Lecture 6: Drugs to Treat Obesity

1) Weight loss: Initial goal: 5% - 10% decrease from baseline weight over 6 months.

2) Maintain lower weight in the long term.

3) Limit weight-induced comorbidities.

Obesity Therapy goals

1200-1500 kcal/day

Suggested calorie intake for females

1500-1800 kcal/day

suggested calorie intake for males

• Increase energy expenditure to exceed energy intake

• Aerobic physical activity of at least 150 minutes/per week

• Start slowly and gradually increase intensity

• May need 200-300 minutes/ week to maintain weight loss

Describe physical activity goals for obesity

Bariatric Surgery

Most effective intervention for obesity

Individual/group behavioral counseling sessions with a clinician minimum of 14 times/6 months

what is the recommended behavioral modifications for obesity?

• BMI > 40 kg/m2

• BMI > 35 kg/m2 with > 1 obesity related

comorbidity

• Must have failed recommended methods of weight loss, meet criteria, understand risks, and willing to follow post-surgery directions

What are the general guidelines for bariatric surgery?

-ADJUNCT TO LIFESTYLE CHANGES

• motivated to lose weight

• have failed to achieve/sustain weight loss with lifestyle changes alone

• have a BMI > 30 kg/m2

OR

BMI >27 kg/m2 with at least 1 weight-related comorbidity

How/When should you use pharmacological therapy for weight loss?

-Phentermine

-Diethylpropion

-Short term weight loss agents

-sympathomimetics

-GLP-1 RAs

-GI Lipase Inhibitor

-Opioid antagonist + Antidepressant

-Sympathomimetic + Anticonvulsant

-MC4 Receptor Antagonist

long term agents

Phentermine

-Sympathomimetic stimulant amine (like amphetamine, ↑ NE, DA release from hypothalamus (↓ appetite)= anorexigenic.

-pregnancy category X

Phentermine

o It used as a short-term adjunct (a few weeks) in a regimen of weight reduction based on exercise, behavioral modification and caloric restriction in the management of exogenous obesity for patients with an initial BMI ≥ 30 kg/m2, or ≥ 27 kg/m2 in the presence of other risk factors

-37.5 mg/day in morning before breakfast or 1 to 2 hours after breakfast. Late evening medication should be avoided because of the possibility of resulting insomnia.

Phentermine

Contraindications:

-history of CVS

-MAOIs

-Hyperthyroidism

-glaucoma

-nursing

-pregnancy

Phentermine

ADVERSE EFFECTS:

-hypertension

-tachycardia

-pulmonary hypertension

-insomnia

-psychosis

-seizures

-tremor

-euphoria

-drug dependency/addiction

-contstipation

-dry mouth

-MAOIs

-Beta-blockers

What drugs should you not take with Phentermine?

C-IV

Phentermine is a schedule ______________________

Diethylpropion

o Sympathomimetic amine with some pharmacologic activity like amphetamines, thus it ↑release of NE, DA, resulting in↓ appetite (anorexigenic)

-pregnancy category B

Diethylpropion

o Short-term use (a few weeks) adjunct in the treatment of obesity.

-It is C-IV, rarely used.

Diethylpropion

Contraindications:

-pulmonary htn

-advanced ateriosclerosis

-hyperthyroidism

-known hypersensitivity to sympathomimetic amines

-glaucoma

-severe htn

Glucagon-like peptide-1 (GLP-1)

-small peptide incretin hormone produced and secreted from intestinal L-cells in response to oral food intake. GLP-1 binds to GLP-1R (a GPCR in pancreatic β cell) to decrease postprandial glucose

Glucagon-like peptide-1 (GLP-1)

Actions:

o Increasing glucose-dependent insulin synthesis and secretion from pancreatic β cells in a glucose-dependent manner.

o Slowing gastric emptying rate.

o Reducing food intake via the reduction of appetite (acting on GLP-1R in brainstem and hypothalamus, thus promotes satiety).

o Promoting pancreatic β cell proliferation.

o Suppressing glucagon secretion.

DPP-4

GLP-1 is rapidly degraded (t½= 2 mins) by _________________________

-Liraglutide

-Semaglutide

FDA-approved GLP-1 R agonists for treatment of obesity

Liraglutide

-GLP1-RA

-SC dosing once daily, age 12+

-Initiate with 0.6 mg once daily for 1 week. In weekly intervals, increase the dose until a dose of 3 mg daily is reached

-Mean weight loss: ̴ 3.7-5.2 kg in 1 year

Semaglutide

-GLP1- RA

-SC dosing, once a week,- age 18+.

-Initiate with 0.25 mg once weekly for 4 weeks. In 4-week intervals, increase the dose until a dose of 2.4 mg daily is reached

-Mean weight loss: ̴10.6-12.7 kg in 1 year

GLP-1 Agonists

-for long term managment of obesity

-slows gastric empty rate and increases satiety

-pregnancy category X

GLP-1 Agonists

Contraindications:

-pregnancy

-personal/family hx of medullary thyroid carcinoma, current endocrine neoplasia syndrome type 2

-hypersensitivity

GLP-1 Agonists

ADVERSE EFFECTS:

-n/v, diarrhea, dyspepsia, tachycardia, low blood sugar

-pancreatitis, cholelitiasis, cholecystitis, suicidal ideation, hypoglycemia, tachycardia, thyroid C-cell tumors

-Heart Rate

-Weight

-Blood glucose

-Pancreatitis symptoms

-Diabetic retinpathy complications

what should you monitor in a pt taking a GLP-1 Agonist?

