Dyslipidemia, Obesity, and Metabolic Syndrome

Correlate Objective Set 4/12

1. AHA/ACC screening recommendations for hyperlipidemia

• Pediatric: once between ages 9–11, again 17–21 • Consider as early as age 2 if concern for genetic dyslipidemia • Adults ≥ 20 years • Screening frequency depends on CV risk assessment

2a. Hyperlipidemia/Dyslipidemia – Risk Factors

• Lifestyle: high‑fat diet, sedentary lifestyle, alcohol • Medications: OCPs, diuretics, β‑blockers, steroids • Endocrine disorders: diabetes, hypothyroidism, Cushing’s, PCOS • Renal disease: CKD, nephrotic syndrome • Liver disease: cirrhosis

2a. Hyperlipidemia/Dyslipidemia – Pathophysiology

• Excess cholesterol accumulates in arterial walls → plaque formation → obstruction • Leads to MI, stroke/TIA, PVD • Primary genetic forms: defective LDL receptors, ApoB defects, ↑PCSK9 activity

2a. Hyperlipidemia/Dyslipidemia – Types

• Hyperlipidemia/dyslipidemia = umbrella term • Hypercholesterolemia = ↑LDL‑C • Hypertriglyceridemia = ↑TG • Primary (genetic) vs Secondary (acquired)

2a. Hyperlipidemia/Dyslipidemia – Clinical Presentation

• Usually asymptomatic • Rare findings: eruptive xanthomas, tendinous xanthomas, xanthelasma

2a. Hyperlipidemia/Dyslipidemia – Workup

• Lipid panel • CMP, A1C • Additional labs: Lp(a), hs‑CRP, ApoB, ApoA1 • ASCVD 10‑yr risk estimator • CAC score

2a. Hyperlipidemia/Dyslipidemia – Diagnosis

• Based on abnormal lipid panel values (TC, LDL‑C, HDL‑C, TG) • Consider secondary causes • Consider genetic forms if severe or early onset

2a. Hyperlipidemia/Dyslipidemia – Management

• Lifestyle: diet, weight loss, exercise, smoking cessation • Statins = first‑line • Add‑ons: ezetimibe, PCSK9 inhibitors, bempedoic acid • TG‑specific: omega‑3, fibrates • Bile‑acid sequestrants, niacin

2a. Hyperlipidemia/Dyslipidemia – Complications

• ASCVD: MI, stroke/TIA, PVD

2a. Hyperlipidemia/Dyslipidemia – Prognosis

• Improved with LDL lowering • Secondary prevention requires aggressive therapy

2b. Hypertriglyceridemia – Risk Factors

• Uncontrolled diabetes • Hypothyroidism • Oral estrogens • Lifestyle contributors (diet, alcohol)

2b. Hypertriglyceridemia – Pathophysiology

• Excess TG accumulation • In familial form: LPL enzyme unable to break down TG‑rich chylomicrons

2b. Hypertriglyceridemia – Types

• Severe: ≥1000 mg/dL • Moderate–Severe: 500–999 mg/dL • Moderate: 150–499 mg/dL • Normal <150 mg/dL

2b. Hypertriglyceridemia – Clinical Presentation

• Often asymptomatic • Very high TG (>1000 mg/dL): eruptive xanthomas possible • Familial form: hepatosplenomegaly in children

2b. Hypertriglyceridemia – Workup

• Fasting lipid panel • Evaluate secondary causes (DM, hypothyroidism, medications)

2b. Hypertriglyceridemia – Diagnosis

• Based on TG thresholds (≥150 mg/dL) • Severe ≥1000 mg/dL

2b. Hypertriglyceridemia – Management

• Address modifiable factors (DM, hypothyroidism, estrogens) • Lifestyle: weight loss 5–10%, reduce sugars/starches/fats, limit alcohol • Pharmacotherapy: omega‑3 fatty acids (Vascepa, Lovaza), fibrates (fenofibrate, gemfibrozil) • Initiate treatment when TG >500 mg/dL

2b. Hypertriglyceridemia – Complications

• Pancreatitis (especially >1000 mg/dL)

