Endocrine

GLP-1 receptor agonists for obesity treatment

Clinical Overview and When to Suspect Obesity Requiring GLP-1 Therapy

— BMI ≥30 kg/m² (Class I obesity or higher), OR

— BMI ≥27 kg/m² with at least one weight-related comorbidity (T2DM, prediabetes, HTN, dyslipidemia, OSA, MASLD, CVD, osteoarthritis, PCOS)

— Patients should also be enrolled in a comprehensive lifestyle intervention (≥500 kcal/day deficit, ≥150 min/week activity, behavioral counseling)

— Failed ≥6 months of structured lifestyle change with <5% weight loss

— Comorbidities worsening despite optimized therapy (e.g., A1c creeping up, BP requiring intensification)

— Patient seeks pharmacotherapy and has realistic expectations

— Semaglutide 2.4 mg: ~15% mean total body weight loss (TBWL)

— Tirzepatide 15 mg: ~21% TBWL

— Liraglutide 3 mg: ~8% TBWL

Step 3 management: In the ambulatory clinic, do not start a GLP-1 RA before documenting BMI, comorbidity profile, contraindication screen (personal/family MTC, MEN2, pancreatitis history, gastroparesis, pregnancy plans), and a counseled lifestyle plan — chart all four or the question will offer a "lifestyle first" distractor.

GLP-1 receptor agonists (GLP-1 RAs) are incretin mimetics that promote satiety, delay gastric emptying, and reduce caloric intake; semaglutide 2.4 mg SC weekly (Wegovy) and tirzepatide (dual GIP/GLP-1, Zepbound) are FDA-approved specifically for chronic weight management.

Indications (AACE/Endocrine Society/Obesity Medicine guidelines):

When to suspect a patient is a candidate at the Step 3 visit:

Expected efficacy at 68 weeks (head-to-head meta-data):

Mechanism beyond appetite: central hypothalamic POMC activation, slowed gastric emptying, modest ↑ insulin/↓ glucagon (glucose-dependent → low hypoglycemia risk as monotherapy).

Cardiometabolic halo: SELECT trial showed semaglutide 2.4 mg reduced MACE 20% in patients with established CVD and BMI ≥27 without diabetes — a major Step 3 talking point for shared decision-making.

Presentation Patterns and Key History

— Weight trajectory: age of onset, max/min adult weight, prior pharmacotherapy (phentermine, orlistat, bupropion-naltrexone), bariatric surgery history

— Eating behavior: binge-eating disorder (consider lisdexamfetamine), night eating, emotional eating — refer for CBT alongside GLP-1

— GI history: gastroparesis, severe GERD, recurrent pancreatitis, IBD, cholelithiasis — all relative or absolute contraindications

— Endocrine red flags: personal or family history of medullary thyroid carcinoma (MTC) or MEN2 = absolute contraindication (boxed warning from rodent C-cell tumors)

— Reproductive: pregnancy plans within 2 months → defer or discontinue; counsel that GLP-1s may reduce oral contraceptive absorption (especially tirzepatide → use barrier method or non-oral contraception for 4 weeks after initiation and each dose escalation)

— Psychiatric: screen for depression, suicidality (FDA reviewed signal — no causal link confirmed but document baseline PHQ-9)

— Substance: heavy alcohol use → ↑ pancreatitis risk

— Concurrent sulfonylurea or insulin → reduce dose 20–50% before starting to avoid hypoglycemia

— Warfarin, levothyroxine, phenytoin — delayed gastric emptying may alter absorption; recheck INR/TSH at 4–6 weeks

Board pearl: A vignette mentioning "chronic diarrhea, flushing, and family history of pheochromocytoma" is screening you for MEN2A — do not prescribe a GLP-1 RA; check calcitonin and refer. Family history alone of MTC is enough to disqualify, regardless of the patient's own thyroid status.

Typical Step 3 vignette: 47-year-old woman, BMI 34, A1c 6.1%, BP 138/86, comes for "help with weight." She has tried Weight Watchers, Mediterranean diet, and a gym membership — lost 4 lb in a year. Asks about "the weekly shot."

History elements that change management:

Medication reconciliation pitfalls:

Physical Exam Findings and Pre-Treatment Assessment

— Height, weight, BMI, waist circumference (>102 cm men, >88 cm women = increased cardiometabolic risk independent of BMI)

— Neck circumference (>17 in men, >16 in women suggests OSA — screen with STOP-BANG)

— BP in appropriately sized cuff (undersized cuff = falsely elevated reading — common Step 3 trap)

— Resting HR — GLP-1 RAs cause a modest ↑ 2–4 bpm; baseline tachycardia warrants workup before initiation

— Orthostatics in elderly or those on antihypertensives

— Thyroid: palpate for nodules; any palpable nodule → ultrasound before GLP-1 initiation (though routine calcitonin screening is not recommended by AACE)

— Acanthosis nigricans, skin tags: insulin resistance markers

— Abdomen: hepatomegaly (MASLD), surgical scars (prior bariatric — efficacy preserved but titrate slower)

— Lower extremities: edema (right heart failure, venous insufficiency), joint exam for OA limiting activity

— Skin: striae, central adiposity, dorsocervical fat pad → screen for Cushing syndrome with overnight dexamethasone suppression if suspected before labeling as "primary obesity"

Key distinction: "Secondary obesity" mimics include hypothyroidism (check TSH), Cushing syndrome (24-h urine cortisol or dex suppression), hypothalamic obesity (post-cranial surgery/radiation), and medication-induced (atypical antipsychotics, glucocorticoids, insulin, gabapentinoids). Always exclude before committing to chronic GLP-1 therapy — the boards love the patient with central obesity, easy bruising, and proximal weakness who "just needs Wegovy."

