Advancements in GLP-1 Receptor Agonists: Where we are and where we're going (Felton, 2/19/25)

 A recording of the presentation is available HERE.

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Many thanks to Dr. Erin Felton for an excellent presentation on a hot topic: GLP-1 Receptor Agonists, the class of medications that is literally taking our nation by storm. As Dr. Felton said during her presentation, direct to patient advertising and word of mouth has led to droves of patients coming to their providers asking for these medications, most commonly, for weight loss. 

A recording is available above.

comorbidities associated w/obesity

Here are my notes:

• obesity is a chronic, relapsing , treatable multifactorial disease
• it is associated with comorbidities (e.g. HF, DM2, uterine cancer) and complications
• BMI, as we know, is not a perfect measure, but it's what we currently have
• According to 2023 CDC data: 1/5 US adults are obese
• By 2030, there are estimates that 1/3 US adults will have a BMI>30
• There are racial and socioeconomic disparities associated with obesity
• these are particularly evident in communities of color (black and Latinx)
• 

We must be aware of our own "fat bias" in medicine

• always ask patients for permission before discussing their weight
• give patients a right to decline weighing in
• focus on chronic disease aspect of obesity (rather than weight)
• consider how to create a supportive environment for obese patients

There are several FDA approved medications for obesity, the GLP-1 Receptor Agonists are the new kids on the block, but see the image below for all meds that are currently approved for long-term usage, short-term usage, and off label usage:

GLP-1 is an endogenous incretin hormone that is produced by the L cells in the distal ileum and colon in response to food intake. GLP-1 receptor agonists mimic this mechanism. In addition, GLP-1 receptors are expressed in multiple organs: GI tract, pancreas, hypothalamus, brainstem, heart, kidney, muscle, fat cells. It is thought that effects on the brain influence appetite and satiety. Receptors in the GI tract decrease gastric emptying and slow gastric motility.

Current GLP-1 Receptor Agonists:

Murphy EJ,”What’s new in Endocrinology”, Medical Management of HIV Conference, 2024

The newer kid on the block are multi-targeted incretin therapies, including GIP, which is secreted more proximally in the small intestine; it stimulates downstream GLP-1, enhances insulin, promotes satiety and seems to be associated with less nausea.

The newest agent, tirzepatide, is a combo of GIP/GLP-1. There are currently two versions of tirzepatide on the market: Mounjaro (indication: DM) and Zepbound (indication: weight loss). Zepbound is currently covered by Partnership medi-cal.

Current combos/multi-targeted incretin therapies:

Specific prescribing info for semaglutide and tirzepatide:

There are no direct head to head trials comparing semaglutide to tirzepatide.

Indirect comparisons suggest more weight loss with tirzepatide, as well as potentially lower side effect profile.

Side Effects

We should definitely be talking to our patients about side effects when we are prescribing these medications.

The most common side effects of GLP-1 medications are GI symptoms (nausea, vomiting, constipation, etc). GI symptoms are extremely common (25-40%) but do decrease over time. In many trials, a large percentage of people self-discontinued the medications due to side effects. 

Going slow can mitigate the GI side effects, as they do abate over time. Reducing meal size and adopting a low fat (and low glycemic index) diet can also reduce side effects. Patients should have some nutritional counseling (even if it's just from the PCP). Increasing fiber may also help. 

Dizziness and dehydration have  also been reported. This could be due to morning hypoglycemia. Small frequent meals and maintaining good hydration are recommended.

As mentioned above, the newer combination medications MAY be better tolerated.

Contraindications:

Contraindications to these medications include: medullary thyroid cancer/MEN2, pregnancy, hx pancreatitis or gallstone disease (relative/not absolute). Of note, there was some post-marketing signal in 2023 suggesting a correlation with suicidality, further assessment in 2024 did not confirm this signal, but consider ongoing assessment in patients with a hx of depression or SI. 

