Pharm: Anti-Obesity Medications

Correlate Objective Set 11/12

Mechanism of Action

• Phentermine: Sympathomimetic; increases norepinephrine release → appetite suppression. - Orlistat: Inhibits gastric/pancreatic lipases → prevents triglyceride absorption. - Phentermine/topiramate: Combines sympathomimetic effect with appetite suppression and satiety enhancement. - Naltrexone/bupropion: Bupropion activates anorexigenic neurons; naltrexone blocks auto-inhibition by β-endorphin. - GLP-1 agonists (liraglutide, semaglutide): Mimic GLP-1 → increase insulin secretion, slow gastric emptying, reduce food intake. - GLP-1/GIP agonists (tirzepatide): Same as GLP-1 plus GIP agonism → enhanced insulin sensitivity, greater appetite suppression.

Therapeutic Indications

• Chronic weight management as adjunct to reduced-calorie diet and increased physical activity. - Some GLP-1 agents also indicated for Type 2 diabetes (Ozempic®, Mounjaro®).

Common Side Effects

• Phentermine: Dry mouth, headache, insomnia, irritability, ↑BP/HR. - Orlistat: GI issues—oily stools, fecal urgency, steatorrhea. - Phentermine/topiramate: Same as phentermine + paresthesia, dysgeusia. - Naltrexone/bupropion: Nausea, constipation, headache, dizziness, insomnia. - GLP-1/GIP agonists: Nausea, diarrhea, constipation, abdominal pain, heartburn.

Significant Adverse Effects

• Phentermine: CV risk (↑BP/HR), contraindicated in CV disease. - Orlistat: Malabsorption, drug interactions. - GLP-1/GIP agonists: Pancreatitis, gallbladder disease; contraindicated in medullary thyroid carcinoma or MEN2.

Route of Administration

• Phentermine, Orlistat, Naltrexone/bupropion: Oral. - GLP-1/GIP agonists: Subcutaneous injection weekly.

Precautions/Contraindications

• Phentermine: CV disease, hyperthyroid, glaucoma, MAOI use. - Orlistat: Chronic malabsorption, cholestasis. - Naltrexone/bupropion: Opioid use, seizure disorder. - GLP-1/GIP agonists: Personal/family history of medullary thyroid carcinoma or MEN2.

Limiting Factors

• Cost (GLP-1/GIP agonists very expensive). - Insurance coverage often limited. - Side effects (GI intolerance, psychiatric concerns).

Drug Interactions

• Orlistat: Levothyroxine, cyclosporine. - Naltrexone/bupropion: Opioid agonists.

Toxicity

• No detailed toxicity data provided beyond adverse effects and contraindications.

Administration

• Phentermine: Oral, once or twice daily depending on dose. - Orlistat: Take with each main meal containing fat; skip if meal is missed or fat-free. - Phentermine/topiramate: Once daily; titrate after 2 weeks. - Naltrexone/bupropion: Titrate up to two tablets twice daily. - GLP-1/GIP agonists: Subcutaneous injection weekly; rotate sites (abdomen, thigh, upper arm); store refrigerated but can remain at room temp for limited time.

Side Effects Counseling

• GI issues common with Orlistat and GLP-1 agonists; advise on managing oily stools and nausea. - CNS effects possible with phentermine/topiramate; monitor mood changes. - Naltrexone/bupropion may cause insomnia and dizziness; take precautions.

Side Effect Management

• For Orlistat: Use low-fat diet to reduce GI symptoms; take multivitamin with fat-soluble vitamins separated by 2 hours. - For GLP-1 agonists: Start low and titrate slowly to minimize nausea; monitor for pancreatitis symptoms.

Monitoring

• Track weight loss progress and waist circumference. - Monitor vital signs (BP, HR) for sympathomimetics. - Watch for hypoglycemia in patients with diabetes. - Assess mood changes and suicidal thoughts for GLP-1 agonists.

Factors Affecting Compliance

• Cost: GLP-1/GIP agonists are very expensive ($1,200–$1,600/month); oral agents like phentermine are cheaper ($40–$60/month). - Insurance Coverage: Medicare generally does not cover AOMs; Medicaid and commercial coverage vary. - Side Effects: GI intolerance (Orlistat, GLP-1 agonists), CNS effects (phentermine/topiramate), psychiatric concerns. - Limited Patient Education: Need counseling on administration, titration, and monitoring. - Cultural/Social Factors: Lifestyle adherence and stigma around obesity treatment.

