Continuing Education Activity

Metabolic syndrome, characterized by a constellation of metabolic abnormalities, including central obesity, insulin resistance, hypertension, and dyslipidemia, poses a significant risk for the development of atherosclerotic cardiovascular diseases and type II diabetes mellitus. The diagnosis of metabolic syndrome necessitates the presence of 3 or more of these metabolic abnormalities, signaling an urgent need for proactive identification and intervention strategies. Alarmingly, the prevalence of metabolic syndrome has surged in recent decades, paralleling the global rise in obesity rates, with over one-fifth of Americans and Europeans currently affected.

This activity details the multifaceted challenges posed by metabolic syndrome, emphasizing the crucial role of interdisciplinary collaboration in its management. By integrating insights from clinicians such as cardiologists, internists, dietitians, pharmacists, and other healthcare professionals, participants gain comprehensive knowledge and practical skills to effectively mitigate the cardiovascular risks and metabolic complications associated with this syndrome. Through evidence-based interventions, including lifestyle modifications and pharmacotherapy, clinicians are empowered to enact meaningful change and improve outcomes for patients grappling with metabolic syndrome and its associated comorbidities.

Objectives:

• Screen patients routinely for signs and symptoms suggestive of metabolic syndrome, utilizing validated screening tools and protocols.
• Apply updated guidelines and emerging research findings in the clinical management of metabolic syndrome.
• Implement evidence-based management for preventing and treating metabolic syndrome, including lifestyle interventions and pharmacotherapy.
• Collaborate regarding care coordination among interprofessional team members to enhance outcomes for patients with metabolic syndrome.

Introduction

Metabolic syndrome is an accumulation of several disorders that raise the risk of atherosclerotic cardiovascular disease, including myocardial infarction, cerebrovascular accidents, peripheral vascular diseases, insulin resistance, and type II diabetes mellitus. The cluster of metabolic disorders that define metabolic syndrome includes central obesity, insulin resistance, hypertension, and atherogenic dyslipidemia.[1] 

The diagnosis of metabolic syndrome requires the presence of 3 or more metabolic abnormalities:

• A waist circumference of more than 40 inches in men and 35 inches in women
• Serum triglycerides level of 150 mg/dL or greater
• Reduced high-density lipoprotein cholesterol, less than 40 mg/dL in men or less than 50 mg/dL in women
• Elevated fasting glucose of l00 mg/dL or greater
• Blood pressure values of systolic 130 mm Hg or higher or diastolic 85 mm Hg or higher [2]

Patients with metabolic syndrome are estimated to have a 2-fold increased risk of atherosclerotic cardiovascular diseases and a 5-fold increased risk of diabetes mellitus, as compared to the general population.[3] Metabolic syndrome is also associated with accelerated atherosclerosis, premature atherosclerotic cardiovascular diseases, and early onset type II diabetes mellitus.[4][5] The sedentary lifestyle and excess consumption of calories have significantly increased the proportion of the population with obesity in the last few decades.[6] Due to this exponential growth in population obesity, the incidence of metabolic syndrome has increased significantly over the last 2 decades.[7] Currently, more than one-fifth of Americans, as well as the European population, are suffering from metabolic syndrome.

Central obesity is the primary component of metabolic syndrome, leading to insulin resistance, hypertension, and dyslipidemia.[8] The clinical presentation of metabolic syndrome is variable and depends on the underlying atherosclerotic cardiovascular disease. The common signs of metabolic syndrome include abdominal obesity with high body mass index and increased waist circumference, elevated blood pressure, and signs of insulin resistance.[9] Metabolic syndrome has serious implications for an individual’s health. The prevalence of metabolic syndrome is rising, and through intervention, the progression can be halted and potentially reversed.[10][11] 

Etiology

The underlying etiology of metabolic syndrome is multifactorial. The proposed causes include genetic predisposition and multiple environmental or lifestyle factors, including obesity, lack of physical activity, and unhealthy dietary habits.[12] The crux of the syndrome is a buildup of fatty tissue, especially in the abdomen, leading to insulin resistance.[13] Proinflammatory cytokines, such as tumor necrosis factor, leptin, adiponectin, plasminogen activator inhibitor, and resistin, are released from the enlarged adipose tissue, which adversely alters and impacts insulin.[14]

Insulin resistance can be acquired or due to genetic predisposition. Impairment of the signaling pathway, insulin receptor defects, and defective insulin secretion can all contribute to insulin resistance. Visceral obesity has been identified as the main trigger of all pathways involved in the pathogenesis of metabolic syndrome, and high-calorie intake is the primary cause of visceral fat accumulation.[8] Over time, the culmination causes the development of metabolic syndrome that presents as vascular and autonomic damage.[15]

Although environmental factors are considered the leading cause of metabolic syndrome and its pathogenesis, genetic factors can not be ignored. Results from studies have shown that the offspring of obese parents have a higher chance of obesity than healthy individuals.[16] Epidemiologic studies have shown that environmental factors in fetal life and the early postnatal period influence disease risk and pathogenesis in adults. Thus, the mother’s lifestyle and intrauterine and postnatal nutrition play an important role in the etiology and pathogenesis of the metabolic syndrome.[17]

