Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ONGOING

all patients

1st line – lifestyle modification

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all patients
1st line – 

lifestyle modification

Primary goal for overweight/obese patients is to reduce total body weight by 10%. Secondary goal is to achieve normal body mass index (i.e., <25 kg/m²).[13]​​

Diet should be low in saturated fats and high in unsaturated fats, high in complex unrefined carbohydrates and fiber (10-25 g/day), and low in added sugars and sodium (restricted to 65-100 mmol daily). Carbohydrates: 40% to 65% of total calorie intake; protein: 10% to 35%; fats: 20% to 35% (of these, saturated fats must be reduced to <7%, trans-fatty acids to <1%, and cholesterol to <200 mg/day).[4][13]​​​[86] Monounsaturated fats (from plant sources: for example, olive oil and soybean oil) should be consumed and n-3-polyunsaturated fatty acids (mainly from fish) should constitute about 10% of calorie intake. The Mediterranean diet, which is rich in fiber, monounsaturated fats, and polyunsaturated fats (with a low ratio of omega-6 to omega-3 fatty acids), low in animal protein, and based mainly on fruit, vegetables, fish, nuts, whole grains, and olive oil, seems to be effective in reducing the prevalence of metabolic syndrome and associated CVD.[60][66] It also reduces the risk of developing diabetes mellitus, especially in patients with high CVD risk.[94]​​

Daily exercise routine of at least 30 minutes of moderate to intense physical activity such as brisk walking is recommended.[4][13]​​[102][103] Activity of greater intensity may carry greater benefit.[35][89]

Exercise-focused intervention using telemonitoring systems has been shown to further reduce metabolic syndrome severity, while also improving mental health and working ability.[105]

Regarding the best strategy for achieving adherence to meaningful lifestyle change, one meta-analysis showed that a team-based, interactive approach with high-frequency contact and motivated patients has the largest and most lasting impact on weight management.[99]

Smoking cessation is mandatory.​[14][85]

Consider – weight reduction pharmacotherapy

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all patients
Consider – 

weight reduction pharmacotherapy

Treatment recommended for SOME patients in selected patient group

Guidelines for obesity recommend considering pharmaceutical therapy for weight loss as an adjunct to diet and exercise in patients with a body mass index ≥30 kg/m², or ≥27 kg/m² in the presence of comorbidities related to excess adiposity.[4][106]​​[107]

Semaglutide is a glucagon-like peptide-1 receptor agonist targeting areas of the brain that regulate appetite and food intake. It is now indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with BMI ≥30 kg/m², or ≥27 kg/m² in the presence of at least one weight-related comorbidity.[108]

Randomized controlled trial data showed that patients receiving semaglutide lost an average of 6% to 16% of their total body weight compared with controls, when combined with other behavioral modifications.[109][110][111]

Phentermine/topiramate is an oral combination therapy containing phentermine, an amphetamine/appetite suppressant, and topiramate, an anticonvulsant. It is approved for chronic weight management as an adjunct to a reduced-calorie diet and increased physical activity. Phentermine/topiramate is effective in reducing weight when combined with lifestyle interventions, and may also improve markers of cardiovascular system function such as blood pressure, total cholesterol, triglycerides, and blood glucose levels.[114]​​[115][116][117]​​ Phentermine/topiramate should be used with caution and at lower doses in patients with hepatic or renal impairment, and in those with hypertension or arrhythmias, due to the adrenergic effects of phentermine. Phentermine is a controlled substance due to its abuse potential, and should not be prescribed for patients with a history of substance abuse. Phentermine/topiramate is only available through a restricted distribution program in some countries.

Orlistat reduces fat absorption by binding to pancreatic lipases, resulting in significant weight loss, but with rebound weight gain if discontinued.[101][118] In association with a hypocaloric diet, it improves blood pressure and fasting glucose, triglyceride, and low-density lipoprotein (LDL)-cholesterol levels.[119] With lifestyle interventions, orlistat reduces incidence of type 2 diabetes mellitus by 37% in high-risk patients.[120]

Bupropion/naltrexone and liraglutide are also approved for the treatment of obesity.[121]​​

See Obesity in adults.