Anthropometrics (document at every visit):

Vitals:

Targeted exam:

Mental status / affect: flat affect or anhedonia → PHQ-9 before adding any anorectic agent

Functional capacity: 6-minute walk or stair climb if surgical/bariatric referral may follow

Diagnostic Workup — Initial Labs and Baseline Evaluation

— CBC — baseline anemia screen

— CMP — Cr/eGFR, LFTs (ALT often elevated in MASLD), electrolytes

— A1c and fasting glucose — establishes diabetes/prediabetes status; reframes drug choice (Ozempic/Mounjaro labeling vs. Wegovy/Zepbound)

— Fasting lipid panel

— TSH — rule out hypothyroidism as obesity contributor

— Lipase — baseline if any abdominal symptoms or prior pancreatitis; not universally required but defensible

— Pregnancy test (β-hCG) in any person of reproductive potential

— MASLD workup: if ALT elevated or imaging shows steatosis → calculate FIB-4; if ≥1.3 (or ≥2.0 if age >65), refer or do elastography

— OSA: STOP-BANG ≥3 → polysomnography

— Cardiovascular: ASCVD risk calculator; ECG if ≥40 y/o or symptoms; consider coronary calcium score in borderline-risk patients

— Cushing screen if hypertension + central obesity + striae: 1 mg overnight dex suppression test

— Vitamin D, B12, iron studies — particularly post-bariatric patients restarting therapy

Step 3 management: Order the A1c, CMP, lipid, TSH, and pregnancy test panel at the same visit you discuss pharmacotherapy — don't make the patient return for a separate "lab visit" unless insurance authorization requires it. Document the 5 As (Ask, Assess, Advise, Agree, Assist) of obesity counseling in the note; some payers require documented behavioral counseling for prior authorization.

Required baseline labs before initiating a GLP-1 RA (ambulatory, fasting where applicable):

Risk-stratified add-ons:

Imaging: Not routine. Thyroid US only for palpable nodule. RUQ US if AST/ALT elevated to evaluate MASLD and exclude gallstones (baseline gallstone documentation matters because rapid weight loss ↑ cholelithiasis).

Diagnostic Workup — Advanced or Confirmatory Studies

— DXA quantifies fat mass, lean mass, visceral adipose tissue — useful in sarcopenic obesity (older adult with high BMI but low muscle mass) where unmonitored GLP-1 therapy can worsen sarcopenia

— Bioelectrical impedance acceptable in clinic for trending

— Early-onset severe obesity (<5 years), hyperphagia, family history → consider MC4R, LEPR, POMC, PCSK1 panel

— Patients with biallelic POMC, LEPR, or PCSK1 deficiency or Bardet-Biedl syndrome → setmelanotide (MC4R agonist), not GLP-1 RA, is first-line

— Cushing screening positive → late-night salivary cortisol ×2 + 24-h urine free cortisol; if confirmed, refer endocrine

— Suspected MEN2 → RET proto-oncogene testing

— Acromegaly: IGF-1 if coarse features, macroglossia, ring/shoe size changes

— Echocardiogram if HFpEF suspected (dyspnea + obesity + HTN) — STEP-HFpEF trial showed semaglutide improved KCCQ and 6MWD

— Coronary calcium or stress imaging if intermediate ASCVD risk and lifestyle decisions hinge on it

— FIB-4 ≥1.3 → transient elastography (FibroScan); if ≥8 kPa or LSM concerning → hepatology

— Resmetirom (THR-β agonist) approved for F2–F3 MASH, but GLP-1 RAs are increasingly used off-label and have strong trial data for hepatic outcomes

— If BMI ≥40 (or ≥35 with comorbidity) and patient is interested in surgery, GLP-1 RAs are NOT a substitute — co-management decision

Board pearl: A child or teen with BMI >140% of the 95th percentile, hyperphagia since infancy, and red hair = think POMC deficiency — order genetic testing and refer for setmelanotide, not semaglutide. This is a classic Step 3 "rare cause, right drug" stem.

Body composition (optional but increasingly board-relevant):

Genetic testing — when to order:

Endocrine confirmatory studies:

Cardiometabolic confirmatory:

MASLD staging:

Pre-bariatric crossover:

Risk Stratification and First-Line Management Logic

— Step 1: Lifestyle (always, always foundational) — 500–750 kcal/day deficit, Mediterranean or DASH pattern, 150–300 min/week moderate activity, behavioral therapy, sleep hygiene, stress management. Expect 3–5% TBWL in 6 months.