Epidemiology

The global incidence of metabolic syndrome rises almost parallel to the incidence of obesity. According to the National Health and Nutrition Examination Survey (NHNES), the prevalence of metabolic syndrome in adults increased from 25.3% to 34.2% in 2012.[2] The survey further revealed that the South Asian American population had a very high incidence of metabolic syndrome, albeit a lower prevalence of obesity as compared to non-Hispanic white men and women.[18] The prevalence of metabolic syndrome peaked at the start of the 21st century in the United States. The prevalence gradually decreased due to early diagnosis and proper treatment of dyslipidemia and hypertension (although the prevalence of obesity was increasing).[19] In the 2009-2010 NHNES report, the prevalence of metabolic syndrome was 22% in women and 24% in men.[20]

In Europe and Latin America, around one-fourth of the general population is reported to have metabolic syndrome.[21][22][23] The incidence of metabolic syndrome in China has also increased over the last 3 decades. However, it is lower than in the United States and was estimated to reach 15.5% in 2017.[24] Metabolic syndrome is no longer a disease of the adult population; this condition is also reported to involve children and adolescents. In 2020, 3% of children and 5% of adolescents were found to have metabolic syndrome globally. The incidence of metabolic syndrome is slightly higher in children of low-income countries, which suggests the high economy of the country is not a predictor of metabolic syndrome.[25] The prevalence of metabolic syndrome increases with increasing age; almost 40% of people have metabolic syndrome in the 6th decade of their lives.[26] Although metabolic syndrome involves both men and women equally, it is slightly more prevalent in women than men in certain ethnic groups.

Pathophysiology

Metabolic syndrome has been studied extensively over the past few decades. Insulin resistance, adipose tissue dysfunction, and chronic inflammation have been proposed as the basic components of the pathogenesis of metabolic syndrome.[27][28] Under normal circumstances, a sudden rise in serum glucose level triggers insulin secretion from the pancreatic β-cells, which promote cellular glucose uptake via glucose transporters. However, in those with insulin resistance, tissues are less sensitive to this acute rise in insulin, resulting in a higher serum glucose level and hyperinsulinemia.[29] The impairment in insulin secretion and abnormal insulin signaling results in impaired glucose metabolism, fat deposition, cardiotoxicity, and chronic inflammation, the characteristic features of metabolic syndrome.[30]

Visceral obesity is another essential component of metabolic syndrome. Free fatty acids released by the adipose tissues promote insulin resistance and inhibit insulin secretion from the pancreatic beta cells.[31] The high-free fatty acids inhibit glucose uptake in skeletal muscles and increase hepatic gluconeogenesis and lipid synthesis by inducing protein kinases. Both insulin resistance and free fatty acids play a major role in the pathogenesis of hypertension, prothrombotic state, and chronic inflammation.[14] Visceral adipose tissues also secrete multiple active metabolites and various pro-inflammatory cytokines, C-reactive protein, leptin, and resistin, which induce chronic inflammation, a possible mechanism of various complications of metabolic syndrome.[32][33]

The inflammatory cytokines further increase insulin resistance in skeletal muscles, liver, and adipose tissues by inhibiting the insulin signaling pathway in these tissues. These cytokines, especially tumor necrosis factor-alpha, promote insulin resistance by inactivating insulin receptors in the skeletal muscles.[34] Insulin resistance further activates inflammatory cytokines and promotes thrombogenesis by increasing the fibrinogen level.[35]

Metabolic syndrome adversely influences several body systems. Insulin resistance causes microvascular damage, predisposing patients to endothelial dysfunction, vascular resistance, hypertension, and vessel wall inflammation. Endothelial damage can impact the body’s homeostasis, causing atherosclerotic disease and the development of hypertension.[36] Furthermore, hypertension adversely affects several body functions, including increased vascular resistance and stiffness, causing peripheral vascular disease, structural heart disease comprising of left ventricular hypertrophy and cardiomyopathy, and leading to renal impairment.

Accumulated effects of endothelial dysfunction and hypertension due to metabolic syndrome can further result in ischemic heart disease. Endothelial dysfunction due to increased levels of plasminogen activator inhibitor-1 and adipokine levels can cause thrombogenicity, while hypertension causes vascular resistance by which coronary artery disease can develop. Dyslipidemia associated with metabolic syndrome can drive the atherosclerotic process, leading to symptomatic ischemic heart disease.[37][38]

History and Physical

History

Although metabolic syndrome is diagnosed based on physical examination findings and laboratory investigations, history is essential to screening patients suspected to have metabolic syndrome. A detailed history of the patient’s lifestyle, eating habits, and family history may help identify the risk factors for metabolic syndrome and guide its management—the history of premature coronary artery disease warrants evaluation of the different components of metabolic syndrome. At the same time, the classic symptoms of polyuria, polydipsia, and polyphagia suggest diabetes mellitus, a well-known element or complication of metabolic syndrome. History and physical exams are vital for disease recognition, treatment, and prevention.[39] Social history should also be obtained to screen for modifiable factors eg, smoking, that can impact the development of cardiovascular complications in metabolic syndrome

