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Definition of Metabolic Syndrome

The association between visceral obesity, hypertension and atherosclerosis was recognized as early as the 1700’s.  There would go on to be further associations between hyperglycemia and hypertension that were recognized within the medical community. These associations led the groundwork for what later came to be termed Metabolic Syndrome This syndrome is a constellation of cardiovascular and metabolic risk factors including abdominal obesity, hyperglycemia, dyslipidemia and hypertension which predisposes one to the development of type 2 diabetes and cardiovascular disease.

 

Each component of the metabolic syndrome is an independent risk factor for cardiovascular disease.  The combination of these risk factors elevates the rate and severity of cardiovascular disease in relation to many conditions including microvascular dysfunction, atherosclerosis, myocardial infarction, and heart failure.

 

Diagnostic Criteria

There has been considerable disagreement over the terminology and diagnostic criteria related to the metabolic syndrome. This has led to some confusion on the part of clinicians regarding how to identify patients with the syndrome. Some controversy also exists as to whether it is a true syndrome or a phenomena of diseases existing concurrently. The first formalized definition of the metabolic syndrome was proposed in 1998 by a group of experts consulting for the World Health Organization (WHO). This group emphasized insulin resistance as the major underlying risk factor and required evidence of insulin resistance for diagnosis. A diagnosis of the syndrome by WHO criteria could be made on the basis of several markers of insulin resistance plus two additional risk factors which included high triglycerides, reduced high density lipoprotein levels, hypertension or microalbuminuria.

 

The other major criteria came from the National Cholesterol Education Program Adult Treatment Panel III (ATP III) in 2001. ATP III criteria did not require documentation of insulin resistance but instead proposed that a patient must have three of the five following criteria: abdominal obesity, elevated triglyceride, reduced high-density lipoprotein cholesterol, hypertension, and impaired fasting glucose or type 2 diabetes mellitus.

 

In 2005, both the International Diabetes Federation (IDF) and the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) attempted to reconcile the different clinical definitions, although their separate recommendations still had differences regarding waist circumference measurements.

 

Abdominal Obesity Thresholds

Current recommended waist circumference thresholds for abdominal obesity differ between the sexes and ethnic groups. This is because risks associated with a particular waist measurement will differ in different populations. 

 

In the United States, currently the recommended waist circumference threshold for abdominal obesity according to AHA/NHLBI (ATP III) guidelines for metabolic syndrome recognize an increased risk for cardiovascular disease and diabetes at waist-circumference thresholds of ≥94 cm in men and ≥80 cm in women and identify these as optional cut points for individuals or populations with increased insulin resistance. The World Health Organization (WHO) further defines men with > 102 cm and women > 88 cm at a very high risk for developing metabolic syndrome.

 

Case 1:

JW comes into your pharmacy and tells you she just read an article on metabolic syndrome and she is scared she may have it. She wants you to help her decide if she meets the criteria for metabolic syndrome. She provides you with the following from her medical history based on her last physician visit.

 

JW is a 72-year-old Mexican American female who was last seen at her PCP 3 months ago. She brings in the printout that she received after her last PCP appointment.

 

Physical exam and lab work:

  • Waist circumference: 87 cm

  • LDL: 84 mg/dl

  • HDL: 47 mg/dl

  • Triglycerides: 147 mg/dl

  • BP: 147/97 mmHg

  • Fasting glucose: 76 mg/dl

Current medications:

  • Enalapril 20 mg QAM

  • ASA 81 mg QAM

  • HCTZ 25 mg QAM

  • St. Johns Wort QPM

  • Calcium/Vitamin D 600 mg BID

 

Clinical Diagnosis for Metabolic Syndrome

The following table defines the criteria for the clinical diagnosis of  metabolic syndrome which is referenced from the 2009 joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and the International Association for the Study of Obesity (Harmonizing definition).

In the following table, a patient must exhibit 3 out of the 5 clinical characteristics to be characterized as having metabolic syndrome.

 

The table defines the criteria for the clinical diagnosis of  metabolic syndrome which is referenced from the 2009 joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and the International Association for the Study of Obesity (Harmonizing definition).

 

Measure

Cut points

Elevated waist circumference (cm)

≥94 in males; ≥80 in females (Europid, sub-Saharan African, Eastern and Middle Eastern, White American, African American)

≥90 in males; ≥80 in females (South Asian, Chinese, and ethnic South and Central American, Mexican American)

≥85 in males; ≥90 in females (Japanese)

Elevated triglycerides (drug treatment for elevatedtriglycerides is an alternate indicator)

≥150 mg/dL

Reduced HDL (drug treatment for reduced HDL is an alternate indicator)

<40 mg/dL in males; <50 mg/dL in females

Elevated blood pressure (antihypertensive drug is an alternate indicator)

Systolic ≥130 and/or diastolic ≥85 mm Hg

Elevated fasting glucose (drug treatment of elevated glucose is an alternate indicator)

≥100 mg/dL

 

Case 1 Results:

JW does indeed meet the following criteria for metabolic syndrome:

  • Elevated waist circumference= ≥80 in Mexican American females

  • Low HDL = <50 mg/dL in females

  • Elevated blood pressure and/or hypertension medication: = Systolic ≥130 and/or diastolic ≥85 mm Hg and taking enalapril and HCTZ

 

As a result of your findings you suggest she make an appointment with her PCP to discuss the complications of metabolic syndrome and what options are available to her.

 

Epidemiology

The prevalence of obesity among US adults has increased steadily since the 1990s and is now at epidemic proportions, with over two-thirds of US adults either overweight or obese. Concurrently, the prevalence of type 2 diabetes and hypertension has also steadily increased, cumulating in substantial increases in the proportion of adults who likely meet the criteria for metabolic syndrome.

 

The prevalence of metabolic syndrome varies around the world, in part reflecting the age and ethnicity of the populations studied and the diagnostic criteria applied. In general, the prevalence of metabolic syndrome increases with age. The highest recorded prevalence worldwide is among Native Americans, with an age-adjusted 53% of women and 45% of men meeting the criteria. In 2012, the overall prevalence of metabolic syndrome in the United States was 33% with a higher prevalence in women than men (36% vs 30%, respectively). When stratified by race/ethnicity, the highest prevalence of metabolic syndrome was 35% in Hispanics followed by 33% in non-Hispanic Caucasians and African Americans.

 

Epidemiology in Children

 

According to estimates from the American Heart Association, more than 9% of U.S. children and adolescents aged 12–19, or nearly three million individuals, have  metabolic syndrome. Among overweight and obese adolescents, this prevalence rate rises to 44%. Two-thirds of adolescents have at least one metabolic abnormality. Children and adolescents with metabolic syndrome are at high risk of developing cardiovascular disease and diabetes as adults. Compared to children without the syndrome, those with metabolic syndrome are 14 times more likely to suffer from cardiovascular disease and 11 times more likely to develop diabetes when they reach adulthood.

 

This rise in the incidence of metabolic syndrome in children is fueled by the rising prevalence of obesity in this age group. From 1980 to 2008, rates of obesity have increased from 5% to 10% among preschool children aged 2–5. During the same time period, obesity increased from 6.5% to nearly 20% among 6-11 year-olds and from 5% to 18% among adolescents aged 12–19. Hypertension among children and adolescents has increased by 1% since 1999 and is estimated to affect 3.6% of those aged 3–18.  Approximately 14% of normal-weight youths aged 12–19 have lipid abnormalities and that figure rises to 22% of overweight youths and nearly 43% of obese youths.

 

Until recently, diabetes in children was typically assumed to be type 1 diabetes. However, according to the Centers for Disease Control and Prevention, recent clinical evidence indicates that the prevalence of type 2 diabetes, is increasing among U.S. children and adolescents. This increase is most notable among African Americans, Asian/Pacific Islanders, Hispanics and American Indians.

 

Risk Factors

Given how common metabolic syndrome is it is essential to be knowledgeable about one’s risk factors to help reduce the likelihood of developing the syndrome. Some risk factors are beyond the scope of one’s control while others can be changed by lifestyle modifications or control of the primary disease state.

There are several risk factors:

  • Obesity/Overweight

  • Sedentary lifestyle

  • Genetic predisposition

  • Age

  • Diabetes

  • Lipodystrophy

  • Other diseases

 

Weight status – Central adiposity is a key feature of the syndrome, and the syndrome’s prevalence reflects the strong relationship between waist circumference and increasing adiposity. However, despite the importance of obesity, patients who are of normal weight may also be insulin-resistant and may have metabolic syndrome. This phenotype is particularly evident for populations in India, Southeast Asia and Central America.

Sedentary lifestyle – Physical inactivity and less cardio fitness are a predictor of cardiovascular events and the related risk of death. Many components of the metabolic syndrome are associated with a sedentary lifestyle, including increased adipose tissue (predominantly central), reduced HDL cholesterol, and an increase in triglycerides, blood pressure and glucose. A study showed that compared with individuals who use electronic media for <1 hour daily versus those who do so for >4 hours daily have a twofold increased risk of the metabolic syndrome.

Genetics – Even if a person is not obese they may have inherited a higher risk for developing metabolic syndrome. No single gene explains the complex phenotype related to metabolic syndrome. A number of genetic variants are associated with the metabolic syndrome. Although many of the loci have unknown function, many others relate to body weight and composition, insulin resistance, and lipid metabolism.

