Obesity Pharmacology & Therapy

Endocrine System

regulates:

• sodium and water balance → control of blood volume and pressure (daily fluctuations in body weight)

• energy expenditure —> controls fuel mobilization and storage

  • excess calories stored in adipose tissue = fat

• appetite/food intake via CNS

Coordinates and integrates the activity of the cells and tissues of the body using signaling molecules called hormones that are carried into circulation

Pancreas

• important role in regulation of energy balance and control of fuel mobilization

• secretes insulin from beta cells in the islet of langerhans

• secretes glucagon from alpha cells in the islet of langerhans

Insulin

• secreted by beta cells in pancreas

• endogenous hormone

• promotes the storage of triglycerides = accumulation of body fat

• promotes the uptake and storage of glucose (including triglycerides in adipose tissues)

• occurs when in a fed state

Insulin Action at Target Sites

• binds to receptors on the surface of target cells

• all tissues express insulin receptors, but energy-storing tissues (liver, muscle, adipose) have a much higher receptor level and are the main target tissues

• @ adipose cells, leads to triglyceride synthesis and storage

What is an insulin receptor like?

• transmembrane glycoprotein consisting of 4 disulfide-linked subunits

• intracellular tyrosine kinase domain

• extracellular insulin binding domain

• insulin binding induces a conformational change

What actions favor triglyceride deposits?

insulin!

• increases the transport of glucose into adipose cells via translocation of GLUT4 to cell membrane

• activates lipogenic enzymes: helps the body make & store fat

  • pyruvate kinase, pyruvate dehydrogenase, acetyl-CoA carboxylase, and glycerol phosphate acyltransferase

• stimulates fatty aid synthesis in liver + other tissues

  • can be transported to adipose tissues via circulation

Lipolysis

the breakdown of stored triglycerides into free fatty acids and glycerol

• triacylglycerol undergoes hydrolysis by a hormone-sensitive lipase

stimulated by epinephrine (for energy)

inhibited by insulin (inhibits the activity of hormone-sensitive lipase)

Glucagon

• secreted from alpha cells in pancreas

• promotes the release of stored nutrients

• occurs when in a fasting state and blood sugar is decreasing

Triglycerides

• 3 fatty acids + glycerol backbone

• adipose tissue stores

• glycerol -metabolized→ glycerol 3-phosphate and exported to adipose cells

• glucose -metabolized→ fatty acid palmitate via pyruvate and acetyl-CoA intermediates

Obesity

energy intake > energy expenditure OVER an extended period of time

• complex etiology with multiple contributing factors

• genetics

• diet - high caloric foods that activate reward pathways

• sedentary lifestyle

• side effect for several common classes of medications

Leptin

• endocrine hormone secreted by adipose cells

• leptin concentrations in the plasma proportional to total fat mass (higher fat mass, higher leptin concentrations)

• decreases appetite

• increases metabolic energy expenditure

• low leptin causes increased appetite and impairs energy-expensive functions

• not many leptin-based drugs

Glucagon-like Peptide-1 (GLP-1)

• produced in enteroendocrine cells (L cells) of the ileum

• released from L cells during nutrient absorption in the GI tract - tells the body to stop eating

• tells the pancreas to increase insulin secretion and suppress glucagon secretion

• tells the stomach to delay gastric emptying (nutrients absorbed over an extended period of time)

• hypothalamus - decreases appetite

• biological form = very low half-life (2 minutes)

• metabolized by DPP-IV enzyme

Gastric Inhibitor Polypeptide (GIP)

• produced by K cells of the GI tract in response to nutrient absorption

• metabolized by DPP-IV enzyme

• stimulates both insulin and glucagon secretion

• slows gastric emptying and reduces GI motility

• acts in the CNS to reduce appetite

GLP-2 Agonists and Mimetics

• molecular modifications to increase bioactivity and T_1/2

Semaglutide

• ozempic - T2DM

  • injectable and oral

• wegovy - weight loss

  • injectable and oral

Oral delivery of GLP-1 RAs

• gi tract contains digestive enzymes that metabolize & break down protein peptides

• pH changes promote chemical degradation

• peptides have higher MW and poor epithelial permeability

Oral semaglutide (Ozempic/Wegovy)

• combined with a surfactant - SNAC

• rapid release of SNAC in the stomach causes local neutralization of stomach acid

• interactions with epithelial membranes greatly increases permeability for semaglutide

Orforglipron (Foundayo)

• ONLY oral GLP-1 RA

• not degraded by digestive enzymes, half life = 1 day

Tirzepatide (Zepbound/Moujaro)

• GIP analgue that is chemically modified GIP peptide

• + agonist for the GLP-1 receptor

• approved for T2DM + weight loss

• less nausea than only GLP-1 due to GIP

• additional increase in glucagon

where does insulin target in the body?

