POTD: Wegovy and Ozempic

GLP-1 class medications have recently grown in popularity. Two of the most popular GLP medications today, Wegovy and Ozempic, both have semaglutide as their active ingredient. They have come into the limelight after a large double-blinded study published in NEJM, showed an average 14.9% decrease in weight in obese patients given semaglutide on top of lifestyle modifications, compared to 2.4% in the control arm (see research summary at end). It should be noted that this study was funded by Novo Nordisk, the pharmaceutical company that produces semaglutide. Coincidentally, Novo Nordisk’s stock valuation has tripled over the last 2 years since the release of the study.  

What are GLP-1 agonists?

GLPs were first hinted at in the 1960s, when scientists using radioimmunoassays to study glucagon formation in the pancreas unexpectedly saw elevated activity in the intestines during their surveys. Over the next decade, gut proteins were isolated and found to have 50% sequence similarity to glucagon, and these proteins were termed glucagon-like peptides 1 and 2 (GLP-1 & 2)1. Further studies suggested that GLP-1 stimulates both synthesis and secretion of insulin via multiple cAMP-dependent pathways.

Of significance to today’s popularity is evidence of GLP-1 mediated suppression of appetite via CNS targets1. Other interesting findings of GLP-1 suggest possible cardioprotective characteristics. Animal studies showed increased myocardiocyte glucose uptake and decreased reperfusion injury in dogs and rodents induced to have MI despite controlling for weight1.

Today, GLPs can be generally classified into 2 categories – long acting (administered once weekly) or short acting (administered daily), though most remain approved only for treatment of DM. In addition to semaglutide, another GLP-1 obtaining FDA approval for weight loss includes tirezepatide (Zepbound)2.

What are the adverse effects I need to be aware of?

Although GLP-1 class medications have been on the market for 2 decades now, rarer serious side effects are now being seen more simply due to recent increases in the number of people on these medications3. One effect that may impact emergency medicine interventions is GLP-1 induced delay in gastric emptying, increasing risk of aspiration in patients with airway compromise. Though the absolute risk of GLP-1 related aspiration during intubation is still low, case studies of large volume emesis in patients who fasted 20 hours have been concerning enough to prompt the American Society of Anesthesiology to issue a guidance suggesting holding GLP-1 agonists prior to elective intubations4,5.

Other serious adverse effects of GLP-1 include 9x increased risk of pancreatitis, 4x increased risk of bowel obstruction, 3x increased risk of gastroparesis, though again the absolute risk of all these events were still < 1% per year.

Do I need to be worried about hypoglycemic events?

GLP-1s do not usually cause hypoglycemia, unless combined with another agent/therapy that is associated with hypoglycemia such as sulfonylureas or insulin injections6,7.

How accessible is semaglutide?

In short, not very. Current demand for the mediation is outpacing production. Novo Nordisk has reported they have run out of stock of Wegovy 1.7mg for the month of December and anticipate possible disruptions of related GLP-1 liraglutide supply8. Wegovy’s demand has crept into increased off-label prescriptions of Ozempic, reducing access for patients with diabetes9. Current prices on GoodRx show $900/month for Ozempic and $1400/month for Wegovy.

References

1. Müller TD, Finan B, Bloom SR, et al. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019;30:72-130. doi:10.1016/j.molmet.2019.09.010

2. FDA Approves New Medication for Chronic Weight Management. U.S. Food and Drug Administration. Accessed December 26, 2023. https://content.govdelivery.com/accounts/USFDA/bulletins/37a0d49

3. Ruder K. As Semaglutide’s Popularity Soars, Rare but Serious Adverse Effects Are Emerging. JAMA. 2023;330(22):2140-2142. doi:10.1001/jama.2023.16620

4. Gulak MA, Murphy P. Regurgitation under anesthesia in a fasted patient prescribed semaglutide for weight loss: a case report. Can J Anaesth J Can Anesth. 2023;70(8):1397-1400. doi:10.1007/s12630-023-02521-3

5. Patients Taking Popular Medications for Diabetes and Weight Loss Should Stop Before Elective Surgery, ASA Suggests. Accessed December 26, 2023. https://www.asahq.org/about-asa/newsroom/news-releases/2023/06/patients-taking-popular-medications-for-diabetes-and-weight-loss-should-stop-before-elective-surgery