Physical Exam

The patient encounter starts with vitals and general appearance, which can point toward the diagnosis of metabolic syndrome. As mentioned above, 3 abnormalities indicate the diagnosis, so specific metrics are necessary. Every patient presenting for the evaluation should have waist circumference measured.[40] The physical examination may reveal signs of insulin resistance, such as acanthosis nigricans, and signs of dyslipidemia, such as xanthomas.[41] 

Evaluation

Initial Laboratory Investigations

After a thorough history and physical examination, the evaluation for metabolic syndrome needs to be complemented with laboratory analysis. The initial blood work should include fasting blood glucose and hemoglobin A1c to screen for insulin resistance and diabetes mellitus. A lipid panel should also be drawn to assess abnormally elevated triglyceride levels, low HDL levels, and elevated low-density lipoprotein levels. The initial evaluation should also include a basic metabolic panel to evaluate for renal dysfunction. Further studies such as C-reactive protein, liver function tests, thyroid studies, and uric acid can be considered in a selected group of patients to evaluate associated disorders.[42] Hypothyroidism is associated with an increased risk of metabolic syndrome, while hyperuricemia is commonly found in patients with metabolic syndrome due to a chronic inflammatory state.[43]

Investigations for Evaluation of Complications

The contemporary guidelines recommend the estimation of atherosclerotic cardiovascular disease (ASCVD) risk in all patients with metabolic syndrome to devise the primary prevention strategy.[44] In asymptomatic patients with a significant risk of ASCVD or a family history of premature ASCVD, coronary calcium score can be considered for the assessment of cardiovascular diseases and appropriate management.[45] Meanwhile, when appropriate, invasive or non-evasive imaging studies should be ordered in symptomatic patients. If warranted, patients should be evaluated further with cardiac stress testing, including an electrocardiogram stress test, stress echocardiography, stress single-photon emission computed tomography, or myocardial perfusion imaging.[46][47]

Treatment / Management

Metabolic syndrome is a global pandemic involving millions of people in different regions of the world. The primary goal of the management is to identify and treat the risk factors and reduce the cardiovascular complications of metabolic syndrome. The management of metabolic syndrome can be divided into lifestyle modifications and medical management.

Lifestyle Modifications

All components of metabolic syndrome are linked with lifestyle; a healthy lifestyle is an effective way of treating the risk factors for metabolic syndrome and preventing associated cardiovascular complications. The primary goal of the intervention is to create a balance between calorie requirement and intake.[31] The recommended lifestyle modifications include physical activity, a healthy diet, avoiding tobacco use, good sleep hygiene, and decreased alcohol consumption. The contemporary guidelines recommend a 7% to 10% reduction in the baseline body weight over 12 months, with physical activity and calorie deficit. The long-term goal is to achieve a body mass index of less than 25 kg/m² and maintain the ideal body weight.[48] The American Heart Association and American College of Cardiology recommend 150 minutes of moderate-intensity or 70 minutes of high-intensity physical activity weekly.[49] A diet rich in vegetables, fruits, legumes, whole grains, nuts, and fish is recommended to reduce cardiovascular diseases. It is also recommended to avoid processed foods, refined carbohydrates, a diet rich in saturated fat, and reduce the amount of sodium.[50] Social support and the management of psychosocial stresses are significant for the maintenance of a healthy lifestyle. Individualized lifestyle modification according to patients' age, gender, and availability of resources helps maintain a healthy lifestyle.

Pharmacologic Managament

It is imperative to ensure the implementation of a healthy lifestyle before considering pharmacologic options for managing metabolic syndrome. In patients with metabolic syndrome, drug therapy is commonly recommended for the treatment of dyslipidemia, hypertension, and insulin resistance or diabetes mellitus. Patients with dyslipidemia should be evaluated for reversible causes, and pharmacotherapies must be advised according to the clinical practice guidelines.[51] Hypertension is another component of metabolic syndrome that requires pharmacotherapy.

The practice guidelines recommend accurate measurement and documentation of blood pressure.[52] It is mandatory to diagnose and treat the reversible causes and aggravating factors of hypertension. At the same time, the choice of antihypertensive drugs depends on the associated co-morbid conditions and other risk factors.[52][53][52] The drugs recommended for treating insulin resistance include metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1(GLP-1) agonists, and pioglitazone.[54][55][56][55] Recent studies have found evidence of plant extracts' role in managing metabolic syndrome and its components; however, contemporary clinical practice guidelines do not recommend them.[57] Further research is required to evaluate medicinal plants' role in managing the metabolic syndrome. Patients with metabolic syndrome require multiple medications for the management of dyslipidemia, hypertension, insulin resistance, and obesity, and it is essential to monitor the patients closely for compliance with the treatment. 