— Step 2: Add pharmacotherapy if BMI ≥30 or ≥27 with comorbidity AND lifestyle alone insufficient at 3–6 months

— Step 3: Intensify with combination therapy or switch agents if <5% TBWL at 12 weeks on maximum tolerated dose

— Step 4: Bariatric/metabolic surgery referral for BMI ≥40, or ≥35 with comorbidity (now ≥30 with T2DM per ASMBS/IFSO 2022)

— Tirzepatide (Zepbound): highest TBWL (~21%); preferred when maximal weight loss desired

— Semaglutide 2.4 mg (Wegovy): ~15% TBWL; preferred when established CVD (SELECT indication) or HFpEF

— Liraglutide 3 mg (Saxenda): daily injection, ~8% TBWL; option when weekly not feasible

— Naltrexone-bupropion, phentermine-topiramate, orlistat: alternatives when GLP-1 contraindicated, unavailable, or cost-prohibitive

— T2DM → semaglutide or tirzepatide (dual benefit)

— Established ASCVD → semaglutide (MACE reduction)

— HFpEF + obesity → semaglutide (STEP-HFpEF)

— CKD stage 3–4 + T2DM + obesity → semaglutide (FLOW trial: renal outcome benefit)

— Binge-eating disorder → lisdexamfetamine first

— Migraine + obesity → topiramate-containing regimen

Step 3 management: Set a 12-week response checkpoint. If TBWL <5% at maximally tolerated dose, discontinue or switch — continuing a non-responder wastes money and exposes the patient to side effects. Document this stop rule at initiation.

Step 3 stepwise approach to obesity in primary care:

Choosing among approved agents (rank order by efficacy and tolerability):

Comorbidity-driven selection:

Pharmacotherapy — First-Line Drug Regimens and Titration

— 0.25 mg weekly × 4 weeks → 0.5 mg × 4 → 1.0 mg × 4 → 1.7 mg × 4 → 2.4 mg maintenance

— If a dose is poorly tolerated, hold at current step for an extra 4 weeks before advancing

— Inject SC abdomen/thigh/upper arm, rotate sites

— 2.5 mg × 4 weeks → 5 mg × 4 → 7.5 mg × 4 → 10 mg × 4 → 12.5 mg × 4 → 15 mg maintenance

— Maintenance dose individualized: 5, 10, or 15 mg based on tolerability and goal

— Inject same day each week (can shift by ≤2 days for semaglutide/tirzepatide)

— Missed dose: if <5 days late (semaglutide) or <4 days (tirzepatide), take ASAP; otherwise skip

— Eat smaller, more frequent low-fat meals; stop eating at first satiety

— Hydrate (2–3 L/day) to prevent AKI from volume depletion

— Anti-emetic PRN (ondansetron) for first 2 weeks

— Nausea (40%), diarrhea (30%), vomiting, constipation, dyspepsia

— Injection-site reactions, fatigue, hair shedding (telogen effluvium from rapid weight loss)

— Rare: pancreatitis, gallbladder disease, ileus, NAION (recently flagged with semaglutide)

Board pearl: Stop GLP-1 RA ≥1 week before elective surgery/endoscopy (ASA 2023 guidance — weekly agents) due to retained gastric contents and aspiration risk; for daily agents, hold the day of procedure. This is the highest-yield perioperative pearl on current Step 3 exams.

Semaglutide 2.4 mg SC weekly (Wegovy) — titration over 16 weeks to minimize GI effects:

Tirzepatide SC weekly (Zepbound) — titration over ≥20 weeks:

Liraglutide 3 mg SC daily (Saxenda): 0.6 mg daily, ↑0.6 mg weekly to 3 mg

Counseling at every titration visit:

Adverse effects (dose-dependent, mostly GI):

Contraindications: personal/family MTC, MEN2, pregnancy, prior serious hypersensitivity, history of severe gastroparesis. Caution: pancreatitis history, severe GERD, retinopathy (rapid glucose drops in T2DM).

Expanded Pharmacology — Combination Therapy, Maintenance, and Off-Label Use

— GLP-1 RA + phentermine (short-term) for added appetite suppression — monitor BP, HR

— GLP-1 RA + SGLT2 inhibitor in T2DM — additive A1c, weight, CV, and renal benefits

— GLP-1 RA + metformin — first-line in T2DM with obesity; metformin neutral-to-modest weight effect

— Avoid combining two incretin-based agents (e.g., semaglutide + tirzepatide, or with DPP-4 inhibitor)

— STEP-4 and SURMOUNT-4 extension data: discontinuation → ~⅔ of weight regained within 1 year

— Obesity is chronic — counsel patients that GLP-1 RA is likely lifelong, similar to antihypertensives

— If patients must stop (cost, supply, pregnancy), intensify lifestyle and consider bridge with oral agents (naltrexone-bupropion, phentermine-topiramate)