Selection Criteria

• BMI and Obesity Class: AOMs considered if BMI ≥30 or ≥27 with comorbidities; GLP-1/GIP agonists for severe obesity or CV risk. - Comorbidities: GLP-1 agonists preferred for patients with CV disease or diabetes; avoid sympathomimetics in CV disease or uncontrolled hypertension. - Renal/Hepatic Function: No specific dose adjustments noted, but monitor for adverse effects. - Cost and Coverage: Phentermine is low-cost; GLP-1/GIP agonists are high-cost and often require insurance or coupons. - Age/Ethnic Factors: Not specifically addressed in slides. - Concurrent Medications: Avoid Orlistat with levothyroxine/cyclosporine; avoid Naltrexone/bupropion with opioids or seizure disorders.

Treatment Goals

• Achieve and maintain clinically meaningful weight loss (≥5% of baseline within 12 weeks at max dose). - Reduce obesity-related comorbidities (CV disease, diabetes risk). - Support long-term weight management through lifestyle modification.

Treatment Approaches

• Lifestyle Therapy (LT): Reduced-calorie healthy meal plan + physical activity + behavioral interventions for all BMI categories. - Pharmacotherapy (AOMs): Add if LT fails or concurrently for BMI ≥30 or ≥27 with comorbidities. - GLP-1/GIP agonists: Preferred for severe obesity or CV risk; injectable weekly with titration. - Monitoring: Weight, waist circumference, vital signs, comorbidities, mental health.

Treatment Selection

• For BMI ≥30 or ≥27 with comorbidities: Initiate AOM if lifestyle therapy fails or concurrently for higher classes of obesity. - GLP-1/GIP agonists (e.g., semaglutide, tirzepatide) preferred for patients with CV risk or severe obesity. - Avoid sympathomimetics (phentermine, phentermine/topiramate) in patients with CV disease, uncontrolled hypertension, or psychiatric instability.

Recommended Monitoring

• Weight loss progress (including waist circumference). - Vital signs: BP and HR for sympathomimetics. - Blood glucose for patients with diabetes (risk of hypoglycemia). - Mental health: monitor for depression or suicidal thoughts with GLP-1 agonists. - Side effects: GI symptoms, pancreatitis signs, gallbladder issues.

Clinical Importance

• No specific mention of serum concentration monitoring for anti-obesity medications in the presentation. - Monitoring focuses on clinical parameters: weight loss progress, vital signs, blood glucose, and mental health status.

Recommended Adjustments

• No adjustments based on serum drug levels provided. - Dose titration for GLP-1/GIP agonists is based on adverse effect tolerance, not serum concentration.

Hypertension

• Avoid sympathomimetics (phentermine, phentermine/topiramate) in patients with hypertension or CV disease due to risk of ↑BP/HR.

Obesity

• GLP-1/GIP agonists (semaglutide, tirzepatide) preferred for severe obesity or CV risk. - Orlistat for patients who prefer oral therapy and have GI tolerance. - Phentermine for short-term use if cost is a barrier and no CV contraindications.

Potential New Agents in Pipeline

• Oral semaglutide (50mg). - Oral orforglipron (GLP-1 RA). - Semaglutide + cagrilintide (GLP-1 + amylin analogue). - Survodutide (Glucagon/GLP-1 RA). - Retatrutide (GIP/GLP-1/Glucagon agonist).

Patient Case Recommendation

• Consider GLP-1 agonist (semaglutide) for patient with CV risk and BMI 28.4 if insurance allows. - If cost/coverage is an issue, phentermine may be used short-term with monitoring. - Counsel on side effects (GI, BP changes) and monitor weight, vitals, and mental health.

FDA Labeled Indications for AOMs

• Chronic weight management as adjunct to reduced-calorie diet and increased physical activity for adults with BMI ≥30 or ≥27 with comorbidities.

Anti-Obesity Medications Overview

• Presented by Maggie Randazzo, PharmD, BCPS.

The Anti-Obesity Medication Journey

• 1997/1998: Fenfluramine/Phenylpropanolamine (FenPhen) → serotonergic activation/sympathomimetic; problems: cardiac valvopathy, pulmonary HTN, stroke. - 1999: Leptin → leptin-receptor agonist; limited weight loss. - 2003: Ephedrine/caffeine + Ma Huang → sympathomimetic; problems: MI/strokes. - 2007: Ecopipam → dopamine agonist; suicidality. - 2008: Tesofensine → triple monoamine reuptake inhibitor; hypertension. - 2010: Capsinoids → thermogenesis; limited effectiveness. - 2011: Sibutramine (Meridia®) → serotonin/norepi reuptake inhibitor; CV disease/strokes. - 2012: Lorcaserin (Belviq®) → serotonin receptor agonist; increased cancer risk.

