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Clinical Feature: Cardiometabolic Syndrome: A Package Deal

Introduction

Cardiometabolic syndrome, also known as “metabolic syndrome,” refers to a constellation of metabolic abnormalities and cardiovascular risk factors clustered in a given patient. The definitions have varied over time, but all retain key features (Table). There has been debate as to whether these abnormalities should be considered as a “syndrome”, however many clinicians feel that recognition of the shared pathology facilitates diagnosis and management of the patient.

The CardioMetabolic Health Alliance Think Tank was convened in 2014 and represented over 30 professional organizations. It highlighted several concepts:

  1. Metabolic syndrome is a chronic and progressive pathophysiological state.
  2. It represents a clustering of risk factors that form a complex syndrome defined by a unifying pathophysiology.
  3. It is associated with increased risk for atherosclerotic cardiovascular disease (ASCVD) and type 2 Diabetes.

The Think Tank members also felt that metabolic syndrome was not, “just a repackaging of its individual components . . . is a clinical entity associated with an increased risk of ASCVD or death, even after controlling for its component risk factors.”1

Prevalence estimates vary according to the definition used. National Health and Nutrition Examination Survey (NHANES) prevalence data from 2007 – 2014 was 35.3% for men and 33.3% for women. In the United States (U.S.), prevalence increases with age and is higher in Black women (40%) compared to white men and women and Black men.2 O’Hearn, et al. using NHANES data found that between 1999-2000 and 2017-2018, U.S. cardiometabolic health was poor and worsening to where only 6.8% of adults had optimal cardiometabolic health.3 The components of metabolic syndrome are influenced by genetics, although there is not a single or common genetic trait directly associated with the syndrome. More important is that the components are influenced by lifestyle factors and can be significantly modified by diet, weight loss, physical activity, and exercise. Recognition that a patient has metabolic syndrome followed by aggressive management are important in both the pediatric and adult populations.

Evolving Definition of Cardiometabolic Syndrome

Metabolic Syndrome was first defined in 1998 (Table) by the World Health Organization (WHO). The objective in creating this definition was to determine the risk of cardiovascular disease among those with insulin resistance.4 Since the statement by WHO, many definitions have arisen. In 1999, the European Group for the Study of Insulin Resistance (EGIR) modified the WHO definition. Insulin resistance remained a core element but was instead defined as a plasma insulin concentration >75th percentile of nondiabetic patients. In addition, body mass index (BMI) was removed, and instead, elevated waist circumference was used.5 In 2001, the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), differed from the two above definitions. Insulin resistance was no longer addressed as a central element. Instead, diagnosis consisted of any three of the following: fasting plasma glucose, waist circumference, hypertension, high triglycerides, and low HDL. Parameters for each are listed in the table below. A benefit of this definition was its simplicity and relevance to clinical practice.6     

The definition proposed by the American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI) had similarities with the NCEP ATP III criteria but recognized the increased risk among those of Asian origin or those with other risk factors such as non-alcoholic fatty liver disease. Thus, waist circumference had lower cut offs for these groups. In addition, the threshold for increased fasting glucose was lowered from 110 mg/dL to 100 mg/dL as a result of a change by the American Diabetes Association (ADA).7     

The International Diabetes Federation (IDF) proposed another definition for metabolic syndrome in 2005. Unique to this definition, central obesity was the focal element for diagnosis. Mirroring the AHA/NHLBI, it added different waist circumference measurements for those of South and East Asian descent. Furthermore, the diagnosis required two of the following: elevated fasting glucose, elevated triglycerides, elevated blood pressure, and reduced high density lipoprotein cholesterol (HDL-C) with or without specific treatment for these conditions.8 In 2009, the AHA, NHLBI and IDF reached a consensus and defined metabolic syndrome as any three of the following: raised waist circumferences, fasting plasma glucose ≥100, hypertension, high triglycerides, and low HDL.9

Given the rising prevalence of metabolic syndrome, it is critical to properly define it so that patients at risk receive proper screening and treatment:

Definitions of Metabolic Syndrome*

WHO, 4

1998 

EGIR,5

1999 

NCEP ATP III,6

2001

AHA/NHLBI,7 2005

 

IDF,8

2005 

IDF, NIH, AHA,9

2009 

High insulin levels, IFG or IGT, and two of the following

Top 25% of the FPG values among nondiabetic individuals and two of the following

 

3 or more of the following

Any three of the following

 

Central obesity as defined by ethnic/racial specific WC, and two of the following

 

3 of the following

 

 

FPG ≥110 mg/dl

 

FPG ≥100 mg/dL

 

FPG ≥100 mg/dl

 

FPG ≥100 mg/dL or on drug treatment for elevated glucose

HDL-C <35 mg/dl

HDL-C <1.0 mmol/liter

HDL-C: <40 mg/dl for men, <50 mg/dl for women

 

HDL-C: <40 mg/dL in men and <50 mg/dL in women, or on treatment

 

HDL-C: <40 mg/dl for men, <50 mg/dl for women

 

HDL-C: < 40 mg/dL in males, < 50 mg/dL in females

TG ≥150 mg/dL

TG ≥ 2.0 mmol/liter 

 

TG ≥150 mg/dL

TG ≥150 mg/dL or on treatment

 

TG ≥150 mg/dL

TG ≥150 mg/dL or on drug treatment for elevated triglycerides

Abdominal obesity: WHR >0.9, BMI ≥30 kg/m2, WC > 37 inches

 

WC: ≥94 cm for men, ≥80 cm for women

 

WC: >40 inches for men, >35 inches for women

 

WC: ≥102 cm in men, ≥ 88 cm in women

 

 

WC: >102 cm in males, >88 cm in females, specific thresholds for Asians

BP ≥140/90 mm Hg

 

BP ≥140/90 mm Hg or antihypertensive medication

 

BP ≥130/85 mm Hg

BP ≥130/85 mm Hg, or on antihypertensive medication

 

BP ≥130/85 mm Hg

BP ≥ 130/85 mm Hg or on drug treatment for hypertension

*Definitions

IGT - impaired glucose tolerance, < 7.0 mmol/L/ 126 mg/dL and 2 hr post glucose load ≥7.8/140) and < 11.1/200

IFG - impaired fasting glucose, ≥6.1/110) and < 7.0/126) and 2 hour < 7.8/140

FPG - fasting plasma glucose

WC - waist circumference 
 

Pathophysiology of Cardiometabolic Syndrome  

As noted above, cardiometabolic syndrome is a cluster of abnormalities, each of which can be viewed independently but are also intertwined, hence the utility of recognizing them as a “syndrome.” Insulin resistance remains an underlying etiology. Insulin resistance can increase liver production of very-low density lipoprotein (VLDL) leading to increased serum triglycerides.10 Insulin resistance also facilitates hypertension by causing microvascular damage and endothelial dysfunction,11 through increased sympathetic nervous system activity, increased angiotensin II and proliferation of vascular smooth muscle cells.10 Insulin resistance also reduces the synthesis of nitric oxide, leading to increase in heart rate and blood pressure.12 

Overweight and obesity are associated with and prevalent in metabolic syndrome. However, the focus with metabolic syndrome is instead on visceral obesity or intraabdominal adipose tissue, which is measured as “waist circumference” in the metabolic syndrome. Visceral obesity is felt to contribute to the pro-inflammatory state of metabolic syndrome.13 Nutritional excess leads to changes in adipocytes that cause macrophage infiltration and the production of proinflammatory mediators, such as Interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and plasminogen activator inhibitor-1 (PAI-1).14 TNF-alpha is particularly expressed in abdominal obesity. It causes a decrease in Glucoese transporter protein type 4 (GLUT-4) translocation which can lead to increased levels of blood glucose and insulin resistance.15