— Retatrutide (triple GIP/GLP-1/glucagon agonist) — phase 3, ~24% TBWL

— Oral semaglutide 50 mg (Rybelsus, weight-loss dose in development)

— CagriSema (cagrilintide + semaglutide)

— Compounded GLP-1s — FDA has cautioned against; counsel patients on safety/quality risks

— Maintenance at lower dose (e.g., semaglutide 1.7 mg) may sustain weight loss in responders

— Oral contraceptives (tirzepatide): use non-oral or backup barrier for 4 weeks after start/dose escalation

— Insulin/sulfonylureas: reduce by 20–50% to prevent hypoglycemia

— Warfarin: recheck INR; delayed absorption may shift dosing

Step 3 management: When a patient on semaglutide 2.4 mg has plateaued at 8% TBWL and wants more, the right answer is usually switch to tirzepatide (higher efficacy ceiling) rather than add a second anorectic agent. Document failure on max tolerated dose to satisfy prior authorization.

Combination strategies (after suboptimal response on monotherapy):

Long-term maintenance:

Emerging/pipeline agents (board-aware):

Dose reduction strategies for cost/supply:

Drug–drug interactions:

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher risk of sarcopenic obesity — loss of lean mass with GLP-1 therapy worsens frailty, falls

— Mandatory resistance training (2–3×/week) and adequate protein intake (1.0–1.2 g/kg/day; up to 1.5 g/kg in those on caloric deficit)

— Slower titration; consider lower maintenance doses

— Monitor for dehydration (blunted thirst), AKI, orthostatic hypotension

— Polypharmacy review: reduce diuretics, antihypertensives, sulfonylureas, insulin proactively

— STEP-HFpEF and SELECT both showed benefits extending to older adults

— GLP-1 RAs are not renally dosed — no adjustment required

— Semaglutide safe down to eGFR ≥15; tirzepatide studied in mild–moderate CKD

— FLOW trial: semaglutide reduced kidney failure, ≥50% eGFR decline, and renal/CV death in T2DM with CKD by 24% — actively recommended in CKD + T2DM + obesity triad (KDIGO 2024)

— Risk: dehydration-induced prerenal AKI during GI side effects — hold dose, hydrate, recheck Cr

— Mild–moderate (Child-Pugh A–B): no adjustment

— Severe (Child-Pugh C): limited data — use with caution

— Patients with MASLD/MASH: GLP-1 RAs improve steatosis and may reduce fibrosis progression

— HFpEF + obesity: semaglutide improves symptoms (STEP-HFpEF), weight, NT-proBNP

— HFrEF: less robust data; not contraindicated but monitor diuretic needs as weight drops

Board pearl: In an 82-year-old on semaglutide for 6 months who reports a fall and "feeling weak climbing stairs," the right next step is to assess for sarcopenia (grip strength, gait speed, DXA lean mass) and intensify protein + resistance training, not necessarily stop the drug. Vague weakness ≠ stop the GLP-1 reflexively.

Elderly (≥65 years):

Chronic kidney disease:

Hepatic impairment:

Heart failure:

Special Populations — Pregnancy, Pediatrics, and Reproductive Health

— GLP-1 RAs are contraindicated in pregnancy — animal data show embryofetal harm; human data limited

— Discontinue ≥2 months before planned conception (semaglutide half-life ~1 week; full washout ~5 weeks)

— Tirzepatide: discontinue ≥1 month before conception (shorter half-life ~5 days, but cover 5 half-lives)

— Unintentional pregnancy on GLP-1: stop immediately, reassure (no proven teratogenicity), refer to MFM if high-risk

— Lactation: not recommended; molecule size suggests low milk transfer but no human data

— Tirzepatide reduces oral contraceptive AUC ~20% due to delayed gastric emptying

— Recommend non-oral contraception (IUD, implant, ring, patch, injection) OR add barrier method for 4 weeks after starting and after each dose escalation

— Semaglutide: smaller effect, but counsel similarly in patients relying solely on OCPs

— Liraglutide 3 mg approved for ages ≥12 with obesity (BMI ≥95th percentile)

— Semaglutide 2.4 mg approved for ages ≥12 (STEP TEENS: 16% TBWL difference vs. placebo)

— Tirzepatide: pediatric studies ongoing; not yet approved <18

— AAP 2023 guideline endorses pharmacotherapy at age ≥12 alongside intensive health behavior and lifestyle treatment (IHBLT); bariatric surgery considered ≥13

— Monitor growth, puberty, mental health (PHQ-A); document height velocity

— GLP-1 RAs improve weight, insulin resistance, ovulation, and menstrual regularity

— Counsel on fertility return — patients may conceive unexpectedly → reinforce contraception

Key distinction: Saxenda (liraglutide 3 mg) and Wegovy (semaglutide 2.4 mg) are pediatric-approved (≥12); Zepbound (tirzepatide) is NOT approved in pediatrics as of current labeling — a frequently tested distinction.