Surgical Management

Patients with severe obesity may benefit from bariatric surgery. Bariatric surgery is considered the most influential single therapy for metabolic syndrome. The most common procedures are laparoscopic adjustable gastric banding, laparoscopic Roux-en-Y gastric bypass, and laparoscopic sleeve gastrectomy. Bariatric surgery is recommended for patients with a BMI ≥40 kg/m² or those with a BMI ≥35 kg/m² and other comorbidities. Patients should have a long-term follow-up after surgery to avoid surgical, nutritional, and psychiatric complications.[58]

Differential Diagnosis

Metabolic syndrome is a combination of different atherosclerotic cardiovascular disease risk factors—the secondary causes of each are a component of the differential diagnosis. Renal parenchymal diseases, renovascular diseases, endocrine disorders, and coarctation of the aorta can be considered.[59] Hypothyroidism is one of the causes of hypertension, dyslipidemia, and obesity, so it is regarded as a close differential of metabolic syndrome.[60] The other differential diagnoses may include polycystic ovarian syndrome, pheochromocytoma, Cushing syndrome, and acromegaly.[61]

Prognosis

The prognosis of patients with metabolic syndrome is determined by the severity of its components and cardiovascular complications. Cardiovascular complications predict poor prognosis in patients with metabolic syndrome, and the risk of cardiovascular complications is proposed to be amplified due to the combination of multiple ASCVD risk factors.[62] Patients with metabolic syndrome have more than 2-fold higher risk of cardiovascular events as compared to those without metabolic syndrome, which predicts a poor prognosis. However, recent advances in managing atherosclerotic cardiovascular diseases have improved outcomes significantly.[63]

Complications

Patients with metabolic syndrome have multiple cardiovascular complications due to the underlying risk factors. These patients are found to have more than two-fold higher incidence of cardiovascular events, including myocardial infarction, cerebrovascular accidents, and heart failure, independent of age, gender, and the presence of diabetes.[64] Diabetes mellitus is another complication of metabolic syndrome. Almost all patients with metabolic syndrome develop diabetes mellitus, which further elevates the risk of cardiovascular diseases and leads to microvascular complications.[65] Obesity-related complications of metabolic syndrome may include obstructive sleep apnea, pulmonary hypertension, and osteoarthritis.

Consultations

The management of metabolic syndrome requires a multidisciplinary team. Following consultations are essential for the appropriate management of patients with metabolic syndrome.

• A cardiologist is required for the management of hypertension and cardiovascular complications.
• An endocrinologist is essential for treating insulin resistance and its complications.
• A dietitian is needed for a comprehensive diet plan.
• A physical trainer is needed to guide and monitor physical activity and exercise.
• A neurologist may be required for the management of cerebrovascular accidents.

Deterrence and Patient Education

The following are recommendations for patients with metabolic syndrome:

• Practice a healthy lifestyle and target a <25 kg/m² BMI.
• Physical activity reduces cardiovascular diseases and improves survival.
• Engage in at least 150 minutes of moderate-intensity physical activity in a week.
• Eat a diet rich in vegetables, fruits, legumes, whole grains, and fish.
• Avoid refined carbohydrates and a diet rich in sodium and saturated fats.
• Quit smoking and avoid excessive alcohol intake. 
• Have adequate sleep and get treated for obstructive sleep apnea, if needed.

Pearls and Other Issues

Sleep health and hygiene should also be discussed with patients who have metabolic syndrome because sleep apnea and sleep deprivation can lead to the development of metabolic syndrome. Studies have shown that 3 months of continuous positive airway pressure can reduce blood pressure in patients with moderate to severe sleep apnea and potentially reverse some metabolic syndrome abnormalities.[66] 

Recognizing the development of metabolic syndrome is crucial to treating, preventing, and reversing the disease process. Through history and physical exam, as well as patient education and workup of the contributing factors, clinicians can treat the metabolic syndrome and potentially alter the trajectory of disease development.

Enhancing Healthcare Team Outcomes

The management of metabolic syndrome is best accomplished with an interprofessional team that includes a dietitian, physical therapist, pharmacist, cardiologist, internist, neurologist, bariatric surgeon, nurse practitioner, endocrinologist, and social worker. The key to managing this disorder is patient education. The patient must be told of the importance of changes in lifestyle and weight loss. The dietitian should educate the patient on a Mediterranean-style diet and the importance of exercise. The patient should be urged to stop smoking and abstain from alcohol. The pharmacist must ensure that the patient is compliant with the medications. Probably the most important intervention is exercise because it can lower body weight, cholesterol, blood pressure, and blood glucose at the same time. Finally, patients with metabolic syndrome should be educated on good sleep hygiene.[67][68]

Patients with metabolic complications can develop a wide range of complications, including heart disease, aortic stenosis, atrial fibrillation, stroke, and thromboembolic disease. Today, evidence seems to indicate that the risk of an ischemic stroke is much higher in patients with metabolic syndrome than previously thought. In addition, other problems associated with metabolic syndrome include a risk for malignancies of the kidney, gallbladder, colon, and prostate gland. Further, the metabolic syndrome may also increase the risk of eclampsia and affect cognitive performance. Finally, patients with metabolic syndrome also face higher medical bills, are more likely to face financial difficulties, and may experience barriers to healthcare.[69][70]

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References

1.

Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC., International Diabetes Federation Task Force on Epidemiology and Prevention. Hational Heart, Lung, and Blood Institute. American Heart Association. World Heart Federation. International Atherosclerosis Society. International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a 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 International Association for the Study of Obesity. Circulation. 2009 Oct 20;120(16):1640-5. [PubMed: 19805654]

2.