2b. Hypertriglyceridemia – Prognosis

• Improved with TG lowering and lifestyle modification

2c. Metabolic Syndrome – Risk Factors

• Visceral obesity • Sedentary lifestyle • Smoking • Age • Menopause

2c. Metabolic Syndrome – Pathophysiology

• Obesity drives metabolic dysfunction • ↓Adiponectin → inflammation + insulin resistance • ↑Cytokines (TNF‑α, IL‑6) → systemic inflammation • ↑Lipolysis → ↑FFA → impaired glucose metabolism, insulin resistance, dyslipidemia • ↑PAI‑1 → prothrombotic state • ↑Angiotensin + Na retention + ↑SNS → hypertension

2c. Metabolic Syndrome – Types

• Not divided into types; defined by meeting ≥3 diagnostic criteria

2c. Metabolic Syndrome – Clinical Presentation

• Visceral obesity • Hypertension • Acanthosis nigricans (neck, axilla, groin; thickened/dark velvety skin)

2c. Metabolic Syndrome – Workup

• Identify metabolic abnormalities: dyslipidemia, hyperglycemia, elevated hs‑CRP • ECG for cardiac risk

2c. Metabolic Syndrome – Diagnosis

Requires ≥3 of the following: • Waist circumference: Men >40 in, Women >35 in • TG ≥150 mg/dL • HDL: Men

2c. Metabolic Syndrome – Management

• Weight loss = cornerstone • Lifestyle: diet, physical activity, behavior modification • Pharmacotherapy for comorbidities: antihypertensives, statins, diabetes meds • Bariatric surgery when indicated

2c. Metabolic Syndrome – Complications

• ↑Risk of ASCVD, stroke, diabetes • Prothrombotic state • Systemic inflammation

2c. Metabolic Syndrome – Prognosis

• Improved with weight loss and risk‑factor modification

3. Identify and interpret diagnostic or therapeutic procedures used in management (lipid panel, Lipoprotein(a), CAC score)

Lipid Panel • Measures TC, LDL‑C, HDL‑C, TG • Used for screening, diagnosis, and monitoring • Repeat 4–12 weeks after starting/changing therapy, then every 3–12 months Lipoprotein(a) • One‑time screening recommended for individuals with personal or family history of premature ASCVD • Subfraction of LDL • Higher levels = higher CV risk ApoB / ApoA1 • ApoB = total number of atherogenic particles • ApoA1 = number of anti‑atherogenic particles • ApoB/ApoA1 ratio: higher = higher CV risk hs‑CRP • Marker of systemic inflammation; used in risk stratification Coronary Artery Calcium (CAC) Score • Non‑invasive CT measuring coronary calcium • Ordered in asymptomatic adults age 40–75 at intermediate ASCVD risk (7.5–<20%) when additional risk stratification is needed • Helps guide shared decision‑making for statin initiation CAC Limitations • Detects calcified plaque only (not stenosis) • May cause anxiety, incidental findings, radiation exposure, unnecessary testing

4. Identify, differentiate, and recognize the benefits of optimal lipid management in primary and secondary prevention of ASCVD

Primary Prevention • Goal: prevent first ASCVD event (MI, stroke/TIA, PVD) • Identify and reduce risk through lifestyle modification ± pharmacotherapy • LDL‑C goal: <100 mg/dL • Statins = first‑line therapy • ASCVD 10‑yr risk estimator guides statin initiation • CAC score used when risk is uncertain Secondary Prevention • Goal: prevent recurrent ASCVD events or progression of known disease • Requires aggressive lipid lowering therapy • LDL‑C goal: <70 mg/dL • Maximum tolerated statin recommended • Combination therapy (statin + ezetimibe and/or PCSK9 inhibitor) preferred over max‑dose statin alone when additional LDL reduction needed Benefits of Optimal Lipid Management • Reduces risk of MI, stroke/TIA, and PVD • Reduces progression of atherosclerotic plaque • Statins reduce LDL up to 50% and increase HDL up to 15% • Omega‑3 fatty acids (Vascepa) reduce acute CV events and CV death in hypertriglyceridemia

5. Recognize and identify factors used to calculate a cardiovascular risk score using the ACC/AHA ASCVD Risk Estimator and identify a treatment plan based on this calculation and AHA/ACC Guidelines