Starting/stopping

There is good evidence that discontinuing GLP-1 meds lead to gaining back a large percentage of weight that was lost (though overall, pts do maintain a small percentage of weight lost). A retrospective cohort study of 125K patients, just released in 2025 found that 53% of patients and 72% of patients had discontinued these medications at 1 and 2 years, respectively. Somewhere between 1/3 and 1/2 of these patients  resumed these medications within 1 year of stopping.

Wilding et al, Step 1 Extension, Diabetes Obes Metab 2022

About insurance:

• Medicare specifically does NOT cover weight-loss drugs. However, as of 3/24, Medicare will cover semaglutide for obese patients for CVD prevention IF they have documented CVD (e.g. prior MI, PVD, etc)
• Only about 20% of Medicaid programs cover weight loss drugs (Medi-Cal does! See the image below showing the current PHP covered medications)
• Only about 25% of employer-based insurance cover weight loss drugs
• Locally, Kaiser does NOT cover weight-loss drugs unless you have another specific indication (e.g. DM2, HFrEF, CVD)
• There has been varying pharmacy supply

Patient Counseling pearls

• There is significant weight regain after discontinuation of GLP1s, though studies so far have still showed a net loss. 
• Most patients who newly initiate treatment with GLP RA discontinue within 2 years. 
• High burden of GI side effects, gets better with time.
• Need for long term therapy due to weight regain?
• Other factors for adherence: high cost, availability of medication
• All studies done at target dose of 2.4mg

Finally, there are more and more studies being published showing benefit in outcomes other than weight loss. These include CVD, OSA, MASN/MAFLD, dementia, Parkinson's, disease, as well as substance use disorder. Stay tuned. 

Model Minority: Asian American Health (Wu, 2/12/25).

Many thanks to Dr. Jimmy Wu for a really great Grand Rounds presentation this week titled Model Minority: Asian American Health. He shared part of his personal journey as well as local and national epidemiological data to explore some of the unique health challenges of some of the diverse AAPI communities.

A recording of the presentation will be available HERE (please check back for the recording).

My notes: 

• The concept of Asian Americans as "the Model Minority" was coined in the 1960s during the Civil Rights Movement when conservative politicians looked for opportunities to divide minority groups. Their goal was to curate the erroneous perception that all Asian Americans were doing well because they were hard working, and why couldn't other BIPOC communities do the same?
• This was propagated through a 1966 NY Times article on Japanese Americans and in the 1980s Time magazine feature on Asian American whiz kids.
• The ultimate goal to pit communities of color against one another, unfortunately, was quite successful.
• For Asian Americans, being labeled as a model minority is NOT a win win
• AAPI is now used as an umbrella term, including: Asian + Native Hawaiin and Pacific Islander
• Important to note that data disaggregation is a real challenge >> AAPI is NOT a huge monolith, diverse populations, cultures and needs

• 

AAPI Demographics

• 24 million AAPI people in US (7.5%), 41% growth from 2010 to 2020
• In CA, 7 million AAPI people, the fastest growing ethnic group
• In SoCo, there are 21K (5%), which is a 10% growth over the last decade
• Filipino>Chinese>Vietnamese>Indian>Japanese>Laotian>Cambodian

Portrait of Sonoma Health Development Index (HDI) is higher than other BIPOC communities:

Mental Health

-Mental health stigma runs strong in AAPI communities

-AAPI youth in SoCo have the second highest youth suicide rate among 9 Bay Area counties

-mental health during COVID was heavily impact by "Asian Hate",

-AAPI have very low help-seeking behaviors for mental health services (36.1% vs. 56.1%) 

Substance Use

-Tobacco use>> high quit attempts without help-seeking

-Gambling

-high rates of ETOH, IVDU

Barriers to Primary Care Access

-insurance (especially Fijian and Samoan caregivers/seniors)

-language

-culture/gender concordance

-use of traditional CAM therapies

-historic mistrust of Western healthcare system (e.g. experiences in Refugee camps)

Preventive Health

-preventive care is not a cultural normal

-lower rates of cancer screenings (esp in AAPI patients with limited English proficiency)

-high rates of ASCVD risk, even with normal BMI

-cancer as leading cause of death in AAPI in US (lung, liver, colon), compared to ASCVD in white population

Elderly AAPI

-caregiver burden, cultural value of filial piety

-mental health>> stigma, saving face

-end of life norms

Updates in HIV Care and Prevention: The Critical Importance of Choice (Pastor, 2/5/2025)

 A recording of this presentation is available HERE.