 

Age – The risk of getting metabolic syndrome rises from 20% in your 40s, to 35% in your 50s, to 45% in your 60s and beyond. The metabolic syndrome affects nearly 50% of the U.S. population aged >60, and at >60 years of age women are more often affected  The age dependency of the syndrome’s prevalence is seen in most populations around the world.

Diabetes – The great majority (~75%) of patients with type 2 diabetes or impaired glucose tolerance have metabolic syndrome. The presence of  metabolic syndrome in these populations relates to a higher prevalence of cardiovascular disease than in patients who have type 2 diabetes or impaired glucose tolerance but do not have the syndrome.

Lipodystrophy – It is quite common for patients who have lipodystrophy to present with metabolic syndrome. Both genetic and acquired lipodystrophy may give rise to severe insulin resistance and many of the components of  metabolic syndrome.

Other Medical Conditions – Metabolic syndrome is associated with a number of medical conditions. These include polycystic ovary syndrome, fatty liver and cholesterol gallstones.

 

Etiology

Although research has been carried out in recent decades on metabolic syndrome, the exact underlying etiology is still not completely understood. Many contributing factors and mechanisms have been proposed including insulin resistance, adipose tissue dysfunction, chronic inflammation, oxidative stress, circadian disruption and genetic factors.

 

Recently, the gut microbiome has emerged as an important contributor to the development of obesity and related metabolic disorders, including the metabolic syndrome. Although the mechanisms remain uncertain, the interaction between diet, bile acid metabolism and the intestinal flora is important. The following slides will discuss the major factors that are thought to be related to the etiology of metabolic syndrome.

 

Etiology: Insulin Resistance

The major underlying pathophysiology of the metabolic syndrome is insulin resistance. This insulin resistance causes defects in how adipose tissue, skeletal and cardiac muscle, and the liver respond to insulin. In the liver, insulin resistance is manifested by defects in the ability of insulin to suppress glucose production. In adipose tissue insulin resistance is manifested as the anti-lipolytic effects of insulin whereas in muscle the defect in insulin mediated glucose uptake results in reductions in glycogen biosynthesis. Thus, insulin resistance indicates a pathophysiological condition in which a normal insulin concentration does not adequately produce a normal insulin response in the peripheral target tissues.

 

In metabolic syndrome, the β-cells in the pancreas secrete more insulin to overcome the hyperglycemia and therefore hyperinsulinemia results. This hyperinsulinemia state contributes to sodium retention leading to hypertension and hepatic steatosis, also known as fatty liver disease. Over time the β-cells will eventually be unable to produce sufficient insulin levels which leads to impaired fasting glucose, impaired glucose tolerance and eventually type 2 diabetes mellitus.

 

Insulin resistance is commonly accompanied by abdominal obesity with a fat accumulation in the visceral depot. Of particular concern is that adipocytes obtained from visceral adipose tissue are much less insulin responsive than adipocytes obtained from subcutaneous depots.  In addition, abdominally obese subjects also demonstrate more insulin resistance than subjects in whom excess body fat distribution is less central.

 

Etiology: Pancreatic β-Cell Dysfunction

 

The function of the β-cell is closely correlated with metabolic syndrome. β-cell dysfunction is highly correlated with the severity of metabolic syndrome and is thought to be independent of sex, body fat, blood lipids, blood pressure, insulin resistance and glucose metabolism. It has been postulated that improving the β-cell function can be an important strategy to ameliorate metabolic syndrome. It is suggested that increased cardiorespiratory fitness is positively associated with enhanced β-cell function in individuals with metabolic syndrome.

 

In recent years, as weight-loss strategies have been evaluated, cardiorespiratory fitness has attracted more attention.  It is suggested that fitness-based interventions rather than weight-loss driven strategies reduce mortality risk overall. Lean body mass is a better indicator for longevity or mortality than BMI, therefore more attention needs to be given to lean mass and cardiorespiratory fitness rather than body weight reduction as a strategy for lowering the risk of metabolic syndrome.

 

Etiology: Leptin Resistance

Leptin resistance also may be a pathophysiologic mechanism to explain the metabolic syndrome. Physiologically, leptin reduces appetite, promotes energy expenditure, and enhances insulin sensitivity. However, when obesity develops, hyperleptinemia ensues, with evidence of leptin resistance in the brain and other tissues resulting in inflammation, insulin resistance, hyperlipidemia, and a plethora of cardiovascular disorders, such as hypertension, atherosclerosis, coronary heart disease and heart failure.

 

Etiology: Pro-Inflammatory Cytokines

Free fatty acids are released in abundance from an expanded adipose tissue mass. In the liver, this results in an increased production of glucose and triglycerides and an increased secretion of very low-density lipoproteins (VLDL), reductions in high-density lipoprotein (HDL) cholesterol and an increase in low-density lipoproteins (LDL). Free fatty acids also reduce insulin sensitivity in muscle by inhibiting insulin-mediated glucose uptake. The increase in circulating glucose, and to some extent the free fatty acids causes an increase in pancreatic insulin secretion, resulting in hyperinsulinemia. This leads to a pro-inflammatory state which causes a number of inflammatory mediators to be released including the enhanced secretion of interleukin 6 and tumor necrosis factor α. This causes more insulin resistance and lipolysis of adipose tissue triglyceride stores. These mediators also enhance hepatic glucose production, VLDL production by the liver, hypertension and insulin resistance in muscle. In turn, this insulin resistance also contributes to increased triglyceride accumulation in the liver. Cytokines and free fatty acids  also increase hepatic production of fibrinogen and adipocyte production of plasminogen activator inhibitor 1 which leads to a pro-thrombotic state.

 

Adiponectin is an anti-inflammatory cytokine produced exclusively by adipocytes. Adiponectin enhances insulin sensitivity and inhibits many steps in the inflammatory process. In the liver, adiponectin inhibits the expression of gluconeogenic enzymes and the rate of glucose production. In muscle, adiponectin increases glucose transport and enhances fatty acid oxidation, partially through the activation of AMP kinase. Reductions in adiponectin levels are common in the metabolic syndrome. 

 

Etiology: Increased Waist Circumference

Waist circumference is an important component of the most recent and frequently applied diagnostic criteria for the metabolic syndrome. However, measuring waist circumference does not reliably distinguish increases in adipose tissue from that in visceral fat. With increases in visceral adipose tissue, adipose tissue–derived free fatty acids reach the liver. In contrast, increases in abdominal subcutaneous fat release lipolysis products into the systemic circulation and therefore have fewer effects on hepatic metabolism. 

 

Relative increases in visceral versus subcutaneous adipose tissue with increasing waist circumference in Asians and Asian Indians may explain the greater prevalence of the syndrome in those populations than in African American men, in whom subcutaneous fat predominates.

 

Etiology: Dyslipidemia

Hypertriglyceridemia is an excellent marker of metabolic syndrome and indicates insulin resistance. Not only is hypertriglyceridemia a feature of metabolic syndrome, but patients with metabolic syndrome have elevated levels of apoC-III carried on VLDLs and other lipoproteins. This increase in apoC-III is inhibitory to lipoprotein lipase, further contributing

to hypertriglyceridemia, and is a marker for an increased risk for atherosclerotic cardiovascular disease.

The other major lipoprotein disturbance in the metabolic syndrome is a reduction in HDL cholesterol. This reduction is a consequence of changes in HDL composition and metabolism. In the presence of hypertriglyceridemia, there is a decrease in the cholesterol content of HDL that make the particle small and dense. This change in HDL composition results in an increased clearance of HDL from the circulation leading to a decreased level of HDL.

 

In addition to HDLs, low-density lipoproteins (LDLs) have alterations in composition in the metabolic syndrome. There is usually a predominance of small, dense LDLs, which are thought to be more atherogenic although their association with hypertriglyceridemia and low HDLs make their independent contribution to cardiac events difficult to assess.  

 

Etiology: Hypertension

The relationship between insulin resistance and hypertension is well established. Under normal physiologic conditions, insulin is a vasodilator with secondary effects on sodium reabsorption in the kidney. However, in the setting of insulin resistance, the vasodilatory effect of insulin is lost but the renal effect on sodium reabsorption is preserved.  Insulin also increases the activity of the sympathetic nervous system which can lead to an increase in blood pressure. Insulin resistance is also associated with pathway-specific impairment in phosphatidylinositol-3-kinase signaling. In the endothelium, this impairment may cause an imbalance between the production of nitric oxide and the secretion of endothelin 1, with a consequent decrease in blood flow. In addition, increases in the angiotensinogen gene expression in adipose tissue of obese subjects results in increases in circulating angiotensin II and thus leading to vasoconstriction. 

 

Etiology: Circadian Rhythm

Our body is under a 24-hour cycle which controls the rhythm of many physiological processes. This circadian clock is intrinsic and influenced by external cues, such as the sun, temperature, amount of light etc.  Individuals with insomnia tend to be more obese and the disruption of the circadian clock has been shown to alter metabolic homeostasis, which can result in metabolic syndrome.

 

Many of the studies on circadian rhythm have been done in mice and not validated in human subjects. Mice have shown that when the circadian rhythm is disrupted, they gained more weight and the macrophage inflammatory responses were exacerbated resulting in more severe insulin resistance.

 

The concept of circadian clock disruption may have a promising future in the treatment and prevention of metabolic syndrome however, more scientific studies are needed.