• liver

• skeletal muscles

• adipocytes - most sensitive to actions of insulin (more glycogen uptake)

insulin is associated with…

weight gain

• insulin secretagogues (sulfonylureas)

GLP-2 receptor and dual GIP/GLP-1 receptor agonists increase insulin secretion...

but other factors such as reduced food intake must predominate to achieve weight loss

How do GLP-1 agonists stimulate weight loss

based on loss of both adipose stores and muscle mass (60%/40%)

What happens if you d/c GLP-1s

weight gain, mostly adipose tissue

• on/off cycling makes GLP-1 agonists less effective over time and results in net increase of body fat percentage

Pipeline drug: retatrutide

• triple GIP/GLP-1/glucagon receptor agonist

• glucagon agonism increases energy expenditure and fat oxidation

pipeline drug: cagrisema

• fixed dose amylin analogue + semaglutide

• amylin compoenent complements appetitie regulation via hypothalamus

survodutide

• dual GLP-1/glucagon receptor agonist

how does dopamine affect the brain

• creates feelings of pleasure, satisfaction, reinforcement

• so does NE and GABA

Bupropion/naltrexone on the Hypothalamic hunger system

• Bupropion increases the firing rate of POMC neuron in vitro, which are associated with the suppression of appetite

• Naltrexone blocks the Beta-endorphin negative feedback loop on POMC neurons, further contributing to appetite suppression

Bupropion/naltrexone on the Mesolimbic Reward System

• reduces food intake when injected directly into the VTA of the mesolimbic circuit in mice, an area associated with regulation of reward pathways that may mediate cravings

what is bupropion

a dopamine-NE reuptake inhibitor

what is phentermine

a sympathomimetic, enforces hypothalamic norepinephrine release to suppress appetite

what is topiramate

• increases GABA activity to reduce food-seeking/reward

• decreases glutamate activity to decrease excitatory pathways involved in appetite and food reward

etiology of obesity

• genetic factors - influences distribution of fat

• environmental factors

  • reduced physical activity or work

  • abundant food supply

  • sedentary lifestyle

  • increased availability of high-fat foods

  • cultural factors

  • religious beliefs

• medical factors

  • cushing syndrome

  • depression

  • insulinoma

  • genetic disorders

• medications (more later)

• neurotransmitters and neuropeptides stimulate or depress the brains appetite network

what neurotransmitters increase appetite?

• ghrelin

• GABA

what neurotransmitters decrease appetitie

• serotonin

• NE

• GLP-1

• PYY

• CCK

• leptin

• insulin

Adipose-based chronic disease (ABCD)

• what is trx: neurohormonal-driven dysregulation of energy balance leading to abnormalities in mass, distribution, and function of adipose

• why we are trx: chronic disease with complications that impair quality of life and confer morbidity and mortality

• goes beyond BMI

Obesity-related complications and diseases

refers to the consequences of health outcomes associated with obesity

what we are trying to prevent

Overweight BMI

25 - 29.9

Class I Obese BMI

30 - 34.9

Class 2 Obese BMI

35 - 39.9

Class 3 Obese BMI

>40

BMI

appropriate for initial screening - may prompt further screening, but does not tell the whole story

• does not consider muscle mass, edema, soft tissue masses, amputations

criteria for cardiometabolic risk

anthropometric components

• waist circumference

  • men > 40 inches

  • women > 34. 5 inches

• waist to height ratio >/= 0.5

Overall trx goals for obesity

• improve health and quality of life by preventing or treating obesity-related complications and diseases

• emphasize whole-person health and de-emphasize BMI and weight-centric approaches

• select therapeutic modality and intensity based on weight-loss target needed to ameliorate an individual’s ORCDs

• eliminate weight-promoting medications

• consider mental health disorder, internalized weight bias, and social determinants of health

• individualize lifestyle and behavioral interventions

• shared-decision making

weight-reduction goal (memorize)