6. Nauck M. Incretin therapies: highlighting common features and differences in the modes of action of glucagon‐like peptide‐1 receptor agonists and dipeptidyl peptidase‐4 inhibitors. Diabetes Obes Metab. 2016;18(3):203-216. doi:10.1111/dom.12591

7. Suran M. As Ozempic’s Popularity Soars, Here’s What to Know About Semaglutide and Weight Loss. JAMA. 2023;329(19):1627-1629. doi:10.1001/jama.2023.2438

8. Supply update. Novo Nordisk. Accessed December 26, 2023. https://www.novonordisk-us.com/content/nncorp/us/en.html

9. McPhillips D. CNN Exclusive: Prescriptions for popular diabetes and weight-loss drugs soared, but access is limited for some patients. CNN. Published September 27, 2023. Accessed December 26, 2023. https://www.cnn.com/2023/09/27/health/semaglutide-equitable-access/index.html

Marine Toxins

Ciguatera:

Background:

Ciguatera is a type of food poisoning caused by consuming fish that have accumulated a heat-stable toxin produced by dinoflagellates. The toxins, known as ciguatoxins, primarily concentrate in large predatory reef fish in tropical and subtropical waters.

Clinical Manifestations:

Symptoms include gastrointestinal issues 3-30 hours after consumption (nausea, vomiting, diarrhea), neurological effects (numbness, tingling, temperature reversal***), and cardiovascular manifestations (bradycardia, hypotension). Neuro symptoms may last for weeks or even months (up to 2% of people have this for years).

***the one time I had a patient I thought may have ciguatera, my dumb a** was at the bedside with a bag of ice on their leg, asking this person if they thought it was hot or cold. They looked at me blankly and told me it was cold….

Clinical Management:

There is no specific antidote for ciguatera. Treatment focuses on supportive care, including intravenous fluids for dehydration and medications to alleviate symptoms such as pain and nausea. Amitriptyline and gabapentin are often used for neuro symptoms.

There is note of mannitol use for neuro symptoms if used in the first two days, but showed no benefit over saline in a RCT.

Clinical Disposition:

Most patients are discharged.

Scombroid Poisoning:

Background:

Scombroid poisoning results from the ingestion of improperly handled or spoiled fish, particularly histidine-rich fish like tuna, mackerel, and mahi-mahi. Bacterial decarboxylation of histidine leads to the formation of histamine. Most common in Hawaii and Florida.

Clinical Manifestations:

Symptoms mimic allergic reactions and include flushing, headache, palpitations, and gastrointestinal distress.

Clinical Management:

Treatment involves antihistamines to alleviate symptoms. In severe cases, epinephrine may be required. Albuterol can be used in cases of respiratory distress.

Clinical Disposition:

Typically patients are discharged.

Tetrodotoxin Poisoning:

Background:

Tetrodotoxin is a potent heat stable neurotoxin found in certain pufferfish species. Ingestion of improperly prepared pufferfish can lead to severe poisoning. The tetrodotoxin binds to and blocks fast-gated sodium channels.

Clinical Manifestations:

Symptoms include rapid onset (30 min) of nausea, vomiting, paralysis, and respiratory failure. Death can occur within hours.

Clinical Management:

There is no specific antidote. Treatment involves supportive care, including respiratory support.

Clinical Disposition:

Admit (floor vs ICU depending on respiratory status)

Friedman MA et al. Ciguatera Fish Poisoning: Treatment, Prevention, and Management. Marine Drugs 2008; 6:456-479

Stratta P, Badino G. Scombroid poisoning. CMAJ. 2012 Apr 3;184(6):674. doi: 10.1503/cmaj.111031. Epub 2012 Jan 9. PMID: 22231690; PMCID: PMC3314039.

Kotipoyina HR, Kong EL, Warrington SJ. Tetrodotoxin Toxicity. [Updated 2023 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507714/

POTD: Angioedema

The direct cause of angioedema is a loss of vascular integrity, which causes localized fluid shift from the blood into swelling in the tissue, hence “angio à edema.” Unlike your typical edema, angioedema tends to be non-pitting and is not gravity dependent.

In general, angioedema can be classified to 3 categories:

• Histamine-mediated

  • Treat w/ antihistamines, steroids, epinephrine

• Bradykinin-mediated

  • Can treat w/ fresh frozen plasma, C1 inhibitor concentrate, or some fancy bradykinin pathway inhibitors.

  • Will not respond to epinephrine, steroids, or antihistamines.

• Other/unknown causes

For your critical patients, assume it is histamine mediated and treat with epinephrine empirically because the histamine pathway is more common, and the swelling tends to worsen very rapidly.