Saklayen MG. The Global Epidemic of the Metabolic Syndrome. Curr Hypertens Rep. 2018 Feb 26;20(2):12. [PMC free article: PMC5866840] [PubMed: 29480368]

3.

Samson SL, Garber AJ. Metabolic syndrome. Endocrinol Metab Clin North Am. 2014 Mar;43(1):1-23. [PubMed: 24582089]

4.

Kazemi T, Sharifzadeh G, Zarban A, Fesharakinia A. Comparison of components of metabolic syndrome in premature myocardial infarction in an Iranian population: a case -control study. Int J Prev Med. 2013 Jan;4(1):110-4. [PMC free article: PMC3570902] [PubMed: 23411742]

5.

Pucci G, Alcidi R, Tap L, Battista F, Mattace-Raso F, Schillaci G. Sex- and gender-related prevalence, cardiovascular risk and therapeutic approach in metabolic syndrome: A review of the literature. Pharmacol Res. 2017 Jun;120:34-42. [PubMed: 28300617]

6.

Caballero B. Humans against Obesity: Who Will Win? Adv Nutr. 2019 Jan 01;10(suppl_1):S4-S9. [PMC free article: PMC6363526] [PubMed: 30721956]

7.

Saltiel AR, Olefsky JM. Inflammatory mechanisms linking obesity and metabolic disease. J Clin Invest. 2017 Jan 03;127(1):1-4. [PMC free article: PMC5199709] [PubMed: 28045402]

8.

Matsuzawa Y, Funahashi T, Nakamura T. The concept of metabolic syndrome: contribution of visceral fat accumulation and its molecular mechanism. J Atheroscler Thromb. 2011;18(8):629-39. [PubMed: 21737960]

9.

Handelsman Y. Metabolic syndrome pathophysiology and clinical presentation. Toxicol Pathol. 2009 Jan;37(1):18-20. [PubMed: 19098117]

10.

van der Pal KC, Koopman ADM, Lakerveld J, van der Heijden AA, Elders PJ, Beulens JW, Rutters F. The association between multiple sleep-related characteristics and the metabolic syndrome in the general population: the New Hoorn study. Sleep Med. 2018 Dec;52:51-57. [PubMed: 30278295]

11.

Kim JY, Yi ES. Analysis of the relationship between physical activity and metabolic syndrome risk factors in adults with intellectual disabilities. J Exerc Rehabil. 2018 Aug;14(4):592-597. [PMC free article: PMC6165970] [PubMed: 30276179]

12.

Xu H, Li X, Adams H, Kubena K, Guo S. Etiology of Metabolic Syndrome and Dietary Intervention. Int J Mol Sci. 2018 Dec 31;20(1) [PMC free article: PMC6337367] [PubMed: 30602666]

13.

Gluvic Z, Zaric B, Resanovic I, Obradovic M, Mitrovic A, Radak D, Isenovic ER. Link between Metabolic Syndrome and Insulin Resistance. Curr Vasc Pharmacol. 2017;15(1):30-39. [PubMed: 27748199]

14.

Fahed G, Aoun L, Bou Zerdan M, Allam S, Bou Zerdan M, Bouferraa Y, Assi HI. Metabolic Syndrome: Updates on Pathophysiology and Management in 2021. Int J Mol Sci. 2022 Jan 12;23(2) [PMC free article: PMC8775991] [PubMed: 35054972]

15.

Cho DH, Kim MN, Joo HJ, Shim WJ, Lim DS, Park SM. Visceral obesity, but not central obesity, is associated with cardiac remodeling in subjects with suspected metabolic syndrome. Nutr Metab Cardiovasc Dis. 2019 Apr;29(4):360-366. [PubMed: 30782509]

16.

Ferguson-Smith AC, Patti ME. You are what your dad ate. Cell Metab. 2011 Feb 02;13(2):115-7. [PubMed: 21284975]

17.

Heijmans BT, Tobi EW, Stein AD, Putter H, Blauw GJ, Susser ES, Slagboom PE, Lumey LH. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci U S A. 2008 Nov 04;105(44):17046-9. [PMC free article: PMC2579375] [PubMed: 18955703]

18.

Palaniappan LP, Wong EC, Shin JJ, Fortmann SP, Lauderdale DS. Asian Americans have greater prevalence of metabolic syndrome despite lower body mass index. Int J Obes (Lond). 2011 Mar;35(3):393-400. [PMC free article: PMC2989340] [PubMed: 20680014]

19.

Correction. Circulation. 2016 Apr 12;133(15):e599. [PubMed: 27067095]

20.

Lovre D, Mauvais-Jarvis F. Trends in Prevalence of the Metabolic Syndrome. JAMA. 2015 Sep 01;314(9):950. [PubMed: 26325567]

21.