ASCVD Risk Estimator — Factors Used • Age 40–79 years • LDL‑C <190 mg/dL • No known ASCVD • Not on LDL‑lowering therapy • Non‑diabetic (for primary prevention calculation) • Lipid values: TC, LDL‑C, HDL‑C, TG • Blood pressure • Smoking status • Diabetes status (affects risk category but excluded from primary prevention calculator criteria) Risk Categories • <5% = Low risk • 5–<7.5% = Borderline risk • 7.5–<20% = Intermediate risk • ≥20% = High risk Treatment Based on Risk Category • Low risk (<5%): lifestyle modification • Borderline risk (5–<7.5%): lifestyle ± consider statin if risk enhancers present • Intermediate risk (7.5–<20%): lifestyle + consider statin; CAC score may guide decision • High risk (≥20%): initiate statin therapy Additional Risk Enhancers • PMH: diabetes, HTN, obesity, systemic inflammatory conditions • FH of early ASCVD • Smoking, sedentary lifestyle • Labs: Lp(a), hs‑CRP, ApoB/ApoA1 • CAC score for further stratification

6. Recognize the risks of untreated/uncontrolled dyslipidemia syndromes

• Excess cholesterol accumulates in arterial walls → plaque formation • Leads to ASCVD, including MI, stroke/TIA, and peripheral vascular disease • Severe hypertriglyceridemia (>1000 mg/dL) → pancreatitis • Chronic systemic inflammation (via cytokines) contributes to metabolic dysfunction • Progression of known ASCVD without aggressive lipid lowering • Increased long‑term cardiovascular morbidity and mortality

7. Recognize the definition of obesity and identify the different classifications of obesity

Definition • Chronic disease of energy intake > energy expenditure → excessive adipose tissue • Defined as BMI ≥ 30 kg/m² • Prevalence: 40.3% of U.S. adults; ~19.7% of children (CDC 2020) • Obesity rates have tripled since 1970s (15% → >40%) Classifications (BMI = weight kg / height m²) • Healthy: 18.5–24.9 • Overweight: 25–29.9 • Class I obesity: 30–34.9 • Class II obesity: 35–39.9 • Class III obesity: ≥40 Additional Notes • BMI limitation: does not distinguish lean vs non‑lean mass or adipose distribution • Waist circumference better predicts obesity‑related health risks: Men ≥40 in, Women ≥35 in

8. Identify the risk factors, basic pathophysiology, general etiology, medical evaluation, treatment options, and health consequences of obesity

Risk Factors • Visceral obesity • Sedentary lifestyle • High‑calorie/processed food intake • Sleep deprivation • Psychosocial factors • Genetics/family history • Age, menopause Basic Pathophysiology • Chronic energy intake > expenditure → adipose accumulation • Adipose tissue becomes hormonally abnormal • ↑Cytokines (TNF‑α, IL‑6) → systemic inflammation • ↓Adiponectin → insulin resistance, HTN, DM, prothrombotic state • Leptin resistance → impaired satiety • ↑FFA → insulin resistance and chronic inflammation • ↑Angiotensinogen → vasoconstriction, Na retention → hypertension General Etiology • Behavioral: diet, inactivity • Physiologic: appetite hormone dysregulation (leptin, ghrelin, PYY, GLP‑1) • Endocrine/metabolic contributors • Genetic predisposition Medical Evaluation • History: onset, weight changes, FH, sleep, diet, exercise, psychosocial factors • Physical exam: BMI, waist circumference, adipose distribution • Screen for comorbidities: HTN, diabetes, dyslipidemia, fatty liver, sleep apnea, MSK issues, depression/anxiety Treatment Options • Lifestyle modification (cornerstone): caloric restriction, Mediterranean diet, avoid processed foods, physical activity (150 min/wk moderate or 75 min vigorous), resistance training • Behavior therapy, dietitian involvement • Pharmacotherapy: BMI ≥30 or ≥27 with comorbidities; includes orlistat, phentermine, phentermine/topiramate, naltrexone/bupropion, GLP‑1 agonists (liraglutide, semaglutide, tirzepatide) • Bariatric surgery: BMI ≥40 or ≥35 with comorbidities; gastric sleeve, RYGB; requires long‑term follow‑up and supplements Health Consequences • >200 obesity‑related conditions • Insulin resistance, diabetes • Hypertension • Dyslipidemia • Fatty liver • Sleep apnea • MSK disorders • Increased systemic inflammation • Increased cardiovascular risk

