PHAR 555 Exam #2 (Review)

obesity (to Banks)

a complex, chronic disease defined as having an abnormal or excessive accumulation of body fat that can impair health

Afferent systems of the body’s energy status generate which signals?

• Ghrelin (stomach)

• Insulin (pancreas)

• Leptin (adipose tissue)

Efferent systems of the body’s energy status carry out what signals?

anabolic and catabolic signals by modulating feeding behaviors or energy expenditure

What are the two sets of neurons related to appetite in the central processing area (arcuate nucleus) of the hypothalamus?

• Neuropeptide Y/agouti-related peptide (NPY/AgRP) signals orexin (ORX)/melanin-concentrating hormone (MCH) in the lateral hypothalamic area → ↑ appetite via the orexigenic pathway

• Pro-opiomelanocortin/cocaine and amphetamine-related transcript (POMC/CART) signals CRH/TRH in the paraventricular area → ↓ appetite via the anorexigenic pathway

currently approved centrally-acting agents for appetite

• Phentermine (Adipex-P)

• Phentermine/topiramate (Qsymia)

• Phendimetrazine (Prelu-2, Bontril, Statobex)

• Diethylpropion (Amfepramone, Anorex, Tenuate)

• Lisdexamphetamine (Vyvanse)

• Bupropion/naltrexone (Contrave)

MOA and SE of phentermine (Adipex-P)

• MOA: Preferential release of DA and NE compared to 5-HT (similar to amphetamine)

  • Approved as short-term treatment as adjunct to low-calorie diet and increased physical activity

• ADRs: 

  • Insomnia (especially with doses administered in afternoon or evening)

  • Increased HR and BP (sympathomimetic)

  • Abuse potential (CIV)

  • Weight regain upon pharmacotherapy termination

• Contraindications:

  • Hyperthyroidism

  • Glaucoma

  • Pregnant women

  • Concomitant MAOIs

MOA and SE of phentermine/topiramate (Qysmia)

• MOA of topiramate: Largely unclear

  • GABA-A receptor agonist and AMPA/kainate receptor antagonist

  • Also a voltage-dependent sodium and calcium channel antagonist

  • Exerts inhibitory effects on orexigenic pathway → Net effect: Decreased appetite

  • Approved as adjunct to reduced-calorie diet and increased physical activity for chronic weight management

• ADRs:

  • Same as phentermine

  • Teratogenic effects from topiramate

MOA and SE of phendimetrazine (Prelu-2, Bontril, Statobex)

• MOA: Prodrug for DA/NE releaser phenmetrazine

  • Approved as short-term treatment for adjunct to low-calorie diet and increased physical activity

• ADRs:

  • Abuse potential (CIII)

  • Sympathomimetic/cardiovascular

  • Weight regain upon pharmacotherapy termination

MOA and SE of diethylpropion (Amfepramone, Anorex, Tenuate)

• MOA: Prodrug for DA/NE releaser ethcathinone

  • Approved as short-term treatment for adjunct to low-calorie diet and increased physical activity

• ADRs:

  • Abuse potential (CIV)

  • Sympathomimetic/cardiovascular

  • Weight regain upon pharmacotherapy termination

MOA and SE of lisdexamphetamine (Vyvanse)

• MOA: Prodrug for DA/NE releaser amphetamine

  • Approved for moderate-to-severe binge eating disorder in adults

• ADRs:

  • Abuse potential (CII)

  • Sympathomimetic/cardiovascular

MOA and SE of bupropion/naltrexone (Contrave)

• MOA: Bupropion is a DA and NE selective uptake inhibitor. Naltrexone is a mu-opioid receptor antagonist

  • Blocking the activation of mu-opioid receptors = Letting the anorexigenic pathway do its thing

  • Approved for long-term use

• ADRs:

  • HTN

  • Insomnia

currently approved lipase inhibitor (peripherally-acting agent) for appetite

• Orlistat (OTC: Alli; Rx: Xenical)

MOA and SE of orlistat (OTC: Alli; Rx: Xenical)

• MOA: Synthetic derivative of lipstatin produced by Strep. toxytricini

  • Binds to and inhibits lipase, preventing it from breaking down fat and absorbing fat from the intestines → Fat is eliminated

  • Attenuates gastric emptying

  • Attenuates secretion of pancreaticobiliary substances

• ADRs:

  • Steatorrhoea

  • GI (directly related to fat content of food): Soft stools, abdominal pain, flatulence, fecal urgency, diarrhea

  • Decreases absorption of fat-soluble vitamins (ADEK)

  • Interactions with drug absorption

    • Cyclosporine

    • Levothyroxine

glucagon-like peptide-1 (GLP-1) receptor agonists

• Works where in the body?

• Includes which drugs

• MOA

• SE

• Works centrally and peripherally

• Includes liraglutide, semaglutide, exenatide, dulaglutide, orforglipron

• MOA:

  • Crosses the blood-brain barrier

  • GLP-1 receptors are G-protein coupled receptors (Gs). GLP-1 receptor activation on POMC/CART neurons decreases appetite and increases satiety (anorexigenic pathway)

  • Slows gastric emptying

  • Increases insulin secretion and decreases glucagon secretion via activation of pancreatic GLP-1Rs

  • Approved for chronic weight management

• ADRs:

  • N/V (most commonly reported, dose-dependent)

  • Increased risk of C-cell carcinoma and thyroid C-cell hyperplasia (in animals)

  • Increased relative risk for osteopenia/osteoporosis

glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 agonist

• Works where in the body?