Scuteri A, Laurent S, Cucca F, Cockcroft J, Cunha PG, Mañas LR, Mattace Raso FU, Muiesan ML, Ryliškytė L, Rietzschel E, Strait J, Vlachopoulos C, Völzke H, Lakatta EG, Nilsson PM., Metabolic Syndrome and Arteries Research (MARE) Consortium. Metabolic syndrome across Europe: different clusters of risk factors. Eur J Prev Cardiol. 2015 Apr;22(4):486-91. [PMC free article: PMC4544872] [PubMed: 24647805]

22.

Cleven L, Krell-Roesch J, Schmidt SCE, Dziuba A, Bös K, Jekauc D, Woll A. Longitudinal association between physical activity and the risk of incident metabolic syndrome in middle-aged adults in Germany. Sci Rep. 2022 Nov 12;12(1):19424. [PMC free article: PMC9653435] [PubMed: 36371479]

23.

Szypowska A, Zatońska K, Szuba A, Regulska-Ilow B. Dietary Inflammatory Index (DII)^® and Metabolic Syndrome in the Selected Population of Polish Adults: Results of the PURE Poland Sub-Study. Int J Environ Res Public Health. 2023 Jan 06;20(2) [PMC free article: PMC9859570] [PubMed: 36673811]

24.

Wang Y, Mi J, Shan XY, Wang QJ, Ge KY. Is China facing an obesity epidemic and the consequences? The trends in obesity and chronic disease in China. Int J Obes (Lond). 2007 Jan;31(1):177-88. [PubMed: 16652128]

25.

Noubiap JJ, Nansseu JR, Lontchi-Yimagou E, Nkeck JR, Nyaga UF, Ngouo AT, Tounouga DN, Tianyi FL, Foka AJ, Ndoadoumgue AL, Bigna JJ. Global, regional, and country estimates of metabolic syndrome burden in children and adolescents in 2020: a systematic review and modelling analysis. Lancet Child Adolesc Health. 2022 Mar;6(3):158-170. [PubMed: 35051409]

26.

Grundy SM. Metabolic syndrome pandemic. Arterioscler Thromb Vasc Biol. 2008 Apr;28(4):629-36. [PubMed: 18174459]

27.

Guess J, Beltran TH, Choi YS. Prediction of Metabolic Syndrome in U.S. Adults Using Homeostasis Model Assessment-Insulin Resistance. Metab Syndr Relat Disord. 2023 Apr;21(3):156-162. [PubMed: 36787450]

28.

Camera A, Hopps E, Caimi G. [Metabolic syndrome: from insulin resistance to adipose tissue dysfunction]. Minerva Med. 2008 Jun;99(3):307-21. [PubMed: 18497727]

29.

Lann D, LeRoith D. Insulin resistance as the underlying cause for the metabolic syndrome. Med Clin North Am. 2007 Nov;91(6):1063-77, viii. [PubMed: 17964909]

30.

Lann D, Gallagher E, Leroith D. Insulin resistance and the metabolic syndrome. Minerva Med. 2008 Jun;99(3):253-62. [PubMed: 18497723]

31.

Rochlani Y, Pothineni NV, Kovelamudi S, Mehta JL. Metabolic syndrome: pathophysiology, management, and modulation by natural compounds. Ther Adv Cardiovasc Dis. 2017 Aug;11(8):215-225. [PMC free article: PMC5933580] [PubMed: 28639538]

32.

Park SE, Rhee EJ, Lee WY, Kim WJ, Yoo SH, Bae JC, Choi ES, Park CY, Oh KW, Park SW, Kim SW. The role of serum adipocyte fatty acid-binding protein on the development of metabolic syndrome is independent of pro-inflammatory cytokines. Nutr Metab Cardiovasc Dis. 2012 Jun;22(6):525-32. [PubMed: 21186114]

33.

Manoharan MP, Raja R, Jamil A, Csendes D, Gutlapalli SD, Prakash K, Swarnakari KM, Bai M, Desai DM, Desai A, Penumetcha SS. Obesity and Coronary Artery Disease: An Updated Systematic Review 2022. Cureus. 2022 Sep;14(9):e29480. [PMC free article: PMC9588166] [PubMed: 36299943]

34.

Hotamisligil GS, Murray DL, Choy LN, Spiegelman BM. Tumor necrosis factor alpha inhibits signaling from the insulin receptor. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4854-8. [PMC free article: PMC43887] [PubMed: 8197147]

35.

Ridker PM, Howard CP, Walter V, Everett B, Libby P, Hensen J, Thuren T., CANTOS Pilot Investigative Group. Effects of interleukin-1β inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial. Circulation. 2012 Dec 04;126(23):2739-48. [PubMed: 23129601]

36.

Wisse BE. The inflammatory syndrome: the role of adipose tissue cytokines in metabolic disorders linked to obesity. J Am Soc Nephrol. 2004 Nov;15(11):2792-800. [PubMed: 15504932]

37.

He Y, Wu W, Wu S, Zheng HM, Li P, Sheng HF, Chen MX, Chen ZH, Ji GY, Zheng ZD, Mujagond P, Chen XJ, Rong ZH, Chen P, Lyu LY, Wang X, Xu JB, Wu CB, Yu N, Xu YJ, Yin J, Raes J, Ma WJ, Zhou HW. Linking gut microbiota, metabolic syndrome and economic status based on a population-level analysis. Microbiome. 2018 Sep 24;6(1):172. [PMC free article: PMC6154942] [PubMed: 30249275]

38.

