Authors

• Mirsala Solak — Medicinski fakultet Sveučilišta u Zagrebu, Klinički bolnički centar Zagreb, Zagreb, Hrvatska — ORCID: 0000-0002-4219-9287

Abstract

Metabolic syndrome is a common clinical problem that encompasses interconnected conditions: hypertension, dyslipidemia, hyperglycemia, and central obesity. It is important because these patients have significantly increased cardiovascular risk and risk of developing Type 2 diabetes. These metabolic disorders more commonly manifest as a syndrome, and together they significantly increase risk in comparison with a single isolated metabolic disorder. Obesity and insulin resistance seem to play a major role in the pathogenesis of metabolic syndrome. Chronic proinflammatory state, endothelial dysfunction, and procoagulant condition contribute as well. Lifestyle modification is the initial intervention of choice, thereby improving all metabolic disorders that are part of this syndrome. Pharmacological treatment should be considered in order to reduce specific risk factors for cardiovascular disease when lifestyle measures fail. The ultimate goal of treatment is the reduction of the systemic effects of metabolic syndrome.

Keywords

KLJUČNE RIJEČI: metabolički sindrom, inzulinska rezistencija, kardiovaskularni rizik, šećerna bolest, pretilost, metabolic syndrome, insulin resistance, cardiovascular risk, diabetes mellitus, adiposity

