Biocidin Academy
December 12, 2024

Managing GLP-1 Side Effects: Strategies for Enhancing Tolerance and Effectiveness

By Emily Hernandez, ND

GLP-1 agonist drugs, initially approved in 2005 and prescribed for Type 2 diabetes, have been gaining popularity over the past decade. According to the Kaiser Family Foundation, one in 8 Americans has tried at least one of these medications. The increase in new prescriptions, however, has primarily been among people with obesity or obesity-related conditions rather than those with diabetes. This reflects the FDA’s more recent approval of these medications (semaglutide, liraglutide, and the dual GLP-1/GIP receptor agonist, tirzepatide) for weight management.

These medicines are incretin mimetics, meaning they mimic the activity of naturally produced GLP-1 and GIP. Their activities include:1

  • Triggering the release of insulin, which promotes lower blood sugar levels 
  • Blocking glucagon (preventing the release of glucose)
  • Slowing gastric emptying 
  • Signaling the areas of the brain that control appetite and satiety

Research into these medicines has also shown they help lower blood pressure and reduce the risk of heart disease and neurodegenerative conditions.

Although they are proven to have significant therapeutic benefits, GLP-1 agonists are not without side effects. Those using these medications for weight loss tend to have more significant side effects than those using them for blood sugar regulation. Dose strength and length of time (higher dose and longer duration) also correlate with more side effects experienced. 

The most common side effects include:2

  • Loss of appetite
  • Nausea – affects 50% of users
  • Vomiting – affects 5-10% of users
  • Diarrhea – affects 10-15% of users
  • Constipation
  • Abdominal pain/dyspepsia
  • Rapid weight loss, resulting in baggy skin (aka “Ozempic face”)
  • Injection site rash, erythema, itching – affects 5-15% of users

Less common but more severe side effects, ranging from 0.1 to 1% of users (depending upon side effect and population studied), can include:3

  • Gastroparesis 
  • Bowel obstruction
  • Cholestasis, leading to gallstone attacks  
  • Pancreatitis (The link to GLP-1 use is controversial, as these patients may have had preexisting conditions that increase their risk of pancreatitis.)2

Regardless of whether side effects are minor or more serious, many patients choose to stop their GLP-1 analog to avoid symptoms. Understanding the mechanisms of these medications and which organ systems are affected allows the practitioner to potentially mitigate side effects by individualizing care. 

Additionally, natural therapeutics can help patients tolerate these medications and even enhance endogenous levels of these naturally occurring peptides by promoting healthy gastrointestinal, liver, and gallbladder function.

Supporting the Liver and Gallbladder 

As GLP-1 agonists enhance fat loss, the liver and gallbladder are put to work dealing with the increase in mobilized toxins stored in fat cells. Additionally, GLP-1 agonists inhibit movement and emptying of bile through the gallbladder, further interfering with the liver’s ability to detoxify and the gut’s ability to digest fats. Impaired hepatobiliary bile production and excretion can result in cholestasis – defined as the suppression of bile flow. This accumulation of bile acids in the liver is highly inflammatory and causes cytotoxic injury (cytolysis) to both bile ducts and hepatocytes.4

Bile plays both a direct and indirect role in the endogenous production of GLP-1. First, bile acids trigger GLP-1 release in the gut.5 Bile also plays a key role in maintaining microbial balance in the small intestine by maintaining a lower pH in the lumen. This serves the vital function of preventing overgrowth of opportunistic microbes and allowing beneficials to flourish. Some of these essential beneficial flora produce short-chain fatty acids (SCFAs), such as butyrate, acetate, and propionate. SCFAs not only protect the gut lining and support immune and brain function, they also stimulate GLP-1 production and release! 

Thus, supporting liver and gallbladder activities and modulating the microbiome can help minimize unpleasant side effects from GLP-1 agonists and enhance the natural production of incretins.  

Nutrients and Herbs to Help Minimize GLP-1 Side Effects

Hepatoprotective Heroes

  • Milk thistle (Silybum marianum) – Widely regarded for its hepatoprotective and anti-fibrotic properties, this hero is also a bitter herb. Among other proven benefits, this potent antioxidant protects the liver cell membrane and promotes liver repair and regeneration.6 Look for researched and bioavailable forms. 
  • Turmeric (Curcuma longa) – Protects the liver from injury and promotes gallbladder contraction, even at low doses. Has antioxidant, anti‐inflammatory, antiarthritic, anti-atherosclerotic, antimicrobial, and wound-healing activities.7;

Bitter Herbs

Bitter herbs help stimulate bile production and enhance liver function. They also help support digestive enzyme production and gastric movement. 