 

Etiology: Stress

Recent research indicates prolonged chronic stress can contribute to metabolic syndrome by disrupting the hormonal balance of the hypothalamic-pituitary-adrenal axis (HPA-axis). A dysfunctional HPA-axis causes high cortisol levels to circulate, which results in raising both insulin and glucose levels, which in turn cause insulin-mediated effects on adipose tissue. This ultimately promotes visceral adiposity, insulin resistance, dyslipidemia, and hypertension, and also has direct effects on the bone, causing osteoporosis. HPA-axis dysfunction may explain the reported risk indication of abdominal obesity to cardiovascular disease, type 2 diabetes, and stroke. It has been well documented that stress is also linked to heart disease.

 

Symptoms

The metabolic syndrome typically is not associated with symptoms in and of itself. The clinician will typically see signs/symptoms of the associated disease states. Patients reporting a history of hypertension, dyslipidemia, or hyperglycemia warrant screening for metabolic syndrome.

 

On physical examination, waist circumference and blood pressure are often elevated. The presence of either or both of these signs should prompt the clinician to search for other abnormalities that may be associated with the metabolic syndrome. This may include the patient presenting with increased thirst and urination, fatigue, or blurred vision. Chest pain or shortness of breath may indicate cardiovascular complications. Less frequently, lipoatrophy or acanthosis nigricans are present on examination. Because these last two physical findings characteristically are associated with severe insulin resistance, the other components of metabolic syndrome are much more common and typically seen in patients who present with hypertension or diabetes.

 

Associated Diseases

As mentioned, cardiovascular disease and type 2 diabetes are strongly correlated with metabolic syndrome. Having metabolic syndrome quintuples the risk of developing type 2 diabetes in naïve patients. In those with impaired glucose tolerance or impaired fasting glucose, the presence of metabolic syndrome doubles the risk of developing type 2 diabetes.

 

The relative risk for new-onset cardiovascular disease in patients with metabolic syndrome who do not have diabetes averages 1.5–3 fold.  The presence of metabolic syndrome is associated with a higher prevalence of cardiovascular disease than found in people with type 2 diabetes or impaired glucose tolerance without metabolic syndrome. The approximate prevalence of metabolic syndrome in people with coronary artery disease is 50%, with a prevalence of 37% in people with premature coronary artery disease (age 45), particularly in women.

 

The presence of metabolic syndrome in association with cardiovascular disease and type 2 diabetes leads to a high mortality rate due to the increased risk of ischemic heart disease, myocardial infarctions, and stroke.

 

In addition to the features specifically used to define the metabolic syndrome, other metabolic alterations are secondary to, or accompany insulin resistance. These include the following diseases:

 

  • Non-alcoholic Fatty Liver Disease

  • Polycystic Ovary Syndrome

  • Obstructive Sleep Apnea

  • Hyperuricemia

Non-alcoholic Fatty Liver Disease

 

This has become the most common liver disease, in part a consequence of the insulin resistance associated with metabolic syndrome. The mechanism relates to increases in free fatty acid flux, reductions in intrahepatic fatty acid oxidation with resultant increases in triglyceride biosynthesis and hepatocellular accumulation, with variable inflammation and oxidative stress. This can lead to the more serious non-alcoholic steatohepatitis, which can eventually cumulate to cirrhosis and end stage liver disease. Of patients with metabolic syndrome, approximately 25–60% have non-alcoholic fatty liver disease and up to 35% have serious non-alcoholic steatohepatitis. As the prevalence of overweight/obesity and the metabolic syndrome increases, non-alcoholic steatohepatitis may become one of the more common causes of end-stage liver disease and hepatocellular carcinoma.

 

Polycystic Ovary Syndrome

 

Polycystic ovary syndrome is highly associated with insulin resistance and metabolic syndrome. Women with polycystic ovary syndrome are 2–4 times more likely to have metabolic syndrome than are women without polycystic ovary syndrome. Polycystic ovary syndrome is a set of symptoms due to elevated androgens in females. Signs and symptoms of polycystic ovary syndrome include irregular or no menses, heavy menses, excess body or facial hair, acne, pelvic pain, infertility, and skin abnormalities. Polycystic ovary syndrome is due to a combination of genetic and environmental factors that include obesity, a lack of physical exercise, and a family history of someone with the condition.

 

Hyperuricemia

 

It has been described that hyperuricemia is associated with metabolic syndrome. Hyperuricemia reflects defects in insulin action on the renal tubular reabsorption of uric acid and may contribute to hypertension through its effect on the endothelium. Elevated serum triglycerides is markedly associated with hyperuricemia. The association between insulin resistance syndrome, hyperuricemia, and hypertriglyceridemia is complicated. In general, the increased level of uric acid is highly correlated with increased levels of serum triglycerides. Considering the potential link to hyperuricemia, more emphasis should be put on the detection and prevalence of hyperuricemia. Interestingly, the incidence of hyperuricemia in males is much higher than that in females. The pathogenic mechanism may be due to estrogen promoting uric acid excretion. In the future, it may be important to closely monitor males and post-menopausal females for high uric acid levels.

 

Obstructive Sleep Apnea

 

Obstructive sleep apnea is commonly associated with obesity, hypertension, increased circulating cytokines, impaired glucose tolerance and insulin resistance. In fact, obstructive sleep apnea may predict metabolic syndrome, even in the absence of excess adiposity. The combination of metabolic syndrome and obstructive sleep apnea has been termed “syndrome Z.”

 

Both obstructive sleep apnea and metabolic syndrome are worldwide epidemics that have gained increasing attention in the medical field. Emerging data suggest that metabolic syndrome may not be just a comorbidity of obstructive sleep apnea but may also be related through a number of possible pathways. Obstructive sleep apnea is associated with alterations in the hypothalamic–pituitary axis that may promote metabolic syndrome. The hypoxia associated with obstructive sleep apnea seems to trigger an oxidative stress that may promote development of metabolic syndrome. Multiple inflammatory mediators including NF-κB, CRP, TNF-α, and IL-6 are elevated in patients with obstructive sleep apnea and may play a role in the development of metabolic syndrome. When biomarkers of insulin resistance are compared between patients with obstructive sleep apnea and weight-matched controls, insulin resistance is found to be more severe in those with sleep apnea. Continuous positive airway pressure treatment improves insulin sensitivity in patients with obstructive sleep apnea.

 

Diagnosis

The diagnosis of the metabolic syndrome relies on fulfillment of the criteria as outlined by the 2009 Joint Interim Statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and the International Association for the Study of Obesity (Harmonizing definition). The reader should review the criteria listed in the table on Slide 9 as a reference point.

 

The medical history should include evaluation of symptoms for obstructive sleep apnea in all patients and polycystic ovary syndrome in premenopausal women. A sleep study should be performed if symptoms of obstructive sleep apnea are present. If polycystic ovary syndrome is suspected based on clinical features and anovulation, testosterone, luteinizing hormone, and follicle-stimulating hormone should be measured. Family history will help determine risk for cardiovascular disease and type II diabetes mellitus. Blood pressure and waist circumference measurements provide information necessary for the diagnosis as well. Measurement of fasting lipids and glucose is needed in determining whether metabolic syndrome is present. The measurement of additional biomarkers associated with insulin resistance can be individualized if necessary. Such tests might include those for apoB, hsCRP, fibrinogen, uric acid, urinary albumin/creatinine ratio and liver function.

 

Case 2:

As a pharmacist in a primary care clinic, you are responsible for the intake of new patients. This includes taking a thorough medical history as well as ordering preliminary lab tests.

 

BJ presents to you as a 46-year-old Caucasian male with a history of hypertension and GERD. He is currently taking candesartan 32 mg once daily and omeprazole 20 mg once daily. Upon physical exam he appears to be overweight and smells of cigarette smoke.

 

He tells you he has been extremely tired lately and says his wife tells him that he snores very loudly and she has noticed pauses in breathing and episodes where he seems to be gasping for air while he is sleeping.

What would you do to determine if the patient has metabolic syndrome? This includes questions during a thorough medical history, lab tests or other diagnostic tests that are necessary for a complete workup.

Case 2 Discussion

 

In order to determine if BJ has metabolic syndrome there are a number of other steps necessary in order to make this assessment. They are as follows:

  • Ask BJ about his family history including grandparents, parents and siblings. This will help determine his likelihood for developing cardiovascular disease and diabetes.

  • Measure his waist circumference. A waist circumference ≥94 cm would indicate metabolic syndrome.

  • Schedule a polysomnogram (sleep apnea test). Since obstructive sleep apnea and metabolic syndrome are closely related and he is experiencing symptoms related to sleep apnea (daytime drowsiness, snoring, gasping for air) this test is warranted.

  • Order a lipid panel to determine if his triglycerides and HDL are at a level indicative of metabolic syndrome. Triglycerides ≥150 mg/dL and HDL <40 mg/dL are indicators of metabolic syndrome.

  • Order a fasting glucose to determine if his glucose level is indicative of metabolic syndrome. A fasting glucose ≥100 mg/dL indicates metabolic syndrome.

  • A uric acid level might be indicated since the incidence of hyperuricemia in males is much higher than that in females.

  • Assess his blood pressure to ensure his hypertension is being properly treated and at goal.

  • Assess his stress level since stress may be a precipitating factor in metabolic syndrome.

All of your tests are completed, and you have the following results:

  • Family History: Paternal grandfather died of a stroke at the age of 67. Father and brother both have hypertension.

  • Waist circumference = 98 cm

  • Sleep apnea test shows obstructive sleep apnea

  • Lipid panel: Triglycerides = 132 mg/dl and HDL = 47 mg/dl

  • Fasting glucose = 82 mg/dl

  • Uric acid = 7.6 mg/dl (levels > 7 mg/dl indicate hyperuricemia)

  • His blood pressure is 127/82 mmHg

  • He rates his stress level as extremely high due to his job. He is in customer service and has a supervisor that is very critical and makes his job very difficult. On most days he comes home with a tension headache he relates to being caused by his job stress.