• Includes which drugs

• MOA

• SE

• Works centrally and peripherally

• Includes tirzepatide

• MOA of glucose-dependent insulinotropic polypeptide (GIP)

  • Inhibitory hormone of secretin family

  • GIP receptors are 7-transmembrane receptors (G_s) found on beta-cells in the pancreas that increase insulin secretion

  • Stimulates glucagon secretion from pancreatic alpha-cells through GIP receptors through undefined mechanisms

  • Some evidence that tirzepatide is a biased GLP-1R agonist favoring the Gs pathway over the beta-arrestin pathway

  • Approved for chronic weight management

• ADRs:

  • NVD, dyspepsia

  • Cholecystitis

  • Mild-to-moderate GI events

  • Anhedonia?

amylin analogs

• Works where?

• Includes which drug?

  • MOA

  • SE

• Works primarily centrally, though it triggers downstream actions that alter peripheral organ function

• Includes pramlintide (Symlin) (MOA and SE below)

• MOA:

  • Decreases appetite and increases satiety via hypothalamic neurons (anorexigenic pathway)

  • Delays gastric emptying

  • Inhibits glucagon secretion

• ADRs:

  • N/V, HA

  • Hypoglycemia

  • Undesirable effects with medication absorption

setmelanotide (Imcivree)

• Works where in the body?

• MOA

• SE

• Works primarily centrally but also peripherally

• MOA: Melanocortin-4 receptor (MC4R) agonist

  • Activates MC4R receptors in the absence of adequate alpha-melanocyte stimulating hormone (alpha-MSH) production

  • Leptin receptor activation causes intracellular proprotein convertase subtilisin/kexin type I (PCSK1) to cleave the pro-opiomelanocortin (POMC) peptide into alpha-MSH. Alpha-MSH is the endogenous ligand for MC4R

  • Approved for treatment of monogenic obesity due to POMC, proprotein convertase subtilisin/kexin type I (PCSK1), or leptin receptor deficiency

• ADRs:

  • Nausea

  • Injection site reactions

obesity (to Sisson)

• Similar to other chronic diseases, obesity requires long-term management and ongoing care

• Maintaining a healthy weight throughout life is one of the most important ways to protect against obesity-related complications

• Obesity in middle-aged patients is a risk factor for many age-related diseases and decreases life expectancy by about 7 years

diseases associated with obesity

There are over 200 of them, including…

• Metabolic: High cholesterol, T2D, MASLD

• Cardiovascular: HTN, heart disease, stroke

• Respiratory: Asthma, sleep apnea

• Mechanical/structural: Osteoarthritis, orthopedic issues

• Renal: CKD

• Cancer-related: CDC-listed cancers

• Immune and infectious severity: Severe COVID-19/flu, impaired immunity

• Pregnancy-related: Gestational diabetes, pregnancy complications

• Mental health and neurologic: Depression, anxiety, IIH

How is weight (obesity) related to diabetes?

• Rather than waiting for the disease to happen, a better approach is weight management so that the disease never occurs

  • For people at risk of diabetes: If you address their weight and help them improve lifestyle, that is more effective than metformin at preventing diabetes. Losing at least 5-10% is preventative

  • For people who have diabetes: When applying the DPP, people who lost weight had a decrease in A1c; a decrease in their fasting plasma glucose; and had their overall health improve. Furthermore, losing 10-15% and > 15% of your weight can actually reverse the need for drug therapy for diabetes

• In summary, there is a direct relationship between weight and increased risk of diabetes, as well as progression of diabetes

How is weight (obesity) related to HTN?

• People who lost 10-15% of their weight had a decrease in BP

• HFpEF is highly related to increased weight

distribution of adults waiting for kidney transplant by BMI

• Almost 50% are overweight or obese

• If BMI > 35, that excludes a patient from being eligible for transplantation because there is an increased risk of postoperative infection (related to insulin and FFA in the blood flow), the wound not healing, and the graft not functioning

  • Plus, we don’t have a surplus of kidney donors, so we want kidney transplants to occur in people who will have the best outcomes

• Dr. Sisson’s clinic receives referrals of people with a BMI > 35 to engage in the DPP (and a GLP-1 if possible)

principles of care for managing obesity

• 64.8% of people without diabetes discontinue GLP-1 one year in due to lack of weight loss

  • Side effects and cost are also issues

• Using motivational interviewing skills on nutrition, physical activity, and behavior—as well as pharmacotherapy and bariatric therapy, can be beneficial

body mass index (BMI)

provides the most convenient population-level measure to estimate excess weight

• Limitation: Represents excess weight and body size rather than excess body fat (can’t help you determine who is “healthy”, so not good from an individual standpoint; doesn’t tell you the full story)

BMI classifications

How do we diagnose clinical obesity?