Pregnancy:

Contraception counseling:

Pediatrics:

PCOS:

Complications and Adverse Outcomes

— Nausea, vomiting, diarrhea, constipation, abdominal pain — manage with slow titration, small low-fat meals, hydration, anti-emetics

— Eructation, sulfur burps (especially tirzepatide)

— Acute pancreatitis: rare (<1%); persistent severe abdominal pain radiating to back → STOP drug, check lipase, imaging. Do not rechallenge after confirmed pancreatitis.

— Cholelithiasis/cholecystitis: rapid weight loss ↑ stone formation. RUQ pain + fever → US, surgical consult.

— Gastroparesis/severe gastric stasis: persistent vomiting, early satiety; may unmask in predisposed patients

— Ileus and bowel obstruction: FDA label update 2023; counsel on progressive constipation, distention

— AKI: prerenal from volume depletion during GI side effects

— Hypoglycemia: only when combined with insulin or sulfonylurea

— NAION (non-arteritic anterior ischemic optic neuropathy): rare signal with semaglutide — sudden painless monocular vision loss → ophthalmology

— Suicidality: FDA reviewed, no causal link, but monitor PHQ-9 in those with psychiatric history

— Diabetic retinopathy progression: rapid A1c drop in T2DM → dilated exam before initiation in patients with known retinopathy

— Thyroid C-cell tumors/MTC: rodent signal; human risk unconfirmed but contraindicated with MEN2/MTC history

— "Ozempic face" — facial volume loss from rapid fat loss; counsel and consider slower titration

— Hair shedding (telogen effluvium) — self-limited

— Loss of muscle mass — mitigate with protein + resistance training

CCS pearl: A patient on semaglutide presents with persistent vomiting, abdominal distention, and obstipation. Order: NPO, IV fluids, NG decompression, CT abdomen/pelvis, lipase, CMP, surgical consult. Hold the GLP-1. The diagnosis on your differential must include ileus and SBO, not just gastroparesis.

Common (GI, mostly first 8–12 weeks):

Serious and board-tested:

Cosmetic/functional:

Injection site: local reactions, lipohypertrophy → rotate sites

When to Escalate Care — Specialist Referral and Inpatient Triage

— Endocrinology/Obesity Medicine: BMI ≥40, multiple comorbidities, failed two pharmacotherapy trials, suspected secondary obesity, complex T2DM

— Bariatric surgery: BMI ≥40, or ≥35 with comorbidity, or ≥30 with T2DM (ASMBS 2022); GLP-1 RAs are bridge, not replacement

— Hepatology: FIB-4 ≥2.67, elastography ≥8 kPa, suspected MASH cirrhosis

— Cardiology: new HF symptoms, uncontrolled HTN, abnormal stress test

— Psychiatry/behavioral health: binge-eating disorder, severe depression, eating disorder history

— Ophthalmology: baseline retinopathy in T2DM before rapid A1c drop; new vision change on therapy

— Suspected pancreatitis: severe epigastric pain, vomiting, lipase >3× ULN → admit, NPO, IV fluids, hold GLP-1

— SBO or ileus: distention, obstipation, vomiting → CT, surgical evaluation

— Severe dehydration/AKI: Cr ↑, oliguria → IV fluids, hold drug

— DKA or HHS (in T2DM patients): if insulin was tapered too aggressively during GLP-1 initiation

— Acute cholecystitis: Murphy sign, fever, leukocytosis → surgical consult

— Anaphylaxis to injection: rare → ED, epinephrine, permanent discontinuation

— Patient on weekly GLP-1 RA presenting for surgery without holding ≥1 week → discuss with anesthesia; may proceed with full-stomach precautions (RSI, gastric US) or delay elective case

— Emergent surgery: proceed with aspiration precautions

Step 3 management: A patient hospitalized for any reason while on a GLP-1 RA → hold the drug during acute illness, NPO status, or anticipated procedures. Resume at discharge if appropriate; do not "skip a week" of titration logic — restart at the prior maintenance dose if interruption <2 weeks, otherwise re-titrate.

Outpatient referral indications:

ED/inpatient triage:

Perioperative escalation:

Key Differentials — Other Causes of Unintentional Weight Loss While On GLP-1

— Concomitant SGLT2 inhibitor or metformin — additive but expected

— Phentermine, bupropion, topiramate — appetite suppressants added by another clinician

— Stimulants (ADHD medications, illicit) — review med list

— Hyperthyroidism unmasked or new — check TSH if weight loss exceeds 1–1.5% TBWL/week, tachycardia, tremor

— Adrenal insufficiency — fatigue, hyponatremia, hyperkalemia

— Type 1 diabetes presenting late in adult on GLP-1 for "T2DM"

— Nonadherence (missed doses, improper storage — must be refrigerated 36–46°F until first use, then room temp ≤86°F for 56 days)

— Counterfeit or compounded product

— Hypothyroidism developing

— Cushing syndrome

— Antipsychotic or steroid use

— Sleep deprivation, OSA

— High alcohol or sugar-sweetened beverage intake

— Genetic causes (MC4R variants — partial response)

— H. pylori gastritis

— Celiac disease

— IBD

— Gallstones (often drug-related but workup needed)

— Functional dyspepsia

— Cyclic vomiting syndrome (especially with cannabis use)

Board pearl: A patient on stable semaglutide with new tachycardia, tremor, heat intolerance, and accelerated weight loss is not "responding extra well" — check TSH and free T4 to rule out hyperthyroidism. GLP-1s do not cause hyperthyroidism, and missing Graves disease here is the classic trap.