 

Does BJ have metabolic syndrome?

 

A patient must exhibit 3 out of the 5 clinical characteristics to be characterized as having metabolic syndrome (2009 Harmonizing definition). BJ has an elevated waist circumference and is on antihypertensive medication. This only qualifies him with 2 clinical characteristics, so he is not yet at the stage of having developed metabolic syndrome. However, as a pharmacist you note that he has many risk factors for developing the syndrome including a stressful work environment, sleep apnea, hyperuricemia, and a family history of cardiovascular disease. You suggest to the medical team that he be closely monitored for the development of metabolic syndrome in the future and counseled on his risk factors. It would likely be beneficial at this point to suggest some mon –pharmacological lifestyle modifications BJ can make.

 

Treatment

The major goals are to treat both the underlying cause of the syndrome, to prevent the development of type 2 diabetes and cardiovascular disease, and also to treat the cardiovascular risk factors if they are present and persist. As has been discussed, a majority of people with metabolic syndrome are overweight and live a sedentary lifestyle. Lifestyle modification becomes a critical factor for treating metabolic syndrome. Weight reduction usually requires a specifically tailored multifaceted program that includes diet and exercise. Smoking cessation is an important component of treatment, and appropriate medications to treat the underlying conditions that are not responsive to lifestyle changes may become necessary.

 

In essence, both non-pharmacological and pharmacological treatment options need to be considered when treating patients with metabolic syndrome. The next slides will discuss all the current treatment options for metabolic syndrome.

 

Treatment Non-pharmacological

Obesity, particularly abdominal obesity, is the driving force behind metabolic syndrome. Currently, the best therapeutic approach for the metabolic syndrome is lifestyle modification including weight loss. With at least a 5% (and more so with 10%) weight reduction, improvement in insulin sensitivity results in favorable modifications in many components of the metabolic syndrome.

 

In general, recommendations for weight loss include a combination of caloric restriction, increased physical activity, and behavior modification. Caloric restriction is the most important component, whereas increases in physical activity are important for maintenance of weight loss. Some but not all evidence suggests that the addition of exercise to caloric restriction may promote greater weight loss from the visceral depot. The tendency for weight regain after successful weight reduction underscores the need for long-lasting behavioral changes.

 

Diet

 

It is crucial for the clinician to understand that it has taken the patient a long time to develop the current expanded fat distribution. Therefore, the correction in weight does not need to occur quickly. There will be many psychological as well as physical issues to work through as the weight loss regimen progresses.

 

Given that approximately 3500 kcal = 1 lb. of fat, then about a 500-kcal restriction daily equates to a weight reduction of 1 lb. per week or cut 1,000 calories a day to lose about two pounds a week. Diets restricted in carbohydrates typically provide a more rapid initial weight loss. However, after one year, the amount of weight reduction is minimally more reduced or no different from that with caloric restriction alone. Thus, adherence to the diet is more important than the chosen diet.

 

Many patients will have problems adhering to a diet with strict restrictions in carbohydrates. Patients who are on a low carbohydrate commonly complain of symptoms similar to depression and these include lethargy, irritability and lack of cognition sometimes referred to as brain fog. Constipation is a possible side effect that can occur, especially during the first time on a low-carbohydrate diet, as the digestive system may need time to adapt. A temporary hair thinning can occur for many different reasons, including any big dietary change. This is especially common when severely restricting calories (e.g. starvation diets, meal replacements) but it can also occasionally happen on a low-carbohydrate diet. Most commonly patients will report feeling like they have flu-like symptoms that include nausea, headache and bowel issues.

 

Moreover, there is concern about low-carbohydrate diets enriched in saturated fat, particularly for patients at risk for cardiovascular disease. Therefore, a high-quality diet should include fruits, vegetables, whole grains, lean poultry, and to maximize overall health benefit in patients with metabolic syndrome.

 

Physical Activity

 

Before prescribing a physical activity program to patients with the metabolic syndrome, it is important to ensure that the increased activity does not incur additional risk. Consider that it may be beneficial for high-risk patients to undergo formal cardiovascular evaluations before initiating an exercise program. For an inactive participant, gradual increases in physical activity should be encouraged to enhance adherence and avoid injury. Although increases in physical activity can lead to modest weight reduction, 60–90 minutes of daily activity is required to achieve this goal. Even if an overweight or obese adult is unable to undertake this level of activity, a significant health benefit will follow from at least 30 min of a moderate-intensity activity daily. Of note, a variety of routine activities, such as gardening, walking, and housecleaning, require moderate caloric expenditure. Thus, physical activity should not be defined solely in terms of formal exercise such as jogging, swimming, or tennis which may be very difficult for the extremely obese patient. Being creative with the exercise regimen and giving patients alternative options may help to increase and sustain motivation to continue physical activity.

 

The following are some interesting facts you might consider sharing with your patient that may help to motivate them and give them perspective on healthy physical activity. It does not have to take the form of grueling and strenuous time spent at a gym. Encouraging your patients to just move every day can go a long way over a lifetime.

 

The following are some tips taken from the American Heart Association’s website that many Americans are doing everyday:

  • 10 minutes of stretching is like walking the length of a football field

  • 2.5 hours of walking every week for a year is like walking across the state of Wyoming

  • 20 minutes of vacuuming is like walking one mile

  • 30 minutes of grocery shopping every other week for a year is like walking a marathon

Other ways to encourage your patients to move may include tips such as:

  • Park your car farther away from your destination to encourage a farther walk

  • While on the phone in your office or at home walk around your space

  • Take the stairs and not the elevator or walk the escalator and do not just ride it

  • Walk or jog in place during the TV commercials

 

Behavior Modification

 

The tendency for weight regain after successful weight reduction underscores the need for long-lasting behavioral changes. Because weight regain so often follows successful weight reduction, the subsequent challenge is the duration of the program and how to maintain this weight loss. Improved long-term outcomes often follow a variety of methods, such as a personal or group counselor, regular meetings with a dietician, access to a physical trainer or telephone follow-up to maintain contact between providers and patients.

 

Encourage your patient to seek out like-minded people who may be having the same struggles. This may go a long way in helping your patient to progress and keep them motivated and accountable to a weight loss and maintenance program. Peer support groups are used in many situations to help people achieve their goals and maintaining a healthy lifestyle is one in which a support group may be crucial to a patient’s success.

 

Treatment – Pharmacological

There are many scenarios in which non-pharmacological treatment may not be enough to help a patient reach their goals. There are many options for pharmacological treatment and these include the following:

 

  • Anti-obesity medications

  • Lipid lowering medications

  • Anti-hypertensive medications

  • Diabetic medications

 

The following slides will discuss each of these drug classes in detail so a pharmacist can have the knowledge necessary to make recommendations to the health care team about appropriate medications in a patient with metabolic syndrome and how to monitor patients on these medications.

 

Treatment – Pharmacological
Anti-Obesity Agents

Orlistat is a reversible inhibitor of gastric and pancreatic lipases, thus inhibiting absorption of dietary fats by 30%. The drug is indicated in obesity management, including weight loss and weight maintenance, when used in conjunction with a reduced-calorie diet; to reduce the risk for weight regain after prior weight loss. Orlistat is indicated for obese patients with an initial body mass index of ≥30 kg/m2 or ≥27 kg/m2 in the presence of other risk factors (eg, hypertension, diabetes, dyslipidemia). Orlistat is available as prescription (Xenical) and as on over-the-counter medication (Alli).

 

A pharmacist needs to be aware of certain precautions when monitoring patients on Orlistat:

 

  • Diabetic patients must be monitored closely as the weight loss may affect glycemic control. Dosage adjustments of antidiabetic medications may be necessary.

  • Patients should be advised to adhere to dietary guidelines; if taken with a diet high in fat (>30% total daily calories from fat), gastrointestinal adverse events may increase. The distribution ofdaily fatshould be divided over three main meals. If the drug is taken with any one meal very high in fat, the possibility of gastrointestinal adverse effects increases.

  • Since orlistat has been shown to reduce the absorption of some fat-soluble vitamins and beta-carotene, patients should be counseled to take a multivitamin supplement that contains fat-soluble vitamins ≥2 hours before or after orlistat administration to ensure adequate nutrition.

 

The most common adverse effects of Orlistat are gastrointestinal related and are included in the following table. The patient needs to be counseled on what adverse effects can be expected and that most adverse reactions (especially gastrointestinal effects) decreases over time.

 

Adverse Effect

Incidence

oily rectal leakage

4% to 27%

abdominal distress/pain

≤26%

flatulence with discharge

2% to 24%

steatorrhea

6% to 20%

oily evacuation

2% to 12%

frequent bowel movements

3% to 11%

bowel urgency

3% to 22%

fecal incontinence

2% to 8%

rectal pain

3% to 5%

cholelithiasis

3%

 

Orlistat Dosing:

 

  • Xenical: 120 mg 3 times daily with each main meal containing fat (during or up to 1 hour after the meal). The dose should be omitted if a meal is missed or contains no fat.

  • Alli: 60 mg 3 times daily with each main meal containing fat (maximum dose: 180 mg/day).

 

Orlistat Monitoring:

 

The following parameters should be monitored for all patients on orlistat: BMI; weight; calorie and fat intake; serum glucose in patients with diabetes; liver function tests in patients exhibiting symptoms of hepatic impairment; and  renal function in patients at risk for renal impairment.

