight/obesity, clinically significant weight loss may protect against COVID-19,^[8] and neck circumference has been associated with increased risk of mechanical ventilation and mortality in hospitalized COVID-19 patients.^[9][10]

Complications

Metabolic syndrome can lead to type 2 diabetes, cardiovascular diseases, stroke, kidney disease and nonalcoholic fatty liver disease.^[11] It is also associated with a significantly increased risk of surgical complications across most types of surgery in a 2023 systematic review and meta-analysis of >13 million individuals.^[12]

Causes

The mechanisms underlying metabolic syndrome are under investigation and only partially elucidated. Most affected people are older, obese, sedentary, and have some degree of insulin resistance. Stress can also contribute. Important risk factors include diet (particularly sugar-sweetened beverages),^[13] genetics,^{[14][15][16][17]} aging, sedentary behaviour^[18] or low physical activity,^[19][20] disrupted chronobiology/sleep,^[21] mood disorders and some medications,^[22][23] and excessive alcohol use.^[24] The pathogenic role of excessive adipose expansion under sustained overeating and resulting lipotoxicity has also been proposed.^[25]

Markers of systemic inflammation including C-reactive protein, fibrinogen, interleukin 6, and tumor necrosis factor-alpha (TNF-α) are often increased. Some research has focused on increased uric acid levels from dietary fructose.^[26][27][28]

Modern "Western diet" patterns with high intake of energy-dense processed foods are a factor in the development of metabolic syndrome.^[29] Rather than total adiposity, the core clinical component is visceral/ectopic fat, and the principal metabolic abnormality is insulin resistance.^[30] A chronic energy surplus unmatched by activity may lead to mitochondrial dysfunction and insulin resistance.^[31]

Stress

Prolonged chronic stress may contribute to metabolic syndrome via dysregulation of the hypothalamic–pituitary–adrenal axis.^[32] Elevated cortisol can raise glucose and insulin levels, promoting visceral adiposity, insulin resistance, dyslipidaemia, and hypertension, and has effects on bone turnover.^[33][34][35]

Pathophysiology

It is common for there to be a development of visceral fat, after which adipocytes increase plasma levels of TNF-α and alter levels of other adipokines (e.g., adiponectin, resistin, PAI-1). TNF-α can induce inflammatory cytokines and may trigger insulin resistance.^[36] Rat models with high-sucrose diets have shown progression from hypertriglyceridaemia to visceral fat accumulation and insulin resistance. Increased adipose tissue elevates immune cells and chronic inflammation, contributing to hypertension, atherosclerosis and diabetes.^[37][38]

The endocannabinoid system may contribute to metabolic dysregulation.^[39][40][41] Overproduction can alter reward circuitry and executive function, perpetuating unhealthy behaviours.^{[medical citation needed]} The brain modulates peripheral carbohydrate and lipid metabolism.^[39][40] Overfeeding with sucrose/fructose, particularly with high-fat intake, can induce features of metabolic syndrome in animals.^[42] Arachidonic acid–derived mediators (eicosanoids; 2-arachidonoylglycerol; anandamide) may link lipid oversupply and inflammation.^[43][41]

Diagnosis

NCEP

As of 2023, the U.S. National Cholesterol Education Program Adult Treatment Panel III (2001) remains widely used.^[4] It requires at least three of the following:^[44]

• Central obesity: waist circumference ≥102 cm (40 in) men; ≥88 cm (35 in) women
• Dyslipidaemia: TG ≥1.7 mmol/L (150 mg/dL)
• Dyslipidaemia: HDL-C <40 mg/dL (men), <50 mg/dL (women)
• Blood pressure ≥130/85 mmHg (or treated for hypertension)
• Fasting plasma glucose ≥6.1 mmol/L (110 mg/dL)

2009 Interim Joint Statement

The International Diabetes Federation Task Force and partner organisations harmonised criteria in 2009.^[45] Diagnosis is three or more of:

• Elevated waist circumference (population- and country-specific)
• Triglycerides ≥150 mg/dL (1.7 mmol/L)
• Reduced HDL-C (≤40 mg/dL (1.0 mmol/L) men; ≤50 mg/dL (1.3 mmol/L) women)
• Elevated blood pressure (systolic ≥130 and/or diastolic ≥85 mmHg)
• Fasting glucose ≥100 mg/dL (5.55 mmol/L)^[45]

This statement recognises population differences in waist risk thresholds and encourages common criteria with agreed cut points for international comparisons.^[45]

The prior IDF and revised NCEP definitions are similar, but differ on assumptions when body mass index ≥30 kg/m² and on geography-specific waist cut points.^{[citation needed]}

WHO

The World Health Organization (1999)^[46] requires one of diabetes mellitus, impaired glucose tolerance, impaired fasting glucose or insulin resistance and two of:

• Blood pressure ≥140/90 mmHg
• Dyslipidemia: TG ≥1.695 mmol/L and HDL-C ≤0.9 mmol/L (men), ≤1.0 mmol/L (women)
• Central obesity: waist:hip ratio >0.90 (men); >0.85 (women), or BMI >30 kg/m²
• Microalbuminuria: urinary albumin excretion ≥20 μg/min or albumin:creatinine ≥30 mg/g

EGIR

The European Group for the Study of Insulin Resistance (1999) requires insulin resistance (top 25% fasting insulin among nondiabetic individuals) and two or more of:^[47]

• Central obesity: waist ≥94 cm (37 in) men; ≥80 cm (31.5 in) women
• Dyslipidaemia: TG ≥2.0 mmol/L (177 mg/dL) and/or HDL-C <1.0 mmol/L (38.61 mg/dL) or treated for dyslipidaemia
• Blood pressure ≥140/90 mmHg or antihypertensive medication
• Fasting plasma glucose ≥6.1 mmol/L (110 mg/dL)

Cardiometabolic index

The Cardiometabolic Index (CMI) estimates risk of type 2 diabetes, non-alcoholic fatty liver disease, and metabolic issues from waist-to-height ratio and triglycerides-to-HDL-C ratio.^[48] CMI has also been explored alongside cardiovascular disease and erectile dysfunction.^[49] Anti-inflammatory dietary patterns may improve related markers.^[50]

Other

High-sensitivity C-reactive protein is used to predict cardiovascular risk in metabolic syndrome and may predict nonalcoholic fatty liver disease.^[51] Reproductive disorders (such as polycystic ovary syndrome in women of reproductive age) and erectile dysfunction or decreased total testosterone in men have also been associated.^[52]

Prevention

Strategies include increased physical activity (e.g., walking 30 minutes daily)^[53] and a healthy, reduced-calorie diet.^[54] Adherence is variable in practice.^[19] The International Obesity Taskforce argues that sociopolitical interventions are required at population level.^[55] Evidence for short-term benefits of a Paleolithic-style diet on some components has been reported.^[56]

Management

Management focuses on reducing cardiovascular and metabolic risk through lifestyle modification, pharmacologic therapy, and, in selected cases, surgery.^[57] Because metabolic syndrome represents a cluster of interrelated conditions, treatment typically targets each component individually rather than the syndrome as a single entity.^[58]

Diet and meal timing

A Mediterranean-style eating pattern—emphasising vegetables, fruits, whole grains, legumes, nuts, and unsaturated fats—is associated with improvements in blood pressure, lipids, insulin sensitivity, and cardiovascular risk.^[59] Reduced-carbohydrate approaches may lower glucose and promote weight loss in insulin-resistant individuals.^[60] Evidence on meal timing suggests time-restricted eating or avoidance of late-night meals can modestly improve glycaemic and lipid markers, though long-term data are limited.^[61] Guidance recommends tailoring dietary advice to personal preference, culture, and access to improve adherence.^[57]