Fulfillment of both of the following:

1. Anthropometric criterion: BMI + at least one other anthropometric criterion (e.g., waist circumference > 35 in women) or direct fat measure

• We can assume the presence of excess adiposity in people with very high levels of BMI (e.g., > 40 kg/m²)

2. Clinical criterion (includes one or both of the following):

• Signs or symptoms of ongoing dysfunction of organ systems

• Age-adjusted limitations of mobility or other basic activities of daily living (e.g., bathing, dressing, toileting, continence, and eating)

What separates clinical obesity from preclinical?

the clinical criterion

diagnostic criteria for clinical obesity

• Metabolism: the cluster of hyperglycaemia, high triglyceride levels, and low HDL-C

• Liver: MASLD with fibrosis

• Renal: Microalbuminuria with reduced eGFR

• Reproductive: PCOS

• Upper airways: apnoea or hypopnoea during sleep (due to increased upper airway resistance)

• CV system: Raised arterial BP

AACE algorithm for caring for persons with overweight/obesity

• Stage 1: A person has no evidence of abnormalities → Discuss nutrition, physical activity, sleep, and medication counseling

• Stage 2: A person has at least one other abnormality → Optimize weight, look for sleep disturbances

  • Patients with sleep apnea are at an increased risk of high BP and mortality, and they have higher levels of excitatory neurotransmitters, making it more difficult to lose weight. We could try putting them on a CPAP

motivational interviewing (MI)

collaborative, patient-centered form of guiding that is used to elicit and strengthen motivation for change

5 As of obesity management for adults

• ASK for permission to discuss weight and explore readiness 

• ASSESS obesity related risks and “root causes” of obesity 

• ADVISE on health risks and treatment options 

• AGREE on health outcomes and behavioral goals 

• ASSIST in accessing appropriate resources and providers

Help people with obesity set SMART goals (What does SMART stand for?)

• Specific

• Measurable

• Attainable

• Relevant

• Time-bound

Compare a typical American diet to a balanced-nutrient, moderate-calorie approach.

• In a typical American diet:

  • Average of 2200 kcal/day

  • Low in fruits, vegetables, dairy, and whole grains

  • High in saturated fat and unrefined carbohydrates

• In a balanced-nutrient, moderate-calorie approach:

  • Typically 1200-1800 kcal/day

  • Recommended reasonable weight loss of 0.5-2 pounds a week

    • To lose about 1 pound a week = 500 calorie reduction (either by decreasing your calorie intake or increasing your physical activity)

psychological intervention strategies for unhealthy eating patterns

• Behavior therapy involves looking at a patient’s thoughts, behavior, and feelings

• Stimulus control:

  • Establish eating patterns that maximize satiety

    • Example: Consuming whole foods with a higher % of their energy from protein and fiber

  • Environmental removal of foods identified as tempting

    • Example: Scheduling and meal planning to prevent temptation at the supermarket

    • “If it’s not in your house, you are less likely to eat it”

• Cognitive restructuring:

  • Encourage patient to:

    • Acknowledge they are capable of positive thoughts and behaviors

    • Replace unhelpful thoughts and behaviors with more productive ones

    • Practice behavior therapy skills between clinician encounters

sleep hygiene and stress management for staving off weight gain

• Insufficient sleep is independently associated with a higher risk of obesity, and obesity may lead to reduced sleep quality

• Sleep deprivation leads to:

  • Increased ghrelin and decreased leptin (to compensate for lack of energy, leads to overeating) + Increased hedonic signaling (leads to more time and opportunities for eating) → More energy intake

  • Decreased physical activity due to fatigue → Less energy expenditure

• Sleep extension may mitigate the risk of obesity. To improve and maintain sleep duration:

  • Avoid caffeine and alcohol in the evening. Avoid nicotine

  • Establish regular bed- and waketimes

  • Minimize stress to avoid pre-sleep arousal (e.g., engage in relaxing activities, mindfulness meditation)

  • Exercise regularly

  • Restrict use of electronic devices near bedtime

How can medications induce weight gain?

Weight gain results from storage of excess calories

• Medications that increase circulating insulin levels or promoting calorie storage may cause weight gain in people who consume excess calories

• Medications that increase fluid retention may contribute to daily weight gain

medications to know for weight GAIN

• Insulin

• Sulfonylureas

• Thiazolidinediones (TZDs)

• SSRIs (paroxetine)

• Clozapine, olanzapine

• Valproic acid

• Glucocorticoids

medication to know for weight LOSS

• Topiramate

dietary recommendations for people with obesity

• Include protein to create satisfying meals and meet nutrient needs

• Include fiber to help increase satiety

• Nonnutritive sweeteners can be a substitute

• Select low-calorie beverages (water is the best choice)

• The Mediterranean diet has the best outcomes for DM, A1c, TG, CVD, weight, LDL, BP, and HDL

• Overall goal: Reduce some proportions of protein, carbohydrate, and fat

DPP lifestyle change program

• Physicians contribute by increasing referrals to and participation in the lifestyle change program

• Goal: Reduce weight by 7% through…

  • Behavior modification

  • Low-fat diet

  • 150 minutes of exercise per week

recommendations for physical activity

• At least 150-300 minutes of moderate-intensity aerobic activity each week (so at least 30 minutes for five days)

• Engage in muscle-strengthening exercises at least 2 days per week

  • Muscle draws calories out of the system

Fogg Behavioral Model (tiny habits)

• Motivation: Select habits that are enjoyable (e.g., swimming)

• Ability: The habit should be easy to perform (e.g., ability to swim, access to a pool)

• Prompts: Link the habit to a daily routine (e.g., after work, morning alarm)

  • Example: After I _____, I will do _____

What is a helpful patient-led health tracking activity for losing weight?