 

Qsymia (Phentermine and Topiramate) is a combination drug that acts as an anorexiant. Phentermine is a sympathomimetic amine with pharmacologic properties similar to amphetamines. The mechanism of action in reducing appetite appears to be secondary to its effects on the central nervous system including stimulation of the hypothalamus to release norepinephrine. Topiramate’s effect on weight management may be due to its effects on appetite suppression and satiety enhancement and based on a combination of potential mechanisms including blocking neuronal voltage-dependent sodium channels, enhancing GABA(A) activity, antagonizing AMPA/kainite glutamate receptors, and weakly inhibiting carbonic anhydrase. Qysmia is indicated as an adjunct to a reduced-calorie diet and increased physical activity, in patients with either an initial body mass index (BMI) of ≥30 kg/m2 or an initial BMI of ≥27 kg/m2 and at least one weight-related comorbid condition (eg, hypertension, dyslipidemia, type 2 diabetes).

 

A pharmacist needs to be aware of certain precautions when monitoring patients on Qysmia:

 

  • Monitoring blood glucose levels during treatment is necessary in patients type 2 diabetes mellitus as the antidiabetic agent requirements may be decreased with weight loss, anorexigens and concomitant dietary restrictions.

  • Since phentermine is pharmacologically related to the amphetamines, which have a high abuse potential; prolonged use may lead to dependency. Patients should be monitored for abuse potential.

  • Resting heart rate can increase when starting or increasing dosage, and in patients with cardiac or cerebrovascular disease. Reduce the dose or discontinue use of the agent in a patient who has a sustained increase in resting heart rate.

 

The most common adverse effects of Qsymia are listed in the following table:

Adverse Effect

Incidence

paresthesia

4% to 20%

insomnia

6% to 11%

xerostomia

7% to 19%

constipation

8% to 16%

cognitive dysfunction

2% to 8%

nausea

4% to 7%

diarrhea

5% to 6%

 

Qsymia Dosing:

 

  • Initially the patient should be started at phentermine 3.75 mg/topiramate 23 mg once daily for 14 days with an increase in dose to phentermine 7.5 mg/topiramate 46 mg once daily for 12 weeks. At this time, the clinician should evaluate the weight loss to date.

  • If 3% of baseline body weight has not been lost, the drug should be discontinued or increased to phentermine 11.25 mg/topiramate 69 mg once daily for 14 days, and then to phentermine 15 mg/topiramate 92 mg once daily.

  • Evaluation of weight loss should occur at 12 weeks after this dose increase and if 5% of baseline body weight has not been lost therapy should be gradually discontinued by reducing one dose every other day for at least one week.

  •  

Qsymia Administration:

 

Administer in the morning without regard to meals and avoid late evening administration due to the potential for insomnia.

Qsymia Monitoring:

 

The following should be monitored for all patients on Qsymia: weight; resting heart rate; glucose, and serum creatinine (at baseline and periodically during treatment); blood pressure;  and suicidality or mood disorders.

 

Contrave (Naltrexone and Bupropion) is a combination drug that acts as an anorexiant. Naltrexone is a pure opioid antagonist, and bupropion is a relatively weak inhibitor of the neuronal reuptake of dopamine and norepinephrine. The exact neurochemical effects of naltrexone/bupropion leading to weight loss are not fully understood. Effects may result from it’s action on areas of the brain involved in the regulation of food intake specifically the hypothalamus (appetite regulatory center) and the mesolimbic dopamine circuit (reward system).

 

Contrave is indicated for chronic weight management in adults with an initial body mass index (BMI) of ≥30 kg/m2 or ≥27 kg/m2 in the presence of at least one weight-related comorbid condition (eg, hypertension, type 2 diabetes mellitus, and/or dyslipidemia). It should be used in conjunction with a reduced-calorie diet and an increased physical activity plan.

 

Pharmacists should be aware of the following precautions when monitoring patients on Contrave:

 

  • Buproprion can increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18 to 24 years of age) with major depressive disorder and other psychiatric disorders. 

  • Patients treated with naltrexone may respond to lower opioid doses than previously used. This could result in potentially life-threatening opioid intoxication. Warn patients that any attempt to overcome opioid blockade during naltrexone therapy is dangerous and could potentially lead to fatal opioid overdose. If chronic opiate therapy is required, naltrexone/bupropion should be stopped; if intermittent opiate therapy is required, temporarily discontinue naltrexone/bupropion and lower doses of opioids may be needed.

  • Bupropion may cause a dose-related risk of seizures. It’s use is contraindicated in patients with a seizure disorder or a history of seizures, current or past diagnosis of bulimia or anorexia nervosa, or those undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates and antiepileptic drugs. To minimize the risk of seizures, increase the dose gradually and limit the daily dose of bupropion to ≤360 mg.

  • Use with caution in patients with cardiovascular disease as Contrave may cause an increase in blood pressure and heart rate.

  • Monitor blood glucose levels at baseline and periodically during treatment. Consider decreases in doses for concurrent antidiabetic medications if hypoglycemia develops during treatment.

 

The most common adverse effects of Contrave are listed in the following table:

Adverse Effect

Incidence

headache

18%

sleep disorder

14%

nausea

33%

constipation

19%

vomiting

11%

hypertension

6%

increased blood pressure

≤6%

Contrave Dosing:

 

The initial dose is one tablet (naltrexone 8 mg/bupropion 90 mg) once daily in the morning for 1 week. At week 2, increase to 1 tablet twice daily administered in the morning and evening and continue for 1 week. At week 3, increase to 2 tablets in the morning and 1 tablet in the evening and continue for 1 week. At week 4, increase to 2 tablets twice daily administered in the morning and evening and continue for the remainder of the treatment course.

Contrave Administration:

 

This drug should not be administered with high fat meals.

Contrave Monitoring:

 

The following parameters should be monitored: Blood pressure and heart rate; blood glucose; weight; renal and liver function (base and periodic); and mental status for depression, suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased).

 

Saxenda (Liraglutide) is a long acting analog of human glucagon-like peptide-1 (GLP-1) which increases glucose-dependent insulin secretion, decreases inappropriate glucagon secretion, increases B-cell growth/replication, slows gastric emptying, and decreases food intake. This agent is used both in type 2 diabetes management (Victoza) and is also indicated for chronic weight management. Saxenda is used an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index of ≥30 kg/m2 (obese) or ≥27 kg/m2 (overweight) in the presence of at least one weight-related comorbid condition (eg, hypertension, type 2 diabetes mellitus, dyslipidemia). Saxenda is considered a preferred pharmacologic weight-loss option in obese and overweight patients with type 2 diabetes mellitus, particularly in patients with atherosclerotic cardiovascular disease.

A pharmacist needs to be aware of certain precautions when monitoring patients on Saxenda:

 

  • Dose-dependent and treatment duration-dependent thyroid C-cell tumors have developed in animal studies with Saxenda therapy. Patients should be counseled on the potential risk and informed of symptoms of thyroid tumors (eg, neck mass, dysphagia, dyspnea, persistent hoarseness).

  • Saxenda is not indicated for the treatment of type 2 diabetes and concomitant use with insulin is not recommended.

 

The most common adverse effects of Saxenda are listed in the following table:

Adverse Effect

Incidence

increased heart rate

34%

headache

14%

hypoglycemia

44% (in combination with a sulfonylurea in type 2 diabetic patients)

16% (monotherapy in type 2 diabetic patients)

3% (non-diabetic patients)

nausea

39%

diarrhea

21%

constipation

19%

vomiting

16%

injection site reaction

3 to 14%

 

Saxenda Dosing:

 

The initial subcutaneous dose is 0.6 mg once daily for 1 week; increase by 0.6 mg daily at weekly intervals to a target dose of 3 mg once daily. If the patient cannot tolerate an increased dose during dose escalation, consider delaying dose escalation for 1 additional week. According to the manufacturer, efficacy has not been established at doses <3 mg/day; however, some experts will continue a patient on the maximum tolerated dose (even if <3 mg/day) if the goal weight loss is achieved on that dose.  After 12 weeks of therapy at the maximum tolerated dose (or 16 weeks after the initiation of therapy) the change in body weight should be evaluated.  The therapy should be discontinued if at least 4% to 5% of baseline body weight loss has not been achieved

 

Saxenda Administration: Inject subcutaneously in the upper arm, thigh, or abdomen without regard to meals or time of day.

 

Saxenda Storage: Saxenda should be refrigerated. The pen should be discarded 30 days after initial use.

Saxenda Monitoring: The following parameters should be monitored: weight, glucose, signs of pancreatitis or gallbladder disease; triglycerides and any suicidal or depressive behavior.

 

Comparison of Anti-Obesity Agents

Brand (Generic)

Results

Qsymia (Phentermine and Topiramate)

Reduces body weight by 6-9%

Contrave (Naltrexone and Bupropion)

Reduces body weight by approximately 10%

Saxenda (Liraglutide)

Reduces body weight by approximately 10%

Orlistat

Reduces body weight by 6%

Treatment – Pharmacological
Lipid Lowering Agents

Statin therapy significantly and substantially reduces cardiovascular risk. Many prospective, randomized trials such as the COmparative study with rosuvastatin in subjects with METabolic Syndrome (COMETS) and the Measuring Effective Reductions in Cholesterol Using Rosuvastatin TherapY I (MERCURYI) trial showed that statins improved atherogenic dyslipidemia in people with metabolic syndrome. Although the use of statins for the primary prevention in subjects with a low cardiovascular disease risk remains questionable in its cost-effectiveness, statin treatment has demonstrated a consistent and significant reduction in cardiovascular and all-cause mortality in people at high risk of cardiovascular disease such as those with metabolic syndrome.

