Metabolic Syndrome Case File

Metabolic Syndrome Case File

Eugene C. Toy, MD, Gabriel M. Aisenberg, MD

Case 2

A 46-year-old man comes to the internal medicine clinic for an annual checkup. He has no current complaints. He has just moved from Michigan, where he was an autoworker. While living in Michigan, he regularly saw his primary care provider once a year. His previous medical records are currently unavailable. The patient reports a history of hypertension, diagnosed 6 years earlier, without known complications. He has been adherent to his prescribed medications of lisinopril/ hydrochlorothiazide. He states that he checks his blood pressure weekly, and that “his numbers are normal.” He smokes 10 cigarettes per day but is open to quitting. On examination, his blood pressure is 140/85 mm Hg, his pulse is regular at 70 beats per minute (bpm), and his temperature is 98 °F. His body mass index (BMI) is 27 kg/m2. His heart examination shows normal S1 and S2 without murmurs, gallops, or rubs. His lungs are clear to auscultation. No bruits are heard on the neck, abdomen, or flank regions. His abdominal and neurologic exams are normal. Preclinic laboratory tests show normal cell blood count, normal liver and kidney function tests, normal urinalysis, hemoglobin A1c (Hb A1c) of 6%, total cholesterol of 210 mg/dL, high-density lipoprotein (HDL) cholesterol of 40 mg/dL, and lowdensity lipoprotein (LDL) cholesterol of 140 mg/dL.

▶ How do his conditions affect his cardiovascular risk?

▶ What is your next management step?

ANSWERS TO CASE 2:

Metabolic Syndrome 

• Summary: A 46-year-old man presents for a checkup with
• Elevated BMI
• Elevated blood pressure while on pharmacological treatment
• Current cigarette use
• Elevated LDL cholesterol and a borderline Hb A1C

How do his conditions affect his cardiovascular risk? The patient has multiple risk factors, such as hypertension, elevated BMI, prediabetes, dyslipidemia, and current cigarette use, which increase his cardiovascular risk.

Next management step: Use the atherosclerotic cardiovascular disease (ASCVD) 10-year risk calculator to determine the patient’s risk of developing cardiovascular disease (CVD), which will guide management of the patient’s conditions.

ANALYSIS

Objectives

1. Define metabolic syndrome. (EPA 12)
2. Recognize the value of the ASCVD calculator for determining patient’s risk. (EPA 1, 4, 7)
3. Outline the treatment options when individual or multiple cardiovascular risk factors are present. (EPA 4)

Considerations

The three most important issues for this patient are (1) the diagnosis of metabolic syndrome based on physical examination and laboratory findings, (2) identification of modifiable risk factors, and (3) incorporating lifestyle modifications and pharmacological therapies to reduce morbidity and mortality.

APPROACH TO:

Metabolic Syndrome 

DEFINITIONS

ASCVD RISK CALCULATOR: Estimates the risk of developing myocardial infarction or stroke over the following 10 years. This risk estimate can help clinicians identify patients who would benefit from primary prevention. Components of the risk calculator are listed in Table 2–1.

Abbreviation: ASCVD, atherosclerotic cardiovascular disease.

Components of the pooled cohort equation to calculate the risk of developing ASCVD over next 10 years.

ATHEROSCLEROTIC CARDIOVASCULAR DISEASE (ASCVD): The disease caused by atherosclerotic plaque buildup in vessel walls, which can lead to coronary artery disease, cerebrovascular disease, peripheral artery disease, and aortic disease.

BODY MASS INDEX (BMI): A measurement of the patient’s body weight in kilograms over the square of height in meters. It is an inexpensive screening tool used alongside other diagnostic tests.

METABOLIC SYNDROME: Metabolic syndrome is a constellation of interconnected risk factors that increase one’s chances of developing diabetes, stroke, and heart disease.

WAIST-TO-HIP RATIO: Ratio of circumference of waist to hip. It is a surrogate marker for abdominal fat distribution. Increased waist-to-hip ratio is highly correlated with increased risk of stroke, myocardial infarction, and premature death.

