Approach Considerations
The initial management of metabolic syndrome involves lifestyle modifications, including changes in diet and exercise habits. [85] Indeed, evidence exists to support the notion that the diet, exercise, and pharmacologic interventions may inhibit the progression of metabolic syndrome to diabetes mellitus. [86]
Treatment of hypertension had been based on the recommendations of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) guidelines, to achieve a goal blood pressure of less than 140/90 mm Hg or, in patients meeting diagnostic criteria for diabetes mellitus, less than 130/80 mm Hg. However, the 2014 report of the Eight Joint National Committee (JNC-8) has led to less stringent recommendations for drug therapy (140/90 mm Hg for most populations, 150/90 mm Hg for patients aged 60 or older), [87] with continued emphasis on the importance of promoting healthy diet and exercise behaviors, as addressed by 2013 guidelines from the American College of Cardiology. [88, 89] Nevertheless, more recent study data continue to support a more aggressive blood pressure goal of 120/80 mm Hg.
Surgical considerations
At present, no surgical interventions for metabolic syndrome have been widely accepted. However, trials of bariatric surgery in patients who were morbidly obese and had metabolic syndrome suggested beneficial results, including decreased insulin resistance and lower levels of inflammatory cytokines. [90]
Importantly, metabolic syndrome raises specific perioperative issues that should be considered in patients with metabolic syndrome undergoing any major surgical procedure. [91]
Treatment of obstructive sleep apnea
Treatment of associated obstructive sleep apnea may play a significant role in the management of metabolic syndrome. [92] In a 2011 study, patients with at least moderate obstructive sleep apnea who used continuous positive airway pressure (CPAP) therapy for 3 months showed significant improvements in their metabolic profile, including reductions in systolic and diastolic blood pressure, LDL-C, triglycerides, and glycated hemoglobin. Furthermore, reversal of metabolic syndrome occurred to a greater degree in the CPAP therapy group than in patients who underwent sham treatment (13% vs 1%, respectively). [93]
Consultations
Patients with diabetes should be referred to a diabetic nutritionist, if not an endocrinologist. Patients with cardiac symptoms (chest pain, shortness of breath, palpitations) or an abnormal stress test may merit referral to a cardiologist. Consider referral to a preventive cardiologist for primary or secondary prevention of cardiovascular disease in these high-risk patients. Consultation with a sleep specialist is indicated if there are symptoms suggestive of sleep apnea, such as excessive fatigue or daytime somnolence, a history of snoring and witnessed apneas, or physical signs of untreated apnea such as resistant hypertension.
Patients who are at high risk for obesity-associated morbidity and mortality with a BMI greater than 40 kg/m2 or with a BMI greater than 35 kg/m2 plus 1 or more significant comorbid conditions may be referred for consideration of bariatric surgery when less invasive methods of weight loss have failed.
Some advocate using the 130/80 mm Hg goal in all patients with metabolic syndrome, as well as using angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) rather than diuretics or beta blockers when medication is indicated. [94]
Pharmacologic Therapy
Correction of LDL-C and HDL-C levels
Management of elevated LDL-C includes consideration of all statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors) at all indicated ranges, as there are several formulations available with different doses and potencies. Statins affect the lipid profile favorably and provide possible pleiotropic benefits. [95] The choice of drug and dose should be individualized to the patient and titrated to achieve guideline-recommended goals. As a class, statins are pregnancy category "X" (contraindicated; benefit does not outweigh risk).
Management of reduced HDL-C remains controversial, but starts with diet/exercise modifications and may include niacin. Certain statins (such as rosuvastatin) may help, but this is not yet a widely accepted indication.