 

Independent of their action upon cholesterol; statins diminish oxidative stress and improve endothelial function. Statins also have anti-inflammatory properties by inhibition of isoprenoid (farnesyl or geranyl) formation and blockage of the activation of the Rho and Rac pathways which are involved in the activation of Nuclear Factor(NF)-κB as well as direct inhibition of tNF-κB activation. With these beneficial effects on other cardiovascular risk as well as lipid-lowering property, statins are recommended as the cornerstone of lipid lowering therapy for patients with metabolic syndrome.

 

Of significant interest, it has been learned that high potency statins increase the risk of developing diabetes compared with low potency statins. The risk increase seems to be highest in the first four months of use. It becomes a clinical quandary on which statin will best benefit the patient with metabolic syndrome. The high potency statin (rosuvastatin, atorvastatin), moderate potency statins (simvastatin) or low potency statins (fluvastatin, lovastatin).

 

Several meta-analyses of randomized controlled trials have suggested more insulin resistance following statin treatment. The mechanisms by which statins aggravate insulin resistance have not been fully elucidated. However, statins may decrease the production of metabolites of HMG-CoA, such as isoprenoids, which down regulate insulin-responsive glucose transporter (GLUT)-4, thereby decreasing glucose uptake. This pharmacological effect has been documented for simvastatin and atorvastatin.  In patients with pre-diabetes, this mechanism could be important in the transition from pre-diabetes to diabetes.  Another mechanism could be the recently described weight gain seen in statin-treated patients. It would be prudent that the risk of deteriorating insulin sensitivity and weight gain in statin-treated patients be balanced with the more substantial benefits in reducing cardiovascular risks.

 

Currently, what is the best strategy to balance the cardio-metabolic benefits and risks of statin treatment? When choosing between lower potency and higher potency statins in secondary prevention patients, perhaps bearing in mind that head-to-head randomized trials of higher potency versus lower potency statins have not shown a reduction in all-cause mortality or serious adverse events in secondary prevention patients with stable disease. Randomized clinical trials to identify the efficacy of these approaches on reducing the risk of developing diabetes mellitus are needed urgently and will help to guide the clinician as to which statin is the most appropriate in the patient with metabolic syndrome. It is currently accepted that despite the reported increases in HbA1c and fasting blood glucose, the benefits of statin therapy far outweigh the risk of dysglycemia.

 

Statin Counseling Points

 

Warnings/Precautions:

 

  • Persistent elevations in serum transaminases have been reported. When there is a dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels.

  • Rhabdomyolysis with or without acute renal failure secondary to myoglobinuria and/or myopathy has been reported. This risk is dose-related and is increased with high doses. Patients should be instructed to report unexplained muscle pain, tenderness, weakness, or brown urine, particularly if accompanied by malaise or fever. Therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed/suspected.

  • Statins should be used with caution in patients who consume large amounts of ethanol or have a history of liver disease. 

  • Statins should be used with caution in patients with severe renal impairment (creatinine clearance not defined); these patients are predisposed to myopathy.

 

The most common adverse effects of Statins are listed in the following table:

 

Adverse Effect

Incidence

abdominal pain

7%

constipation

7%

gastritis

5%

nausea

5%

myalgia

4%

headache

7%

 

Statin Monitoring Parameters:

 

  • Lipid profile (fasting or non-fasting) should be obtained before initiating treatment. Fasting lipid profile should be rechecked 4 to 12 weeks after starting therapy and every 3 to 12 months thereafter. If two consecutive LDL levels are <40 mg/dL, consider decreasing the dose.

  • Baseline measurement of hepatic transaminase levels (AST and ALT) should be obtained. Measure AST, ALT, total bilirubin, and alkaline phosphatase if symptoms suggest hepatotoxicity during therapy.

  • CPK should not be routinely measured. A baseline CPK measurement is reasonable for some individuals (eg, a family history of statin intolerance or muscle disease, or concomitant drug therapy that may increase risk of myopathy). Measure CPK in any patient with symptoms suggestive of myopathy. These symptoms include pain, tenderness, stiffness, cramping, weakness, or generalized fatigue.

 

 

Fibrates are useful for the treatment of dyslipidemia, particularly for patients with hypertriglyceridemia and low levels of HDL. Fibrates also diminish circulating levels of inflammatory mediators and can lead to improvement of vascular function. Most studies have shown that fibrates reduce triglyceride levels by 30–45% and increase HDL by up to 25 % but most often by <10%. Fenofibrate also decreased fibrinolysis inhibitor concentrations and improved endothelial function in metabolic syndrome patients, suggesting another potential mechanism for protection against cardiovascular disease. In some patients, the treatment for dyslipidemia requires two drugs with different targets. A statin and fibrate combination is a good combination for the treatment of lipid components and cardiovascular disease risk in metabolic syndrome patients.

 

Fenofibrate is indicated as adjunctive therapy to diet for the reduction of low-density lipoprotein cholesterol (LDL), total cholesterol, triglycerides, and apolipoprotein B (apo B), and to increase high-density lipoprotein cholesterol (HDL) in adults with primary hypercholesterolemia or mixed dyslipidemiia.

A pharmacist needs to be aware of certain precautions when monitoring patients on Fenofibrate:

 

  • This drug may cause cholelithiasis and should be discontinued if gallstones are found in gallbladder studies. Patients should be monitored for signs and symptoms of gallbladder abnormalities.

  • Hepatic transaminases can become significantly elevated and is usually dose related. Baseline and regular monitoring of liver function tests is required and discontinue therapy in patients whose enzyme levels persist above 3 times the upper limit of normal.

  • Myositis, myopathy, or rhabdomyolysis can occur but is rare. The risk is increased in the elderly, those receiving concomitant HMG-CoA reductase inhibitors or colchicine, and patients with diabetes mellitus, renal insufficiency, or hypothyroidism. Instruct patients to report unexplained muscle pain, tenderness, weakness, especially if accompanied with malaise or fever, or brown urine

  • Use Fenofibrate with caution in patients with mild to moderate renal impairment.

 

The most common adverse effects of Fenofibrate are listed in the following table:

 

Adverse Effect

Incidence

abdominal pain

5%

constipation

2%

arthralgia

≥3%

limb pain

≥3%

myalgia

≥3%

 

Fenofibrate Administration: This drug is independent of food administration.

 

Fenofibrate Monitoring: The lipid profile should be monitored regularly. Monitor LFTs regularly and discontinue therapy if levels remain greater than three times the normal limits. Monitor renal function in patients with renal impairment or in those at an increased risk for developing renal impairment.

 

Gemfibrozil is indicated for the treatment of hypertriglyceridemia.

 

A pharmacist needs to be aware of certain precautions when monitoring patients on Gemfibrozil:

 

  • This drug may cause cholelithiasis and should be discontinued if gallstones are found in gallbladder studies. Patients should be monitored for signs and symptoms of gallbladder abnormalities.

  • Elevations in serum transaminases may be seen with use and therefore, periodic monitoring recommended.

  • Myositis or rhabdomyolysis has occurred but is not common with Gemfibrozil. Patients should be monitored and instructed to report unexplained muscle pain, tenderness, weakness, or brown urine.

  • This drug should be used with caution in patients with mild-to-moderate renal impairment and is contraindicated in patients with severe impairment.

 

The most common adverse effects of Gemfibrozil are listed in the following table:

 

Adverse Effect

Incidence

dyspepsia

20%

abdominal pain

10%

nausea

3%

vomiting

3%

fatigue

4%

 

Gemfibrozil Administration: Gemfibrozil should be administered 30 minutes prior to breakfast and dinner.

 

Gemfibrozil Monitoring: Serum cholesterol should be monitored routinely and LFTs should be checked periodically.  A CBC should be obtained periodically during the first year of therapy because this drug may cause mild decreases in hemoglobin, hematocrit and white blood cells upon initiation, but this usually stabilizes with long-term therapy.

 

Treatment – Pharmacological
Anti-hypertensive Agents

Many different pathophysiologic mechanisms have been proposed to explain the development of hypertension in a patient with metabolic syndrome. In general, the presence of insulin resistance, the presence of obesity, the activation of the sympathetic nervous system and sodium retention are the prevailing mechanisms.  Insulin resistance activates the sympathetic nervous system, upregulates angiotensin II receptors and reduces the synthesis of nitric oxide, leading to increases in heart rate and blood pressure. Furthermore, increased actions of leptin, the activation of the hypothalamic-pituitary-adrenal axis, and the presence of obstructive sleep apnea in metabolic syndrome further contribute to the activation of the sympathetic nervous system. Finally, in obese patients there is an increase in renal tubular reabsorption with a consequent sodium retention, further contributing to the development of hypertension. It is evident that the development of hypertension in metabolic syndrome patients is a complex procedure that involves many different pathophysiologic pathways.

 

There is an important relationship between the renin angiotensin system (RAS), insulin resistance and endothelial dysfunction, which are found in people with metabolic syndrome and obesity-related hypertension. Angiotensin II inhibits insulin signaling and produces oxidative stress that accelerates hyperglycemia and atherosclerosis. Therefore, blockers of the RAS are an important component of therapeutic agents for metabolic syndrome especially when considering an anti-hypertensive agent.  The following slides will discuss the classes of the two available RAS inhibitors: angiotensin converting enzyme (ACE) inhibitors and angiotensin-II receptor blockers (ARBs).