4%

discontinue Liraglutide if weight loss < _______% after 16 weeks.

5%

discontinue Semaglutide if weight loss < _______% after 12 weeks.

Orlistat

GI Lipase Inhibitor

Orlistat

-Reversibly inhibits gastric and pancreatic lipases; blocks the absorption of ~30% of ingested fats.

Orlistat

-INDICATION: Obesity management. Weight loss: ~3.4 kg at 1 year.

o ↓ absorption of oral contraceptives and other drugs.

o ↓ absorption of fat-soluble vitamins (A,D, E, K); may need to supplement with MVI at bedtime.

o ↓ Cyclosporine, ↓ levothyroxine, warfarin (↓ vitamin K absorption), anticonvulsants, HIV-ARVs.

Orlistat

ADVERSE REACTIONS:

-steatorrhea

-oily rectal leakage

-flatulence with discharge

-bloating

-cramping

-increased urinary oxalates

Maintain a strict-low fat diet

how do you minimize the adverse reactions of orlistat?

Orlistat

Contraindications:

-pregnancy X

-malabsorption issues

-cholestasis

Orlistat

Taken at time of or up to 1 hour after each meal containing fat; dosed 3x/day.

Phentermine/Topiramate ER

Sympathomimetic + Anticonvulsant

Topiramate ER

-effect may be due to its effects on both appetite suppression and satiety enhancement

-augmenting the activity of the neurotransmitter GABA, modulation of voltage-gated ion channels, or inhibition of carbonic anhydrase

Phentermine/Topiramate ER

ADVERSE EFFECTS:

-dry mouth

-dizziness

-paresthesia

-constipation

-insomnia

-dizziness

-cardiovascular effects

-nephrolithiasis

-depression/suicidal ideation

-metabolic acidosis

-promotes kidney stone formation

Topiramate ER

inhibits carbonic anhydrase activity by reducing urinary citrate excretion and

increasing urine pH, resulting in promotion of kidney stone formation

Phentermine/Topiramate ER

Contraindications:

-pregnancy

-glaucoma

-MAOIs

-hyperthyroidism

-lactation

Resting heart rate, blood pressure, suicidality, symptoms of secondary angle closure

glaucoma, symptoms of acute acidosis , labs: serum bicarbonate, potassium, glucose, and serum creatine.

what should you monitor in a pt on Phentermine/Topiramate ER?

Naltrexone/bupropion ER

Opioid Antagonist + Antidepressant

Naltrexone/bupropion ER

INDICATION:

o Chronic weight management in adults with an initial BMI of ≤ 30 kg/m2(obese) or 27 kg/m2 (overweight)

in the presence of at least one weight-related comorbidity (hypertension, type 2 DM, or dyslipidemia).

Naltrexone/bupropion ER

increased the firing rate of hypothalamic proopiomelanocortin (POMC) neurons in vitro, which are associated with regulation of appetite

Naltrexone/bupropion ER

ADVERSE EFFECTS:

-nausea, constipation, vomiting, diarrhea

-headache, dizziness

-insomnia

-dry mouth

Naltrexone

an opioid antagonist used for AUD and OUD.

Bupropion

DA and NE re-uptake inhibitor used for depression and smoking cessation.

Naltrexone/bupropion ER

CONTRAINDICATIONS:

o Uncontrolled hypertension (bupropion is DA and NE re-uptake inhibitor).

o Seizure disorders (bupropion can cause seizures), anorexia nervosa or bulimia, or undergoing abrupt

discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs.

o Chronic opioid use (naltrexone is an opioid receptor antagonist).

• Monoamine oxidase inhibitors (MAOI) (bupropion is DA and NE re-uptake inhibitor) .

• Known allergy to any of the ingredients.

• Pregnancy (high potential fetal risk).

high fat

Naltrexone/bupropion ER should not be taken with ____________ meals

5%

Stop treatment of Naltrexone/bupropion ER if

Setmelanotide

o Chronic weight management in adult and pediatric patients 6 years of age and older with obesity due to one of the following rare genetic conditions: (1) proopiomelanocortin (POMC), (2) proprotein convertase subtilisin/kexin type 1 (PCSK1), or (3) leptin receptor (LEPR) deficiency.

Setmelanotide

MC4 receptor agonist

Setmelanotide

ADVERSE EFFECTS:

o Skin hyperpigmentation and darkening.

o Spontaneous penile erection (disturbance of sexual arousal).

o Depression and suicidal ideation.

o Pain at the site of injection, fatigue, diarrhea, vomiting, abdominal pain, dry mouth.

5%

If a patient on Setmelanotide has not lost at least ____% of baseline body weight or

______% of baseline BMI for patients with continued growth potential, discontinue

Garcinia cambogia

remedy that has been assoc with hepatic failure

Ma huang (ephedra alkaloid)

remedy that can cause prolonged duration of action, peripheral and central actions on adrenergic receptors which is a safety concern due to CVS events, stroke, seizures, and death