Current Management of Obesity

• Lifestyle therapy first: healthy meal plan + physical activity. - Add anti-obesity medications (AOMs) if lifestyle therapy fails or concurrently for higher BMI classes.

Obesity Classification & Guideline Recommendations

• Underweight: BMI <18.5. - Healthy weight: BMI 18.5–24.9 → healthy meal plan + physical activity. - Overweight: BMI 25–29.9 → lifestyle therapy (LT). - Obesity: BMI ≥30 → LT + AOM if LT fails. - Class 1: BMI 30–34.9 → LT + AOM if target not met; consider concurrent initiation. - Class 2: BMI 35–39.9 → LT + AOM concurrently; consider bariatric surgery. - Class 3: BMI ≥40 → LT + AOM concurrently; consider bariatric surgery.

Current AOM Landscape

• Orlistat (Xenical®, Alli®). - Phentermine/topiramate (Qsymia®). - Phentermine (Adipex-P®). - Naltrexone/bupropion (Contrave®). - GLP-1/GIP agonists.

General AOM Considerations

• Avoid in pregnancy. - Use caution in diabetes (risk of hypoglycemia). - Use caution in hypertension (BP drops possible). - Avoid in active eating disorders. - Discontinue if <5% weight loss after 12 weeks at max dose. - Avoid combining AOMs. - Monitor weight, vitals, and lifestyle adherence.

Phentermine (Adipex-P®, Lomaira®)

• Mechanism: sympathomimetic; ↑ norepinephrine → appetite suppression. - Dosing: oral once or twice daily. - Side effects: nausea, constipation, dry mouth, headache, insomnia, irritability, ↑BP/HR. - Contraindications: CV disease, hyperthyroid, glaucoma, MAOI use, drug abuse history. - Controlled substance (Schedule IV); short-term use only.

Orlistat (Xenical®, Alli®)

• Mechanism: inhibits gastric/pancreatic lipases → prevents triglyceride absorption. - Dosing: with each main meal containing fat; skip if meal missed or fat-free. - Side effects: oily stools, flatus with discharge, fecal urgency, steatorrhea. - Contraindications: chronic malabsorption, cholestasis. - Requires multivitamin with fat-soluble vitamins (A, D, E, K) separated by 2 hours. - Drug interactions: levothyroxine, cyclosporine.

Phentermine/Topiramate ER (Qsymia®)

• Mechanism: phentermine (sympathomimetic) + topiramate (appetite suppression, satiety enhancement). - Dosing: once daily; titrate after 2 weeks. - Side effects: same as phentermine + paresthesia, dysgeusia, mood changes. - Contraindications: same as phentermine. - Important: CNS effects (cognitive dysfunction, psychiatric disturbances) higher with rapid titration.

Naltrexone/Bupropion (Contrave®)

• Mechanism: bupropion activates anorexigenic neurons; naltrexone blocks β-endorphin auto-inhibition. - Dosing: titrate up to two tablets twice daily. - Side effects: nausea, constipation, headache, dizziness, insomnia, ↑BP/HR. - Contraindications: opioid use, seizure disorder. - Important: consider in patients with depression or smoking cessation goals; opioid-free period required before starting.

Insurance Coverage/Cost (Non-GLP-1 AOMs)

• Orlistat: $400–$600/month; GoodRx coupon $207.55; Medicare: NO; Medicaid: Maybe; some commercial coverage. - Phentermine: $40–$60/month; GoodRx coupon $17.77; similar coverage limitations. - Phentermine/topiramate: $200–$300/month; coupon $149.10; manufacturer savings available. - Naltrexone/bupropion: $700–$800/month; manufacturer savings available.

GLP-1/GIP Agonists

• Liraglutide (Saxenda®) 2014. - Semaglutide (Wegovy®) 2021. - Tirzepatide (Zepbound®) 2023.

GLP-1 Agonist Mechanism of Action

• Long-acting analogs of GLP-1 (incretin hormone). - Increase glucose-dependent insulin secretion. - Decrease inappropriate glucagon secretion. - Decrease hepatic glucose output. - Increase beta-cell growth/replication. - Slow gastric emptying. - Decrease food intake.

GLP-1/GIP Agonist Mechanism of Action

• Same as GLP-1 agonists PLUS: - Agonism of GIP pathways. - Enhanced insulin sensitivity. - Greater appetite suppression. - Reduced adverse effects.