 

ACE inhibitors competitively inhibit the angiotensin-converting enzyme which prevents the conversion of angiotensin I to angiotensin II (a potent vasoconstrictor).  This results in lower levels of angiotensin II which causes an increase in plasma renin activity and a reduction in aldosterone secretion causing its anti-hypertensive effects.

A pharmacist needs to be aware of certain precautions when monitoring patients on ACE inhibitors:

 

  • At any time during treatment (especially following the first dose) angioedema may occur however, this is a rare occurrence. It may involve the head and neck (potentially compromising the airway) or the intestine (presenting with abdominal pain). African Americans may be at an increased risk. 

  • An ACE inhibitor cough is a dry, hacking, non-productive cough that usually occurs within the first few months of treatment and should generally resolve within 1 to 4 weeks after discontinuation of the ACE inhibitor.

  • Hyperkalemia nay occur and is more likely in patients with renal dysfunction, diabetes mellitus, concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salts.

  • Syncope can occur with ACE inhibitors and is usually likely with the first several doses. Effects are most often observed in volume-depleted patients.

 

The most common adverse effects of ACE inhibitors are listed in the following table:

 

Adverse Effect

Incidence

orthostatic hypotension

2%

dizziness

4% to 8%

headache

2% to 5%

cough

1% to 2%

fatigue

2% to 3%

                                         

ACE inhibitors Administration: These drugs can be administered without regard to meals.

 

ACE inhibitor Monitoring: Blood pressure, serum creatinine and potassium should be monitored regularly.

 

Angiotensin-II receptor blockers (ARBs) are antagonists at the Angiotensin II receptor. By blocking the actions of Angiotensin II there is a resulting blockade in vasoconstriction and the release of aldosterone. This blocks aldosterone’s potent effects on the reabsorption of sodium as well as water in the kidneys leading to an overall decrease in blood pressure.

A pharmacist needs to be aware of certain precautions when monitoring patients on ARBs:

 

  • At any time during treatment (especially following first dose) angioedema may occur however, this is a rare occurrence. It may involve the head and neck (potentially compromising the airway) or the intestine (presenting with abdominal pain).

  • Hyperkalemia may occur with ARBS. Risk factors include renal dysfunction, diabetes mellitus, concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium containing salts. If used with these agents or disease states potassium should be closely monitored.

  • Symptomatic hypotension may occur upon initiation of an ARB in patients who are volume depleted.

 

The most common adverse effects of ARBs are listed in the following table:

 

Adverse Effect

Incidence

hyperkalemia

19%

orthostatic hypotension

5%

dizziness

5%

fatigue

4%

 

ARBs Administration: These drugs can be administered without regard to meals.

 

ARBs Monitoring: Monitor blood pressure, electrolytes, serum creatinine and BUN as well as a periodic urinalysis.

 

Treatment – Pharmacological
Diabetic Agents

Several drug classes increase insulin sensitivity and because insulin resistance is the primary pathophysiologic mechanism for metabolic syndrome, representative drugs in these classes reduce its prevalence and are beneficial in patients with metabolic syndrome.  Drugs that are primarily thought to be insulin sensitizers are the biguanides and  thiazolidinediones. Metformin is a biguanide and can be found either as a single drug agent or in combination with other glucose lowering agents. The thiazolidinediones (also called glitazones) refer to the agents rosiglitazone and pioglitazone.

 

Other new diabetic agents are being used to treat patients with metabolic syndrome. These include glucagon like peptide-1 (GLP-1) agonists and sodium glucose transporter-2 (SGLT-2) inhibitors. The GLP-1 agonists include exenatide, liraglutide, lixisenatide and semaglutide  The SGLT-2 inhibitors include canagliflozin, dapagliflozin, empagliflozin and ertugliflozin.

 

Metformin exhibits its mechanism of action by decreasing hepatic glucose production, decreasing intestinal absorption of glucose and improving insulin sensitivity by increasing peripheral glucose uptake and utilization.

 

A pharmacist needs to be aware of certain precautions when monitoring patients on Metformin:

 

  • Metformin is contraindicated in patients with severe renal dysfunction (eGFR <30 mL/minute/1.73 m2) and acute or chronic metabolic acidosis with or without coma (including diabetic ketoacidosis).

  • Lactic acidosis should be suspected in any patient with diabetes receiving metformin with evidence of acidosis but without evidence of ketoacidosis. Discontinue use in patients with conditions associated with dehydration, hypoperfusion, sepsis, or hypoxemia. Temporarily discontinue therapy in patients with restricted food and fluid intake. The risk of accumulation and lactic acidosis increases with the degree of impairment of renal function. Metformin-associated lactic acidosis cases have resulted in death, hypothermia, hypotension and resistant bradyarrhythmias.

  • Metformin may be used in patients with stable heart failure but should be avoided in unstable or hospitalized patients with heart failure. The risk of lactic acidosis may be increased secondary to hypoperfusion and may exacerbate underlying myocardial dysfunction. 

  • The manufacturer recommends to avoid use in patients with hepatic impairment due to the potential for lactic acidosis. 

 

The most common adverse effects of Metformin are listed in the following table:

 

Adverse Effect

Incidence

diarrhea

ER tablet: 10% to 17%

IR tablet: 12% to 53%

nausea and vomiting

IR tablet: 26%

ER tablet: 7%

flatulence

4% to 12%

Infection

21%

headache

6%

weakness

9%

Metformin Dosing:

 

Immediate release should initially start at 500 mg once or twice daily or 850 mg once daily. The dose should be increased gradually to minimize gastrointestinal adverse effects. Titration strategies vary widely, but usually are accomplished by increasing in 500 mg or 850 mg increments every 7 days. The usual maintenance dose is 1 g twice daily or 850 mg twice daily.

Extended release should initially start at 500 mg to 1 g once daily. The dose should be increased gradually to minimize gastrointestinal adverse effects. Titration strategies vary widely but are usually accomplished by increasing in 500 mg increments every 7 days. The maximum dose is 2 g/day and if glycemic control is not achieved at the maximum dose given once daily then it may be divided and administered twice daily.

Metformin Administration:

 

Metformin should be administered with a meal to decrease gastrointestinal upset. If administering it in once daily dosing it should be taken with the evening meal.

 

Metformin Monitoring:

 

A urine test for glucose and ketones, fasting blood glucose and hemoglobin A1c at least twice yearly in patients who have stable glycemic control and are meeting treatment goals and quarterly in patients not meeting treatment goals or with therapy change.

 

Initial and annual monitoring of hematologic parameters and renal function should be conducted as well as monitoring vitamin B12 serum concentrations every 2 to 3 years is required.

 

Thiazolidinediones decrease blood glucose by improving target cell response to insulin without increasing pancreatic insulin secretion. This class of drugs has a mechanism of action that is dependent on the presence of insulin for activity. Pioglitazone and rosiglitazone are potent and selective agonist for peroxisome proliferator-activated receptor-gamma (PPARgamma). Activation of the PPARgamma receptors influences the production of a number of gene products involved in glucose and lipid metabolism. PPARgamma is abundant in the cells within the renal collecting tubules as well and fluid retention results from stimulation by the thiazolidinediones which increases sodium reabsorption. This necessitates that this class o fdrugs is to be used in caution in patients with heart failure.

 

A pharmacist needs to be aware of certain precautions when monitoring patients on Thiazolidinediones:

 

  • These drugs can cause or exacerbate congestive heart failure in some patients. After initiation and after dose increases, observe patients carefully for signs and symptoms of heart failure and if signs and symptoms develop, manage the heart failure according to the current standards of care. Consideration should be given to discontinue or reduce the dose. These drugs are not recommended in patients with symptomatic heart failure and initiation in patients with established New York Heart Association (NYHA) class III or IV heart failure is contraindicated.

  • Dose-related edema, including new-onset or exacerbation of existing edema, has been reported with thiazolidinediones.

 

A pharmacist needs to be aware of certain precautions when monitoring patients on Thiazolidinediones (continued):

 

  • Hepatic failure, including fatalities, have been reported with this drug class. Monitor for signs/symptoms of liver injury closely during therapy.

  • The risk of hypoglycemia is increased when these agents are combined with insulin or other diabetic medications. Consider dosage adjustment of concomitant hypoglycemic agents if necessary.

  •  

Thiazolidinedione Administration: May be administered without regard to meals.


Thiazolidinedione Monitoring:

 

  • Liver enzymes should be tested prior to initiation for all patientsand continued periodic monitoring during treatment should be done only in patients with liver disease or suspected liver disease.

  • HbA1c should be done at least twice yearly in patients who have stable glycemic control and are meeting treatment goals. Perform this lab work along with blood glucose levels quarterly in patients who are not meeting treatment goals or with therapy changes.

  • Signs and symptoms of fluid retention or heart failure should be monitored for regularly.

 

The most common adverse effects of Thiazolidinediones are listed in the following table:

 

Adverse Effect

Incidence

edema

≤27%

hypoglycemia

≤27%

cardiac failure

≤8%

bone fracture

females: ≤5%

myalgia

5%

headache

9%

 

The Glucagon like peptide-1 (GLP-1) agonists include the following agents: exenatide, liraglutide, lixisenatide and semaglutide. GLP-1 agonists improve hyperglycemia by enhancing glucose-stimulated insulin secretion through activation of cyclicadenosine monophosphate (cAMP). Increased cAMP upregulates protein kinase A (PKA) which leads to rapid increases in intracellular calcium and insulin exocytosis in a glucose-dependent manner. Beneficially, GLP-1 agonists have the potential to reduce insulin resistance which helps reverse the insulin resistance-associated defects in the failing β-cells. GLP-1 is also known to reduce endoplasmic reticulum stress through activation of PKA.