9. Given a clinical scenario, appropriately diagnose and recommend treatments and/or managements of obesity

Diagnosis (based on file criteria) • BMI ≥30 kg/m² = obesity • Classify as Class I (30–34.9), Class II (35–39.9), Class III (≥40) • Waist circumference: Men ≥40 in, Women ≥35 in → visceral obesity • Evaluate for obesity‑related comorbidities (HTN, DM, dyslipidemia, fatty liver, sleep apnea, MSK issues, depression/anxiety) Management (based on file) • Lifestyle modification = cornerstone – Caloric restriction, avoid processed foods – Mediterranean diet – Physical activity: 150 min/wk moderate or 75 min vigorous + resistance training – Behavior counseling; dietitian involvement • Pharmacotherapy (BMI ≥30 or ≥27 with comorbidities; after unsuccessful lifestyle attempts) – Orlistat – Phentermine – Phentermine/topiramate – Naltrexone/bupropion – GLP‑1 agonists: liraglutide, semaglutide, tirzepatide • Bariatric surgery – BMI ≥40 or ≥35 with comorbidities – Gastric sleeve or Roux‑en‑Y gastric bypass – Requires long‑term follow‑up and vitamin/iron supplementation Additional Clinical Considerations • 5–10% weight loss significantly reduces obesity‑related conditions • Obesity is a chronic, relapsing disease • Stopping GLP‑1 agents leads to weight regain (~9.7 kg within months to a year) • RYGB: median weight regain ~20–25% of initial loss by 5–6 years

10. Given a clinical scenario, appropriately diagnose and recommend treatments and/or managements of the disorders listed above

General Diagnostic Approach (from file) • Use lipid panel to diagnose dyslipidemia or hypertriglyceridemia • Use ASCVD 10‑yr risk estimator for primary prevention decisions • Consider CAC score for intermediate‑risk adults (7.5–

Dyslipidemia

• Umbrella term for lipid abnormalities in total cholesterol, LDL-C, triglycerides (TG), or HDL-C

Hyperlipidemia

• General term for elevated lipid levels in blood

Hypercholesterolemia

• Elevated LDL-C levels

Hypertriglyceridemia

• Elevated triglyceride levels

Cholesterol

• Waxy, fat-like lipid essential for body functions • Sources: majority from liver, some from diet

ASCVD (Atherosclerotic Cardiovascular Disease)

• Excess cholesterol accumulates in arterial walls forming plaques • Obstructs blood flow, increasing risk of MI, stroke/TIA, and PVD • Leading cause of death in the US

Endogenous Cholesterol Production

• Cholesterol synthesized in liver via Mevalonate pathway • Rate-limiting enzyme: HMG-CoA reductase • Regulated by SREBPs (Sterol Regulatory Element-Binding Proteins)

Cholesterol Synthesis Regulation

• SREBPs are major regulatory proteins • HMG-CoA reductase activity increases when cholesterol levels are low

Exogenous Cholesterol Metabolism

• Cholesterol from diet absorbed via NPC1L1 in small intestine • Chylomicrons transport triglycerides • Lipoprotein lipase (LPL) breaks down chylomicrons into free fatty acids for storage or energy

Lipoproteins

• Cholesterol transport vehicles in blood • Four main types: Chylomicrons, VLDL, LDL, HDL • Differ by lipid composition and function

Apolipoproteins

• Proteins on lipoprotein surface directing lipid transport and metabolism • ApoB: atherogenic (LDL-C) • ApoA-1: anti-atherogenic (HDL-C)

Apolipoproteins

• Proteins on lipoprotein surface directing lipid transport and metabolism • ApoB: atherogenic (LDL-C) • ApoA-1: anti-atherogenic (HDL-C)