Cholesteryl ester transfer protein (CETP) inhibitors have been studied as potential agents to raise HDL-C levels in a clinically meaningful manner. Though torcetrapib increased HDL-C levels, it failed to improve clinical outcomes in the ILLUSTRATE (Investigation of Lipid level Management Using Coronary Ultrasound To Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation) trial. [96] Another CETP inhibitor, anacetrapib, remains in development, and the ongoing DEFINE (Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib) trial is expected to shed light on this agent’s potential for reducing clinical cardiovascular events. [97]
Fibrate therapy may serve as an important adjunct in overweight patients with elevated triglyceride and low HDL-C levels (a combination known as atherogenic dyslipidemia). [98]
Niacin raises low HDL-C levels and reduces cardiovascular events but may exacerbate hyperglycemia, especially in high doses (>1500 mg/day), so careful monitoring is recommended. [99]
The latest cholesterol guidelines from the American College of Cardiology emphasize the use of statins over nonstatin therapies, and recommend re-emphasis on adherence to statin and lifestyle therapies before resorting to nonstatin therapies. [100]
Triglyceride treatment
When lifestyle modifications fail, medical therapy for elevated triglycerides may include niacin and fibrates, though a distinction should be made between gemfibrozil and fenofibrate/fenofibric acid due to their different dosing patterns and different propensities for drug interactions, particularly if combined with a statin. The addition of omega-3 fatty acids to treatment is also likely to help lower triglyceride levels. [101]
Hyperglycemia treatment
Drug therapy for hyperglycemia in patients with metabolic syndrome typically begins with an insulin-sensitizing agent, such as metformin. Some literature suggests that metformin may help to reverse the pathophysiologic changes of metabolic syndrome. This includes when it is used in combination with lifestyle changes [102] or with peroxisome proliferator-activated receptor agonists, such as the fibrates [103] and thiazolidinediones (eg, pioglitazone, rosiglitazone), [104, 105] each of which may produce favorable metabolic alterations as single agents in patients with metabolic syndrome. [106]
Management of diabetes mellitus, including screening for end-organ complications, should proceed under current guidelines. [107]
Preventive cardiovascular treatment
Aspirin therapy may be helpful in the primary prevention of cardiovascular complications, [108] particularly in patients with at least an intermediate risk of suffering a cardiovascular event (ie, >6% 10 y risk). [109]
Complementary and alternative medicine
The use of complementary and alternative medications for metabolic syndrome has limited literature support. Traditional Chinese medicines may have a role, as a variety of agents, including ginseng, berberine, and bitter gourd, have demonstrated some favorable metabolic effects, but large-scale clinical trials are needed to fully investigate their safety and efficacy. [110]
A variety of other complementary and alternative treatments may have a potential role in the management of metabolic syndrome [111] and additional study remains warranted.
Diet
Lifestyle change and weight loss are considered the most important initial steps in treating metabolic syndrome. Studies comparing ethnically similar populations exposed to different dietary environments suggested that Westernized diets are strongly associated with a higher risk of developing metabolic syndrome. [5]
On the other hand, diets rich in dairy, fish, and cereal grains may be associated with a lower risk of developing metabolic syndrome. [112, 113] Not surprisingly, Mediterranean-style diets appear to be associated with a much lower risk and possibly with resolution of metabolic syndrome in patients who have met diagnostic criteria, especially when coupled with adequate exercise regimens. [114]
A meta-analysis of multiple population studies associated chocolate consumption with a substantial risk reduction (approximately 30%) for cardiometabolic disorders, including coronary disease, cardiac deaths, diabetes, and stroke. [115] The apparent benefits of chocolate may accrue from a beneficial impact of polyphenols present in cocoa products that increase the bioavailability of nitric oxide.
Epidemiologic studies, particularly in males, suggest that moderate wine intake may protect against the development and complications of metabolic syndrome, an effect that is at least partially attributable to polyphenols, such as resveratrol, found in red wines. [116, 117]
The impact of sugar consumption on the risk of developing metabolic syndrome is controversial. Evidence suggests that absolute fructose intake may relate to incident metabolic syndrome. [118] Higher fructose diets have been blamed for elevated rates of metabolic syndrome in African American populations. [119]
However, glycemic load or intake does not appear to predispose persons to the development of metabolic syndrome, though avoidance of high-glycemic-index foods in patients with metabolic syndrome may improve characteristic parameters such as atherogenic dyslipidemia. [120]