Follow-up and equity considerations

Ongoing follow-up includes monitoring waist circumference, body weight, blood pressure, lipids, and fasting glucose or HbA1c.^[57] Recent guidance emphasises equitable care through culturally appropriate counselling, affordable medication access, and community-based support.^[62]

Medications and therapies

Treatment of individual risk factors follows established cardiovascular and diabetes guidelines.^[58]

• Blood pressure: First-line agents include thiazide-type diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers. Selection depends on comorbid conditions and tolerance.^[58]
• Dyslipidaemia: Statins remain first-line therapy for lowering low-density lipoprotein cholesterol (LDL-C). Fibrates or omega-3 fatty acids may be added for persistent severe hypertriglyceridaemia.^[63]
• Glucose control: Lifestyle intervention is the foundation of therapy. When medications are required, glucose-lowering agents with demonstrated cardiovascular and renal benefits—such as glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors—are preferred for individuals with type 2 diabetes or elevated cardiovascular risk.^[64]
• Obesity management: Pharmacotherapies such as semaglutide and tirzepatide produce clinically significant weight loss and improvements in blood pressure, lipids, and glycaemic control. Randomized controlled trials have reported reduced major adverse cardiovascular events in adults with overweight or obesity and established cardiovascular disease.^[65][66]

Physical activity and weight reduction

Weight loss of ~7–10% over 6–12 months improves BP, lipids, and insulin sensitivity.^[57] Public-health guidance advises ≥150 min/week moderate aerobic activity (or 75 min vigorous) plus muscle-strengthening ≥2 days/week.^[67]

Sleep, tobacco, and alcohol

Inadequate/irregular sleep and untreated obstructive sleep apnoea increase metabolic and CV risk.^[68] Smoking increases insulin resistance and CV risk; cessation reduces adverse outcomes.^[58] High alcohol intake raises BP, TGs, and hepatic steatosis; moderation is advised.^[69]

Surgery

Metabolic (bariatric) surgery is considered when lifestyle and pharmacotherapy are insufficient. Surgery is associated with durable weight loss and partial or complete remission of type 2 diabetes, hypertension, and dyslipidaemia.^[70] Guidelines endorse surgery for BMI ≥35 kg/m², or ≥30 kg/m² with metabolic complications.^[71]

Epidemiology

Main article: Epidemiology of metabolic syndrome

Approximately 20–25% of the world’s adults have metabolic syndrome.^[72] In 2000, ~32% of U.S. adults met criteria;^[73][74] more recent estimates are ~34%.^[74][75]

In young children, there is no consensus on measurement; age-specific cut points are not well established.^[76] Continuous risk scores are often used instead.^[77] Microbiome composition and some conditions have been associated with metabolic syndrome, sometimes with gender-specific patterns.^[78][79]

History

In 1921, Joslin reported the association of diabetes with hypertension and hyperuricaemia.^[80] In 1923, Kylin expanded on this triad.^[81] In 1947, Vague observed that upper-body obesity predisposed to diabetes, atherosclerosis, gout and calculi.^[82] The term metabolic syndrome began appearing in the late 1950s. In 1967, Avogaro, Crepaldi and coworkers described moderately obese people with diabetes, hypercholesterolemia, and marked hypertriglyceridemia that improved on hypocaloric, low-carbohydrate diets.^[83] In 1977, Haller used the term for associations of obesity, diabetes mellitus, hyperlipoproteinemia, hyperuricemia, and hepatic steatosis.^[84] The same year, Singer used it for associations of obesity, gout, diabetes, and hypertension with hyperlipoproteinemia.^[85] In 1977–1978, Gerald B. Phillips proposed a "constellation of abnormalities" (glucose intolerance, hyperinsulinemia, hypercholesterolemia, hypertriglyceridemia, hypertension) and hypothesised sex hormones as a linking factor.^[86][87] In 1988, Gerald M. Reaven’s Banting lecture proposed insulin resistance as the underlying factor and coined syndrome X.^[88]

See also

• Metabolic disorder
• Portal-visceral hypothesis