CLINICAL APPROACH

Epidemiology

Metabolic syndrome is a constellation of interrelated clinical syndromes of insulin resistance, central obesity, raised triglycerides, reduced HDL, and hypertension. Overall, the prevalence of metabolic syndrome is approximately 34% in the United States. The prevalence is over 50% in Americans older than 60. The prevalence of metabolic syndrome has been historically higher in older adults, but it is now increasing among younger patients due to increasing obesity and diabetes rates. There are also significant variations in the prevalence of metabolic syndrome among different ethnicities. Native Americans, African Americans, and Mexican Americans have higher rates of metabolic syndrome as compared to age-matched non-Hispanic white Americans or Chinese Americans, likely due more to social factors than genetic predisposition. In addition, there are geographic variations in the rates of diabetes, obesity, hypertension, and dyslipidemia. The 500 Cities project, a collaboration between the Centers for Disease Control and Prevention (CDC), the CDC Foundation, and the Robert Wood Johnson Foundation, revealed significant differences in the rates of chronic diseases and health outcomes among 500 of the largest cities in the United States (https://www.cdc .gov/500cities/index.htm). For example, the prevalence of hypertension is 35.2% in Charleston, West Virginia, compared to 10.7% in College Station, Texas. This varying prevalence of chronic conditions may lead to significantly different local prevalence of metabolic syndrome compared to national averages. Those with metabolic syndrome are five times more likely to develop diabetes mellitus (DM), three times more likely to develop ASCVD, and two times more likely to develop chronic kidney disease; therefore, it is imperative to screen and treat patients in the primary care setting.

Pathophysiology

The pathophysiology of metabolic syndrome is not well understood, but it is likely multifactorial. The most well-accepted hypothesis is that metabolic syndrome stems from resistance of peripheral tissue to insulin, which in turn causes the pancreas to release more insulin to maintain euglycemia. This hyperinsulinemia leads to increased lipolysis and the release of more free fatty acids (FFAs). Increased circulation of FFAs not only further reduces insulin sensitivity of the peripheral tissue but also leads to increased production of glucose and triglycerides, as well as altered cholesterol metabolism in the liver. In addition, FFAs generate reactive oxygen species, which causes endothelial dysfunction. Hyperinsulinemia can activate the sympathetic nervous system. These mechanisms together can likely lead to the hypertension, hyperlipidemia, and hyperglycemia observed in patients with metabolic syndrome.

Clinical Presentation

There are no specific clinical symptoms associated with metabolic syndrome. A patient may present to the primary care clinic with symptoms associated with obesity, insulin resistance, hypertension, and dyslipidemia. Diagnostic criteria for metabolic syndrome are listed in Table 2–2.

Diagnostic criteria per International Diabetes Foundation (IDF) worldwide definition of metabolic syndrome. The diagnosis of metabolic syndrome requires three of the five criteria. Of note, the criteria for central obesity are country and ethnicity specific, and the United States specific guidelines are listed in the table. Please refer to IDF consensus guidelines for other country-specific central obesity cutoffs.

Data from International Diabetes Federation. The IDF consensus worldwide definition of the metabolic syndrome. 2020. Copyright © International Diabetes Federation.

Patients often seek medical care due to obesity. Though imperfect, BMI is a noninvasive and an inexpensive screening tool that has been correlated with adverse cardiovascular events. As the BMI measurement does not account for body composition, gender, or age, BMI may not be accurate in elderly patients (who tend to have more adipose tissue compared to younger patients), women (who have higher total body fat for the equivalent BMI), or muscular individuals (who have lower body fat for the equivalent BMI). Recent studies have demonstrated that waist circumference, waist-to-hip ratio, and neck circumference are additional surrogate markers that are associated with increased risk of insulin resistance, diabetes, and coronary artery disease. In addition, patients may present to the clinic for an evaluation of menstrual cycle abnormalities, hirsutism, daytime sleepiness, or chronic fatigue due to polycystic ovary syndrome and obstructive sleep apnea.

Patients with severe insulin resistance may have acanthosis nigricans. Those who have already developed DM may have polyuria, polydipsia, polyphagia, blurry vision, peripheral neuropathy, or recurrent urinary tract infections. Uncontrolled hypertension may manifest as visual disturbances or episodic headaches.

In addition to hypertension and obesity on the physical examination, the patient’s blood work may reveal elevated fasting serum glucose, Hb A1C, triglycerides, LDL, or reduced HDL. Patients who have diabetes or hypertension may also have proteinuria on urinalysis.

Treatment

Screening. Patients at risk of developing metabolic syndrome should be screened routinely. In addition to measuring BMI, waist circumference, blood pressure, fasting blood glucose levels, and lipid panel, level and intensity of daily physical activity and typical food intake should be assessed. In the absence of management recommendations based on randomized controlled trials, clinicians should focus on individual components of metabolic syndrome to reduce the risk of developing CVD and DM.

Lifestyle Modification. Lifestyle modification is the mainstay of treatment. Smoking is one of the biggest modifiable risk factors for developing CVD. Patients’ tobacco use should be assessed at every visit, and smoking cessation interventions should be provided to all patients. The United States Preventive Services Task Force recommends the 5A approach for smoking cessation: Ask about tobacco use, Advise to quit, Assess willingness to quit, Assist to quit, and Arrange for follow-up. Patients who are ambivalent about quitting may benefit from a brief motivational interview, which can help resolve a patient’s ambivalence about smoking cessation. A combination of counseling and pharmacologic therapy, including nicotine replacement therapy, bupropion, or varenicline, is more effective than either counseling or medications alone.