Histamine-mediated

Pathophysiology

• Most commonly caused by allergen exposure causing IgE activation

  • Initial exposure to allergen à sensitization and plasma cell formation à repeat exposure à IgE mediated mast cell activation and histamine release

• Some medications cause generalized mast cell activation

  • Opioids and radiocontrast dyes can do this

  • Will have severe reaction, even on initial exposure

• COX inhibition

  • Caused by NSAIDs

  • Drives precursor molecules towards formation of leukotrienes à mast cell activation and histamine release

Bradykinin-mediated

Pathophysiology: Disruptions to kinin pathway cause increased concentration of bradykinin, leading to angioedema1. This is caused by 2 mechanisms:

• Too much production of bradykinin

  • Hereditary/acquired angioedema causes too little functional C1 esterase inhibitor (C1-INH), which normally regulates bradykinin formation. This essentially releases the breaks and allows uncontrolled bradykinin formation.

  • TPA leads to increased bradykinin precursor as well.

• Too little breakdown of bradykinin

  • ACE inhibitors prevent ACE from breaking down bradykinin

How do I tell what type of angioedema my patient has?

• Testing for C1-INH is not useful in ED due to long turnaround times.

• Histamine-mediated

  • Tends to be more acute and shorter lasting.

  • Usually caused by exposure to allergen

• Bradykinin-mediated

  • Is not usually itchy

  • More commonly affects gastrointestinal mucosa, causing GI symptoms

  • Can be caused by stressor to body – i.e. surgical/dental procedure, infection, emotional stress.

  • ACE-inhibitor mediated. 43% occur within first month of treatment, although can happen years into the course.

  • TPA-mediated usually occurs in conjunction w/ ACE-inhibitor use.

Treatment

• Follow normal ABC pathway

  • Airways can rapidly deteriorate. If intubating, you should have dual setup for surgical airway. Consider awake fiber-optic intubation in airway allows.

  • Fluids and pressors as needed for shock

  • In critically ill patients, follow the histamine-mediated pathway first because this pathway will have patients deteriorate more rapidly.

• Histamine-mediated angioedema

  • 0.3-0.5mg IM epinephrine (1mg/ml)

    • 0.01mg/kg for pediatrics

    • Repeat q5-15min PRN up to 3 doses

    • Consider epi drip if refractory

    • In patients on beta-blocker, consider glucagon 1-5mg IV push, then 1-5mg/h infusion, to bypass beta-blockade.

  • Antihistamines

    • Benadryl, Pepcid

  • Steroids

    • Thought to reduce biphasic reactions, though recent studies are starting to question this2.

• Bradykinin-mediated

  • Fancy drugs

    • Replacement options for C1-INH. These are plasma derived human concentrates.

      • Berinert – FDA approved for acute intervention

      • Cinrynze – FDA approved for prophylaxis only

    • Kallikrein inhibitors to cause decreased bradykinin production

      • Ecallantide

    • Block bradykinin receptors

      • Icatibant

  • Fresh frozen plasma, 2 units.

    • Will have physiologic levels of C1-INH, replacement ACE (a.k.a kininase II). Physiologic concentrations are much lower concentrations than the fancy drugs above, so requires larger volumes3.

    • Paradoxically, will also have physiologic levels of bradykinin and may have autoantibodies to C1-INH that can make angioedema acutely worse4. Case studies suggest this is rare, but be ready to intubate!

References

1.           EM:RAP CorePendium. EM:RAP CorePendium. Accessed December 22, 2023. https://www.emrap.org/corependium/chapter/recgmcfxPSDNkQRTU/Angioedema

2.           Lewis J, Foëx BA. BET 2: in children, do steroids prevent biphasic anaphylactic reactions? Emerg Med J EMJ. 2014;31(6):510-512. doi:10.1136/emermed-2014-203854.2

3.           Chaaya G, Afridi F, Faiz A, Ashraf A, Ali M, Castiglioni A. When Nothing Else Works: Fresh Frozen Plasma in the Treatment of Progressive, Refractory Angiotensin-Converting Enzyme Inhibitor–Induced Angioedema. Cureus. 9(1):e972. doi:10.7759/cureus.972

4.           Long BJ, Koyfman A, Gottlieb M. Evaluation and Management of Angioedema in the Emergency Department. West J Emerg Med. 2019;20(4):587-600. doi:10.5811/westjem.2019.5.42650