Nutrition and Metabolism Quiz

Pharmacotherapy in Obesity

• Obesity pharmacotherapy involves using medications to manage obesity.
• Early drug approvals focused on efficacy, not risk-benefit analyses. This changed in 1962.
• Several amphetamine derivatives for weight loss were removed from the market due to safety concerns.
• Recently approved medications face stricter regulations and clinical efficacy standards.

BMI and All-Cause Mortality

• A systematic review and meta-analysis of 230 cohort studies (with 3.74 million deaths among 30.3 million participants) examined the relationship between BMI and mortality.
• The analysis revealed a non-linear dose-response relationship.
• A nadir of relative risk was observed at BMIs between 23 and 24 for never smokers and 20 to 22 for longer follow-up periods.

History of Anti-Obesity Medications

• Initial drug approvals (1940s) only required demonstration of efficacy exceeding placebo.
• Desoxyephedrine's approval in 1947 led to numerous amphetamine derivatives for weight loss.
• Due to subsequent safety concerns, many amphetamine derivatives have been removed from the market.
• Modern regulations require stringent safety evaluation and proof of clinical efficacy for new anti-obesity medications.

Recently Recalled Anti-Obesity Medications

• Sibutramine (Meridia): Removal due to increased risk of cardiovascular events in high-risk patients.
• Lorcaserin (Belviq): Removal following a safety analysis that indicated an increased incidence of certain cancers.

FDA-Approved Medications for Weight Management

• Nine FDA-approved anti-obesity medications (AOMs) remain on the market.
• Six approved for long-term weight loss, one of which targets specific monogenic obesity mutations.
• Another is a "device" that functions as a medication.

Approved for Short-Term Use

• Phentermine (Adipex, Lomaira): Sympathomimetic to suppress appetite.
• Diethylpropion (Tenuate): Sympathomimetic to suppress appetite.

Approved for Long-Term Use

• Orlistat (Alli, Xenical): Inhibits intestinal lipase, reducing fat absorption.
• Phentermine-topiramate (Qsymia): Combination of sympathomimetic and carbonic anhydrase inhibitor to decrease appetite and binge eating.
• Bupropion-naltrexone (Contrave): A combination of dopamine and norepinephrine reuptake inhibitor along with mu-opioid receptor antagonist.
• Liraglutide 3.0mg (Saxenda): GLP-1 receptor agonist to decrease appetite, increase fullness, and satiety.
• Gelesis100 (Plenity): Superabsorbent hydrogel particles of cellulose-citric acid matrix that increase fullness.
• Setmelanotide (Imciveree): Melanocortin-4-receptor agonist to decrease appetite.
• Semaglutide 2.4mg (Wegovy): GLP-1 receptor agonist that reduces hunger and increases satiety.

Safety and Side Effects – Orlistat

• Side effects include fatty/oily stools, fecal urgency, oily spotting, increased defecation, and fecal incontinence.
• Orlistat may reduce absorption of fat-soluble vitamins (A, D, E, and K).
• Possible side effects are liver failure, oxalate nephropathy, and nephrolithiasis.
• The medication's mechanism may include unabsorbed fat producing calcium soaps, reducing calcium availability, and increasing renal oxalate excretion leading to supersaturation of oxalate in renal tubules and possibly kidney stones.

Safety and Side Effects (General)

• Many AOMs have potential side effects including nausea, vomiting, abdominal pain, diarrhea, dizziness, dry mouth, constipation, insomnia, anxiety, injection site reactions, skin darkening, sexual dysfunction, and depression.
• AOMs should be used with caution in certain medical conditions, including hypertension, coronary disease, glaucoma, hyperthyroidism, and individuals taking MAOIs.
• Pregnant women need medical advice before using these drugs.

IMCIVREE (Setmelanotide)

• It's the first FDA-approved therapy for obesity due to specific rare genetic conditions (e.g., POMC, PCSK1, and LEPR deficiencies).
• Administered as a daily subcutaneous injection.
• It targets specific brain areas controlling appetite, satiety, and metabolism.
• Potential side effects include sexual function issues, depression, skin darkening, and benzyl alcohol toxicity. Additional common side effects include injection site reactions, nausea, headache, diarrhea, abdominal pain, back pain, fatigue, and vomiting. 

Usage of IMCIVREE

• Use is restricted to people who have confirmed POMC, PCSK1, or LEPR deficiency related obesity with genetic testing.
• It's not for general or other types of obesity.

Why Use IMCIVREE

• Targeting POMC, PCSK1, or LEPR deficiency, to help people who struggle with extreme, insatiable hunger and food cravings.
• Addresses deep hunger that feels like constant need for food.
• Can help people maintain healthy weights throughout their lives, and may be especially helpful for managing obesity in infants and children with abnormal weight gain patterns.

Semaglutide 2.4mg (Wegovy)

• The FDA approved Semaglutide for obesity in adults.
• It's a long-acting GLP-1 analog for weekly subcutaneous injections.
• It slows gastric emptying to reduce hunger and energy intake.
• It has direct effects on the brain, contributing to satiety.

SEMAGLUTIDE 2.4 Safety Considerations

• Possible side effects linked to nausea, diarrhea, vomiting, and constipation.
• Known as a cause of gastrointestinal issues, hepatobiliary disorders, gallbladder disorders, and mild pancreatitis, this complication is mostly moderate to mild.
• Semaglutide is contraindicated for those with documented or suspected medullary thyroid cancer or MEN2 history.
• Semaglutide 2.4 mg use should be discontinued two months prior to conception, per manufacturer recommendation.

Gelesis100 (Plenity)

• The FDA-approved AOM, Gelesis100, is a hydrogel matrix.
• Capsules are ingested with water 30 minutes before meals to promote fullness by occupying around one-fourth of stomach volume.
• It's a medication for overweight/obese adults (BMI 25-40).