METABOLIC SYNDROME

EPIDEMIOLOGY:

Metabolic syndrome is increasing in prevalence, paralleling an increasing epidemic of obesity. In the United States, where almost two thirds of the population is overweight or obese, more than one fourth of the population meets diagnostic criteria for metabolic syndrome.⁽¹⁾ In the United States, data from a 1999-2000 survey showed that the age-adjusted prevalence of metabolic syndrome among adults aged 20 years or older had risen from 27% (data from 1988-1994) to 32%.⁽²⁾

The prevalence of metabolic syndrome in Pakistan according to different definitions is reported to be from 18% to 46%, comparable to the data from other South Asian countries.⁽³⁾

PATHOPHYSIOLOGY:

Target organ damage occurs through multiple mechanisms in metabolic syndrome. The individual diseases leading to metabolic syndrome produce adverse clinical consequences. For example, hypertension in metabolic syndrome causes left ventricular hypertrophy, progressive peripheral arterial disease, and renal dysfunction.⁽⁴⁾ However, the cumulative risk for metabolic syndrome appears to cause microvascular dysfunction, which further amplifies insulin resistance and promotes hypertension.⁽⁵⁾

Metabolic syndrome promotes coronary heart disease through several mechanisms. It increases the thrombogenicity of circulating blood, in part by raising plasminogen activator type 1 and adipokine levels, and it causes endothelial dysfunction.⁽⁶⁾ Metabolic syndrome may also increase cardiovascular risks by increasing arterial stiffness.⁽⁷⁾ Additional mechanisms include oxidative stress,⁽⁸⁾ which has been associated with numerous components of metabolic syndrome.⁽⁹⁾

NATURAL HISTORY:

The metabolic syndrome is a constellation of risk factors of metabolic origin that are accompanied by increased risk for cardiovascular disease and type 2 diabetes. These risk factors are atherogenic dyslipidemia, elevated blood pressure, elevated plasma glucose, a prothrombotic state, and a proinflammatory state. The two major underlying risk factors for the metabolic syndrome are obesity and insulin resistance; exacerbating factors are physical inactivity, advancing age, and endocrine and genetic factors. The condition is progressive, beginning with borderline risk factors that eventually progress to categorical risk factors. In many patients, the metabolic syndrome culminates in type 2 diabetes, which further increases risk for cardiovascular disease. Primary treatment of the metabolic syndrome is lifestyle therapy—weight loss, increased physical activity, and anti-atherogenic diet. But as the condition progresses, drug therapies directed toward the individual risk factors might be required. Ultimately, it might be possible to develop drugs that will simultaneously modify all of the risk factors.⁽¹⁰⁾

SIGN AND SYMPTOMS:

The physical examination is crucial in patients with metabolic syndrome, as the findings of elevated blood pressure and abdominal obesity are 2 of the 5 diagnostic criteria. Measurement and documentation of waist circumference are important routines when screening for metabolic syndrome.

Clinical manifestations of metabolic syndrome include the following:

• Hypertension
• Hyperglycemia
• Hypertriglyceridemia
• Reduced high-density lipoprotein cholesterol (HDL-C)
• Abdominal obesity
• Chest pains or shortness of breath: Suggesting the rise of cardiovascular and other complications
• Acanthosis nigricans, hirsutism, peripheral neuropathy, and retinopathy: In patients with insulin resistance and hyperglycemia or with diabetes mellitus
• Xanthomas or xanthelasmas: In patients with severe dyslipidemia

DIAGNOSTIC TESTS:

According to guidelines from the National Heart, Lung, and Blood Institute (NHLBI) and the American Heart Association (AHA), metabolic syndrome is diagnosed when a patient has at least 3 of the following 5 conditions:

• Fasting glucose ≥100 mg/dL (or receiving drug therapy for hyperglycemia)
• Blood pressure ≥130/85 mm Hg (or receiving drug therapy for hypertension)
• Triglycerides ≥150 mg/dL (or receiving drug therapy for hypertriglyceridemia)
• HDL-C < 40 mg/dL in men or < 50 mg/dL in women (or receiving drug therapy for reduced HDL-C)
• Waist circumference ≥102 cm (40 in) in men or ≥88 cm (35 in) in women; if Asian American, ≥90 cm (35 in) in men or ≥80 cm (32 in) in women

To address variation between professional guidelines, the NHLBI, AHA, International Diabetes Foundation (IDF), and others have proposed a harmonized definition of metabolic syndrome.⁽¹¹⁾

Complaints of chest pain, dyspnea, or claudication (symptoms of possible complications) may warrant additional studies, including the following:

• Electrocardiography (rest/stress ECG)
• Ultrasonography (vascular, or rest/stress echocardiography)
• Stress single-photon emission computed tomography (SPECT) or cardiac positron emission tomography (PET)

Investigation into other causes of or exacerbating factors in metabolic syndrome should be considered. For example, sleep-related breathing disorders, such as obstructive sleep apnea, are becoming increasingly relevant and novel risk factors for metabolic syndrome.⁽¹²⁾

PATIENT SELECTION FOR TREATMENT:

Health care providers should assess individuals for metabolic risk at routine clinic visits. The Endocrine Society clinical guidelines suggest evaluation at three-year intervals in individuals with one or more risk factors.⁽¹³⁾ The assessment should include measurement of blood pressure, waist circumference, fasting lipid profile, and fasting glucose.

In patients identified as having the metabolic syndrome, aggressive lifestyle intervention (weight reduction, physical activity) is warranted to reduce the risks of type 2 diabetes and CVD. Assessment of 10-year risk for CVD, using a risk assessment algorithm, such as the Framingham Risk Score or Systematic Coronary Risk Evaluation (SCORE), is useful in targeting individuals for medical intervention to lower blood pressure and cholesterol.