DOI

Full Text

## Controversies related to the terminology and definition A number of controversies have existed for years regarding the existence of metabolic syndrome. It is defined as a set of interconnected conditions that include arterial hypertension, dyslipidemia (entailing elevated triglycerides and/or lowered HDL-cholesterol), hyperglycemia, and central obesity. It is important in everyday clinical work because it has been shown that it increases the risk for the development of Type 2 diabetes by approximately five times, and doubles the risk of cardiovascular disease over a period of 5-10 years (1). Metabolic syndrome represents a significant public health and clinical challenge due to urbanization, the sedentary modern lifestyle, and increased incidence of obesity. An increasing number of people in the global population are overweight, do not adhere to healthy lifestyle habits, consume high-calorie foods, and lead sedentary lifestyles, which ultimately leads to conditions and diseases characteristic of metabolic syndrome. The term itself has been in widespread use since 2001, but there have been some controversies regarding the term and its definition in the past. It was mentioned for the first time in 1988 by Gerald Reaven, who coined the term “syndrome X” to describe the association between insulin resistance and obesity, dyslipidemia, glucose intolerance, and arterial hypertension (2). However, the Swedish physician Kylin was the first to notice the association between hypertension, hyperglycemia, and gout as early as 1923 (3). Different organizations in the past have tried to define metabolic syndrome on the basis of specific criteria in the absence of clear diagnostic tests. The World Health Organization (WHO) proposed a definition in 1999, according to which the establishment of the diagnosis of metabolic syndrome requires the presence of glucose intolerance or insulin resistance with at least two concurrent disorders such as arterial hypertension, central obesity, and dyslipidemia (4). The definition was revised two years later by the National Cholesterol Education Program (NCEP) on the basis of the same criteria, but without requiring the existence of glucose intolerance (5). In the meantime, the National Cholesterol Education Programme Adult Treatment Panel III (NCEP ATP III) and American Association of Clinical Endocrinologists (AACE) gave their own comments on metabolic syndrome and focused on the potentially increased cardiovascular risk. The International Diabetes Federation (IDF) finally presented a definition of metabolic syndrome in 2005, according to which the central type of obesity (measured by waist circumference) was, along with other criteria, a requirement for the establishment of the diagnosis of metabolic syndrome (6). It was IDF that, taking the weight circumferences of specific populations into consideration, addressed the unique characteristics and differences of ethnic and racial groups in metabolic syndrome, which ultimately result in differences in cardiovascular risk and risk of diabetes. Although some experts deny the existence of metabolic syndrome, it is evident that the abovementioned metabolic disorders more commonly manifest together, significantly increasing cardiovascular risk in comparison with the risk carried by each disorder individually. The risk also increases with the number of disorders present in a case of metabolic syndrome. ## Epidemiology of metabolic syndrome The prevalence of metabolic syndrome varies from 84 % depending on the examined population, urban or rural setting, age, sex, and ethnic background of the examined group, and of course on the definition of the syndrome (7). IDF estimates that one quarter of the global population has metabolic syndrome. It is more common in persons with higher body mass index (BMI) and older persons, but it has also been found to be more common in women in menopause, where the incidence is between 32.6 to 41.5 % (8). ## Pathophysiology of metabolic syndrome The basic disorder in metabolic syndrome is insulin resistance and the compensatory hyperinsulinemia, but chronic proinflammatory condition, endothelial dysfunction, and procoagulatory condition play an important role as well. Insulin resistance, which can be defined as a suboptimal biological response to a normal level of insulin, is influenced by genetic and lifestyle factors. Excess body weight and physical activity are the two most important lifestyle variables with a large (50 %) influence on insulin resistance, while the other 50 % is based on genetic burden. Many tissues, including the muscles, liver, and fat tissue, can be resistant to insulin. Insulin resistance has negative effects on glucose metabolism but also on the reproductive system, skin changes, and the musculoskeletal system (shown in **Table 1**). ### Table 1: Systemic effects of metabolic syndrome (adapted from Cardiol Res Pract. 2014;2014:943162.) | Cardiovascular system | Coronary heart disease, myocardial infarction, cerebrovascular accident | | --- | --- | | Kidney | Microalbuminuria, focal segmental glomerulosclerosis, hyperfiltration, hypofiltration, chronic kidney disease | | Liver | NASH, NAFLD, liver fibrosis and cirrhosis | | Eyes | Nondiabetic retinopathy, cataract, glaucoma, oculomotor nerve palsy, central retinal artery occlusion | | Sleep | OSA | | Reproductive system | Hypogonadism, erectile dysfunction, PCOS | | Cancers | Breast, pancreas, prostate | | Skin | Acantosis nigricans, SLE, lichen planus, androgenetic alopecia, psoriasis | [†] NASH = nonalcoholic steatohepatitis; NAFLD = nonalcoholic fatty liver disease; OSA = obstructive sleep apnea; PCOS = polycystic ovarian syndrome; SLE = systemic lupus erythematosus. It is known that visceral fat tissue is an active organ secreting numerous proinflammatory and anti-inflammatory cytokines from adipocytes, which is facilitated by the macrophage infiltration of the fat tissue (9). In metabolic syndrome, the levels of proinflammatory cytokines (leptin, IL-6, and TNF-α) are elevated, while the levels of anti-inflammatory cytokines (adiponectin) are reduced. Such disbalance in favor of chronic inflammatory states leads to dysfunction of endothelial cells, which causes the loss of their antithrombotic, vasodilatory, and antiatherogenic characteristics. Recently, there has been an increasing amount of evidence indicating that natriuretic peptides (NP) have a certain role in the pathophysiology of metabolic syndrome (10). These are “heart hormones” that are secreted in the atriums and ventricles of the heart as well as endothelial cells, and are important for homeostasis and controlling water balance, sodium, potassium transport, lipolysis in adipocytes, and blood pressure regulation. Recent studies have found NP insufficiency in obese patients and in patients with Type 2 diabetes. Studies are underway that could create opportunities for new therapeutic possibilities by acting upon the NP system. ## Treatment Since there is no known singular cause of metabolic syndrome, it cannot be treated as such, however the ultimate goal is reducing cardiovascular risk. Because obesity and insulin resistance form the base of metabolic syndrome, treatment is based primarily on adherence to healthy lifestyle habits, balanced diet, and regular physical activity. It has been found that these measures affect the improvement of all metabolic disorders that metabolic syndrome consists of. Pharmacotherapy is focused on reducing specific risk factors for cardiovascular diseases, if these basic healthy lifestyle measures do not lead to the desired effect, and the ultimate goal is to avoid the manifestation of the systemic effects of metabolic syndrome (**Table 1**). The reduction of body weight is paramount in the treatment of metabolic syndrome. It has been shown that a reduction of only 10 % can significantly reduce triglyceride levels and increase HDL-cholesterol (11), positively influence arterial hypertension and hyperglycemia. This can be achieved by adhering to healthy lifestyle habits and exercise, but behavioral therapy and bariatric surgery can be considered as well. It is interesting to note that removing fat tissue using liposuction does not improve insulin resistance or reduce cardiovascular risk, indicating that it is the negative energy balance achieved by diet and exercise that is irreplaceable in achieving the metabolic advantages of weight loss (12). Liraglutide, a glucagon-like peptide-1 (GLP-1), has garnered special attention in recent years due to its successful use for the treatment of Type 2 diabetes and is effective in reducing body weight at a dose of 3.0 mg. There are indications that it also affects the reduction of arterial pressure and that it might have cardioprotective effects (13). There are no studies specifically investigating the treatment of hyperglycemia in patients with metabolic syndrome who are not diabetics. It is recommended to treat glucose intolerance using dietary measures and increased physical activity with the goal of losing 5–10 % of body mass. Routine application of pharmacotherapy is not recommended; however, metformin can be considered in some patients with glucose intolerance. It has been indubitably demonstrated that patients with diabetes require therapy. Reducing insulin resistance, which is the base of metabolic syndrome, is primarily achieved using metformin but often also using thiazolidinediones, which increase insulin sensitivity. Dyslipidemia, arterial hypertension, and diabetes are treated in order to reduce increased cardiovascular risk, and smoking cessation is recommended. The most effective drugs for dyslipidemia are statins, which in addition to reducing LDL-cholesterol and triglycerides as well as increasing HDL-cholesterol also have pleiotropic effects and positively affect chronic proinflammatory states, endothelial dysfunction, and cardiovascular events, thus contributing to the treatment of patients with metabolic syndrome (14, 15). It is estimated that a reduction of systolic pressure of 5 mmHg in the general population leads to a total reduction in mortality from cerebrovascular events of 14 %, a reduction of 9 % for cardiovascular events, and a 7 % reduction of total mortality (16). Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers represent the first line of treatment in patients with metabolic syndrome, especially if they also have diabetes. They have been demonstrated to be effective in the reduction of the incidence of albuminuria and progression of diabetic nephropathy. The long-term effectiveness and safety of beta-blockers and diuretics has been demonstrated in large studies such as the *Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial* (ALLHAT), which included more than 40 000 participants (17). This study showed that treatment with thiazide diuretics is superior for the reduction of cardiovascular events in patients with metabolic syndrome in comparison with calcium channel blockers, beta-blockers, and ACE inhibitors. ALLHAT and the *United Kingdom Prospective Diabetes Study* (UKPDS) have shown that drugs like thiazide diuretics and beta-blockers reduce the risk of cardiovascular events even in patients with diabetes (18, 19). Since most patients with arterial hypertension require multiple drugs, fixed dose drug combinations represent a useful and simple therapeutic option. We can debate whether metabolic syndrome is a myth, but the individual metabolic parameters of the syndrome are a reality not only in the endocrinology clinic but for any physician. Timely recognition and treatment are important in order to ultimately reduce the risk of diabetes and cardiovascular diseases.

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