Dyslipidemia in metabolic syndrome consists of a profile of high triglycerides and low HDL-C. Elevated triglycerides are also associated with an increased concentration of VLDL-VLDL1 which are atherogenic.16 Once secreted from the liver, VLDL1 can be delipidated, leading to the formation of smaller VLDL2, intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL). The LDL particles when in the subendothelial space can be oxidized and taken up by macrophages, form foam cells, which initiate the formation of the atherosclerotic plaque, thus increasing risk of a cardiovascular event. High HDL-c is beneficial as this particle acts as an anti-inflammatory and antioxidant by blocking adhesion of monocytes, stabilizing the endothelium by promoting the synthesis of nitric oxide, and reducing platelet aggregation and promoting fibrinolysis17; HDL is often low in metabolic syndrome. 

Integrated Clinical Management

In a 2015 statement, the CardioMetabolic Health Alliance highlights a management model that is interdisciplinary and integrated with input directed to each component or abnormality that a patient may have.1 This model was developed along the three concepts noted above in the introduction emphasizing that metabolic syndrome is a pathophysiologic state which underlies the individual components.

Lifestyle interventions are critical to management of metabolic syndrome. The following provides guidance on an integrated approach to lifestyle interventions in metabolic syndrome:

Physical Activity18

  • Goal is for adults is ≥ 150-300 minutes/week of moderate intensity OR ≥ 75-150 minutes/week of vigorous-intensity aerobic activity. 
  • Counseling on ways to be more active and/or engage in regular exercise sessions and include ways to be more active in daily activities (take stairs instead of elevators).
  • Cardiac Rehabilitation Phase II for patients with qualifying diagnoses.
  • Cardiac Rehabilitation Phase III may be available at local facilities at low-cost.

Diet19

  • Referral to a registered dietician for medical nutrition counseling (note that not all insurances will reimburse).
  • Note that ketogenic diet (5% carbohydrate, 75% from fat and 20% protein) can raise LDL-C and is not recommended for long-term management.
  • Intermittent fasting (16-24 hours or intermittent full-day fasting) is not recommended.
  • A Mediterranean-type and Dietary Approaches to Stop Hypertension (DASH) diet is recommended: fruits, vegetables, whole grains, healthy sources of protein, fat-free or low-fat foods, low salt.

Weight Loss20

  • Goal is reduction in body mass index (BMI) and waist circumference.
  • Overweight = BMI > 25 kg/m2 obese = BMI > 30 kg/m2.
  • Referral to a registered dietician for medical nutrition counseling (note that not all insurances will reimburse).
  • Consider pharmacologic (weight loss medications) or surgical therapies (bariatric surgery).

Smoking Cessation23

  • Provide counseling and/or refer to smoking cessation clinic.
  • Nicotine replacement therapy.
  • Pharmacologic treatment.
  • Use of e-cigarettes to aid smoking cessation is not recommended.

It’s important to screen for key features of metabolic syndrome, e.g., disorders of glucose metabolism and dyslipidemia, as well as associated disorders like sleep apnea and polycystic ovary syndrome. Once a diagnosis of metabolic syndrome is made, along with identifying associated conditions, an integrated and tailored management plan is important for an optimal outcome, as illustrated below:

Elevated Blood Glucose24

  • Blood tests: fasting glucose and HbA1c which is diagnostic of prediabetes or diabetes:
    • HbA1c: Normal < 5.7%, prediabetes 5.7-6.4%, diabetes ≥ 6.5%.
    • Fasting glucose: Normal < 100 mg/dL, prediabetes 100-125 mg/dL, diabetes ≥ 126 mg/dL (2 separate tests are important for diagnosis).
  • Treat with diet (lower carbohydrate, low fat) and weight loss.
  • Counsel on regular exercise/physical activity.
  • Consider pharmacologic therapy with agents that will benefit metabolic syndrome:
    • If diabetic, optimize glucose control.
    • Metformin, a biguanide derivative, is generally first-line, although depends on comorbidities. Will reduce insulin resistance and decrease liver production of glucose.
    • Use other medications (e.g., GLP-1 receptor agonists, SGLT2 inhibitors) if considered high-risk (ASCVD, heart failure, CKD). 
    • Thiazolidinediones, synthetic ligands for peroxisome proliferator-activated receptors gamma, increase glucose uptake and utilization, decrease liver production of glucose, reduce insulin resistance.