Primary options

semaglutide: 0.25 mg subcutaneously once weekly for 4 weeks, increase dose gradually according to response, maximum 2.4 mg/week

OR

phentermine hydrochloride/topiramate: 3.75 mg (phentermine)/23 mg (topiramate) orally once daily in the morning for 14 days, increase gradually according to response, maximum 15 mg (phentermine)/92 mg (topiramate)/day

OR

orlistat: 120 mg orally three times daily with each meal containing fat

OR

naltrexone/bupropion hydrochloride: (8 mg naltrexone/90 mg bupropion per tablet) 1 tablet orally (extended-release) once daily in the morning for 1 week, followed by 1 tablet twice daily for 1 week, then 2 tablets in the morning and 1 tablet at night for 1 week, then 2 tablets twice daily thereafter

OR

liraglutide: 0.6 mg subcutaneously once daily for 1 week, increase by 0.6 mg/day at weekly intervals according to response, target dose 3 mg/day

Consider – bariatric surgery

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all patients
Consider – 

bariatric surgery

Treatment recommended for SOME patients in selected patient group

National Institutes of Health guidelines for surgical therapy of class III obesity (body mass index [BMI] ≥40); bariatric surgery should be considered in patients with a BMI ≥40 kg/m², or ≥35 kg/m² in the presence of significant comorbidities.[122]

Surgical procedures include gastric banding, gastric bypass (principally Roux-en-Y), gastroplasty (principally vertical banded gastroplasty), biliopancreatic diversion, biliary intestinal bypass, ileogastrostomy, and jejunoileal bypass.

Bariatric surgery significantly ameliorates all components of metabolic syndrome and is associated with substantial postoperative weight loss (20% to 32% depending on the procedure) and reduced overall mortality compared with conventional therapy.[123][124][125][126]

In one meta-analysis, bariatric surgery was the most effective strategy in preventing type 2 diabetes, compared with diet and/or physical activity or antidiabetic drugs in morbidly obese subjects.[128]

Consider – low-dose aspirin

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all patients
Consider – 

low-dose aspirin

Treatment recommended for SOME patients in selected patient group

As metabolic syndrome is also regarded as a prothrombotic and proinflammatory state, low-dose aspirin may be considered for patients ages 40 to 59 years who have a 10-year CVD risk 10% or more.[129] For lower-risk patients, the benefit of aspirin must be weighed against the risk of hemorrhage.

Primary options

aspirin: 75-81 mg orally once daily

Plus – metformin or pioglitazone

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all patients
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with insulin resistance
Plus – 

metformin or pioglitazone

Treatment recommended for ALL patients in selected patient group

Metformin reduced the progression to type 2 diabetes mellitus (DM) in patients with impaired glucose tolerance and reduced development of new-onset cardiovascular disease in obese patients with type 2 DM in the United Kingdom Prospective Diabetes Study (UKPDS).[130][131] However, there are no cardiovascular end-point studies on patients with metabolic syndrome treated with metformin.

Pioglitazone significantly reduced the risk of death, nonfatal myocardial infarction, and stroke in patients with type 2 DM and, in addition to other drugs used in the secondary prevention of diabetes and cardiovascular disease, reduced signs of macrovascular disease in the prospective pioglitazone clinical trial in macrovascular events (PROACTIVE) study.[134]

Primary options

metformin: 850 mg orally (immediate-release) once daily, increase according to response, maximum 2550 mg/day

Secondary options

pioglitazone: 15-45 mg orally once daily

Plus – statin

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all patients
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with dyslipidemia
Plus – 

statin

Treatment recommended for ALL patients in selected patient group

Low-density lipoprotein (LDL)-cholesterol is the main target of cholesterol-lowering therapy.[139][140]​​ Initiating treatment for LDL-cholesterol depends on absolute risk of coronary heart disease based on the number of risk factors and risk stratification.​[139][140]​​​

Statins (HMG-CoA reductase inhibitors) are the major LDL-cholesterol-lowering agents. They reduce LDL-cholesterol by 30% to 60% depending on the dose and specific type of statin used, increase high-density lipoprotein (HDL)-cholesterol by 5% to 10%, and reduce triglycerides by 7% to 30%.[4][14][85]

Treatment of dyslipidemia according to the American Heart Association/American College of Cardiology guidelines depends on presence of risk factors:[140]