Reverse Cholesterol Transport

• Process of cholesterol excretion via HDL-C • ABCA1: transporter removing cholesterol from peripheral tissues • ApoA1: carries cholesterol to liver for excretion • LCAT: converts cholesterol into esters for excretion

Primary Dyslipidemia

• Genetic origin • Familial Hypercholesterolemia: marked LDL increase • Familial Chylomicronemia: marked TG increase

Familial Hypercholesterolemia

• Heterozygous: LDL-C 2–3× normal, early adult ASCVD • Homozygous: LDL-C up to 8× normal, pediatric ASCVD • Pathophysiology: absent/defective LDL receptors, ApoB defect, increased PCSK9 activity

Familial Chylomicronemia

• Very high TG (>1000 mg/dL) • LPL enzyme unable to break down TG-rich chylomicrons • Clinical findings: hepatosplenomegaly, ↑ pancreatitis risk

Secondary Dyslipidemia

• Acquired causes • Lifestyle: high-fat diet, sedentary, alcohol • Medications: OCP, diuretics, β-blockers, steroids • Underlying conditions: diabetes, hypothyroidism, Cushing’s, PCOS, CKD, liver disease

Clinical Manifestations of Dyslipidemia

• Often asymptomatic • Rare signs: eruptive xanthomas (TG >1000 mg/dL), tendinous xanthomas (Achilles, patellar), xanthelasma (cholesterol deposits around eyes)

Eruptive Xanthomas

• Reddish-yellow pruritic papules on buttocks or pressure-sensitive surfaces • Associated with TG >1000 mg/dL

Tendinous Xanthomas

• Fatty deposits appearing as yellow-orange, smooth, firm bumps on tendons (Achilles, patellar, hands)

Xanthelasma

• Yellow, soft to solid cholesterol deposits under the skin around the eyes

AHA/ACC Lipid Screening Guidelines (2018)

• Pediatric: once between ages 9–11 and again at 17–21 • Consider as early as age 2 if genetic dyslipidemia suspected • Adults: ≥20 years; frequency depends on CV risk

USPSTF Lipid Screening Guidelines (2016)

• Screen adults ≥20 only if CV risk factors present (DM, HTN, obesity, family history, tobacco) • Men: start at 35 without risk factors • Women: start at 30–35 without risk factors • Repeat every 5 years for low-average risk

ASCVD Risk Assessment

• Primary prevention: prevent first CV event • Secondary prevention: reduce recurrence or progression of ASCVD • Risk enhancers: diabetes, HTN, obesity, smoking, family history

ASCVD Risk Estimator

• Tool for 40–79 y/o without ASCVD • LDL <190 mg/dL, non-diabetic • Risk categories: <5% low, 5–<7.5% borderline, 7.5–<20% intermediate, ≥20% high

Coronary Artery Calcium (CAC) Score

• Non-invasive CT measuring calcium in coronary arteries • Used for intermediate-risk adults (40–75 y/o) to guide statin initiation • Limitations: detects calcified plaque only, radiation exposure, cost, incidental findings

LDL-C Therapeutic Range (AHA/ACC)

• Maximum tolerated statin recommended to reduce CV events • LDL goal: <100 mg/dL for primary prevention • LDL goal: <70 mg/dL for secondary prevention

Nonpharmacologic Treatment

• Lifestyle changes for all patients • Dietary: low cholesterol, low saturated fat, high fiber, Mediterranean diet • Weight management • Physical activity • Smoking cessation • Clinical pearl: weight loss, smoking cessation, and aerobic exercise help raise HDL

Pharmacologic Treatment

• Statins: first-line therapy for all-cause hyperlipidemia • Ezetimibe: cholesterol absorption inhibitor • PCSK9 inhibitors • Bempedoic acid • Omega-3 fatty acids: TG only • Fibrates: TG only • Bile-acid sequestrants • Niacin

Statins

• MOA: HMG-CoA reductase inhibitor, decreases cholesterol production, improves LDL receptor sensitivity • First-line for primary and secondary prevention • Effects: up to 50% LDL reduction, up to 15% HDL increase • Adverse effects: myalgia (common), arthralgia, hepatotoxicity, rare rhabdomyolysis

