414.3 🩺 內科專科考前版

414.3.0.1 📌 䞀頁重點

  • 22E:
    • Setmelanotide (Imcivree, FDA 2020) for MC4R pathway monogenic obesity (POMC, LEPR, BBS)
    • GLP-1 + tirzepatide transforming obesity treatment
    • Retatrutide triple agonist (GLP-1+GIP+glucagon) phase 3 — ~24% weight loss
    • Cagrilintide + semaglutide combo (REDEFINE) — amylin agonist + GLP-1
    • Survodutide (GLP-1 + glucagon) phase 3
    • Bardet-Biedl + Alström + setmelanotide approved for syndromic
  • Taiwan: 國健眲 obesity 蚈畫; 健保 metformin/GLP-1/SGLT2 條件 (DM); 健保 phentermine 條件; 健保 orlistat; tirzepatide/setmelanotide/retatrutide 自費 倚

414.3.0.2 🌟 Pearls (10)

  1. Adaptive thermogenesis after weight loss — RMR drops more than expected; persistent hunger
  2. Bariatric surgery alters multiple hormones (ghrelin ↓ via sleeve, GLP-1 ↑ via RYGB) → biological resetting beyond restriction
  3. Microbiome + obesity: emerging therapeutic target (FMT trials, prebiotics)
  4. Sleep < 6 hr → leptin ↓ + ghrelin ↑ → ↑ appetite
  5. Cortisol-driven visceral obesity: chronic stress + iatrogenic
  6. MC4R: heterozygous mutation = severe; homozygous very severe
  7. POMC mutation: red hair + adrenal insufficiency + obesity
  8. Setmelanotide MC4R agonist: bypass mutation upstream pathway
  9. Brown adipose tissue (BAT) activation: emerging therapeutic (cold exposure, mirabegron, irisin); not yet clinically used for obesity
  10. Childhood obesity programming: in-utero + early-life exposure influences lifetime risk

414.3.0.3 📍 Taiwan + 健保

414.3.0.3.1 國健眲
  • 體重 / BMI 國民健康調查
  • Childhood / adolescent obesity prevention 蚈畫
  • WC 量枬暙準 (Asian)
414.3.0.3.2 Drugs
  • 健保 metformin
  • 健保 GLP-1 RA (CV/CKD/DM 條件)
  • 健保 SGLT2 (CV/CKD 條件)
  • 健保 phentermine (短期, 條件)
  • 健保 orlistat
  • 健保 naltrexone-bupropion 自費 倚
  • Tirzepatide (Mounjaro/Zepbound) 自費 倚 / 條件 expanding
  • Setmelanotide (Imcivree) 自費 (rare 眕病)
  • Liraglutide (Saxenda) 自費 倚
414.3.0.3.3 Surgery
  • 健保 bariatric BMI ≥ 37.5 (or 32.5 + comorbidity, NHIA 2020)
  • 健保 sleeve gastrectomy + RYGB
414.3.0.3.4 孞會 + 指匕
  • TES + DAROC + Taiwan Obesity Society + Taiwan Bariatric & Metabolic Surgery Society
  • AACE 2024 Obesity
  • ADA 2026
  • WHO

414.3.0.4 🎓 內專必懂 (10)

  1. Energy balance + set point biology
  2. Hunger / satiety hormone circuits
  3. Hypothalamic POMC/AgRP/NPY/MC4R pathway
  4. Visceral vs subcutaneous adipose
  5. Adipokine biology
  6. Genetic + syndromic obesity + setmelanotide
  7. Drug-induced obesity recognition
  8. Microbiome + sleep + stress contributions
  9. BAT therapeutic potential (research)
  10. 22E new: setmelanotide expansion, GLP-1/tirzepatide/retatrutide paradigm shift

414.3.0.5 ⚙ MC4R Pathway (內專)

Leptin (from adipose) crosses BBB
    ↓
Activates POMC neurons in arcuate nucleus
    ↓
POMC cleaved → α-MSH
    ↓
α-MSH binds MC4R in paraventricular nucleus
    ↓
↓ Appetite + ↑ Energy expenditure

Inhibitory pathway (parallel):
AgRP from arcuate → MC4R antagonist → ↑ Appetite

Mutations causing obesity:
- LEPR mutation: leptin signal blocked
- POMC mutation: no α-MSH (also hypoadrenal, red hair)
- MC4R mutation: receptor not respond
- LEP mutation: no leptin (very rare)
- All result in inadequate satiety signal

Setmelanotide (FDA 2020):
- MC4R agonist
- Bypasses upstream mutations (acts directly on MC4R)
- Approved for: POMC, LEPR, BBS, MC4R+ (some)
- SC daily; weight loss + hunger reduction substantial

414.3.0.6 ⚙ GLP-1 + GIP + Glucagon Pharmacology (內專)

Hormone Effects:
- GLP-1: ↑ insulin (glucose-dependent), ↓ glucagon, ↓ gastric emptying, ↑ satiety, ↓ food reward
- GIP: ↑ insulin, ↑ adipose lipolysis (in lean), neuroprotective; controversial direct adipose effect
- Glucagon: ↑ energy expenditure, ↑ lipolysis, ↑ hepatic glucose (counter-regulatory)

Drug Combinations:
- GLP-1 alone: semaglutide (~ 15% weight)
- GIP+GLP-1: tirzepatide (~ 20%)
- GLP-1+glucagon (survodutide): in trials
- GLP-1+GIP+glucagon (retatrutide): ~ 24% in trials
- Amylin+GLP-1 (cagrilintide+semaglutide / CagriSema, REDEFINE): emerging
- Setmelanotide (MC4R agonist): for monogenic

Mechanism for Weight Loss:
- Direct hypothalamic appetite suppression
- Slower gastric emptying
- Reward pathway modulation (less food preference)
- Some metabolic effects (energy expenditure, glucose, lipid)

Side Effects (Class):
- GI: nausea, vomiting, diarrhea, constipation (most prominent)
- Pancreatitis (rare; class warning)
- Gallbladder (gallstones, cholecystitis)
- MTC risk (rodent; family Hx MEN2 contraindication)
- Sleep apnea improvement (with weight)
- Cardiovascular: improvements in trials
- Diabetic retinopathy: rapid HbA1c drop concern

414.3.0.7 ⚙ Bariatric Biology (内專)

Procedure-specific physiologic effects:

Roux-en-Y Gastric Bypass (RYGB):
- Restriction (small pouch) + malabsorption (bypass duodenum + jejunum)
- ↑ GLP-1, PYY, GIP (via accelerated nutrients to ileum)
- ↓ Ghrelin (sometimes)
- T2DM remission ~ 60-80%
- Weight loss ~ 25-30%
- Risks: dumping syndrome, hypoglycemia, vitamin/mineral deficiencies, anastomotic leak/stricture
- DEXA, B12, iron, Ca/D supplementation lifelong

Sleeve Gastrectomy (LSG):
- Restriction (75-80% stomach removed)
- ↓ Ghrelin (significant due to fundal removal)
- ↑ GLP-1 (some)
- Less malabsorption
- Most common procedure now
- T2DM remission ~ 50-60%
- Weight loss ~ 20-25%
- Risks: GERD worsening, leak

Adjustable Band:
- Restriction only
- Less effective long-term
- Less common now
- Reversible

Biliopancreatic Diversion (BPD)/Duodenal Switch:
- Aggressive malabsorption
- For severe / failed primary surgery
- High risk vitamin def

Endoscopic options:
- Intragastric balloon (temporary)
- Endoscopic sleeve gastroplasty
- Less invasive but less weight loss

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