Multiple studies have shown that moderate-intensity physical activity for at least 150 minutes per week is associated with weight loss. Modest weight loss of 5% to 10% has been shown to improve insulin sensitivity, fasting blood glucose, HDL, and triglyceride levels as well as hypertension. In addition to physical activity, diets rich in fruits, vegetables, fiber, unsaturated fats, and complex carbohydrates in which patients avoid saturated fats and sodium can prevent development of CVD and DM.

Pharmacotherapy. Though the lifestyle modifications are offered as a first-line option, they are often insufficient in addressing metabolic syndrome. Patients should be offered pharmacologic therapies for dyslipidemia, hypertension, and diabetes to prevent the development of CVD, myocardial infarction, and cerebrovascular accidents. Using the ASCVD risk calculator, a patient’s 10-year risk of developing CVD should be assessed. Those with borderline risk (5%-7.5%) and chronic kidney disease, metabolic syndrome, DM, HIV, rheumatoid arthritis, psoriasis, or South Asian ethnicity should be started on moderate-intensity statins. Patients who have intermediate risk (7.5%-20%) should also be placed on moderate- or high-intensity statins. All high-risk patients (> 20%) should be prescribed high-intensity statin therapy.

Clinicians should consider initiating metformin for patients who have impaired glucose tolerance (IGT). Metformin suppresses hepatic glucose production and enhances peripheral tissue insulin sensitivity. A large cohort study in the United Kingdom showed that treatment of patients with IGT with metformin delayed development of metabolic syndrome and DM. Thiazolidinediones have also been shown to improve insulin sensitivity and delay onset of DM in patients with prediabetes. Newer agents such as glucagon-like peptide-1 (GLP1) receptor agonists and sodium glucose transport-2 (SGLT2) inhibitors may potentially be useful in treatment of metabolic syndrome as they cause weight loss, improve insulin sensitivity, and reduce ASCVD; however, more studies are needed to assess their efficacies.

Similarly, pharmacologic therapies should be considered in patients with blood pressure > 140/90 mm Hg. An ACE inhibitor (ACEI) and angiotensin receptor blockers (ARBs) may be useful particularly in patients with metabolic syndrome or DM. Angiotensin II affects hypertension by increasing reactive oxygen species production and impairing nitric oxide generation. Furthermore, angiotensin II augments hepatic gluconeogenesis and insulin resistance. A large-scale metanalysis has shown that ACEi and ARBs not only improve hypertension but also reduce development of new-onset DM.

Bariatric Surgery. Patients with BMI > 35 and DM, hypertension, or severe sleep apnea—for whom lifestyle modifications have been insufficient—should be offered bariatric surgery. Bariatric surgery was associated with improvement in fasting glucose, blood pressure, obesity, waist circumference, and cholesterol. As patients with morbid obesity have increased perioperative complications with bariatric surgeries, patients should be advised on perioperative as well as long-term risks associated with the procedure.

CASE CORRELATION

• See also Case 1 (Health Maintenance), Case 6 (Hypertension, Outpatient), and Case 51 (Type 2 Diabetes Diagnosis and Management).

COMPREHENSION QUESTIONS

2.1 A 51-year-old man is being seen for an annual physical examination. The patient’s BMI is 28 kg/m2, blood pressure is 141/72 mm Hg, and heart rate is 73 bpm. Laboratory tests showed normal complete blood count (CBC), normal basic metabolic panel (BMP), Hb A1C of 7%, and total cholesterol of 245 mg/dL. The patient has smoked 1 pack per day for the last 30 years. He exercises 30 minutes daily. What is the best step in management of this patient?

A. Calculate the patient’s ASCVD risk score

B. Initiate statin therapy

C. Initiate metformin therapy

D. Assess readiness for smoking cessation

E. Schedule an appointment for a blood pressure check in 1 week

2.2 A 38-year-old woman is being seen by her primary care provider for a regular follow-up. The patient’s BMI is 34 kg/m2 with significant abdominal adiposity. The patient has hypothyroidism, hypertension, diabetes, and hyperlipidemia, which are well controlled with levothyroxine, lisinopril, metformin, and atorvastatin. She works as an executive assistant. She has never smoked cigarettes and does not drink alcohol. What is the next best step in management of the patient’s metabolic syndrome?

A. Recheck Hb A1C, fasting lipid panel, triiodothyronine (T3), and thyroid-stimulating hormone (TSH)

B. Refer the patient for bariatric surgery

C. Encourage the patient to perform moderate-intensity physical exercise

D. Obtain an electrocardiogram (ECG)

2.3 A 55-year-old man is presenting for an annual examination. The patient’s BMI is 24 kg/m2. His blood pressure is 123/77 mm Hg with a heart rate of 71 bpm. The patient’s total cholesterol is 171 mg/dL, HDL is 45 mg/dL, and LDL is 90 mg/dL. Last year, his Hb A1C was 5.2% and 10-year ASCVD risk score was 4.8%. Laboratory tests drawn today are unremarkable except for elevated Hb A1C at 7%. He currently takes no medications. He does not smoke or drink. What is the next best step in management?