Cӑtoi AF, Pârvu AE, Andreicuț AD, Mironiuc A, Crӑciun A, Cӑtoi C, Pop ID. Metabolically Healthy versus Unhealthy Morbidly Obese: Chronic Inflammation, Nitro-Oxidative Stress, and Insulin Resistance. Nutrients. 2018 Sep 01;10(9) [PMC free article: PMC6164113] [PubMed: 30200422]

39.

Giannopoulos CK, Tzima IG, Tentolouris NK, Vasileiadis IA. Common Pathogenetic Pathways of Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus. Curr Diabetes Rev. 2023;19(9):e160223213720. [PubMed: 36797616]

40.

Huang PL. A comprehensive definition for metabolic syndrome. Dis Model Mech. 2009 May-Jun;2(5-6):231-7. [PMC free article: PMC2675814] [PubMed: 19407331]

41.

Leung AKC, Lam JM, Barankin B, Leong KF, Hon KL. Acanthosis Nigricans: An Updated Review. Curr Pediatr Rev. 2022;19(1):68-82. [PubMed: 36698243]

42.

Khatiwada S, Sah SK, Kc R, Baral N, Lamsal M. Thyroid dysfunction in metabolic syndrome patients and its relationship with components of metabolic syndrome. Clin Diabetes Endocrinol. 2016;2:3. [PMC free article: PMC5471726] [PubMed: 28702239]

43.

Puig JG, Martínez MA. Hyperuricemia, gout and the metabolic syndrome. Curr Opin Rheumatol. 2008 Mar;20(2):187-91. [PubMed: 18349749]

44.

Bittner V. The New 2019 AHA/ACC Guideline on the Primary Prevention of Cardiovascular Disease. Circulation. 2020 Dec 22;142(25):2402-2404. [PubMed: 30879338]

45.

Dzaye O, Dudum R, Reiter-Brennan C, Kianoush S, Tota-Maharaj R, Cainzos-Achirica M, Blaha MJ. Coronary artery calcium scoring for individualized cardiovascular risk estimation in important patient subpopulations after the 2019 AHA/ACC primary prevention guidelines. Prog Cardiovasc Dis. 2019 Sep-Oct;62(5):423-430. [PubMed: 31715194]

46.

Klimova B, Kuca K, Maresova P. Global View on Alzheimer's Disease and Diabetes Mellitus: Threats, Risks and Treatment Alzheimer's Disease and Diabetes Mellitus. Curr Alzheimer Res. 2018;15(14):1277-1282. [PubMed: 30251605]

47.

Chiarelli F, Mohn A. Early diagnosis of metabolic syndrome in children. Lancet Child Adolesc Health. 2017 Oct;1(2):86-88. [PubMed: 30169210]

48.

Alberti KG, Zimmet P, Shaw J. Metabolic syndrome--a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med. 2006 May;23(5):469-80. [PubMed: 16681555]

49.

Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, Himmelfarb CD, Khera A, Lloyd-Jones D, McEvoy JW, Michos ED, Miedema MD, Muñoz D, Smith SC, Virani SS, Williams KA, Yeboah J, Ziaeian B. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019 Sep 10;74(10):e177-e232. [PubMed: 30894318]

50.

Eckel RH, Jakicic JM, Ard JD, de Jesus JM, Houston Miller N, Hubbard VS, Lee IM, Lichtenstein AH, Loria CM, Millen BE, Nonas CA, Sacks FM, Smith SC, Svetkey LP, Wadden TA, Yanovski SZ., American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014 Jul 01;63(25 Pt B):2960-84. [PubMed: 24239922]

51.

Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC, Sperling L, Virani SS, Yeboah J. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Jun 18;139(25):e1082-e1143. [PMC free article: PMC7403606] [PubMed: 30586774]

52.

Whelton PK, Carey RM, Aronow WS, Casey DE, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA, Williamson JD, Wright JT. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018 May 15;71(19):e127-e248. [PubMed: 29146535]

53.

Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, Clement D, Coca A, De Simone G, Dominiczak A, Kahan T, Mahfoud F, Redon J, Ruilope L, Zanchetti A, Kerins M, Kjeldsen S, Kreutz R, Laurent S, Lip GYH, McManus R, Narkiewicz K, Ruschitzka F, Schmieder R, Shlyakhto E, Tsioufis K, Aboyans V, Desormais I., List of authors/Task Force members: 2018 Practice Guidelines for the management of arterial hypertension of the European Society of Hypertension and the European Society of Cardiology: ESH/ESC Task Force for the Management of Arterial Hypertension. J Hypertens. 2018 Dec;36(12):2284-2309. [PubMed: 30379783]

54.

Herman R, Kravos NA, Jensterle M, Janež A, Dolžan V. Metformin and Insulin Resistance: A Review of the Underlying Mechanisms behind Changes in GLUT4-Mediated Glucose Transport. Int J Mol Sci. 2022 Jan 23;23(3) [PMC free article: PMC8836112] [PubMed: 35163187]

55.