• 5-10% from baseline for clinically meaningful benefit

• 0.5% - 1.0% of starting body weight per week

System level obesity interventions

• improve access to healthy foods

• improve infrastructure for physical activity

• encourage workplace and institutional changes

• reduce access to low-nutrient, high-density foods

• decrease barriers to access healthcare

• expand coverage for behavioral, pharmacotherapy, and surgical interventions

• reduce weight stigma

Lifestyle/Behavioral Interventions to obesity

• dietary/nutritional changes

• physical activity

• sleep

• mental health

Pharmacotherapy interventions to obesity

• incretin mimetics

• phentermine ± topiramate

• bupropion + naltrexone

• orlistat

Nutrition for obesity

• no single diet has emerged as the best treatment

• focus = reduced-calorie diet, while maintaining diet quality

• adopt healthful meal patterns (mediterranean diet)

• prioritize minimally processed, nutrient-dense foods

• limit energy-dense foods and beverages

• ensure adequate intake of protein, fiber, iron, calcium, and other micronutrients

• consider referral to registered dietitian

• ensure the patient knows how to read food labels, understand macronutrients, can set meaningful and realistic SMART goals

Physical activity for obesity

• tailor to patient preferences and functional ability

• incorporate aerobic activity, resistance training (helps preserve lean muscle mass during significant weight loss), reduced sedentary behavior

• gradually increase intensity and volume as tolerated

  • eventual target = 150 minutes/week of moderate intensity (divided over 3 or more days)

    • incorporate 2-3 days per week of resistance training

Sleep and Mental Health on Obesity

• suboptimal sleep (< 7-8 hours) and poor sleep quality can promote dysregulated energy intake, metabolic disturbances and obesity

• mental health disorders and internalized weight bias negatively affects health-related quality of life and can compromise the ability to adhere to the therapeutic plan

Medications that contribute to weight gain

• insulin

• corticosteroids

• tricyclic antidepressants (amitriptyline)

• sulfonylureas (glipizide)

• hormonal contraceptives (esp depot injection)

• mood stabilizers

• anticonvulsants (pregabalin, gabapentin)

• SSRIs (sertraline, paroxetine, escitalopram

consider benefits versus consequences of being on these meds, alternatives?

Orlistat MOA & mean weight reduction

• lipase inhibitor

• 4%

Phentermine MOA & mean weight reduction

• NE-releasing agent

• 5-6%

Phentermine + Topiramate MOA & mean weight reduction

• NE-released agent + GABA receptor modulation

• 9.5%

Naltrexone + Bupropion MOA & mean weight reduction

• Opioid receptor antagonist + DA-NE reuptake inhibitor

• 4-5%

Liraglutide (Subq) MOA & mean weight reduction

• GLP-1 RA

• 9%

Orforglipron (oral) MOA & mean weight reduction

• GLP-1 RA

• 11%

Semaglutide (oral or subq) MOA & mean weight reduction

• GLP-1 RA

• 15%

Tirzepatide MOA & mean weight reduction

• GIP/GLP-1 RA

• 20%

When would you use medications for obesity?

• BMI >/= 30 kg/m2

• BMI >/= 27 kg/m2 with >/= 1 weight associated comorbidity

• criteria used for pediatrics based on weight percentile

• approved for use in combination with diet and exercise

• NEVER USE IN PREGNANCY

Saxenda

• Liraglutide

• once daily SUBQ injection

• titrate every 1 week

Semaglutide (injection)

• wegovy or wegovy HD

• once weekly subq injection

• titrate every 4 weeks

semaglutide (oral)

• wegovy

• once daily oral pill

• titrate dose every 30 days

tirzepatide

• zepbound

• once weekly subq injection

orforglipron

• foundayo

• once daily oral tablet

• tirtrate dose every 30 days

How do you take oral semaglutide (wegovy)

• take on empty stomach

• with small sip of water (4 ounces)

• wait at least 30 minutes before eating, drinking or taking other oral medications

• store at room temperature in original container

• if a dose is missed, skip the day’s dose and resume the next day

  • DO NOT TAKE 2 doses in the same day

How do you take oral orforglipron (foundayo)

• does not matter with food or not

• no water restrictions

• store at room temperature

• if a dose is missed, take as soon as possible

• do not take 2 doses in the same day

Administration instruction pearls for subcutaneous injections

• injection sites: abdomen, thigh, back of upper arm

  • choose an anatomical area

  • rotate injection site each week (within the selected anatomical area)

• store unused pens in fridge

• multi-use pens can be stored at room temperature for a designated amount

When should you inject subq injections?

• once weekly: pick one day a week and be consistent (time of day does not matter)

• once daily injections: can be taken any time of day without regard to meal, but should be taken around the same time each day

How should you handle missed doses for once weekly injections?