When a patient on a GLP-1 RA loses more weight than expected or unexpectedly, do not attribute it solely to the drug. Differentials within the metabolic/anorectic category:

When weight loss is inadequate despite max-dose GLP-1, consider:

GI symptom differentials (not all are drug-related):

Key Differentials — Other Categories of Obesity Pharmacotherapy

— Phentermine-topiramate ER (Qsymia): sympathomimetic + GABA modulator; ~9% TBWL; CI in pregnancy (teratogen — cleft palate), glaucoma, hyperthyroidism, MAOI use. Useful with migraine comorbidity.

— Naltrexone-bupropion (Contrave): ~5% TBWL; CI in seizure disorder, uncontrolled HTN, eating disorders, opioid use, MAOI. Useful with depression or smoking cessation needs.

— Orlistat (Xenical/Alli): GI lipase inhibitor; ~3% TBWL; steatorrhea, fat-soluble vitamin deficiency. CI in chronic malabsorption, cholestasis.

— Phentermine (short-term, ≤12 weeks per FDA; longer off-label): sympathomimetic; CI in CVD, uncontrolled HTN, hyperthyroidism, glaucoma, MAOI.

— Setmelanotide: MC4R agonist for genetic obesity (POMC, LEPR, PCSK1, Bardet-Biedl).

— Roux-en-Y gastric bypass (RYGB): 25–35% TBWL, best T2DM remission

— Sleeve gastrectomy: 20–30% TBWL, fewer nutritional complications, more GERD

— Adjustable gastric band: largely abandoned

— Duodenal switch: highest TBWL but highest complications

Key distinction: Phentermine-topiramate is the right answer when an obese patient also has chronic migraine (topiramate covers both). Naltrexone-bupropion is the right answer with comorbid depression or active smoking cessation (bupropion synergy). GLP-1 RAs remain first-line for T2DM, CVD, CKD, HFpEF, or MASLD comorbidities.

Non-GLP-1 FDA-approved chronic weight management drugs (know mechanism, niche, contraindications):

Metabolic/bariatric surgery (definitive for severe obesity):

Endoscopic options: intragastric balloon, endoscopic sleeve gastroplasty — 10–15% TBWL.

When NOT to start a GLP-1 (use alternative): MTC/MEN2 family history, severe gastroparesis, recurrent pancreatitis, pregnancy/planning, intolerance to prior incretin therapy, cost barrier without insurance coverage, genetic obesity syndromes (use setmelanotide).

Long-Term Plan — Secondary Prevention and Maintenance

— STEP-4 trial: stopping semaglutide after 20 weeks → regain ~⅔ of lost weight within 1 year

— SURMOUNT-4: stopping tirzepatide → 14% regain at 1 year

— Counsel patients pre-initiation: this is a long-term, likely lifelong therapy akin to antihypertensives

— Continue maintenance dose indefinitely if tolerated and effective

— Re-evaluate annually: BMI, comorbidities, side effects, cost, patient preference

— If patient must discontinue, taper while intensifying lifestyle and consider transition to another agent (oral phentermine-topiramate or naltrexone-bupropion) to mitigate regain

— As weight, A1c, BP, lipids improve, de-escalate antihypertensives, insulin, sulfonylureas, statins (per LDL goals)

— Re-evaluate sleep study after 10% TBWL — OSA may resolve

— Reassess MASLD with elastography at 1 year

— Vitamin D 800–1000 IU/day, calcium 1000–1200 mg/day from diet

— Resistance training 2–3×/week

— Protein 1.0–1.5 g/kg/day

— DXA every 2 years in postmenopausal women with substantial weight loss

Board pearl: A patient on semaglutide who has lost 18% body weight and whose A1c dropped from 8.2 to 5.8 should have their insulin and sulfonylurea tapered or stopped to avoid hypoglycemia, but continue the GLP-1 RA — the drug is doing the work, and stopping it is the wrong answer.

Conceptualize obesity as a chronic relapsing disease:

Maintenance strategy:

Co-management of comorbidities (de-prescribing opportunities):

Bone health and sarcopenia prevention:

Cardiovascular secondary prevention (if established ASCVD): high-intensity statin, antiplatelet, BP <130/80, semaglutide as MACE-reducing agent per SELECT

Cancer screening: reaffirm age-appropriate screening (colon, breast, cervical, lung) — obesity-related cancer risk drops with sustained weight loss

Follow-Up, Monitoring Parameters, and Counseling Cadence

— Initiation visit: baseline labs, counseling, prescribe starter dose, schedule 4-week f/u

— Every 4 weeks during titration (in person or telehealth): tolerance, side effects, BP, HR, weight, dose escalation decision

— 12-week checkpoint: assess TBWL — if <5%, reconsider therapy

— Every 3 months for first year: weight, BP, HR, A1c (if diabetic), CMP, symptom review

