emDOCs Podcast – Episode 94: GLP-1 Agonist Complications

Background:

GLP-1 agonists are used for weight loss and diabetes; include the following:

• Semaglutide (Wegovy) GLP-1 agonist FDA approved for weight loss by SQ injection
• Liraglutide (Saxenda) GLP-1 agonist FDA approved for weight loss by SQ injection
• Semaglutide (Ozempic) GLP-1 agonist FDA approved for type 2 diabetes by SQ injection
• Semaglutide (Rybelsus) GLP-1 agonist FDA approved for type 2 diabetes by oral route
• Liraglutide (Victoza) GLP-1 agonist FDA approved for type 2 diabetes by SQ injection
• Tirzepatide (Mounjaro) glucose-dependent insulinotropic polypeptide (GIP) receptor and GLP-1 agonist FDA approved for type 2 diabetes
  • Under review for FDA approval for weight loss

Why have these become so popular?

• Obesity affects over 40% of U.S. adults; over 11% of the American population suffering from diabetes.
  • Both associated with significant morbidity and mortality.
• Multiple well-designed, multicenter, multinational studies suggest GLP-1 agonists are associated with improved glucose control in diabetes type 2 and approximately a 15% reduction in weight over 1-2 years (around 2/3s of patients regain weight if treatment is stopped).
  • STEP-1: semaglutide 2.4 mg once weekly – 14.9% weight reduction over 68 weeks.
  • STEP-2: greater weight reduction with semaglutide 2.4 mg vs. 1 mg.
  • STEP-3: greater weight reduction with semaglutide vs. low calorie diet.
  • STEP-4 and 5 found semaglutide reduced weight compared to placebo.
• American Gastroenterological Association issued a practice guideline in November 2022 recommending that semaglutide 2.4 mg be utilized for treatment of obesity over other pharmacologic treatments.

How do they work?

• GLP-1 is an incretin hormone produced in the small intestine.
• There are receptors for the hormone in the pancreatic beta cells and ducts, gastric mucosa, lungs, heart, kidneys, immune cells, and hypothalamus.
• GLP-1 primarily stimulates glucose-dependent release of insulin from the pancreatic islets.
• GLP-1 reduces gastric emptying and food intake by increasing feelings of satiety, it inhibits release of inappropriate post-meal glucagon, and has direct effects on the central nervous system
• GLP-1 agonists reproduce and even enhance these effects but with longer half-lifes (1 week for semaglutide and 12 hours for liraglutide vs minutes).
• That’s how they help with weight loss and glucose control.
• GLP-1 agonists are also associated with improved ejection fraction, coronary blood flow, and cardiac output while reducing the risk of cardiovascular events, infarction size, and all-cause mortality.
• The effects of GLP-1 agonists are associated with the dose. Higher doses of GLP-1 agonists are associated with weight loss.
  • Take for example semaglutide. Ozempic is utilized for DM2 in doses of 0.5, 1, or 2 mg administered via the SQ route weekly. Wegovy is the one approved for weight loss, it’s administered in doses of 2.4 mg SQ every week. Liraglutide is dosed daily starting at 0.6 mg SQ and is increased to 3 mg over 5 weeks.

Who can use a GLP-1 agonist therapy?

• BMI > 30
• BMI > 27 and weight related condition (HTN, DM, HLD)

Who can’t use them?

• Hypersensitivity reaction to a GLP-1 agonist, type 1 diabetes mellitus, and pregnancy.
• Not recommended in those with personal or family history of multiple endocrine neoplasia 2A, multiple endocrine neoplasia 2B, or medullary thyroid cancer due to concern for long-term thyroid effects (data in human studies are lacking though).

What are the complications?