A. Start statin therapy

B. Start metformin therapy

C. Start statin and metformin therapy

D. No further changes necessary

2.4 A 28-year-old woman is presenting to the primary care clinic for an annual physical. Her BMI is 48 kg/m2, blood pressure is 145/91 mm Hg, and Hb A1C is 8.4%. Her past medical history is remarkable for hypertension, dyslipidemia, DM, and obstructive sleep apnea. She is currently taking lisinopril, hydrochlorothiazide, atorvastatin, and insulin. The patient’s weight has remained unchanged since the last visit despite starting moderate-intensity exercise and dietary modifications. The patient endorses chronic fatigue and daytime somnolence. Which of the following is the next best step for management of metabolic syndrome?

A. Refer the patient for bariatric surgery

B. Increase insulin dose

C. Add nifedipine

D. Prescribe continuous positive airway pressure (CPAP) therapy

ANSWERS

2.1 D. The patient should be evaluated for readiness to quit smoking. If appropriate, the patient should be counseled on smoking cessation and prescribed nicotine replacement therapy. Smoking is one of the biggest risk factors for developing CVD, and smoking cessation is the most appropriate next step in managing this patient.

2.2 C. The patient has metabolic syndrome as she has hypertension, diabetes, abdominal obesity, and hyperlipidemia. Lifestyle modification is the first step of metabolic syndrome treatment. Studies have shown that 150 minutes of moderate-intensity exercise per week can significantly improve hypertension, obesity, diabetes, and hyperlipidemia.

2.3 C. This patient is presenting with a new-onset diabetes. The patient had a 10-year ASCVD risk score of 4.8% last year, which has now increased to 9.8% with newly diagnosed diabetes. In addition to encouraging moderate-intensity exercise, pharmacologic therapies for dyslipidemia and diabetes are indicated in this patient. Metformin is a first-line agent to treat diabetes. Per the American Heart Association guidelines, a 10-year ASCVD risk score between 7.5% and 20% is considered intermediate risk and would necessitate moderate-intensity statins to lower LDL.

2.4 A. This patient has metabolic syndrome (obesity, hypertension, dyslipidemia, and DM). Though lifestyle modifications are the first-line interventions for metabolic syndrome, they are often insufficient. Patients with uncontrolled diabetes, hypertension, and dyslipidemia remain at increased risk of developing CVD. To reduce cardiovascular morbidities and mortality, these patients should be offered bariatric surgery evaluation. Bariatric surgery can improve fasting glucose level, lipid profile, hypertension, and obesity.

   CLINICAL PEARLS   

▶ Metabolic syndrome is a constellation of interconnected risk factors that increase one’s chances of developing diabetes, stroke, and heart disease.

▶Abdominal obesity, elevated triglycerides, reduced HDL, insulin resis-tance, and hypertension are the hallmarks of metabolic syndrome.

▶Lifestyle modifications are the mainstay of treatment. Pharmacologic therapy should be offered if lifestyle modifications are insufficient.

▶Smoking is the key risk factor for developing CVD. Smoking cessation can be promoted with counseling and pharmacologic interventions.

▶Metformin has been shown to delay onset of DM in patients with IGT.

▶ACE inhibitors and ARBs are noted to improve hypertension and insulin sensitivity.

▶An ASCVD risk calculator can be used to estimate a patient’s 10-year risk of developing CVD.

REFERENCES

Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: executive summary. Circulation. 2019;140(11):e563-e595. 

Aroda VR, Knowler WC, Crandall JP, et al. Metformin for diabetes prevention: insights gained from the Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study. Diabetologia. 2017;60(9):1601-1611. 

Cornier M-A, Dabelea D, Hernandez TL, et al. The metabolic syndrome. Endocr Rev. 2008;29(7):777-822. 

Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365(9468):1415-1428. 

Lim S, Eckel RH. Pharmacological treatment and therapeutic perspectives of metabolic syndrome. Rev Endocr Metabolic Disord. 2014;15(4):329-341. 

Stump CS, Hamilton MT, Sowers JR. Effect of antihypertensive agents on the development of type 2 diabetes mellitus. Mayo Clin Proc. 2006;81(6):796-806. 

Yadlowsky S, Hayward RA, Sussman JB, McClelland RL, Min Y-I, Basu S. Clinical implications of revised pooled cohort equations for estimating atherosclerotic cardiovascular disease risk. Ann Intern Med. 2018;169(1):20-29.

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