Patients with atherosclerotic cardiovascular disease (ASCVD) who are at very high risk of future events are treated with high-intensity statin therapy (daily dose lowers LDL-cholesterol by ≥50%) or maximal statin therapy. Very high risk is defined as a history of multiple major ASCVD events (recent acute coronary syndrome [within the past 12 months], myocardial infarction other than the recent acute coronary syndrome, ischemic stroke, symptomatic peripheral arterial disease [claudication with ankle brachial index <0.85, previous revascularization, or amputation]) or one major ASCVD event and multiple high-risk conditions (age ≥65 years, heterozygous family history, history of previous coronary artery bypass graft or percutaneous coronary intervention, diabetes mellitus, hypertension, chronic kidney disease, current smoking, persistently elevated LDL-cholesterol [≥100 mg/dL] despite maximally tolerated therapy, history of congestive heart failure). Patients with ASCVD not at very high risk of future events and ages ≤75 years are treated with high-intensity statin therapy or with moderate-intensity statin therapy (daily dose lowers LDL-cholesterol 30% to <50%) if high-intensity therapy is not tolerated; patients ages >75 years are treated with moderate- or high-intensity statin therapy.

People ages 20-75 years without ASCVD but who have LDL-cholesterol ≥190 mg/dL should be treated with high-intensity statin therapy, or moderate-intensity statin therapy if they are not a candidate for high-intensity statin therapy.

People ages 40-75 years without ASCVD but who have diabetes mellitus should be started on moderate-intensity statin therapy regardless of 10-year ASCVD risk. In adults with diabetes and LDL-cholesterol 70-189 mg/dL, it is reasonable to assess 10-year ASCVD risk and start high-intensity statin therapy in those who have multiple ASCVD risk factors.

People with metabolic syndrome, without ASCVD or diabetes, ages 40-75 years with LDL-cholesterol 70-189 mg/dL: estimate 10-year ASCVD risk and if borderline risk (5.0% to <7.5%) then discuss moderate-intensity statin therapy; the patient-clinician discussion should consider the potential for ASCVD risk-reduction benefits and adverse effects, drug-drug interactions, and patient preferences for treatment. If intermediate risk (≥7.5% to <20%) start moderate-intensity statin therapy; if uncertain can use coronary artery calcification (CAC) score (CAC=0: lowers risk; consider no statin unless diabetes, family history of premature coronary heart disease, smoking; CAC=1-99: favors statin, especially if age >55 years; CAC=100+ and/or ≥75th percentile: begin statin). If high risk, ≥20%, start high-intensity statin therapy.

Statins are also recommended as the drug of choice for reducing cardiovascular disease risk in high-risk individuals with hypertriglyceridemia (triglyceride level >200 mg/dL).[140]

See Hypercholesterolemia and Hypertriglyceridemia.

Primary options

High-intensity statin

atorvastatin: 40-80 mg orally once daily

OR

High-intensity statin

rosuvastatin: 20-40 mg orally once daily

OR

Moderate-intensity statin

atorvastatin: 10-20 mg orally once daily

OR

Moderate-intensity statin

rosuvastatin: 5-10 mg orally once daily

OR

Moderate-intensity statin

simvastatin: 20-40 mg orally once daily; increased risk of myopathy with 80 mg/day dose

OR

Moderate-intensity statin

pravastatin: 40-80 mg orally once daily

OR

Moderate-intensity statin

lovastatin: 40-80 mg orally (immediate-release) once daily

OR

Moderate-intensity statin

fluvastatin: 40 mg orally (immediate-release) twice daily; 80 mg orally (extended-release) once daily

OR

Moderate-intensity statin

pitavastatin: 1-4 mg orally once daily

Plus – consider adding ezetimibe

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all patients
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with dyslipidemia
Plus – 

consider adding ezetimibe

Treatment recommended for ALL patients in selected patient group

For patients with atherosclerotic cardiovascular disease (ASCVD) at very high risk of future events, and those up to 75 years of age and not at very high risk, ezetimibe may be added if the patient is on maximal statin therapy and LDL-cholesterol level remains ≥70 mg/dL.[140]

Patients are considered to be at very high risk of future events if they have a history of multiple major atherosclerotic CVD events (recent acute coronary syndrome [ACS] [within the past 12 months], myocardial infarction other than the recent ACS, ischemic stroke, symptomatic peripheral arterial disease [claudication with ankle brachial index <0.85, previous revascularization or amputation]) or one major atherosclerotic CVD event and multiple high-risk conditions (age ≥65 years, heterozygous family history, history of previous coronary artery bypass graft or percutaneous coronary intervention, diabetes mellitus, hypertension, chronic kidney disease, current smoking, persistently elevated LDL-cholesterol [≥100 mg/dL] despite maximally tolerated therapy, history of congestive heart failure).[140]

Addition of ezetimibe may also be considered in patients without ASCVD who have baseline LDL-cholesterol ≥190 mg/dL and <50% reduction in LDL-cholesterol or LDL-cholesterol ≥100 mg/dL, and in those without ASCVD who have diabetes, a 10-year ASCVD risk ≥20%, and a <50% reduction in LDL-cholesterol.