  • Artichoke (Cynara cardunculus) – Artichoke has hepatoprotective, choleretic (bile promoting), antioxidant, and anti-inflammatory properties.8 It protects the liver from damage and prevents the depletion of glutathione (GSH), a critical antioxidant that promotes bile flow and hepatic detoxification.9
  • Bupleurum (Bupleurum chinense) – A tonic in traditional Chinese medicine, known to relieve liver stagnation and elevate Yang Qi.10 Bupleurum has hepatoprotective, antioxidant, and anti-inflammatory properties. It has been shown to support intestinal barrier function and inhibit metabolic inflammation.

Motility Herbs

  • Ginger (Zingiber officinale) –  Has been traditionally used for treating a variety of gastrointestinal conditions, including nausea, dyspepsia, bloating, and epigastric pain.11 Ginger has anti-inflammatory, hepatoprotective, and digestive-stimulant effects, including stimulating the migrating motor complex and enhancing gastric emptying.12

Water-Soluble Bile Acids

  • TUDCA (Tauroursodeoxycholic Acid) – A naturally occurring hydrophilic and cytoprotective bile acid that alters the constitution of bile, thinning and promoting its flow. Thinner bile protects the liver by reducing the risk of cholestasis and cytolysis and by regulating lipid concentrations.13

Personalizing Treatment

While GLP-1 agonist medications offer significant therapeutic benefits for managing conditions like Type 2 diabetes and obesity, they are not without their potential side effects. Understanding the physiological mechanisms behind these side effects allows for more personalized treatment strategies, including adjusting dosages and exploring natural supplements that support liver, gallbladder, and gastrointestinal health. By addressing these concerns through both pharmacological and holistic approaches, patients can better navigate the challenges of GLP-1 therapy and enhance its overall effectiveness in managing chronic health conditions.

For more support, see our Incretins and the Microbiome Protocol.

 

  1. https://my.clevelandclinic.org/health/treatments/13901-glp-1-agonists
  2. https://pmc.ncbi.nlm.nih.gov/articles/PMC5397288/
  3. https://jamanetwork.com/journals/jama/fullarticle/2810542
  4. Hirschfield GM, Heathcote EJ, Gershwin ME. Pathogenesis of cholestatic liver disease and therapeutic approaches. Gastroenterology. 2010 Nov;139(5):1481-96.
  5. Brighton, Cheryl A et al. “Bile Acids Trigger GLP-1 Release Predominantly by Accessing Basolaterally Located G Protein-Coupled Bile Acid Receptors.” Endocrinology vol. 156,11 (2015): 3961-70. doi:10.1210/en.2015-1321
  6. Zhang X, Liu M, Wang Z, et al. A review of the botany, phytochemistry, pharmacology, synthetic biology and comprehensive utilization of Silybum marianum. Front Pharmacol. 2024 Jul 11;15:1417655.
  7. Kunnumakkara AB, Bordoloi D, Padmavathi G, et al. Curcumin, the golden nutraceutical: multitargeting for multiple chronic diseases. Br J Pharmacol. 2017 Jun;174(11):1325-1348.
  8. Porro C, Benameur T, Cianciulli A, et al. Functional and Therapeutic Potential of Cynara scolymus in Health Benefits. Nutrients. 2024 Mar 17;16(6):872.
  9. Gebhardt R. Antioxidative and protective properties of extracts from leaves of the artichoke (Cynara scolymus L.) against hydroperoxide-induced oxidative stress in cultured rat hepatocytes. Toxicol Appl Pharmacol. 1997 Jun;144(2):279-86.
  10. Ran S, Peng R, Guo Q, et al. Bupleurum in Treatment of Depression Disorder: A Comprehensive Review. Pharmaceuticals (Basel). 2024 Apr 16;17(4):512.
  11. Crichton M, Marshall S, Marx W, et al. Therapeutic health effects of ginger (Zingiber officinale): updated narrative review exploring the mechanisms of action. Nutr Rev. 2023 Aug 10;81(9):1213-1224.
  12. Nikkhah Bodagh M, Maleki I, Hekmatdoost A. Ginger in gastrointestinal disorders: A systematic review of clinical trials. Food Sci Nutr. 2018 Nov 5;7(1):96-108.
  13. Crosignani A, Battezzati PM, Setchell KD, et al. Tauroursodeoxycholic acid for treatment of primary biliary cirrhosis. A dose-response study. Dig Dis Sci. 1996 Apr;41(4):809-15.