THERAPY CONSIDERATIONS:

The initial management of metabolic syndrome involves lifestyle modifications, including changes in diet and exercise habits. Indeed, evidence exists to support the notion that the diet, exercise, and pharmacologic interventions may inhibit the progression of metabolic syndrome to diabetes mellitus.⁽¹⁴⁾

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),⁽¹⁵⁾ with continued emphasis on the importance of promoting healthy diet and exercise behaviors, as addressed by 2013 guidelines from the American College of Cardiology.^(16,17) Nevertheless, more recent study data continue to support a more aggressive blood pressure goal of 120/80 mm Hg.

TREATMENT OPTIONS:

LIFE STYLE MODIFICATIONS:

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.⁽¹⁸⁾

On the other hand, diets rich in dairy, fish, and cereal grains may be associated with a lower risk of developing metabolic syndrome.^(19,20) 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.⁽²¹⁾

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.⁽²¹⁾ 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.⁽²²⁾

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.⁽²³⁾ Higher fructose diets have been blamed for elevated rates of metabolic syndrome in African American populations.⁽²⁴⁾

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.⁽²⁵⁾

Activity: Exercise is thought to be an important intervention,⁽²⁶⁾ 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.⁽²⁷⁾  Achieving moderate intensity activity for 120 to 150 minutes a week may reduce the risk of developing metabolic syndrome.⁽²⁸⁾  Among patients who already have metabolic syndrome, physical activity correlates with a much lower (about 50%) risk of developing coronary heart disease.⁽²⁹⁾

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.⁽³⁰⁾ 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.⁽³¹⁾

PHARMACOLOGICAL:

The following medications can be used to treat dyslipidemia and other manifestations of metabolic syndrome:

Atorvastatin, Rosuvastatin, Fluvastatin and Lovastatin: are HMG-CoA reductase inhibitors that inhibit the rate-limiting step in cholesterol biosynthesis by competitively inhibiting HMG-CoA reductase.

Niacin: Niacin is used in tissue respiration, lipid metabolism, and glycogenolysis. Nicotinic acid has lipid-lowering properties, but nicotinamide and niacinamide do not. Inositol hexanicotinate is a "no flush" form that may not release enough niacin to be effective. In addition to improving low HDL-C levels, niacin may lower triglycerides and LDL-C levels.

Fenofibrate: Increases VLDL catabolism by enhancing synthesis of lipoprotein lipase, fatty acid oxidation, and elimination of triglyceride-rich particles. This results in decreased triglyceride levels by 30-60%; HDL may increase.

Fenofibric acid: Increases VLDL catabolism by enhancing synthesis of lipoprotein lipase, fatty acid oxidation, and elimination of triglyceride-rich particles. This results in decreased triglyceride levels by 30-60%; HDL may increase.

Gemfibrozil: Gemfibrozil may decrease serum VLDL levels by inhibiting lipolysis, decreasing subsequent hepatic fatty acid uptake, and by inhibiting hepatic secretion of VLDL.

Omega-3 fatty acids: Prescription medical food specifically formulated to correct an omega-3 deficiency in cardiovascular patients

Metformin: Metformin reduces hepatic glucose output, decreases intestinal absorption of glucose, and increases glucose uptake in the peripheral tissues (muscle and adipocytes). It is a major drug for use in patients who are obese and have type 2 diabetes. Metformin enhances weight reduction and improves lipid profile and vascular integrity. Individualize treatment with monotherapy or in combination with insulin or sulfonylureas.

Aspirin: Aspirin is a stronger inhibitor of prostaglandin synthesis and platelet aggregation than are other salicylic acid derivatives.

Aspirin irreversibly inhibits platelet aggregation by inhibiting platelet cyclooxygenase. This, in turn, inhibits conversion of arachidonic acid to prostaglandin I2 (potent vasodilator and inhibitor of platelet activation) and thromboxane A2 (potent vasoconstrictor and platelet aggregating agent). Platelet inhibition lasts for the life of the cell (approximately 10 days).

Aspirin may be used in low dose to inhibit platelet aggregation and improve complications of venous stases and thrombosis. It reduces the likelihood of myocardial infarction and is also very effective in reducing the risk of stroke. Early administration of aspirin in patients with acute myocardial infarction may reduce cardiac mortality in the first month.

SURGICAL:

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.⁽³²⁾

Importantly, metabolic syndrome raises specific perioperative issues that should be considered in patients with metabolic syndrome undergoing any major surgical procedure.⁽³³⁾

GOALS OF THERAPY:

In 2001, the Adult Treatment Panel III (ATP III) recommended two major therapeutic goals in patients with the metabolic syndrome. These goals were reinforced by a report from the American Heart Association (AHA) and the National Institutes of Health (NIH) (and by clinical guidelines from The Endocrine Society :

• Treat underlying causes(overweight / obesity and physical inactivity) by intensifying weight management and increasing physical activity.
• Treat cardiovascular risk factors if they persist despite lifestyle modification.

GUIDELINES:

Treatment for Metabolic Syndrome is based on guidelines from the prestigious societies such as IDF and AHA/NHLBI.

To review the IDF guidelines, click on the link below

https://www.idf.org/webdata/docs/IDF_Meta_def_final.pdf

To review the AHA/NHLBI, click on the link below

http://www.aafp.org/afp/2006/0915/p1039.html

LONG TERM MONITORING:

• Regular follow-up to monitor progress in reducing cardiovascular risk.
• Arguably, a glucose tolerance test should be performed for people with the metabolic syndrome who have normal fasting glucose, as this may identify some with occult diabetes.⁽³⁴⁾

CONSULTATION AND COUNSELING:

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.⁽³⁵⁾

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