Primary options

ezetimibe: 10 mg orally once daily

Plus – consider adding a PCSK9 inhibitor

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all patients
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with dyslipidemia
Plus – 

consider adding a PCSK9 inhibitor

Treatment recommended for ALL patients in selected patient group

A proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor may be added to maximal statin and ezetimibe therapy if LDL-cholesterol level remains ≥70 mg/dL or non-HDL-cholesterol is ≥100 mg/dL in patients with atherosclerotic cardiovascular disease (ASCVD) at very high risk of future events.[140] Secondary analysis of the FOURIER trial found that addition of evolocumab to statin therapy significantly reduced cardiovascular events in patients with ASCVD and metabolic syndrome without an increase in serious safety events, including new-onset diabetes.[153]

In patients without ASCVD, ages 40-75 years with baseline LDL-cholesterol ≥220 mg/dL receiving maximally tolerated statin and ezetimibe therapy, addition of a PCSK9-inhibitor should be considered if the LDL-cholesterol remains ≥130 mg/dL.

Primary options

alirocumab: 75-150 mg subcutaneously every 2 weeks; or 300 mg subcutaneously every 4 weeks

OR

evolocumab: 140 mg subcutaneously every 2 weeks; or 420 mg subcutaneously once monthly

Plus – consider additional lipid-lowering drug

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all patients
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with dyslipidemia
Plus – 

consider additional lipid-lowering drug

Treatment recommended for ALL patients in selected patient group

If low-density lipoprotein (LDL)-cholesterol goal is not achieved, other drugs can be added to statins. Choice of lipid-lowering agent is based on the patient's lipid profile.

Bile acid sequestrants (e.g., colesevelam) reduce LDL-cholesterol by 15% to 30%.[148] Addition of a bile acid sequestrant may be considered in patients ages 20-75 years with baseline LDL-cholesterol ≥190 mg/dL receiving maximally tolerated statin and ezetimibe therapy, if there is a less than 50% reduction in LDL-cholesterol and fasting triglyceride level is ≤300 mg/dL.[140]

Fibrates (e.g., fenofibrate) decrease triglycerides by 25% to 50% and LDL-cholesterol by 30%, and increase HDL-cholesterol by 5% to 15%. When LDL-cholesterol is controlled, they are the most effective agent for reducing triglycerides and increasing HDL-cholesterol.

Omega-3 polyunsaturated fatty acids (e.g., eicosapentaenoic and docosahexaenoic acids) decrease triglycerides by 20% to 40%, although they raise LDL-cholesterol 5% to 10% with no effect on HDL-cholesterol.[4] However, atrial fibrillation has been identified as a common, dose-dependent adverse reaction in patients taking high doses of omega-3-acid ethyl esters, especially at doses of 4 g/day. Healthcare professionals should monitor patients for signs of atrial fibrillation and discontinue omega-3-acid ethyl esters if atrial fibrillation develops. Patients should be advised to report symptoms such as palpitations, dizziness, or irregular heartbeats promptly. Meta-analyses looking at the association between omega-3 fatty acids and risk of cardiovascular events have shown inconsistent results.[157][158][159][160]​ In high-risk patients with triglyceride levels between 135 and 499 mg/dL despite statin treatment, icosapent ethyl (the ethyl ester of the omega-3 fatty acid eicosapentaenoic acid) should be considered in combination with a statin.[140]​​

Creatine kinase and aminotransferases can rise due to lipid-lowering medication, especially statins and fibrates, and should be monitored. Caution should thus be taken with the coadministration of statins and fibrates.

Primary options

colesevelam: 1.9 g orally twice daily

OR

fenofibrate micronized: dose differs depending on brand; consult specialist for guidance on dose

OR

omega-3-acid ethyl esters: 4 g/day orally given in 1-2 divided doses

More

OR

icosapent ethyl: 2 g orally twice daily

Plus – antihypertensive

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all patients
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with hypertension
Plus – 

antihypertensive

Treatment recommended for ALL patients in selected patient group

Target blood pressure is <130/80 mmHg for most patients.[169][170]​ If lifestyle modification cannot achieve target, antihypertensive medication is required.