Check back for my notes soon!

Reflection and Connection: Surviving Residency and the Start of Personal and Professional Development Groups (Addison, 1/29/25)

See a recording of this session HERE. 

Many thanks to Dr. Ritch Addison, long time behavioral health faculty and foundation layer for our Personal and Professional Development (P&PD) Groups that still run every Thursday at Santa Rosa Family Medicine Residency. 

He spent his time with us on Wednesday morning reflecting on the experience of residency training: the constant pressure, the feeling of never enough time, too much to do with the time, dying patients, asking for help vs. not asking for help, learning the ropes and the conflict and contradiction of ideals/values and visions with every day practices. 

I cannot do his 40+ years of wisdom justice with a summary here (just watch the recording), but I do want to highlight and remind us of his model for Surviving Residency:

1) Covering over> the focus on mastering the procedures of medicine, which requires putting on blinders so that you can do what you have to do to get through your day/rotation/year/training.

2) Over reflecting>> too many reflections, filled with painful self-doubt, feelings of imposter syndrome, Did I make the right choice?

And, as Ritch stressed, neither state is stable. In fact, it's the jarring motion between the two modes that is what is so challenging in residency. "You need time to unload one experience and load the next, and you just don't have time". 

The answer? Ritch says, is connection. A place where you can do just this -- unload the conflictual and unconscious feelings, take a step outside those jarring moments>> P&PD. 

The Pelvic Exam through a Trauma Informed Lens (Goldberg-Boltz, 1/22/25)

A recording of the presentation is available HERE. 

Many thanks to Dr. Nicole Boltz for an excellent presentation this week on The Pelvic Exam through a Trauma-Informed Lens. This was both a practical and meaningful presentation -- one which will stick wit you as you move quickly through your clinic day.

Here are my notes:

• If you do intimate/pelvic exams, consider reading this letter: Dear Doctor: A letter from a survivor or sexual trauma to all medical professionals, by Carol Chandler

• We should all be doing universal sexual assault screening for ALL patients (do not leg bias guide you). There are many ways to do this screening that are patient-centered, but there is no one right way. Remember it may take many visits (or many years) for a patient to feel comfortable enough to disclose. Meet the patient where they are.

• The four Rs of a trauma-informed approach (SAMHSA)
• Realize: Understand the impact of trauma on people and communities
• Recognize: Identify the signs and symptoms of trauma
• Respond: Integrate knowledge about trauma into policies, procedures, and practices
• Resist re-traumatization: Take action to prevent re-traumatizing individuals

• Find humor even in the hard things we do: https://www.instagram.com/reel/C7kbKUpsuAD/?igsh=NTc4MTIwNjQ2YQ%3D%3 (this is super funny!!!!!!)

Okay, onto the Pelvic Exam:

• Prepare a safe and non-judgmental space
• ideally meet the patient prior to the exam or procedure (when dressed!)
• set the ground for empowerment: they are in charge, we go at their pace, they can stop whenever
• explain the procedure and purpose
• ask if they want to see/touch/listen to the instruments
• ask of they want a support person in the room
• ask if they want you to know anything before the exam
• ask what can be done to make the exam more comfortable
• ask for any questions
• Language, language, language
• the goal is to use non-triggering language
• empower the patient with your language (they are in charge)
• framing matters: "when/if you are able" and "you MIGHT feel" and "would you like me to proceed or shall I pause?" and "tell me when you're ready"
• consider these substitutions: exam table (instead of bed), drape (rather than sheet), foot rests (rather than stirrups), instruments (rather than device names)
• Body positions matter: for some, certain positions can be triggering. Ask which position is most comfortable for them
• in/out footrests, frog legged, on exam table
• never force legs open
• ask permission to move/touch body, considering tapping knee to get legs to drop
  