Keep a food log

• Goal: Lets people know if they have realistically modified their intended food plan to reduce something and add something healthier and/or whether goals for physical activity were achieved

efficacy of existing weight loss interventions

• Lifestyle interventions have about 3-5% weight loss

• Very low-calorie diets have about 6-10% weight loss

• The anti-obesity medications (AOMs) are great, with about 3-17%

• The most weight loss comes from surgery (e.g., gastric band, sleeve, bypass)

approved anti-obesity medications

• Many work centrally on the satiety/feeding centers

  • Phentermine/topiramate: sympathomimetic amine anorectic and ER antiepileptic → GABA-R receptors

  • Bupropion/naltrexone: opioid antagonist/dopamine and norepinephrine reuptake inhibitor → D/NE receptors 

• Some work peripherally

  • Orlistat: pancreatic lipase inhibitor → pancreatic lipase

• Some work centrally and peripherally

  • Liraglutide and semaglutide: GLP-1R agonists → GLP-1 receptors

  • Tirzepatide: dual GLP-1R/GIP agonist → GLP-1 and GIP receptor

    • Wins in terms of average weight loss

(Note: The placebo group that didn’t receive medications in trials still lost weight because they are engaging in lifestyle interventions)

orlistat

• MOA

• Weight loss

• ADRs

• Cautions

• MOA: Lipase inhibitor

• Weight loss: 4% (52 weeks)

• ADRs:

  • Flatulence

  • Fecal urgency

  • Oily stools

  • Fat-soluble vitamin (ADEK) and drug malabsorption

• Cautions:

  • ∴ Organ transplant (interferes with drugs used for immunosuppression)

  • Cholestasis

phentermine

• MOA

• Weight loss

• ADRs

• Cautions

• Effects for:

  • HTN

  • ASCVD

• MOA: NE-releasing agent

• Weight loss: 5-6% (28 weeks)

• ADRs:

  • Restlessness

  • Insomnia

  • Dry mouth

  • Tachycardia (avoid in h/o of CAD)

• Cautions:

  • Active CAD

  • Uncontrolled HTN

  • Hyperthyroidism

  • Agitated states

• Effects for:

  • HTN - Monitor HR and BP (CI in uncontrolled HTN)

  • ASCVD - CI

phentermine/topiramate ER

• MOA

• Weight loss

• ADRs

• Cautions

• Effects for:

  • HTN

  • ASCVD

• MOA: NE-releasing agent/GABA receptor modulator

• Weight loss: 9.6-9.9% (52 weeks)

• ADRs:

  • Restlessness

  • Insomnia

  • Dry mouth

  • Constipation

  • Tachycardia (avoid in h/o of CAD)

  • Mental clouding/mood changes (from working centrally)

• Cautions:

  • Hyperthyroidism

  • Metabolic acidosis

• Effects for:

  • HTN - Monitor HR and BP

  • ASCVD - Monitor HR and BP

naltrexone ER/bupropion ER

• MOA

• Weight loss

• ADRs

• Cautions

• Effects for:

  • HTN

  • ASCVD

• MOA: Opioid receptor antagonist/DA-NE reuptake inhibitor

• Weight loss: 4.2-5.2% (52 weeks)

• ADRs:

  • Nausea

  • Insomnia

  • Dry mouth

  • Constipation

  • Agitation/mood changes (from working centrally)

• Cautions:

  • Seizure risk

  • Uncontrolled HTN

  • Chronic opioid use

• Effects for:

  • HTN - Monitor HR and BP (CI in uncontrolled HTN)

  • ASCVD - Monitor HR and BP

liraglutide

• MOA

• Weight loss

• ADRs

• Cautions

• Effects for:

  • HTN

  • ASCVD

  • CKD

• MOA: GLP-1R agonist

• Weight loss: 9.2% (56 weeks)

• ADRs:

  • NVD

  • Constipation

• Cautions:

  • MTC/MEN2

  • Pancreatitis

• Effects for:

  • HTN - BP benefit

  • ASCVD - Benefit in T2D

  • CKD - Benefit in T2D

semaglutide

• MOA

• Weight loss

• ADRs

• Cautions

• Effects for:

  • HTN

  • ASCVD

  • CKD

• MOA: GLP-1R agonist

• Weight loss: 16.9% (68 weeks)

• ADRs:

  • NVD

  • Constipation

• Cautions:

  • MTC/MEN2

  • Pancreatitis

  • Diabetic retinopathy

• Effects for:

  • HTN - BP benefit

  • ASCVD - Benefit in T2D

  • CKD - Benefit in T2D

tirzepatide

• MOA

• Weight loss

• ADRs

• Cautions

• Effects for:

  • HTN

  • ASCVD

  • CKD

• MOA: GIP/GLP-1R agonist

• Weight loss: 22.5% (72 weeks)

• ADRs:

  • NVD

  • Constipation

• Cautions:

  • MTC/MEN2

  • Pancreatitis

  • Diabetic retinopathy

• Effects for:

  • HTN - BP benefit

  • ASCVD - Benefit in T2D

  • CKD - Benefit in T2D

the overall benefits of GLP-1R agonists

• The reason why people end up with CKD and on dialysis is high BP and BG 

  • This class has CV benefits

  • Adding a GLP-1R agonist for those awaiting kidney transplant but are not on dialysis appears to be a good thing because of its multiple benefits

• However, visit attendance (even of those who weren’t on a GLP-1R agonist) is a stronger predictor of weight loss than GLP-1 therapy

  • Counseling is important because the drugs themselves don’t work

candidates for bariatric surgery

• Not responding to past weight loss attempts + BMI is > 40 kg/m², OR

• BMI is > 35 or > 45 kg/m² + 1 or more severe weight-related comorbidities (e.g., T2D, HTN, sleep apnea, NAFLD, OA, or GI disorders)

relative contraindications and adverse effects of bariatric surgery

• Relative contraindications:

  • Severe HF

  • Unstable coronary artery disease

  • End-stage lung disease

  • Active cancer treatment

  • Portal HTN

  • Drug/alcohol dependency

• Adverse effects:

  • NVD

  • Nutritional/vitamin deficiencies

  • Gallstones

What are the two most common bariatric surgery procedures? (Compare them.)

• Vertical sleeve gastrectomy (VSG)

  • Leads to 15-30% weight loss

  • Patients with GERD are poor candidates

• Roux-en-Y gastric bypass surgery

  • Leads to 30-35% weight loss (more effective than VSG)

  • Highest 30-day rate of major adverse events

  • Resolves GERD in patients with known GERD prior to surgery

micronutrient deficiencies post-bariatric surgery (due to restrictive and malabsorptive effect of the procedure)

• Most common: Calcium, vitamin D, iron, vitamin B12, thiamin

• Less common: Zinc, copper, vitamin A, vitamin E, vitamin K

management of post-bariatric patients

• Regular micronutrient monitoring

• Diet review to ensure dietary sources are optimized

• Daily multivitamin and multimineral supplementation

• Identify any previously undetected causes for the deficiencies

Life’s Essential 8

• Manage weight

• Eat better: Aim for an overall healthy eating pattern that includes whole foods (like vegetables, resources from the garden)

• Be more active: 150 minutes of moderate or 75 minutes of vigorous physical activity

• Get healthy sleep: Adults should aim for an average of 7-9 hours

• Control cholesterol

• Manage blood sugar: A1c < 6.5%

• Manage blood pressure: < 120/80 mmHg is optimal

• Quit tobacco 

What did studies uncover about the incretin system’s role in normal glucose homeostasis?

• People who are orally fed meals have better glycemic control than patients hospitalized and having to get their nutrition intravenously. Why?

  • There must be some signaling mechanism at play that is causing insulin to rise and glucagon to go down

• People with diabetes don’t make much GLP-1 and insulin at mealtime but still maintain a steady output of glucagon. Meanwhile, the levels of glucagon in people without diabetes fall when they eat. Why?

  • The purpose of glucagon is to release glucose from your liver so that you have enough energy to maintain in between meals. Thus, when your body senses you’re eating, glucagon levels fall

glycemic controllers

• Beta cells in the pancreas secrete insulin + amylin

• L cells in the gastrointestinal tract secrete GLP-1

• K cells in the small intestine secrete GIP and PYY

glucagon-like peptide-1 (GLP-1)

• Secreted from the intestines upon ingestion of food

• Functions:

  • ↑ insulin release from pancreatic beta cells

  • ↓ glucagon release from pancreatic alpha cells → ↓ hepatic glucose production

  • Slows gastric emptying to retrieve as many nutrients from the food you ate as possible

  • Promotes satiety and reduces appetite in the brain

• Inactivated by dipeptidyl peptidase (DPP-4)

• Not only are people with T2D deficient in insulin, but they are also deficient in GLP-1

GLP-1 receptor agonists

• Exenatide (discontinued)

• Liraglutide

• Lixisenatide (discontinued)

• Exenatide ER (discontinued)

• Semaglutide and dulaglutide

• Tirzepatide

exenatide (discontinued)

• Synthetic version of salivary protein found in gila monster (Heloderma suspectum)

• Has 53% overlap (homology) with human GLP-1

• Can bind to known human GLP-1 receptors on beta cells (in vitro)

• Resistant to DPP-4 inactivation

• BID dosing

• Dose is limited by nausea

• Administer within 60 minutes prior to morning and evening meal

liraglutide ❤

• Has 97% overlap with human GLP-1 

• QD dosing

• Dose is limited by nausea (but less nausea compared to exenatide)

• Administer at any time of day

lixisenatide (discontinued)

• QD dosing

• Dose is limited by nausea

• Administer within 60 minutes prior to morning and evening meal

exenatide ER (discontinued)

• Weekly dosing

• Administer immediately after dose is prepared – mix for > 15 seconds  👎

semaglutide and dulaglutide ❤

• More potent, giving you 1.4-1.6% and 0.7-1.6% A1c reduction, respectively

• Weekly dosing (less nausea)

• Administer any time of day. Give within 3 days of missed dose

tirzepatide ❤

• GLP-1/GIP receptor agonist

• Even more potent, giving you 1.7-2.3% A1c reduction

• Weekly dosing (less nausea)

• Administer any time of day. Give within 3 days of missed dose

• May decrease absorption of oral contraceptives

absorption mechanics of oral semaglutide

• Because GLP-1 receptor agonists are peptides, they degrade easily in the stomach when taken orally. To counteract this, semaglutide has been formulated with sodium N-[8-(2-hydroxybenzoyl amino]caprylate (SNAC)

• As the tablet erodes in the stomach, semaglutide and SNAC are released

  • SNAC exerts a local buffering effect, protecting semaglutide from degradation by the stomach enzyme, pepsin

  • Once SNAC and semaglutide reach systemic circulation, the two molecules disassociate

administration instructions for oral semaglutide

• Take first thing in the morning

• On an empty stomach

• Use only a sip of water (no more than 4 oz)

• Do not split, crush, chew or dissolve in any solution

• Wait 30 minutes before eating, drinking, or taking any other oral medications to ensure proper absorption

How can patients switch from Wegovy tablet to pen?