Zhong J, Maiseyeu A, Davis SN, Rajagopalan S. DPP4 in cardiometabolic disease: recent insights from the laboratory and clinical trials of DPP4 inhibition. Circ Res. 2015 Apr 10;116(8):1491-504. [PMC free article: PMC4394189] [PubMed: 25858071]

56.

Bednarz K, Kowalczyk K, Cwynar M, Czapla D, Czarkowski W, Kmita D, Nowak A, Madej P. The Role of Glp-1 Receptor Agonists in Insulin Resistance with Concomitant Obesity Treatment in Polycystic Ovary Syndrome. Int J Mol Sci. 2022 Apr 14;23(8) [PMC free article: PMC9029608] [PubMed: 35457152]

57.

Arozal W, Louisa M, Soetikno V. Selected Indonesian Medicinal Plants for the Management of Metabolic Syndrome: Molecular Basis and Recent Studies. Front Cardiovasc Med. 2020;7:82. [PMC free article: PMC7218133] [PubMed: 32435657]

58.

Cordero P, Li J, Oben JA. Bariatric surgery as a treatment for metabolic syndrome. J R Coll Physicians Edinb. 2017 Dec;47(4):364-368. [PubMed: 29537411]

59.

Hegde S, Ahmed I, Aeddula NR. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Jul 30, 2023. Secondary Hypertension. [PubMed: 31335025]

60.

Gluvic Z, Sudar E, Tica J, Jovanovic A, Zafirovic S, Tomasevic R, Isenovic ER. Effects of levothyroxine replacement therapy on parameters of metabolic syndrome and atherosclerosis in hypothyroid patients: a prospective pilot study. Int J Endocrinol. 2015;2015:147070. [PMC free article: PMC4363579] [PubMed: 25821465]

61.

Chen W, Pang Y. Metabolic Syndrome and PCOS: Pathogenesis and the Role of Metabolites. Metabolites. 2021 Dec 14;11(12) [PMC free article: PMC8709086] [PubMed: 34940628]

62.

Kaplan NM. The deadly quartet and the insulin resistance syndrome: an historical overview. Hypertens Res. 1996 Jun;19 Suppl 1:S9-11. [PubMed: 9240756]

63.

Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Judd SE, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Mackey RH, Magid DJ, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER, Moy CS, Mussolino ME, Neumar RW, Nichol G, Pandey DK, Paynter NP, Reeves MJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Wong ND, Woo D, Turner MB., American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Executive summary: heart disease and stroke statistics--2014 update: a report from the American Heart Association. Circulation. 2014 Jan 21;129(3):399-410. [PubMed: 24446411]

64.

de Simone G, Devereux RB, Chinali M, Best LG, Lee ET, Galloway JM, Resnick HE., Strong Heart Study Investigators. Prognostic impact of metabolic syndrome by different definitions in a population with high prevalence of obesity and diabetes: the Strong Heart Study. Diabetes Care. 2007 Jul;30(7):1851-6. [PubMed: 17440172]

65.

Russo MP, Grande-Ratti MF, Burgos MA, Molaro AA, Bonella MB. Prevalence of diabetes, epidemiological characteristics and vascular complications. Arch Cardiol Mex. 2023;93(1):30-36. [PMC free article: PMC10161833] [PubMed: 36757785]

66.

Dopp JM, Reichmuth KJ, Morgan BJ. Obstructive sleep apnea and hypertension: mechanisms, evaluation, and management. Curr Hypertens Rep. 2007 Dec;9(6):529-34. [PubMed: 18367017]

67.

Carson C, Lawson HA. Epigenetics of metabolic syndrome. Physiol Genomics. 2018 Nov 01;50(11):947-955. [PMC free article: PMC6293117] [PubMed: 30240346]

68.

Albert Pérez E, Mateu Olivares V, Martínez-Espinosa RM, Molina Vila MD, Reig García-Galbis M. New Insights about How to Make an Intervention in Children and Adolescents with Metabolic Syndrome: Diet, Exercise vs. Changes in Body Composition. A Systematic Review of RCT. Nutrients. 2018 Jul 06;10(7) [PMC free article: PMC6073719] [PubMed: 29986479]

69.

Cichos KH, Churchill JL, Phillips SG, Watson SL, McGwin G, Ghanem ES, Ponce BA. Metabolic syndrome and hip fracture: Epidemiology and perioperative outcomes. Injury. 2018 Nov;49(11):2036-2041. [PubMed: 30236796]

70.

Chen YY, Fang WH, Wang CC, Kao TW, Chang YW, Yang HF, Wu CJ, Sun YS, Chen WL. Association of Percentage Body Fat and Metabolic Health in Offspring of Patients with Cardiovascular Diseases. Sci Rep. 2018 Sep 14;8(1):13831. [PMC free article: PMC6138631] [PubMed: 30218093]

Disclosure: Supreeya Swarup declares no relevant financial relationships with ineligible companies.

Disclosure: Intisar Ahmed declares no relevant financial relationships with ineligible companies.

Disclosure: Yulia Grigorova declares no relevant financial relationships with ineligible companies.

Disclosure: Roman Zeltser declares no relevant financial relationships with ineligible companies.