• take within 4 days - inject as soon as you remember

• if it is within more than 4 days, skip the missed dose and wait to take it on your next regularly scheduled day

• make sure there are at least THREE days between two doses

• if you miss more than 2 weeks worth of doses, you need to contact your PCP to researt at a lower dose to avoid adverse effects

Populations to avoid with incretin mimetics

• contraindicated in personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN2)

• caution in history of pancreatitis

• avoid in pregnancy or breastfeeding

Common adverse reactions of incretin mimetics

• GI-related

  • nausea, vomiting, diarrhea, constipation, heartburn, appetite changes

• fatigue

• injection site reactions (will get better with time)

Rare but serious side effects of incretin mimetics

• pancreatitis and gallbladder disease

• sudden vision loss/non-arteritic anterior ischemic optic neurpathy (NAION)

A/e to screen for and monitor in higher risk patients

• AKI can occur due to volume depletion (vomiting, CKD, diuretics)

• hypoglycemia (diabetes, taking other meds to lower glucose)

• diabetic retinopathy (diabetes, other diabetes meds)

• pulmonary aspiration during General Anesthesia/deep sedation

  • patients should inform HCP if they are taking a GLP-1 and have a planned surgery

other random s/e of incretin mimetics

• hair shedding/alopecia

  • common tho due to rapid weightloss

• dysethesia - tingling, burning, prickling feeling (will go away, but consider changing)

• menstrual changes

which two incretin memetic drugs should you be cautious with when taking COCs

• tirzepetide - decreases availability of COCs

• orforglipron (ot evaluated, but be cautious)

Liraglutide (Saxenda) FDA-Approved indications

Obesity

Orforglipron (foundayo) FDA-approved indications

Obesity

Semaglutide (Wegovy) FDA approved indications

• obesity

• cardiovascular risk reduction in obesity without T2DM

• Metabolic Dysfunction Associated hepatitis (MASH) - only subQ

Tirzepatide (Zepbound) FDA-approved indications

• obesity

• obstructive sleep apnea with obesity

First-tier medications for weight loss (2)

• semaglutide

• tirzepatide

  • better at lowering weight and lowering glucose/A1C

  • better tolerated (GIP decreases nausea)

When should you chose tirzepatide over semaglutide?

obstructive sleep apnea

when should you choose wegovy over zepbound?

• MASH (subQ ONLY)

• knee osteoarthritis (subQ)

• Cardiovascular risk reduction (oral or subQ)

MOA of Phentermine & Topiramate

phentermine = increases norepinephrine in hypothalamus to suppress hunger signals

topiramate = enhances GABA activity and inhibits excitatory pathways to reduce appetite and cravings

populations to avoid phentermine

• established CVD

• arrhythmias

• uncontrolled HTN

• history of substance use disorder

when should you avoid topiramate

• pregnancy (teratogenic risk)

  • can also decrease effetiveness of COCs

• history of kidney stones

• unstable mental health conditions

s/e of phentermine & topiramate

Phentermine

• activating (sort of like caffeine) - anxiety, insomnia

• headache

• increased BP and HR

Topiramate

• drowsiness

• cognitive (word-finding difficulty)

• paresthesia

• metallic taste

other benefits beyond weight loss with phentermine + topiramate

• sleep apnea

• migraine prophylaxis (topiramate)

Which weight-loss drug has rems?

brand qsymia (phentermine.topiramate)

MOA of bupropion & Naltrexone

bupropion = increases dopamine and norepinephrine to decrease appetite

Naltrexone = works synergistically with bupropion to dampen the reward response to reduce cravings

Populations to avoid with bupropion

• seizure disorder

• eating disorder

• severe anxiety or other uncontrolled mental health conditions

• uncontrolled HTN

populations to avoid with naltrexone

• opioid users → will cause withdrawal sx

Adverse effects of Bupropion & naltrexone

bupropion:

• headache

• increased anxiety

• increased blood pressure

• dry mouth

Naltrexone:

• nasea headache

potential benefits beyond weight loss for Contrave

• smoking cessation (bupropion)

• depression (bupropion)

Populations to avoid Xenical (Orlistat)

• malabsorption disorders

• history of kidney stones

adverse effects of xenical

• steatorrhea

• incontinence

• oily spotting

• frequent bowel movements

• abdominal pain

• flatulence

• feval urgency

• decreased fat-soluble vitamin absorption

Retatrutide

• once weekly subq injection

• GLP-1/GIP/glucagon receptor agonist

• many indications

• weight reduction of 20-28%

benefits of glucagon agonism

• increases energy expenditure and thermogenesis

• enhanced hepatic fatty acid oxidation and reduced lipogenesis