General GLP-1/GIP Agonist Considerations

• Administration: injectable (subcutaneous) once weekly. - Dosing: start low, titrate slowly based on adverse effects. - Monitoring: weight loss progress, waist circumference, side effects, comorbidities. - Side effects: abdominal pain, constipation (11–24%), diarrhea (19–30%), nausea (28–44%), heartburn; pancreatitis, gallbladder disease. - Contraindications: personal/family history of medullary thyroid carcinoma or MEN2.

Semaglutide (Wegovy®)

• Same active ingredient as Ozempic® and Rybelsus®. - Wegovy®: FDA-approved for chronic weight management. - Available as autoinjector in multiple strengths (0.25mg–2.4mg). - Store refrigerated; room temp up to 28 days uncapped. - Inject abdomen, thigh, or upper arm weekly; any time of day; built-in needle.

Evidence: Semaglutide (SELECT Trial)

• Patients: overweight/obese + CV disease. - Design: multicenter, double-blind, randomized, placebo-controlled. - Outcome: semaglutide reduced major adverse CV events by 20% (HR 0.80). - Paved way for Medicare coverage for Wegovy® for CV risk patients.

Tirzepatide (Zepbound®)

• Same active ingredient as Mounjaro®. - FDA-approved for chronic weight management. - Autoinjector doses: 2.5mg–15mg. - Store refrigerated; room temp up to 21 days uncapped. - Inject abdomen, thigh, or upper arm weekly; built-in needle.

Evidence: Tirzepatide (SURMOUNT-MMO Trial)

• Patients: overweight/obese + CV disease or risk factors. - Design: multicenter, double-blind, randomized, placebo-controlled. - Outcome: pending; study closes in 2027.

Weight Loss % Comparison

• GLP-1/GIP agonists show highest weight loss compared to other AOMs (visual chart provided in slides).

Insurance Coverage/Cost: GLP-1 RAs

• Liraglutide: $1600/month; manufacturer savings reduce cost to $30 or less with commercial insurance. - Semaglutide: $1600/month; coupon reduces to $650 uninsured; as little as $0 with commercial insurance. - Tirzepatide: $1275/month; coupon reduces to $650 uninsured; as little as $25 with commercial insurance.

Psychiatric Concerns/Side Effects

• Mental illness and obesity share pathogenic pathways. - Reports of suicidal thoughts with GLP-1 agonists; preliminary evaluation shows lack of evidence. - FDA recommends monitoring for depression, suicidal thoughts, mood changes.

Compounded GLP-1s

• FDA shortage resolved; compounded drugs are not FDA-approved. - Adverse events reported: 346 with compounded semaglutide; 136 with compounded tirzepatide. - FDA plans enforcement against unapproved compounding pharmacies.

Discontinuation of GLP-1s

• Significant weight regain after stopping semaglutide. - Strategies: slow dose down-titration, lifestyle program enrollment, consider restarting GLP-1 RA if rapid regain occurs.

Pipeline Agents

• Oral semaglutide (50mg): 12.7% weight loss. - Oral orforglipron (GLP-1 RA): 14.7% weight loss. - Semaglutide + cagrilintide (GLP-1 + amylin analogue): 17% weight loss. - Survodutide (Glucagon/GLP-1 RA): 14.9% weight loss. - Retatrutide (GIP/GLP-1/Glucagon agonist): 24% weight loss.

Medications That Can Increase Weight

• TZDs (pioglitazone, rosiglitazone): fluid retention, increased subcutaneous fat mass. - Sulfonylureas (glimepiride, glipizide, glyburide): increase insulin release → increased glucose absorption (converted to fat). - Insulin: increased glucose absorption → converted to fat. - Glucocorticoids: increase cortisol → increase glucose → increase insulin. - TCAs (amitriptyline, nortriptyline): increased appetite, interfere with metabolism. - Mirtazapine: increased appetite. - Atypical antipsychotics (olanzapine, clozapine, quetiapine, risperidone): significantly contribute to insulin resistance. - Lithium: increased appetite/metabolic effects. - Valproic acid: increased appetite/metabolic effects.

Patient Case

• 53-year-old female with hyperlipidemia, hypertension, smoker; BMI 28.4; BP 134/82; ASCVD risk: 8.6% (10-year), 50% (lifetime). - Medications: amlodipine, valsartan/HCT, spironolactone, rosuvastatin, aspirin. - Labs: TC 170, TG 182, HDL 54, LDL 110, HbA1c 5.8. - Reports DASH diet adherence and moderate exercise. - Inquiring about AOM. - Questions: Is AOM appropriate? Which AOM to start? What if insurance coverage is an issue? What side effects to counsel? How to manage side effects? What is follow-up monitoring?