• Adverse events are common in those using GLP-1 agonists, but the vast majority of these are minor.
• GI adverse effects are most common (20-70% of patients). Greater rate of GI effects with higher doses.
  • Most common problems: nausea (overall most common), vomiting, and diarrhea. Others included abdominal pain, dyspepsia, and constipation.
  • Symptoms are typically more severe within the first four weeks of therapy or with sudden escalation of therapy and tend to decrease over time.
  • Thought to be due to reduced gastric emptying and activation of centers involved in appetite regulation and nausea.
  • Severe diarrhea and vomiting may lead to volume loss, dehydration, and hypotension (not common).
  • There is an association with pancreatitis. GLP-1 agonists may stimulate pancreatic islet beta cells and exocrine duct cells leading to overgrowth and smaller duct size, which increase the pancreatic weight and risk of ductal occlusion.
    • Retrospective study published in 2022 of 81,752 adverse events associated with GLP-1 agonist therapy found an increased risk of pancreatitis, particularly with liraglutide (ROR 32.67; 95% CI 29.44-36.25). 2023 observational study found increased risk of pancreatitis (adjusted HR of 9.09, 95% CI 1.25-66).
  • Other GI issues include gallbladder and biliary tract disease (usually after 26 weeks of therapy and included cholelithiasis, cholecystitis, cholangitis), elevated LFTs, hepatitis, liver injury.
• Hypersensitivity/dermatologic: GLP-1 agonists are synthetic peptides; may lead to antibody formation and allergic reaction/injection site reaction.
  • Reactions are usually minor: transient warmth, pruritis at injection site that resolves.
  • Anaphylaxis and angioedema have been reported, primarily with exendin-based therapies such as exenatide and lixisenatide.
  • Other reactions: urticaria, pustular rash, vesicular eruption, psoriasiform eruption, panniculitis, hyperhidrosis, alopecia, and maculopapular rash.
• Ozempic face:
  • Many patients are concerned about premature “aging”. This is not aging but associated with rapid loss of fat and weight. This increases of skin folds and causes more sagging of the skin.
• Renal:
  • Due to the medication itself or the result of other adverse events (GI losses).
  • AKI associated with GLP-1 agonist therapy is prerenal in nature and associated with nausea, vomiting, diarrhea, and reduced oral intake. Increased risk in those with preexisting CKD, other risk factors for renal disease (HTN or CAD), and those on ACEIs/ARBs.
  • Acute interstitial nephritis and acute tubular necrosis have also been associated with exenatide and liraglutide.
• Metabolic
  • Hypoglycemia does not occur with GLP-1 agonists alone or if combined with metformin, but may occur if it’s combined with a sulfonylurea or insulin (overall risk is low).
• Ocular:
  • Reported increased risk of diabetic retinopathy with use of SQ GLP-1 agonists, specifically semaglutide, exenatide, and dulaglutide.

Current issues with the medications?

• There are currently no generic versions; cost is a major problem. Ozempic > $900, Wegovy > $1400, and Saxenda > $1400 for a one-month supply.
• National shortage due to medication popularity.
• Many patients are resorting to obtaining medications by other means.
  • Drug compounding is the combining, mixing, or alteration of ingredients to create a custom-tailored medication; typically entails the combination of two or more drugs.
  • Compounding is not FDA-approved; there are no means of verifying the effectiveness or safety of compounded medications.
  • Legitimate compounding pharmacies are regulated by state boards.
  • Beyond these state board regulated compounding pharmacies, other avenues for obtaining medications include online pharmacies, weight loss and wellness clinics, and medical spas.
  • Most common compounded form of GLP-1 agonist includes doses of semaglutide derived from a salt, as well as other active ingredients.
    • The compounded medication is chemically different from FDA-approved semaglutide.
    • FDA has also received reports of clinics and compounding pharmacies using toaster ovens for sterilization, non-sterile handling of sterile products, and pet beds located near sterile compounding areas.
  • FDA recommendations:
    • Patients should not use a compounded medication if an approved form of that medication is available.
    • Patients should only obtain these medications from a licensed care provider and from FDA registered, state-licensed pharmacies or outsourcing facilities.

References:

1. Centers for Disease Control and Prevention. National Diabetes Statistics Report. Available at https://www.cdc.gov/diabetes/data/statistics-report/index.html. Last updated June 29, 2022.
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6. Shetty R, Basheer FT, Poojari PG, et al. Adverse drug reactions of GLP-1 agonists: A systematic review of case reports. Diabetes Metab Syndr. 2022 Mar;16(3):102427.
7. FDA Approves New Drug Treatment for Chronic Weight Management, First Since 2014. FDA. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014. Published June 04, 2021.
8. https://www.novo-pi.com/ozempic.pdf. Accessed October 4, 2023.
9. https://www.novo-pi.com/wegovy.pdf. Accessed October 4, 2023.
10. https://www.novo-pi.com/rybelsus.pdf. Accessed October 4, 2023.
11. https://www.novo-pi.com/saxenda.pdf. Accessed October 4, 2023.
12. https://www.novo-pi.com/victoza.pdf. Accessed October 4, 2023.
13. https://uspl.lilly.com/mounjaro/mounjaro.html#pi Accessed October 4, 2023.
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