  
  
  
• During exam
• Consider distractions: toe wiggling, tapping on knees in a pattern, tapping on chest, deep breathing
• Getting dressed: After the exam, allow patient to get dressed before you discuss findings/assessment/plans. Then explain what you did, what you saw, what are the next steps.

Assessing Preferences for Patients who Lack Decision Making Capacity (Andereck & Fulbright 1/15/25)

 A recording of this presentation is available HERE.

Deep gratitude to Dr. William Andereck and Robert Fulbright for a thought-provoking presentation this week on Decision-making Capacity. This is an issue that we encounter with surprising frequency on the inpatient medicine service, and the distress that decision-making capacity causes on patients and providers is intense. 

This is definitely a presentation that is better watched than summarized, but I did take a few notes. 

The concept of Patient Consent first arose in 1914, Benjamin Cardoza, "Every human being with a sound mind has a right to determine what he does with his own body."

This concept, of course, was brought to light in the context of the Tuskegee Study (which ran 1932-1972) and the subsequent Belmont Report (published in 1979). It was the Belmont Report (which I don't think I have ever heard of before this lecture) in which Informed Consent became a thing. 

The Belmont Report outlined 3 principles:

1. Beneficence
2. Justice
3. Respect for persons (which was ultimately morphed into Respect for the autonomy of the person)

Non-maleficence (do no harm) was not included.

Of note, Dr. Andereck stressed, autonomy at the time was not meant to be interpreted as "the right to demand whatever you want". Rather, it was meant as a freedom from interference, the right to say "no". Somewhere along the last 50 years, it has become interpreted as a "positive right". From Dr. Andereck's perspective, early bioethicists were clear that if a medical intervention does not benefit the people, there is no obligation. 

Competence is defined as 1) having values and goals 2) the ability to communicate those and 3) reasons to do or not do something related to this goals. Competence is NOT the same as Capacity. 

Capacity is specific>> the question should always be capacity for what?

Capacity it temporal>> it can wax and wane

Capacity is the perspective of a 3rd party>> patients never tell us that they are incapacitated. It must be observed from an outside party.

Applied to medicine, then, capacity becomes

1. the ability to 

Long COVID (Siqueiros, 1/8/25)

A recording of this presentation is available HERE.

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This week's Grand Rounds on Long COVID was a practice-changing presentation! If you are caring for patients in a primary care setting or know someone who is suffering from Long COVID, I highly recommend you watch the entire presentation by Dr. Marcos Siqueiros, of KP Santa Clara. Dr. Siqueiros covered a TON of material, including what is known about Long COVID's epidemiology, risk factors, pathophysiology, and both medication and lifestyle/behavioral recommendations for management of Long COVID. 

Here are my notes:

Unfortunately, there are a number of different definitions of Long COVID

• CDC: symptoms persist >4 weeks after COVID (live virus no longer detectable)
• WHO: symptoms present >3 months after acute COVID illness, lasting at least 2 months
• National Academies of Science: infection-associated chronic conditions after SARS-COV2 infection, present for at least 3 months as either continuous, relapsing/remitting or progressive, affecting one or more organ systems.
• PASC: Post-Acute Sequalae of COVID, lasting 4 weeks or longer

Epidemiology

17-18% of all US adults reported having long COVID at some point since 2020, ~7% having ongoing symptoms

20 million adults in US, 2 million adults in CA are experiencing Long COVID today

Long COVID numbers have declined, but rate has been consistent 6-7%

Characteristics of  those who develop Long COVID

-higher rates of comorbid/preexisting health conditions, tend to have experienced more severe COVID illness or were hospitalized