For patients who work their way up to but cannot tolerate the Wegovy 25 mg pill because of GI side effects, consider switching to the equivalent Wegovy 1.7 mg pen

oral semaglutide versus orforglipron

• Molecular type

• Formulation

• Bioaailability

• Dose range

• Expected weight loss

• GI tolerability

FDA indications for GLP-1R agonists

• T2D

• Chronic weight management

T2D

• Semaglutide (Ozempic) injection - Adults

• Tirzepatide (Mounjaro) - Adults, pediatric > 10

• Liraglutide (Victoza) - Adults, pediatric > 10

• Dulaglutide (Trulicity) - Adults, pediatric > 10

Chronic weight management

• Semaglutide (Wegovy) injection - Adults, pediatric > 12 w/ obesity

• Tirzepatide (Zepbound) - Adults with obesity/overweight

• Liraglutide 3 mg (Saxenda) - Adults, pediatric > 12 w/ obesity

FDA indications for GLP-1R agonists (continued)

• CVD

• Other indications

CVD

• Semaglutide (Ozempic) injection - Reduce risk of MACE in adults with T2D + CVD

• Semaglutide (Wegovy) injection - MACE reduction in adults with obesity/overweight + established CVD

• Tirzepatide (Mounjaro) - MACE indication pending FDA decision

• Liraglutide (Victoza) - Reduce risk of MACE in adults with T2D + CVD

• Dulaglutide (Trulicity) - Reduce risk of MACE in adults with T2D + CVD or multiple CV risk factors

Other indications

• Semaglutide (Ozempic) injection - Reduce risk of worsening kidney disease in adults with T2D + CKD

• Semaglutide (Wegovy) injection - Treatment of non-cirrhotic MASH with moderate-advanced fibrosis

• Tirzepatide (Mounjaro) - Treatment of moderate-severe obstructive sleep apnea in adults with obesity

CV trials on incretin mimetics

• In PIONEER 6 (oral semaglutide versus placebo): Noninferior 21% relative risk reduction in 3-point MACE (defined as CV death, nonfatal MI, and nonfatal stroke) was observed for semaglutide—regardless of route

  • Semaglutide significantly reduced cardiovascular mortality and all-cause mortality

  • No significant reductions observed for nonfatal MI and nonfatal stroke

• In controlled studies of GLP-1R agonists: Consistent benefit in reduction of 3-point MACE with GLP-1R agonistss—regardless of route

  • Exception: Lixisenatide in FREEDOM-CVO, which is why we’re don’t use it

renal trials on incretin mimetics

• Semaglutide was found to have 24% lower risk of primary-outcome events than placebo

• In controlled studies of GLP-1R agonists: Consistent GLP-1R agonist benefit across all kidney outcomes

metabolic dysfunction-associated steatotic liver disease (MASLD)

presence of steatotic liver disease (fat buildup in the liver) + > 1 cardiometabolic risk factor associated with insulin resistance (e.g., prediabetes, diabetes, atherogenic dyslipidemia, or hypertension) without other identifiable causes of steatosis

• Must be in the absence of ongoing or recent consumption of significant amounts of alcohol (defined as > 21 standard drinks per week in men and > 14 standard drinks per week in women over a 2-year period preceding evaluation) OR any other secondary causes of hepatic steatosis

• Occurs when fat deposits in the liver and damages liver cells → leads to liver inflammation, scarring, cirrhosis and possible need for liver transplant

metabolic dysfunction-associated steatohepatitis (MASH)

inflammation of the liver caused by excess fat cells; hepatic steatosis (histologically as having ≥ 5%) with inflammation and hepatocyte injury (hepatocyte ballooning), with or without evidence of liver fibrosis

• Resembles hepatitis caused by alcohol use, but it stems from excess weight, high blood lipids, and high blood sugar

screening for MASLD in diabetes

• Goal

• Risk factors

• Diabetes algorithm

• Goal: Identify people with at-risk MASH to prevent future cirrhosis, hepatocellular cancer (HCC), liver transplantation, and all-cause mortality

• Risk factors:

  • Central obesity

  • Cardiometabolic risk factors or insulin resistance

  •  > 50 years of age

  • Persistently elevated plasma aminotransferases (AST and/or ALT > 30 units/L for > 6 months)

• Diagnostic algorithm: If their FIB-4 score is greater than 1.3, they should be referred to a gastroenterologist for additional screening

lifestyle interventions for MASLD

• Diabetes Self-Management Education and Support (DSMES)