 

Specifically, among GLP-1 agonists, Saxenda (liraglutide) has been approved by the US FDA as an anti-obesity drug (refer back to pharmacological treatment with anti-obesity drugs). In addition to stimulation of insulin release and the decrease of glucagon secretion in response to hyperglycemia, liraglutide at higher doses (3 mg) has resulted in more weight loss presumably by greater reductions in appetite and energy intake.

 

GLP- 1 agonists seem to be a good candidate as a drug class for metabolic syndrome patients with hyperglycemia and overweight/obesity since they enhance insulin sensitivity and reduce body weight as well as increases insulin secretory function.

 

A pharmacist needs to be aware of certain precautions when monitoring patients on GLP-1 agonists:

 

  • Use of GLP-1 agonists may increase the risk of gallbladder and bile duct disease. Gallbladder studies and further clinical assessment are indicated if cholelithiasis is suspected.

  • The most common reactions to these agents are gastrointestinal related. These symptoms may be dose related and may decrease in frequency and severity with gradual titration and continued use.

  • Acute renal failure and chronic renal failure has been reported with this class of drugs. Renal dysfunction was usually reversible with appropriate corrective measures and discontinuation of the GLP-1 agonist.

  • Dose-dependent and treatment duration-dependent thyroid C-cell tumors have developed in animal studies. Patients should be counseled on the potential risk and informed of the symptoms of thyroid tumors (e.g., neck mass, dysphagia, dyspnea, persistent hoarseness).

  • Cases of acute pancreatitis (including hemorrhagic and necrotizing with some fatalities) have been reported with these agents. Patients should be monitored for signs and symptoms of pancreatitis (eg, persistent severe abdominal pain that may radiate to the back, and that may or may not be accompanied by vomiting).

 

GLP-1 agonists Monitoring: Blood glucose and HbA1c should be performed at least twice yearly in patients who have stable glycemic control and are meeting treatment goals. These tests should be done quarterly in patients who are not meeting treatment goals or with a therapy change. Renal function and signs/symptoms of pancreatitis and gallbladder disease should be monitored periodically throughout therapy.

 

The most common adverse effects of GLP-1 agonists are listed in the following table:

 

Adverse Effect

Incidence

nausea

11%

diarrhea

10%

constipation

3% to 6%

injection site reaction

10%

hypoglycemia

2% to 5%

 

Each agent has slightly differing adverse effect profiles. Please refer to the individual drug monograph for specific Information on a particular agent.

Sodium glucose transporter-2 (SGLT-2) inhibitors. include canagliflozin, dapagliflozin, empagliflozin and ertugliflozin. By inhibiting sodium-glucose cotransporter 2 in the proximal renal tubules, these drugs reduce the reabsorption of filtered glucose from the tubular lumen and lower the renal threshold for glucose (RTG). SGLT-2 is the main site of filtered glucose reabsorption. Reduction of filtered glucose reabsorption and lowering of RTG results in increased urinary excretion of glucose leading to reduced plasma glucose concentrations.

 

A pharmacist needs to be aware of certain precautions when monitoring patients on SGLT-2 inhibitors:

 

  • SGLT-2 inhibitors may cause symptomatic hypotension due to intravascular volume depletion especially in patients with renal impairment and patients on other anti-hypertensives or those with low systolic blood pressure. 

  • Treatment with SGLT-2 inhibitors increases the risk for urinary tract infections and patients should be monitored for signs and symptoms of urinary tract infections and treated as needed. Patients who developed infections were more likely to experience recurrence.

  • SGLT-2 inhibitors may cause hyperkalemia and patients should be monitored for signs/symptoms.

  • Some of these agents have been shown to increase the risk of lower limb amputation and bone fractures. For information on each specific agent refer to individual drug monograph.

 

The most common adverse effects of SGLT-2 agonists are listed in the following table:

 

Adverse Effect

Incidence

genitourinary fungal infection

females: 12%

males: 4%

hypotension

3%

hypoglycemia

4%

hypovolemia

3%

increased thirst

3%

increased urine output

3%

vulvovaginal pruritus

3%

Each agent has slightly differing adverse effect profiles. Please refer to the individual drug monograph for specific Information on a particular agent.

 

SGLT-2 Administration: These drugs are recommended to be administered in the morning without regard to meals.

 

SGLT-2 Monitoring: Blood glucose and HgbA1c should be monitored at least twice yearly in patients who have stable glycemic control and are meeting treatment goals. These values should be monitored quarterly in patients not meeting treatment goals or with a therapy change.  Renal function should be done at baseline and periodically throughout treatment. Monitor patients for volume status (including blood pressure), urinary tract infections, and lower limb and feet sores.

 

Treatment – Pharmacological
Cilostazol

Cilostazol has properties that would be helpful for metabolic syndrome subjects. Cilostazol is a selective phosphodiesterase-3 (PDE-3) inhibitor and acts as an antithrombotic agent with vasodilating properties. Cilostazol also appears to exert a beneficial effect against hepatic steatosis by suppressing mitogen-activated protein kinase (MAPK) activation induced by oxidative stress. In a clinical trial, cilostazol has been shown to reduce triglycerides and increase HDL by increasing lipoprotein lipase activity. Thus, cilostazol may be a beneficial drug for patients with metabolic syndrome who are at high risk of atherosclerosis.

 

A pharmacist needs to be aware of certain precautions when monitoring patients on Cilostazol:

  • Cilostazol is contraindicated in patients with heart failure of any severity.

  • Cilostazol may induce tachycardia, palpitation, tachyarrhythmia, and/or hypotension.

  • Cases of thrombocytopenia or leukopenia progressing to agranulocytosis have occurred but are reversible upon discontinuation of the drug.

  • Use with caution in patients with moderate to severe hepatic impairment and in patients with severe renal impairment.

 

The most common adverse effects of Cilostazol are listed in the following table:

 

Adverse Effect

Incidence

headache

27% to 34%

diarrhea

12% to 19%

abnormal stools

12% to 15%

infection

10% to 14%

rhinitis

7% to 12%

palpitations

5% to 10%

peripheral edema

7% to 9%

tachycardia

4%

dizziness

9% to 10%

nausea

7%

dyspepsia

6%

back pain

7%

 

Cilostazol Administration: Cilostazol should be taken 30 minutes before or two hours after meals (breakfast and dinner).

 

Cilostazol Monitoring: Platelets and WBC counts should be monitored periodically. The development of a new systolic murmur or cardiac symptoms should be monitored for periodically.

 

Long Term Consequences of Metabolic Syndrome

Each component of the metabolic syndrome is an independent risk factor for cardiovascular disease and the combination of these risk factors elevates the rates and severity of cardiovascular disease in a patient with metabolic syndrome. The clustering of causally inter-related risk factors including abdominal obesity, impaired glucose tolerance and insulin resistance, hypertriglyceridemia, decreased HDL cholesterol, and/or hypertension is associated with activation of the sympathetic nervous system, renin-angiotensin-aldosterone system, increased levels of pro-inflammatory adipokines and cytokines and  increased levels of oxidative stress. All of these factors have profound cardiovascular consequences including an increased heart rate, increased blood volume, increased vascular resistance, and an increase in cardiac output as well as a change in myocardial metabolism.

 

The consequences of these changes include microvascular dysfunction, cardiac contractile dysfunction, atherosclerotic disease, vascular calcification, cardiac hypertrophy, myocardial infarction and eventually lead may lead to heart failure. Other consequences that are non-cardiovascular in nature include kidney disease, stroke, non-alcoholic fatty liver disease and peripheral artery disease.

 

The very severe nature of the long-term consequences makes it critical for the patient with metabolic syndrome to be treated appropriately. The key to preventing these complications is to have a firsthand knowledge of the appropriate treatment options as well as to develop a therapeutic alliance with the patient who presents with metabolic syndrome.

 

Conclusion

It has been estimated that 30% of overweight and 60% of obese men and women meet the criteria for the diagnosis of metabolic syndrome. In other words, most obese people carry the concurrent risk factors that identify them as carrying a significant risk for cardiovascular disease. Therefore, in parallel with the obesity epidemic, the metabolic syndrome is a growing epidemic as well, affecting approximately 20% of adults in the Western world.

 

Each component of the metabolic syndrome is an independent risk factor for cardiovascular disease that together produce a wide spectrum of vascular and cardiac diseases. There have been some advances in understanding the etiology and consequences of this complex disorder however the full spectrum of observed cardiovascular pathologies remains to be efficiently explained. Therefore, we must use our current knowledge and combine it with our understanding of pharmacological and non-pharmacological treatment options to provide optimal health care and support to the patient with metabolic syndrome. 

Active Learning Activity

For more information on the cardiovascular consequences of metabolic syndrome please read the following article. The authors present knowledge regarding the pathophysiological consequences of obesity and the metabolic syndrome on cardiovascular function and disease. This includes considerations of potential physiological and molecular mechanisms that may contribute to these adverse outcomes.

 

The article can be downloaded free of charge at the following website:

https://pubmed-ncbi-nlm-nih-gov.neomed.idm.oclc.org/28130064/

 

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