-unvaccinated, greater # of infections PRIOR to vaccination increases risk of Long COVID

-adult population slightly lower (3x rate for people in 50s compared to 80s)

-higher rates in Females, Latinx/Hispanic

-increased rates in white Americans, rural regions, lower income households

-bisexual/transgender more likely to report Long COVID sx

Economic costs of Long COVID

-2-4 million people in US out of work due to disability to due Long COVID

-$168 billion/year, revised to $3.7 trillion/year

Clinical Manifestations

Long COVID symptoms can lingers weeks, months, longer. Severity and type can vary. Most patients will experience resolution of their symptoms by 1 year. Patience is key.

>200 symptoms under the Long-COVID umbrella, extremely non-specific, hard to categorize broadly

Symptoms tend to wax and wane, can be linked to any severity of acute infection (most people now only get mild COVID)

Symptoms vary according to variant

Pathophysiology

A complete understanding of pathophysiology is not established, but basic science is working to understand mechanism/pathways that can explain symptoms. 

-Direct AND indirect mechanisms

-ACE2 receptors ubiquitous and expressed in various tissues in the body (heart, lungs, GI), involved in breaking down Angiotensin 2 to promote homeostasis, also downregulates inflammation. If left unchecked/unregulated, can get uncontrolled/chronic inflammation. When COVID infects the host, binds to ACE2 receptor sites, which makes it less available to break down Angiotensin 2>> release of cytokines and inflammatory mediators>> immune dysregulation and chronic inflammation

Clinical management 3 common conditions:

1) Chronic Fatigue is the MOST common symptom reported with Long COVID, can last weeks/months/years. Lingers the longest. This is profound and unusual persistent sense of exhaustion after simplest of activities, including ADLs. By definition, Chronic Fatigue must be present >6 months, otherwise it is called Long-COVID with prolonged post-viral fatigue. 

Post-Exertional Malaise (PEM) commonly expressed by people with Long COVID. Can be induced by either physical or cognitive activities. Sudden drop of energy and profound fatigue that leads to struggle to complete activities for the day. Can be hours to days. Creates frustration, discouragement and fear. 

A small observational 2023 study from Amsterdam found that abnormalities due to PEM are due to significant defects in skeletal muscle due to exercise-induced myopathy with infiltration of immune t cells and amyloid deposits. Also severe reduction of mitochondrial enzyme activity>> premature lactic acid buildup in skeletal muscles. This explains marked reduction in exercise capacity. 

Treatment/Management for Long-COVID associated Chronic Fatigue

Medication

Low dose naltrexone (LDN), non selective opioid antagonist, seems to help with chronic fatigue. Well tolerated, reduced CNS inflammation, upregulates endorphins.

Dosed at bedtime 0.5mg-4.5mg (start low go slow, increase q2-3 weeks)

Side effects: vivid dreams, insomnia, GI upset (mild). If sleep disturbances, can give earlier in day

Anecdotally, about 1/2 of people that try LDN report some improvement in fatigue and brain fog

Lifestyle 

Stress relief, sleep, nutrition 

People able to reduce sugar and caffeine intake demonstrate less fatigue

Avoiding dehydration is key

Review meds and others substances that can worsen fatigue

Control comorbid chronic conditions that also exacerbate fatigue (DM, OSA)

Pacing is a mindset of learning to conserve energy balancing time spent on activity vs. time spent on rest with goal to increase participation in activities. Deliberate self-management strategy. Has evidence in Long COVID to improve energy and endurance

2) Brain fog is an umbrella term used to describe cognitive dysfunction associated with Long COVID. It is vague. No way to distinguish. Areas of cognition impacted: memory (working memory), attention (conversation details, following complex stories, multi-tasking), fluency (word finding), executive function (step by step actions, organizing or performing cognitive tasks). 