• Mediterranean eating pattern with best evidence for improving liver health, with high-fiber and whole foods that are low in saturated fat and added sugar

• Perform > 150 min/week of moderate-intensity aerobic activity and resistance activities 2-3 times per week

  • Both aerobic and resistance training improve MASLD in proportion to treatment engagement and intensity

• Weight loss goal of a minimum of 5% but preferably > 10%

• Minimize alcohol intake in MASLD. Abstain if moderate fibrosis is present (> F2)

• Promote stress reduction, screen for depression and anxiety annually, and advise adequate sleep and quitting smoking

• Obesity pharmacotherapy may assist with weight loss in the context of lifestyle modification if not achieved by lifestyle modification alone

diabetes pharmacotherapy by stage of MASLD

• For people who are in Stages 1-3 of MASLD, we are thinking about a GLP-1 or GLP/GIP

• We might even use it in combination with pioglitazone. In adults with T2D and biopsy-proven MASH or those at high risk for liver fibrosis (based on noninvasive tests):

  • Pioglitazone, a GLP-1R agonist, or a dual GIP/GLP-1R agonist is preferred for glycemic management because of potential beneficial effects on MASH

  • Combination therapy with pioglitazone + GLP-1R agonist can be considered for treating hyperglycemia in adults with T2D with biopsy-proven MASH or those at high risk of liver fibrosis (identified with noninvasive tests) because of potential beneficial effects on MASH

• There is data with SGLT2I, but they are weaker

dose-dependent mechanism of GLP-1R agonists on weight

• As you increase the dose of GLP-1R agonists, you lose more weight

  • When studies pushed the liraglutide dose all the way to 3 mg (Saxenda), there was no more lowering in A1c but greater weight loss regardless

• The question became: Can you use GLP-1R receptor agonists for people who simply want to lose weight?

  • Yes! They are phenomenal in weight loss!

  • Tirzepatide > Semaglutide > Liraglutide 3 mg

  • However, in reality, 20-50% of patients abandon therapy within 1 year due to unmanaged GI adverse events, side effects, and costs. Overall, only 27% continue at the 1-year mark

safety profile of GLP-1R agonists

• Adverse effects:

  • Gastrointestinal (NVD, constipation) - Most common

  • Reduced bowel motility

  • Decreased gastric emptying → Increased bile production → Gallbladder disease

  • AKI - Not likely

• Possible:

  • Sarcopenia

  • Neuropsychiatric events

• Doubtful:

  • Retinopathy

  • Thyroid cancer

  • Pancreatitis or pancreatic cancer

educating on GI side effects of GLP-1R agonists

• For nausea…

  • Do NOT eat if not hungry

  • Reduce meal size. Eat half the usual amount, drink 8 oz of water, and reassess hunger

  • Stop eating once full

  • Decrease intake of high-fat or spicy food

  • Slow dose titration (allow at least 2-4 weeks between dose increases)

• For constipation…

  • Maintain adequate water intake

  • Consider stool softeners (e.g., docusate sodium)

  • Consider polyethylene glycol (MiraLAX) for persistent constipation

AVOID GLP-1R agonists in people with a history of…

• Gastroparesis

• Irritable bowel syndrome (IBS)

dose titration strategies for GLP-1R agonists

• Strategy #1: Forced escalation

  • Escalate dose every 4 weeks in the absence of adverse effects

  • Advantages:

    • Replicates clinical trial procedures

    • Expect similar outcomes to those observed in clinical trials

• Strategy #2: Individualization

  • Increase dose based on weight loss and tolerance

    • A healthy weight loss rate is 0.5-2 pounds per week

    • Increase dose if weight loss plateaus or is less than 1-2 pounds per week

  • Advantages:

    • Use the lowest, effective dose to achieve goals

    • Minimizes adverse effects and DDIs

Note: A higher number of dosing options coupled with longer duration at the dose decreases GI side effects and improves drug persistence

pancreatitis with GLP-1R agonists

• The most common causes of acute pancreatitis are gallstones and alcohol abuse

• Diabetes increases the risk of pancreatitis 3-fold

• Monitor all patients for signs and symptoms of pancreatitis

  • Use with caution in patients with a history of pancreatitis

  • Persistent severe abdominal pain, sometimes radiating to the back, with or without vomiting

  • Promptly discontinue GLP-1 agonists and other potentially suspect drugs if symptoms develop

• In controlled studies of GLP-1R agonists: No significant increase in severe hypoglycemia, retinopathy, or pancreatitis across all trials

  • The concern for pancreatitis was related to the site of action of incretins

  • The concern for retinopathy was related to fluid shifts resulting from rapid weight loss, as it appeared patients were stopping not only eating but drinking water in general. It is recommended patients with a history of retinopathy get a baseline eye exam to ensure it is not progressing

thyroid C-cell tumors with GLP-1R agonists

• Similar FDA warning for all GLP-1 receptor agonists

• Long-term exposure of rats and mice to liraglutide stimulates calcitonin release from thyroid C-cells and causes hyperplasia of the thyroid gland

• However, this phenomenon was not apparent in monkeys and the relevance of this to humans is unknown

  • FDA concluded that the benefits of liraglutide outweigh the potential risks suggested by the rodent data

  • A cancer registry was established to monitor medullary thyroid cancer  incidence over the next 15 years