Although no specific class of antihypertensive drug is regarded as uniquely efficacious for metabolic syndrome, ACE inhibitors (e.g., ramipril, quinapril, enalapril) or angiotensin-II receptor antagonists (e.g., valsartan, irbesartan, telmisartan) are the preferred drugs, particularly in the presence of type 2 diabetes mellitus or chronic kidney disease, as they significantly reduce incidence of albuminuria and progression to nephropathy.[4][85]

See Essential hypertension.

Primary options

ramipril: 2.5 to 10 mg orally once daily

OR

quinapril: 5-40 mg orally once daily

OR

enalapril: 10-40 mg orally once daily

OR

lisinopril: 10-40 mg orally once daily

OR

valsartan: 80-320 mg orally once daily

OR

irbesartan: 150-300 mg orally once daily

OR

telmisartan: 40-80 mg orally once daily

Plus – testosterone replacement therapy

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all patients
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with male hypogonadism
Plus – 

testosterone replacement therapy

Treatment recommended for ALL patients in selected patient group

Testosterone replacement therapy may improve metabolic control as well as central obesity in patients with metabolic syndrome and hypogonadism.[48]​​​[49]​​​

See Hypogonadism in men.

Consider – hormone-replacement therapy (HRT)

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all patients
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with female hypogonadism
Consider – 

hormone-replacement therapy (HRT)

Treatment recommended for SOME patients in selected patient group

In women, hormone-replacement therapy (HRT) has been shown to improve lipid profiles, insulin sensitivity and secretion, and visceral adiposity, but the effects depend on the type, dose, and route of administration of the HRT.[50][172]​ CVD risk may be reduced if HRT is initiated during the early postmenopausal period (women ages <60 years or within ten years since the final menstrual period). There are many different types and formulations of HRT available; consult your local guidelines or drug information source for more information.

Consider – referral to a gynecologist or endocrinologist

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all patients
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with polycystic ovary syndrome (PCOS)
Consider – 

referral to a gynecologist or endocrinologist

Treatment recommended for SOME patients in selected patient group

PCOS seems to aggravate insulin resistance and metabolic risk factors in obese women, whereas in those of normal weight, PCOS is not associated with impaired insulin sensitivity.[46]

Patients with PCOS share features of metabolic syndrome such as obesity, insulin resistance, and dyslipidemia; these components are treated separately as per guidelines. Patients also require referral to a gynecologist or endocrinologist.

See Polycystic ovary syndrome.

Consider – pioglitazone or vitamin E

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all patients
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with metabolic dysfunction-associated steatotic liver disease (MASLD)
Consider – 

pioglitazone or vitamin E

Treatment recommended for SOME patients in selected patient group

MASLD is considered the hepatic manifestation of metabolic syndrome and is associated with obesity, dyslipidemia, and type 2 diabetes mellitus.[173][174]

Lifestyle modification, including weight loss, physical activity, and dietary changes, is the first-line therapy. There are no licensed drug treatments for MASLD, although use of pioglitazone or vitamin E may be considered for selected patients. Note that pioglitazone may already be in use as it is also indicated for insulin resistance.

See Steatotic liver disease.

Consider – liver transplantation

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all patients
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with metabolic dysfunction-associated steatotic liver disease (MASLD)
Consider – 

liver transplantation

Treatment recommended for SOME patients in selected patient group

Liver transplantation is an option for those with end-stage liver disease.

Plus – multidisciplinary team management

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all patients
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with chronic kidney disease
Plus – 

multidisciplinary team management

Treatment recommended for ALL patients in selected patient group

Metabolic syndrome and its components (obesity, hypertension) are associated with development and progression of chronic kidney disease (CKD).[177]​ Renal injury may occur directly through renal compression and lipotoxicity and indirectly through hypertension and insulin resistance.[177]

Optimizing management of the metabolic syndrome components is important to slow the progression of CKD. However, some drugs should be used with caution in patients with renal impairment and a dose adjustment may be required. Some drugs may also be contraindicated in patients with renal impairment. Check your local drug information source for more information.

An individualized multidisciplinary approach is recommended for patients with metabolic syndrome and CKD, including consultation with nephrology and endocrinology specialists.[177]

See Chronic kidney disease.

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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