Obesity drugs Flashcards
What is the mechanism of action of orlistat?
Orlistat alters fat digestion by inhibiting pancreatic lipases, fat is incompletely hydrolyzed and fecal fat excretion is increased
What are the indications for Orlistat?
- Weight loss and maintenance of weight loss in patients with a BMI>30 or BMI >27 + weight related comorbidities
What side effects are associated with Orlistat?
GI- borborygmi, flatus (some discharge), cramps, fecal incontinence, oily spotting
- Malabsorption of fat soluble vitamins A, D, E and K
(should supplement these vitamins)
- Oxalate induced kidney injury
- Fat binds to calcium and more free oxalate is delivered to the colon
- Intestinal oxalate absorption and urinary excretion are increased
What are some of the other benefits of Orlistat?
- Modest weight loss (9-10 kg vs. 3 kg in placebo
- Improves total cholesterol, hypertension, hyperglycemia, hyperlipidemia
- Less conversion from glucose intolerance to diabetes
- Better results when added to behavioral change
- Covered by medicaid
How long does Orlistat work?
Weight loss maintained up to 36 months
- After which weight comes back
What is the mechanism of action of lorcaserin?
- Serotonin (5-HT) decreases food intake in humans
- Selective 5-HT2C receptor agonist
- 5-HT2C receptor activation of proopiomelanocortin (POMC) neurons => alpha -MSH activation of melanocortin-4 receptor
- Increases satiety
- Nonselective agonist also cause weight loss but are associated with cardiac valvular disease (fenfluramine/dexfenfluramine)
What is the indication for lorcaserin?
- Weight loss and maintenance of weight loss in patients with a BMI>30 or BMI >27 + weight related comorbidities
What are the benefits of lorcaserin?
- Mean difference in weight loss between lorcaserin and placebo is 3-4 kg (5.8 kg lorcaserin vs 2.2 kg placebo)
- Decreases heart rate and BP
- Decreases in HgA1c and fasting blood sugar
- However, it is often NOT covered by insurance and is very expensive
What side effects are associated with lorcaserin?
- Upper respiratory infections, headache, dizziness, nasopharyngitis, and nausea
- most side effects improve with use
What is the mechanism of action of combination phentermine/topiramate (Qsymia)?
- Phentermine
- Sympathomimetic amine with pharmacologic activity similar to amphetamine
- Weight management is likely mediated by release of norepinephrine in the hypothalamus, resulting in reduced appetite and decreased food consumption.
- Topiramate
- Fructose monosaccharide derivative with sulfamate functionality.
- The effect on chronic weight management is not known.
What is the most effective medical therapy for weight loss?
Phentermine/topiramate combination therapy => 12 weeks (due to tolerance)
What are the major side effects of phentermine/topiramate?
- Paresthesias, Dry mouth, Constipation, Dysgeusia, Insomnia
- Pregnancy category X, Topiramate-teratogenic-oral cleft defects
What is the mechanism of Naltrexone-Bupropion combination therapy (Contrave) ?
Bupropion
- Dopamine/noradrenaline reuptake inhibitor
- Stimulates POMC neurons in the arcuate nucleus which release a-MSH and b-endorphin.
- A-MSH acts on MC4 receptors and decrease appetite and increase energy expenditure
Naltrexone
- Opioid receptor antagonist.
- B-endorphin is an auto antagonist of POMC pathway and causes increase in food intake in rodents.
- Blocking the opioid receptor decreases the effect of endogenous b-endorphin
*makes food less rewarding
What is the indication for naltrexone-bupropion?
Indication: weight loss and maintenance of weight loss in patients with a BMI>30 or BMI >27 + weight related comorbidities
What are the major side effects of naltrexone-bupropion?
- Nausea 30% => main reason for stopping treatment
- Headache, constipation, dizziness, vomiting and dry mouth
- Transient increase BP 1.5 mmHg followed by decrease 1 mmHg
- Cautious of suicidal ideation in young adults (18-24 yrs.)
What are the contraindications for naltrexone-bupropion?
- Contraindicated in uncontrolled hypertension, seizures, eating disorders, chronic opioid use, MAOI’s
What is the mechanism of action of liraglutide?
Long-acting GLP-1 analog; subcutaneous injection
- Slows gastric emptying
- Increases insulin release
- Decreases hepatic glucagon production
What is the indication for liraglutide?
Indication: weight loss and maintenance of weight loss in patients with a BMI>30 or BMI >27 + weight related comorbidities
What are the benefits of liraglutide?
- 4.8-7.2 kg (2.8 kg more than placebo)
- Sustained mean weight loss 7.6 kg at 2 yrs.
- Decreases blood pressure
- Improves blood sugar control
What are the major side effects associated with liraglutide?
Nausea 37-47%
Vomiting 12-14%
Pancreatitis
* avoid in patients with thyroid tumors
What is the most common type of bariatric surgery?
Roux-en-Y Gastric Bypass- 80%
- Malabsorptive procedure
What is the result/benefit of bariatric surgery?
5% of US population meets criteria for bariatric surgery, 1/3 of patients undergoing surgery have a BMI>50 => after surgery BMI>35
- Significant resolution or improvement of type 2 diabetes mellitus, hypertension, dyslipidemia and sleep apnea seen.
What are the types of bariatric surgery?
1) Restrictive procedures
- Vertical banded gastroplasty
- Laparoscopic adjustable gastric banding)
2) Malabsorptive procedures
- Biliopancreatic diversion with duodenal switch
- Roux-en-Y gastric bypass
Describe the mechanism of a restrictive procedure.
A small pouch restricts the volume of food intake, causing early satiety while allowing the normal absorption of fat, protein, and carbohydrates.
Describe the mechanism of a malabsorptive procedure.
Through surgical alteration of the intestinal tract, food bypasses the portions of the small intestine where normal digestion and absorption occur.
What is the most effective treatment for obesity?
Bariatric surgery
- significant weight loss maintained for 15 years
What are the FDA requirements for anti-obesity drugs?
- Decrease weight ≥ 5% in 12 months.
OR 35% of participants must lose > 5% (if double the placebo and has achieved statistical significance). - Evidence needed for improvements in comorbidities e.g. lipids, glycaemia, blood pressure etc.
- Weight loss should be predominantly from fat
- Large focus is on potential for abuse, psychiatric side effects, drug withdrawal issues, fetal development and cardiovascular safety.
Which gene codes for leptin?
The OB gene was one of the first of many genes found linked to obesity
- It codes for leptin which is expressed in adipose.
What is leptin and what is its role in obesity?
- Leptin is a hormone which can decrease appetite and stimulate metabolism.
- Paradoxically many obese patients have high levels of leptin
Where do long and short term signals for satiety come from?
Long term => leptin and adiponectin (adipose tissue)
Short term => PP, insulin, and amylin (pancreas); Ghrelin (GI tract)
What are the criteria for anti-obesity medication usage?
- BMI ≥ 30 kg/m2
OR
- BMI ≥ 27 kg/m2 and at least 1 concomitant obesity-related risk factor or disease:
- Type 2 diabetes
- Heart disease
- Atherosclerosis
- Sleep apnea
- Excessive waist circumference
- DyslipidemiaAnti-obesity pharmacotherapy must be combined with what other therapy?
Anti-obesity pharmacotherapy must be combined with a weight management program => reduced calorie diet and increased physical activity
What is considered an “excellent” response to anti-obesity pharmacotherapy?
An excellent response is 10-15% total body weight lost over 12 months