— Every 6 months after stable maintenance: weight, comorbidity labs, mental health screen

— Annually: lipid panel, A1c, TSH, comprehensive review, age-appropriate cancer screening

— Weight, BMI, waist circumference, BP, HR

— GI symptoms, hydration, urinary output

— Hypoglycemia symptoms (if on insulin/SU)

— Mental health (PHQ-9, GAD-7 — at least every 6 months)

— Adherence and injection technique

— Medication reconciliation

— Protein priority (lean meats, legumes, dairy) — 1.0–1.5 g/kg/day

— Resistance training 2–3×/week + 150 min aerobic

— Sleep ≥7 hours

— Hydration ≥2 L/day

— Limit alcohol (potentiates GI side effects, pancreatitis risk)

— Smaller portion sizes; stop at first satiety

— Refer to RD for medical nutrition therapy (covered by Medicare for obesity)

— Group programs, CBT for emotional eating, app-based tracking

— Intensive Behavioral Therapy (IBT) for obesity: Medicare covers 22 visits in 12 months in primary care setting

Step 3 management: The 12-week, 5% TBWL stop rule is the single most testable cadence point — at the 12-week visit, if a patient on max-tolerated GLP-1 dose has <5% TBWL, discontinue or switch agents. Document this in your initial plan to set expectations.

Visit schedule (ambulatory cadence):

Monitoring parameters at each visit:

Lifestyle counseling — reinforce at every visit:

Behavioral support:

Ethical, Legal, and Patient Safety Considerations

— Chronic, likely lifelong therapy with weight regain on discontinuation

— Boxed warning: thyroid C-cell tumors (rodent data) — patient acknowledges no personal/family MTC or MEN2

— Risks: pancreatitis, gallbladder disease, ileus, AKI, NAION, retinopathy progression

— Pregnancy contraindication and need for contraception (especially with tirzepatide and OCPs)

— Perioperative aspiration risk — patient must inform all providers and surgeons

— Prescribing semaglutide/tirzepatide to a non-obese patient (BMI <27) for cosmetic weight loss is off-label, ethically problematic, and may violate insurance contracts

— Counsel patients seeking the drug for non-medical reasons; document refusal if appropriate

— FDA-issued warnings about compounded semaglutide/tirzepatide due to dosing errors, contamination, salt forms (semaglutide sodium/acetate not FDA-approved)

— Document counseling against compounded products when FDA-approved versions are available

— Cost ~$1,000–1,350/month without insurance — significant access disparity

— Step therapy and prior authorizations common — advocate with documentation

— Medicare Part D historically excluded obesity drugs; recent expansion for CV indication (semaglutide in SELECT-eligible patients)

— At hospital admission, document GLP-1 use prominently — anesthesia, surgery, endoscopy must know

— At discharge, reconcile: hold during acute illness, resume on schedule, re-titrate if interrupted >2 weeks

— Communicate dose changes to PCP and pharmacy in writing

— Report serious adverse events to FDA MedWatch (suspected pancreatitis, NAION, ileus)

— Pediatric prescribing: document parental consent and adolescent assent

Board pearl: The Step 3 ethics stem: a healthy-weight patient (BMI 23) requests semaglutide for "a wedding." The correct response is to decline, explain why, address body image concerns, and screen for eating disorder — not to prescribe, even if the patient pays cash.

Informed consent essentials (document explicitly):

Off-label and cosmetic prescribing:

Compounded GLP-1s:

Equity and access:

Transition-of-care safety:

Mandatory reporting / safety signals:

High-Yield Associations and Rapid-Fire Clinical Facts

— GLP-1 = incretin from L-cells; ↑ glucose-dependent insulin, ↓ glucagon, ↓ gastric emptying, ↑ satiety

— Tirzepatide = dual GIP + GLP-1 agonist

— Retatrutide (investigational) = triple GIP + GLP-1 + glucagon

— STEP trials → semaglutide for obesity (STEP-1 through STEP-TEENS, STEP-HFpEF)

— SURMOUNT trials → tirzepatide for obesity

— SELECT → semaglutide CV outcomes in non-diabetic CVD patients

— FLOW → semaglutide renal outcomes in T2DM + CKD

— SUSTAIN, PIONEER → semaglutide T2DM trials

— LEADER → liraglutide CV outcomes (T2DM)

— Semaglutide 2.4 mg → ~15% TBWL at 68 wks

— Tirzepatide 15 mg → ~21% TBWL at 72 wks

— Liraglutide 3 mg → ~8% TBWL at 56 wks

— Lifestyle alone → 3–5% TBWL

— Bariatric surgery (RYGB) → 25–35% TBWL

— BMI ≥30 OR ≥27 with comorbidity → pharmacotherapy eligible

— 12-week, 5% TBWL stop rule

— Hold weekly GLP-1 ≥1 week before elective surgery

— Stop ≥2 months before planned pregnancy

— Daily protein 1.0–1.5 g/kg + resistance training to prevent sarcopenia

Key distinction: Wegovy = semaglutide 2.4 mg for obesity; Ozempic = semaglutide up to 2 mg for T2DM. Same molecule, different labeled doses and indications — boards distinguish them.