Elevated Triglycerides21

  • Goal is < 150 mg/dL.
  • Triglyceride-lowering through low carbohydrate, low saturated fat diet and weight loss.
  • Improved glycemic control.
  • Medication if not at goal with lifestyle modification and improved glycemic control:
    • Statins (if indicated) will provide some triglyceride lowering (10-30%).
    • Omega three fatty acids lower triglycerides 20-44%.
    • Fibrates lower triglycerides 20-50%.

Low HDL-C22

  • Defined as < 40 mg/dL in men and < 50 mg/dL in women.
  • Reduce elevated triglycerides.
  • Increase physical activity.
  • Counsel and provide assistance for smoking cessation.
  • Increase dietary monosaturated fatty acids (MUFA).
  • Note: While low HDL-C is inversely associated with ASCVD risk, HDL-C is not considered a target of therapy at this time and there are no specific medications currently used to raise HDL-C.

Sleep Apnea25

  • Suspicion for sleep apnea: daytime somnolence, snoring at night, history of poor sleep at night, body habitus (overweight, large neck circumference).
  • Referral for sleep evaluation and testing.
  • Weight loss.
  • Sleep equipment (CPAP) if indicated.

Polycystic Ovary Syndrome26

  • Endocrine disorder in women that includes insulin resistance.
  • Screen when clinically indicated in women.
  • Rotterdam Criteria for diagnosis (2 of 3 criteria: oligo-anovulation, hyperandrogenism, polycystic ovaries).
  • Metformin can be used as part of the treatment plan.

Conclusion

People with cardiometabolic syndrome are at risk for cardiovascular disease. Early diagnosis and management of cardiometabolic syndrome are opportunities to prevent cardiovascular disease in both children and adults. The features of this syndrome are closely interrelated and should be treated with an integrated and interdisciplinary plan incorporating lifestyle interventions and, if indicated, pharmacologic therapies.     

 