Possible mechanisms of brain fog: 

Direct: COVID enters CNS by retrograde transport along olfactory nerves, virus can cause direct toxic injury

Indirect: disrupted blood brain barrier, more permeable and porous. Disruption of BBB allows entry of inflammatory mediators to enter the CNS, disrupting cognitive function (2023 study in Nature Neuroscience found elevated biomarkers in people with long COVID and brain fog similar to TBI patients). Further study needed.

Off label Medications

• Guanfacine (old drug used for hypertension, selective alpha 2 receptor agonist, thought to improve working memory, improved attention. Used in TBI, ADD). Can drop BP. Protocol out of Yale combine guanfacine with NAC. (see below)
• Also SSRI/SNRI, stimulants (care w/habituation, tolerance, should be used rarely), amantadine (influenza anti-viral) increases dopamine release and prevents reuptake (used in TBI and CFS, 100mg BID)
• LDN (see above)

Lifestyle 

Stress reduction, screening for and management of anxiety/depression

Reduce neuroinflammation with healthier eating (low in carbs, simple sugar, low in caffeine)

Avoid neurotoxic substances: ETOH, cannabis, other drugs

Limit screen time (neuro-stressor), too much screen time can overtax brain and worsen brain fog

Quantity/quality of sleep: sleep hygiene rests nervous system, reduces neuroinflammation (turn off electronic devices)

3) Orthostatic Intolerance (OI) and Postural orthostatic tachycardia syndrome (POTS)

OI: uncomfortable symptoms that arise when moving to an upright position (faint, dizzy, palpitations, chest pain, SOB, blurry vision, coat-hanger headache). Often patients with OI need to lay down or sit to make symptoms to stop.

POTS: Same symptoms of OI, accompanied by HR increases >30 bpm within 10 minutes of standing

OI and POTS are both due to dysregulation of Sympathetic and Parasympathetic balance, probably involves Vagus nerve. Need to r/o underlying cardiac conditions! 

NASA lean test can distinguish OI vs. POTS

Three pillars of management of OI/POTS:

1. Hydration: ultra hydration, drink at least 2L of fluid/day, wake up and hydrate first thing int he AM, hydrate every 2-3 hours
2. Salt Loading: increase sodium intake to at least 3000mg/day, can go as high as 10,000mg/day (very high), add salt or sodium tablets
3. Compression: compression garments in lower limbs, torso

                    mid-thigh/waste-high compression stocking (20-30mmHg compression)

                    belly/abdominal binders

                   commercial body shapewear (e.g. Spanx)

Also, discourage people from laying around in bed for prolonged time, can worsen symptoms in the long run. If rest needed, avoid resting flat (HOB up by 6-10 inches) to minimize orthostasis. Get up slowly, give CNS chance to accommodate posture

Avoid anything that worsens dehydration: alcohol, caffeine, hot temperature (stream baths, hot day)

Medications (see image below)

Non-selective BB, e.g. propranolol

Flourinef (BP)

Midodrine

Ivabradine

IV saline boluses

Additional Notes:

-Paxlovid not shown to treat or prevent Long COVID

-Vaccines do prevent Long COVID, if shots tolerated, they are probably beneficial (large multi-national studies). The more boosters you get prior to getting COVID, less likely you are to get Long-COVID. For some people, vaccination improved Long COVID symptoms. However, vaccination (and reinfection) can also aggravate long COVID symptoms. Shared decision-making needed. Reasonable to pursue vaccination even in setting of long COVID. 

Be holistic, flexible, tailor to patient's individual needs.

Multidisciplinary approach is key, including PT/OT/SLT, nutrition, health education, mental health services

Advocate for patients. Validation and support are important. Bring patients in office for in person exam (no later than 3 months after symptoms started, rule out other chronic conditions)

There are no biomarkers to identify Long COVID, it's a clinical diagnosis

Look for red flag conditions (e.g. heart disease, metabolic/endocrine, etc) and optimize underlying chronic conditions.

Patience is key.