Mechanism rapid-fire:

Trial-name pearls:

Numbers worth memorizing:

Threshold pearls:

Boxed warning: medullary thyroid carcinoma (rodent), MEN2 → contraindication

Synergy partners: SGLT2i, metformin (in T2DM); avoid stacking with DPP-4 inhibitors

NAION: newer safety signal with semaglutide — vision change → ophthalmology

Common pitfall: failing to reduce insulin/sulfonylurea at initiation → hypoglycemia

Storage: refrigerate until first use; pens stable at room temp ≤86°F for 56 days (semaglutide) / 21 days (tirzepatide post-first-use varies)

Board Question Stem Patterns

Step 3 management: When two answer choices look right (lifestyle vs. drug), pick the one matching the time horizon in the stem. "6 months of lifestyle, plateau" → drug. "First visit, never tried lifestyle" → lifestyle + behavioral referral, not drug.

Pattern 1 — The candidate selection stem: 45 y/o woman, BMI 32, prediabetes (A1c 6.0), HTN, has done 6 mo of lifestyle with 3% weight loss. No personal/family thyroid cancer. → Initiate semaglutide 2.4 mg weekly with titration (eligible by BMI ≥27 + comorbidities).

Pattern 2 — The contraindication stem: Patient requests semaglutide; mother had MTC at age 50. → Do not prescribe; offer alternative (phentermine-topiramate or naltrexone-bupropion) or bariatric referral.

Pattern 3 — The perioperative stem: Patient on tirzepatide presents for elective cholecystectomy tomorrow; took last dose 4 days ago. → Postpone elective case (need ≥1 week hold) OR proceed with full-stomach/aspiration precautions per anesthesia.

Pattern 4 — The pregnancy stem: Patient on semaglutide reports positive pregnancy test. → Stop immediately, reassure, refer to OB; no proven teratogenicity but contraindicated in pregnancy.

Pattern 5 — The complication stem: Patient on semaglutide × 6 weeks with severe epigastric pain radiating to back, lipase 950. → Acute pancreatitis: admit, NPO, IVF, hold drug, do not rechallenge.

Pattern 6 — The non-response stem: Patient on semaglutide 2.4 mg × 12 weeks, TBWL 3%, tolerating well. → Switch to tirzepatide or escalate strategy; do not continue indefinitely.

Pattern 7 — The hypoglycemia stem: Patient on insulin + sulfonylurea + new semaglutide develops hypoglycemia. → Reduce/discontinue sulfonylurea first, then taper insulin.

Pattern 8 — The contraception stem: Woman on OCPs starts tirzepatide. → Add barrier method or switch to non-oral contraception for 4 weeks after start and each dose escalation.

Pattern 9 — The pediatric stem: 14 y/o BMI 38 after 6 mo of IHBLT, no response. → Liraglutide 3 mg or semaglutide 2.4 mg (FDA-approved ≥12); not tirzepatide.

Pattern 10 — The CV outcomes stem: 58 y/o BMI 28, prior MI, no diabetes. → Semaglutide 2.4 mg (SELECT trial: MACE reduction in CVD + overweight/obese non-diabetics).

One-Line Recap

GLP-1 receptor agonists (semaglutide 2.4 mg, tirzepatide, liraglutide 3 mg) are first-line pharmacotherapy for chronic obesity in adults with BMI ≥30 or ≥27 with a weight-related comorbidity, delivering 8–21% sustained weight loss when combined with lifelong lifestyle intervention, while requiring vigilance for thyroid (MTC/MEN2) contraindications, perioperative aspiration risk, pregnancy washout, and the 12-week/5% response checkpoint.

Board pearl: The single most-tested integration point on Step 3 is the perioperative hold — a patient on a weekly GLP-1 RA presenting for elective surgery without a ≥1-week medication pause is an aspiration risk, and the correct management is to either postpone the elective case or proceed with full-stomach precautions and anesthesia consultation. Memorize this rule; expect it in surgery, GI, and primary care contexts on the same exam.

Eligibility: BMI ≥30 OR ≥27 + comorbidity + ≥3–6 mo lifestyle trial; document the 5 As of counseling.

Agent choice: tirzepatide for maximal weight loss; semaglutide 2.4 mg for CVD (SELECT), HFpEF (STEP-HFpEF), or CKD+T2DM (FLOW); liraglutide if weekly impractical or pediatric.

Safety non-negotiables: contraindicated in MTC/MEN2 personal or family history and in pregnancy; hold weekly agents ≥1 week before elective surgery/endoscopy; reduce sulfonylureas and insulin at initiation; counsel on contraception (especially tirzepatide + OCPs).

Long-term frame: obesity is chronic — discontinuation → ⅔ regain; plan lifelong therapy with annual reassessment, protein + resistance training to prevent sarcopenia, and de-prescribing of antihypertensives, insulin, and sulfonylureas as comorbidities improve.