In a single-blind, parallel, controlled, dietary intervention study, subjects with metabolic syndrome (n=472) from 8 European countries classified by different insulin resistance (IR) levels according to a homeostasis model assessment of insulin resistance (HOMA-IR) were randomly assigned to 4 diets: a high-saturated fatty acid (HSFA) diet; a high-monounsaturated fatty acid (HMUFA) diet; a low-fat, high-complex carbohydrate (LFHCC) diet supplemented with long-chain n-3 polyunsaturated fatty acids (1.2 g/d); or an LFHCC diet supplemented with placebo for 12 weeks (control). The results provided evidence that subjects’ degree of insulin resistance determines response to the quantity and quality of dietary fat on metabolic syndrome risk factors. [121]
Activity
Exercise is thought to be an important intervention, [122] and the current recommendation is for patients to perform regular moderate-intensity physical activity for at least 30 minutes continuously at least 5 days per week (ideally, 7 days per week). Maintaining long-term adherence, however, remains a challenge. [123] Achieving moderate intensity activity for 120 to 150 minutes a week may reduce the risk of developing metabolic syndrome. [124] Among patients who already have metabolic syndrome, physical activity correlates with a much lower (about 50%) risk of developing coronary heart disease. [125]
In a prospective study, cardiorespiratory fitness was linked to the risk of developing metabolic syndrome in a dose-dependent manner, with male patients in the highest category of fitness having the lowest risk of developing new-onset metabolic syndrome. [126]
Evidence suggests that excessive sitting and other behaviors that are low in activity and energy expenditure may trigger unique cellular responses that contribute to the development of metabolic syndrome. [127]
Deterrence and Prevention
In 2010, the American Heart Association-American Stroke Association (AHA-ASA) updated their guidelines for the primary prevention of stroke. These are described below. [128]
Hypertension
Regular blood pressure screening, lifestyle modification, and drug therapy are recommended. A lower risk of stroke and cardiovascular events are seen when systolic blood pressure levels are less than 140 mm Hg and diastolic blood pressure is less than 90 mm Hg. In patients who have hypertension with diabetes or renal disease, the blood pressure goal is less than 130/80 mm Hg. However, the 2014 JNC-8 guidelines recommend more lenient targets (150/90 mm Hg in patients ≥60 y, and 140/90 mm Hg for most other populations).
Diabetes
Blood pressure control is recommended in types 1 and 2 diabetes. Hypertensive agents that are useful in the diabetic population include ACE inhibitors or ARBs.
Treating adults with diabetes with statin therapy, especially patients with other risk factors, is recommended, and monotherapy with fibrates may also be considered to lower stroke risk. Taking aspirin is reasonable in patients who are at high cardiovascular disease risk. However, the benefit of taking aspirin in diabetic patients for the reduction of stroke risk has not been fully demonstrated.
Dyslipidemia
Statin therapy is recommended in patients with coronary heart disease and certain high-risk conditions for the primary prevention of ischemic stroke. In addition to statin therapy, therapeutic lifestyle changes and LDL-cholesterol goals are also recommended.
Niacin may be used in patients with low HDL cholesterol or elevated lipoprotein (a), but its efficacy in preventing ischemic stroke is not established. Fibric acid derivatives, niacin, bile acid sequestrants, and ezetimibe may be useful in patients who have not achieved the target LDL-C level with statin therapy or who cannot tolerate statins; however, their effectiveness in reducing the risk of stroke has not been established.
Diet and nutrition
A diet that is low in sodium and high in potassium is recommended to reduce blood pressure. Diets that promote the consumption of fruits, vegetables, and low-fat dairy products, such as the DASH (Dietary Approaches to Stop Hypertension)–style diet, help to lower blood pressure and may lower the risk of stroke.
Physical activity
Increases in physical activity are associated with a reduction in the risk of stroke. The goal is to engage in at least 30 minutes of moderate intensity activity on a daily basis
Obesity and body fat distribution
Weight reduction among persons who are overweight or obese is recommended to reduce blood pressure and risk of stroke.
Sleep health
Care should be taken to ensure that patients with metabolic syndrome practice healthy sleep behaviors. Even in patients who do not have sleep apnea or suspected sleep apnea, some studies have suggested a relationship between sleep deprivation or inadequate sleep time and metabolic syndrome. [129] Shift workers, who tend to have poor quality sleep, may also be at higher risk of developing metabolic syndrome. [130]
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- Overview
- Presentation
- DDx
- Workup
- Treatment
- Medication
- Medication Summary
- Antidiabetics, Biguanides
- Antidiabetics, Thiazolidinediones
- Lipid-Lowering Agents, Statins
- ACE Inhibitors
- Angiotensin II Receptor Blockers (ARBs)
- Lipid-lowering Agents, Non-Statin
- Lipid-Lowering Agents, Non-Statin
- Antiplatelet Agents, Cardiovascular
- Antidiabetics, SGLT2 Inhibitors
- Antidiabetics, Glucagon-like Peptide-1 Agonists
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