Metabolic Syndrome

Metabolic syndrome is a cluster of related risk factors, centred on central obesity and insulin resistance, that together raise the risk of type 2 diabetes about fivefold, and cardiovascular disease about twofold. It is diagnosed when central obesity occurs with at least two of raised triglycerides, low HDL cholesterol, raised blood pressure and raised fasting glucose.

• Diagnostic criteria: waist circumference 94 cm or more in men and 80 cm or more in women (Europid; lower thresholds of 90 cm in men and 80 cm in women for South Asian, Chinese and Japanese populations; 102 cm and 88 cm are used in some settings), plus two or more of: triglycerides 1.7 mmol/L (150 mg/dL) or more or on treatment; HDL cholesterol below 1.03 mmol/L (40 mg/dL) in men or below 1.29 mmol/L (50 mg/dL) in women, or on treatment; blood pressure 130/85 mmHg or more, or on treatment; fasting glucose 5.6 mmol/L (100 mg/dL) or more, or diagnosed diabetes.
• Prevalence is about 20 to 35 percent of adults, rising with age and obesity.
• Associated conditions: non-alcoholic fatty liver disease (steatotic liver disease), obstructive sleep apnoea, polycystic ovary syndrome, hyperuricaemia and gout, chronic kidney disease, hypogonadism in men, and some cancers.
• Causes: excess energy intake, sedentary lifestyle, genetic susceptibility, ageing, ethnic differences in fat distribution, medicines (antipsychotics, corticosteroids, antiretrovirals).

• Usually asymptomatic; central (abdominal) obesity, acanthosis nigricans, skin tags, and hypertension are the usual findings.
• Symptoms of components: snoring and daytime sleepiness (sleep apnoea), menstrual irregularity and hirsutism (polycystic ovary syndrome), joint pain and gout, fatigue, right upper quadrant discomfort (fatty liver).
• Examination: weight, height, body mass index, waist circumference, blood pressure (appropriate cuff), pulse, skin, abdomen (hepatomegaly), and ankle swelling.
• Family history of diabetes, hypertension, cardiovascular disease.

• Measure waist circumference (at the midpoint between the lowest rib and iliac crest), blood pressure, fasting glucose or HbA1c, fasting lipid profile.
• HbA1c 42 to 47 mmol/mol is prediabetes; 48 mmol/mol or more is diabetes (confirm).
• Liver tests (ALT, AST, gamma glutamyl transferase) and a fibrosis score from age, AST, ALT and platelets (FIB-4); a score of 1.3 or more (2.0 or more in those over 65) needs liver stiffness measurement.
• Urea, creatinine, eGFR, urine albumin to creatinine ratio, uric acid, thyroid stimulating hormone.
• Screening for obstructive sleep apnoea with a questionnaire, and for polycystic ovary syndrome in women with oligomenorrhoea or hirsutism.
• 10 year cardiovascular risk estimation; electrocardiogram when risk is high.
• Differentials: Cushing syndrome, hypothyroidism, lipodystrophy, drug induced weight and metabolic changes.

Lifestyle (the main treatment)

• Weight loss of at least 7 to 10 percent over 6 to 12 months by an energy deficit of 500 to 750 kcal per day; Mediterranean diet, with vegetables, fruit, whole grains, legumes, nuts, olive oil, fish; avoid sugar sweetened drinks, refined carbohydrate, processed meat; alcohol under 14 units per week.
• Activity: 150 to 300 minutes of moderate (or 75 to 150 minutes of vigorous) aerobic exercise per week, and resistance exercise twice weekly; reduce sitting time.
• Stop smoking; sleep 7 to 8 hours; treat obstructive sleep apnoea with continuous positive airway pressure.

Treat each component

• Blood pressure: target below 130/80 mmHg. First line ramipril 2.5 to 10 mg daily or candesartan 8 to 32 mg daily (or losartan 50 to 100 mg), then amlodipine 5 to 10 mg, then indapamide 1.5 mg modified release. Avoid beta blockers and high dose thiazides as first choice because they worsen glucose and weight.
• Lipids: atorvastatin 20 to 40 mg at night when 10 year risk is 10 percent or more or in diabetes; fenofibrate 145 mg daily for persistent triglycerides above 5.6 mmol/L; add ezetimibe 10 mg if LDL-C is not at target.
• Glucose: prediabetes with BMI above 30 or other high risk: metformin 500 mg increasing to 1 g twice daily (check eGFR above 30, B12 yearly). Diabetes: metformin and, when cardiovascular or kidney disease is present, an SGLT2 inhibitor (empagliflozin 10 mg or dapagliflozin 10 mg daily) or a GLP-1 receptor agonist.
• Fatty liver: weight loss of 7 to 10 percent, avoid alcohol; pioglitazone 15 to 30 mg or semaglutide for fibrosis under specialist care.
• Aspirin is not advised for primary prevention unless risk is clearly high and bleeding risk is low.

Weight loss drugs or surgery (when lifestyle is not enough)

• BMI 30 kg/m2 or more (27 or more with comorbidity): semaglutide 2.4 mg subcutaneously weekly (start 0.25 mg weekly for 4 weeks, then 0.5 mg, 1 mg, 1.7 mg, each for 4 weeks, to 2.4 mg), tirzepatide 2.5 mg weekly rising by 2.5 mg every 4 weeks to 5 to 15 mg weekly, or liraglutide 3 mg daily (start 0.6 mg, increase by 0.6 mg weekly); orlistat 120 mg with each main meal. Stop GLP-1 treatment if pregnancy is planned.
• Bariatric surgery for BMI 40 or more, or 35 or more with complications (30 or more with recent onset type 2 diabetes, and lower thresholds in Asian populations).

Special groups

• Women with polycystic ovary syndrome: lifestyle, metformin 500 mg increased to 1.5 to 2 g daily, and contraception advice.
• Adolescents: family based lifestyle programmes; medicines only under specialist care.
• Older adults: avoid very restrictive diets because of muscle loss; encourage strength training.

Follow up

• Review at 3 months, then every 6 months: weight, waist, blood pressure, glucose, lipids and liver tests; annually for diabetes screening.
• Refer for resistant hypertension, fibrosis on liver testing, severe obesity, or sleep apnoea.