Additional Lipid Therapy

• Add-on if statin results suboptimal or statin intolerance • Non-statin options: Ezetimibe, PCSK9 inhibitors, Bempedoic acid, Omega-3 fatty acids (TG only), Fibrates (TG only), Bile acid sequestrants, Niacin

Hypertriglyceridemia

• TG classification: – Severe: ≥1000 mg/dL – Moderate to severe: 500–999 mg/dL – Moderate: 150–499 mg/dL – Normal:

Hypertriglyceridemia Treatment

• Address modifiable factors: uncontrolled DM, hypothyroidism, oral estrogens • Lifestyle: weight loss (5–10%), reduce sugars, refined starches, saturated/trans fats, limit alcohol • Pharmacotherapy: Omega-3 fatty acids (Vascepa, Lovaza), Fibric acid derivatives (Fenofibrate, Gemfibrozil)

Monitoring Treatment (ACC/AHA)

• Fasting lipid panel 4–12 weeks after starting/changing dose • Repeat every 3–12 months as clinically indicated

Clinical Pearls

• LDL target: <100 mg/dL low risk, <70 mg/dL high risk with ASCVD • Lifestyle modifications essential • Statin: first-line for LDL-C reduction • Combo therapy (statin + ezetimibe/PCSK9) preferred over max dose statin • Omega-3 fatty acids (Vascepa) best for CV event and death risk reduction

ASCVD Risk Assessment – Case 1

• 55-year-old man, no PMH, non-smoker, BP 130/80 • Labs: TC 220, LDL-C 140, HDL-C 35, TG 120 • Hesitant to start medication – requires risk calculation and lifestyle counseling

ASCVD Risk Assessment – Case 2

• 55-year-old man with diabetes, non-smoker • Same lipid profile as Case 1 • Diabetes increases ASCVD risk – pharmacologic therapy strongly advised

Obesity

• Chronic disease: energy intake > energy expenditure • Excess adipose tissue • Defined by BMI ≥30 kg/m² • Prevalence: ~40.3% adults, ~19.7% children (CDC 2020) • Rates tripled since 1970s

Etiology of Obesity

• Multifactorial: genetics, environment, lifestyle • Increased caloric intake, sedentary behavior, hormonal influences

Appetite Regulation

• Controlled by GI hormones, adipokines, and CNS signals • Balance between orexigenic and anorexigenic neurons in hypothalamus

Key Appetite Hormones

• Leptin (adipocytes): suppresses appetite • Ghrelin (stomach): increases hunger • Insulin (pancreas): suppresses appetite • Peptide YY (small intestine): promotes satiety • GLP-1: promotes satiety, slows gastric emptying

Adipose Tissue / Adipokines

• Adipose tissue acts as endocrine organ • Secretes adipokines regulating appetite, lipid metabolism, insulin sensitivity, BP, inflammation, coagulation, fertility • Dysregulation contributes to obesity-related comorbidities

Obesity Pathophysiology

• Satiety deregulation → increased caloric intake • Processed foods blunt satiety center • High sugar/fat/salt combinations activate dopamine reward center • Adipocytes increase in size and number • Adipose tissue becomes hormonally abnormal, driving metabolic disease

Consequences of Excess Adipose Tissue

• ↑ cytokines (TNF-α, IL-6) → systemic inflammation • ↓ adiponectin → insulin resistance, hepatic gluconeogenesis, HTN, prothrombotic state • Development of leptin resistance → impaired satiety • ↑ free fatty acids → insulin resistance and chronic inflammation • ↑ angiotensinogen → vasoconstriction, Na retention → hypertension

Medical Evaluation of Obesity

• History: age of onset, recent weight changes, family history, sleep patterns, eating/exercise habits, prior weight loss attempts, psychosocial factors • Physical: BMI, waist circumference (better predictor of risk), adipose distribution

Obesity Classifications

• Healthy: BMI 18.5–24.9 • Overweight: BMI 25–29.9 • Class I: BMI 30–34.9 • Class II: BMI 35–39.9 • Class III: BMI ≥40 • Limitation: BMI does not distinguish lean vs fat mass or adipose distribution

Visceral Obesity Measurement

• Waist circumference predicts heart disease and diabetes risk • Women ≥35 in, Men ≥40 in