References

  1. Sperling LS, Mechanick JI, Neeland IJ, et al. The CardioMetabolic Health Alliance: Working Toward a New Care Model for the Metabolic Syndrome. J Am Coll Cardiol. 2015;66(9):1050-1067. doi:10.1016/j.jacc.2015.06.1328
  2. Tsao CW, Aday AW, Almarzooq ZI, et al. Heart Disease and Stroke Statistics-2022 Update: A Report From the American Heart Association. Circulation. 2022;145(8):e153-e639. doi:10.1161/CIR.0000000000001052
  3. O'Hearn M, Lauren BN, Wong JB, Kim DD, Mozaffarian D. Trends and Disparities in Cardiometabolic Health Among U.S. Adults, 1999-2018. J Am Coll Cardiol. 2022;80(2):138-151. doi:10.1016/j.jacc.2022.04.046
  4. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med. 1998;15(7):539-553. doi:10.1002/(SICI)1096-9136(199807)15:7<539::AID-DIA668>3.0.CO;2-S
  5. Balkau B, Charles MA. Comment on the provisional report from the WHO consultation. European Group for the Study of Insulin Resistance (EGIR). Diabet Med. 1999;16(5):442-443. doi:10.1046/j.1464-5491.1999.00059.x
  6. Expert Panel on Detection, Evaluation. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA. 2001; 285:2486-2497.
  7. Grundy, Scott M. Metabolic syndrome scientific statement by the American Heart Association and the National Heart, Lung, and Blood Institute. Arteriosclerosis, Thrombosis, and Vascular Biology. 2005:25: 2243-2244.
  8. Alberti KG, Zimmet P, Shaw J, IDF Epidemiology Task Force Consensus Group The metabolic syndrome--a new worldwide definition. Lancet. 2005;366:059–1062.
  9. Alberti, Kurt GMM, et al. 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;120: 1640-1645.
  10. Roberts CK, Hevener AL, Barnard RJ. Metabolic syndrome and insulin resistance: underlying causes and modification by exercise training. Comprehensive physiology. 2013;3:1-58.
  11. Swarup S, Goyal A, Grigorova Y, Zeltser R. Metabolic Syndrome. In: StatPearls. Treasure Island (FL): StatPearls Publishing; May 2, 2022.
  12. Katsimardou, Alexandra, et al. "Hypertension in metabolic syndrome: novel insights." Current Hypertension Reviews. 2020:16: 12-18.
  13. Ritchie SA, Connell  JMC. The link between abdominal obesity, metabolic syndrome and cardiovascular disease. Nutrition, Metabolism and cardiovascular diseases. 2007:17: 319-326.
  14. McCracken E, Monaghan M, Sreenivasan S. Pathophysiology of the metabolic syndrome." Clinics in Dermatology. 2018;36: 14-20.
  15. Smith MM, Minson CT. Obesity and adipokines: effects on sympathetic overactivity. The Journal of physiology. 2012;8: 1787-1801.
  16. Packard CJ, Boren J, Taskinen M-R. Causes and consequences of hypertriglyceridemia. Frontiers in endocrinology. 2020;11: 252.
  17. Bloomgarden, ZT. Dyslipidemia and the metabolic syndrome. Diabetes Care.2004;27: 3009-3016.
  18. Physical Activity Guidelines for Americans 2 Edition Nd. https://health.gov/paguidelines/second-edition/pdf/Physical_Activity_Guidelines_2nd_edition.pdf
  19. Dietary Guidelines for Americans, 2020-2025 and Online Materials | Dietary Guidelines for Americans. www.dietaryguidelines.gov. Published 2020. https://www.dietaryguidelines.gov/resources/2020-2025-dietary-guidelines-online-materials
  20. Powell-Wiley TM, Poirier P, Burke LE, et al. Obesity and Cardiovascular Disease: A Scientific Statement From the American Heart Association. Circulation. 2021;143(21):e984-e1010. doi:10.1161/CIR.0000000000000973
  21. Stone NJ, Grundy SM. The 2018 AHA/ACC/Multi-Society Cholesterol guidelines: Looking at past, present and future. Prog Cardiovasc Dis. 2019;62(5):375-383. doi:10.1016/j.pcad.2019.11.005l
  22. Garber AJ, Handelsman Y, Grunberger G, et al. CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM - 2020 EXECUTIVE SUMMARY. Endocr Pract. 2020;26(1):107-139. doi:10.4158/CS-2019-0472
  23. US Preventive Services Task Force, Krist AH, Davidson KW, et al. Interventions for Tobacco Smoking Cessation in Adults, Including Pregnant Persons: US Preventive Services Task Force Recommendation Statement. JAMA. 2021;325(3):265-279. doi:10.1001/jama.2020.25019
  24. American Diabetes Association Professional Practice Committee. Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes – 2022. Diabetes Care 2022;45(Suppl. 1):S125-S143.
  25.  Krahn LE, Arand DL, Avidan AY, et al. Recommended protocols for the Multiple Sleep Latency Test and Maintenance of Wakefulness Test in adults: guidance from the American Academy of Sleep Medicine [published correction appears in J Clin Sleep Med. 2022 Aug 1;18(8):2089]. J Clin Sleep Med. 2021;17(12):2489-2498. doi:10.5664/jcsm.9620
  26. Huddleston HG, Dokras A. Diagnosis and Treatment of Polycystic Ovary Syndrome. JAMA. 2022;327(3):274-275. doi:10.1001/jama.2021.23769

 

Disclosures: Dr. Merle Myerson has no financial relationships to disclose. Ms. Mariana Henry has no financial relationships to disclose. 

 

 

Article By:

Mariana L. Henry, MPH

Geisel School of Medicine at Dartmouth ‘23

Hanover, NH

Merle Myerson, MD, EdD, FACC, FNLA

Heart and Vascular Center

Dartmouth Hitchcock Medical Center

Lebanon, NH

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