  • Counsel patients regarding risk of medullary thyroid carcinoma (MTC)

  • Avoid in patients with a personal or family history of MTC or in patients with multiple endocrine neoplasia syndrome type 2 (MEN2)

• In controlled studies of GLP-1R agonists in humans: No significant increase in cancer risk with GLP-1R agonist therapy

  • GLP-1R agonists are safe for use in people with hypothyroidism without a history of MTC or MEN2

  • However, avoid in patients with a personal or family history of MTC or in patients with multiple endocrine neoplasia syndrome type 2 (MEN2)

ASA guidance on holding GLP-1R agonists before surgery

• Assess risk factors

  • Anesthesiologists should assess individual patient risk factors for delayed gastric emptying, such as higher doses of GLP-1R agonists, recent dose escalation, or pre-existing gastrointestinal symptoms

  • Consider rapid sequence intubation, longer liquid fast, or POC ultrasound to reduce risk

• If a patient has been on a GLP-1R agonist for a long time and have had no GI side effects for the entire therapy, there is no need to hold the medication

• If we do decide that we have to hold the GLP-1R agonist because the patient just recently uptitrated their dose or has frequent nausea…

  • For daily formulations: 1 day prior

  • For weekly formulations: 1 week prior

when to stop GLP-1R agonists when used for weight loss

• Consider stopping GLP-1 receptor agonists after weight loss goal is maintained for at least six months to reinforce positive lifestyle changes

• The long half-life of once-weekly agents does not require tapering

• Note: Dulaglutide 4.5 mg provides modest weight loss, but is indicated only for people with type 2 diabetes

physiology of the body (without diabetes)

• After eating, carbohydrates are broken down into glucose, which enters the bloodstream. Increased blood glucose stimulates pancreatic β-cells to release insulin

  • Insulin binds to receptors on target cells → promotes glucose uptake into skeletal muscle and adipose tissue + promotes glucose storage as glycogen in the liver and muscle → decreases glucose levels

  • Insulin also inhibits hepatic glucose production and promotes an overall fed/storage state → maintains glucose within a normal range

• When you’re low on glucose in your blood, glucagon targets the liver to break down glycogen stores and release glucose back into the bloodstream to raise levels

pathophysiology of diabetes

• Diabetes mellitus (DM) = chronic hyperglycemia due to inadequate insulin secretion, impaired insulin action, or both

• Type 1 DM: autoimmune destruction of pancreatic β-cells → absolute insulin deficiency → little/no insulin → decreased glucose uptake + increased hepatic glucose production → hyperglycemia

• Type 2 DM: insulin resistance develops → cells become desensitized to insulin over time → β-cells initially compensate by increasing insulin secretion → progressive β-cell dysfunction eventually leads to relative insulin deficiency → hyperglycemia

• Persistent hyperglycemia → nonenzymatic glycation and metabolic/vascular damage → microvascular and macrovascular complications.

pathophysiology of T1D

• Pancreatic β-cell destruction leading to absolute insulin deficiency

• Can either be…

  • Immune-mediated: cellular-mediated autoimmune destruction of β-cells defined by presence of one or more autoimmune markers (e.g., autoantibodies to insulin, GAD, etc.)

  • Idiopathic: permanent insulinopenia but have no evidence of autoimmunity; unknown cause

clinical presentation of T1D

• Sudden onset (usually < 35 y.o.)

• Majority BMI < 25 kg/m²

• Polydipsia (excessive thirst)

• Polyphagia (excessive hunger)

• Polyuria (excessive urination)

• Fatigue

• Weight loss

(The 3 Ps are classic symptoms of hyperglycemia)

pathophysiology of T2D

• Insulin resistance

• Progressive impaired insulin secretion

• Result: Need for insulin rises + progressive reduction in β-cell mass and function

clinical presentation of T2D

• Typically asymptomatic

• Gradual onset (usually > 35 y.o.)

• Majority overweight or obese

• Polydipsia and/or polyphagia

• Polyuria

• Blurred vision

• Fatigue

screening for T1D

Screening is not recommended in asymptomatic general population

screening for T2D

• All adults age > 35 years, regardless of weight

• Asymptomatic adults of any age who are overweight or obese (BMI > 25 kg/m² or 23 kg/m² in Asian Americans) and have at least one additional risk factor*

• People diagnosed with gestational diabetes should be screened every 3 years (lifelong)

• People with HIV, exposure to high-risk medicines, or history of pancreatitis

• If tests are normal → Repeat at a minimum of 3-year intervals

• If significant risk factors or pre-diabetes (A1c > 5.7%, impaired glucose tolerance (IGT), impaired fasting glucose (IFG)) → Screen yearly

risk factors for developing T2D

• Age (testing should begin no later than 35 y.o. for all people)

• First-degree relative with diabetes (parent, sibling, child)

• High-risk ethnicity (African American, Latino, Native American, Asian American)

• History of CVD

• Individuals with polycystic ovary syndrome (PCOS)

• HTN (BP > 130/80) or on HTN therapy

• Certain lab values

  • HDL < 35 mg/dL

  • Triglycerides > 250 mg/dL

• Certain medications (glucocorticoids, statins, thiazides, some HIV medications, second-generation antipsychotics)

• Physical inactivity

• Other clinical conditions associated with insulin resistance (severe obesity, acanthosis nigricans)