Screening for Weight-Related Conditions

• Hypertension, diabetes, dyslipidemia, fatty liver, sleep apnea, musculoskeletal complaints, depression/anxiety

Treatment Goals

• Set realistic short- and long-term goals • Patient education • 5–10% weight loss significantly reduces obesity-related conditions • Greater weight loss = greater reduction in comorbidities

Obesity Treatment

• Lifestyle modifications: cornerstone of management • Behavior therapy and dietitian support • Pharmacotherapy for BMI ≥30 or ≥27 with comorbidities • Bariatric surgery for BMI ≥40 or ≥35 with comorbidities

Lifestyle Modification

• Patient-centered approach • Dietary: avoid processed foods, caloric restriction, Mediterranean diet • Physical activity: 150 min/week moderate or 75 min vigorous exercise • Resistance training + cardio • Behavior counseling

Modifiable Factors Affecting Appetite Hormones

• High-fat diet and obesity → leptin insensitivity (drives hunger) • High-protein diet → ↓ ghrelin, ↑ PYY (suppresses hunger) • Sleep deprivation → ↑ ghrelin, ↓ PYY (increases hunger)

Pharmacotherapy for Obesity

• Indicated if BMI ≥30 or ≥27 with comorbidities and lifestyle changes fail • FDA-approved drugs: – Orlistat (Xenical, Alli) – Phentermine (Adipex-P) – Phentermine/Topiramate (Qsymia) – Naltrexone/Bupropion (Contrave) – GLP-1 agonists: Liraglutide (Saxenda), Semaglutide (Wegovy), Tirzepatide (Zepbound)

Bariatric Surgery

• Significant and sustainable weight loss (up to 30% in first year) • Indicated for BMI ≥40 or ≥35 with comorbidities after failed lifestyle/pharmacotherapy • Common procedures: Gastric Sleeve, Roux-en-Y Gastric Bypass • Requires long-term follow-up and vitamin supplementation

Additional Facts

• SELECT trial: semaglutide reduces major CV events by up to 20% • Obesity is a chronic relapsing disease • Stopping GLP-1 drugs leads to ~9.7 kg weight regain within months to a year • Post-bariatric surgery: median weight regain ~20–25% of initial loss by 5–6 years

Metabolic Syndrome

• Combination of metabolic irregularities increasing risk of ASCVD, stroke, and diabetes • Prevalence: ~1 in 3 adults (~35%) in U.S. • Risk factors: visceral obesity, sedentary lifestyle, smoking, age, menopause

Diagnostic Criteria for Metabolic Syndrome

• Requires ≥3 of the following: – Waist circumference: Men >40 in, Women >35 in – TG ≥150 mg/dL – HDL-C: Men

Pathophysiology of Metabolic Syndrome

• Obesity dominates risk factor • ↓ adiponectin → inflammation and insulin insensitivity • ↑ cytokines (TNF-α, IL-6) → systemic inflammation • ↑ lipolysis → ↑ FFAs → impaired glucose metabolism, ↓ insulin sensitivity, promotes dyslipidemia • ↑ PAI-1 → prothrombotic state • ↑ angiotensin and Na, ↑ SNS activity → hypertension

Clinical Features

• Visceral obesity • Hypertension • Acanthosis Nigricans: thickened, dark velvety skin in axilla, groin, neck due to insulin resistance

Diagnostic Workup

• Focus on identifying metabolic abnormalities • Bloodwork: dyslipidemia, hyperglycemia, elevated hs-CRP • Cardiac risk assessment: ECG

Treatment and Prevention

• Address multiple risk factors simultaneously • Weight loss: cornerstone of treatment • Lifestyle modifications: diet, physical activity, behavior changes • Pharmacotherapy for comorbidities: antihypertensives, statins, diabetes meds • Bariatric surgery for severe cases

Metabolic Syndrome Recap

• Combination of insulin resistance, visceral obesity, ↓ HDL-C, ↑ TG, and hypertension • Significantly increases risk of CV disease and diabetes • Strongest risk factors: obesity, atherogenic diet, physical inactivity • Lifestyle interventions reduce risk • Multifactorial approach targeting dyslipidemia, BP, and hyperglycemia