GLP-1 Agonists: Support Protocol

A comprehensive plan for patients taking GLP-1s is crucial—no matter how you feel about it.

When GLP-1 agonists first hit the market, frustrated Americans eagerly embraced them as a miracle cure for weight loss, obesity and diabetes. Since then, the use of GLP-1s has skyrocketed, with some data showing a forty-fold increase between 2017 and 2021. In the fourth quarter of 2022, an estimated 9 million prescriptions were written for GLP-1 drugs, suggesting 2 to 3 percent of the U.S. population may be taking one of these medications—despite known adverse effects and a dearth of research on their long-term aftermath.^{1, 2}

GLP-1 agonists mimic the action of the glucagon-like peptide-1 hormone, stimulating insulin release, inhibiting the secretion of glucagon, slowing gastric emptying and sending fullness signals to the brain. While they’re effective in improving blood glucose control and helping patients eat less, GLP-1s are linked with a range of gastrointestinal side effects including constipation, nausea, vomiting and diarrhea, and the significant loss of appetite associated with these drugs can lead to nutrient deficiencies, low energy, decreased muscle mass and a troubling variety of detrimental consequences.^{3, 4}

You may or may not agree with GLP-1 treatment—but chances are some of your patients are using them. Given their widespread popularity, a comprehensive program that includes nutrition, lifestyle and supplements is essential.

“Supplemental protocols create the opportunity to maximize the benefits of GLP-1 agonists, while reducing the side effects,” says Arland Hill, DC director of clinical education for Biotics Research. “For example, the proactive use of nutrients like magnesium in lower bioavailability form can assist with bowel motility by supporting a flushing effect. However, in cases where this is not the ideal approach, the bowel can still be nurtured with the use of 5-HTP, bile acid supplementation, botanicals such as artichoke and ginger, and forms of magnesium with higher bioavailability.”

A strategic protocol not only minimizes adverse effects and corrects for nutritional gaps but also enhances the efficacy of GLP-1s and lowers the risk of rebound weight gain when medication is stopped. Here’s how to support patients taking GLP-1 agonists—no matter how you feel about it.

Dietary changes.

Reduced appetite and rapid weight loss associated with GLP-1 drugs often lead to nutrient deficiencies. Additionally, gastrointestinal side effects can impact digestion, nutrient absorption and retention, and studies show people taking GLP-1s are more susceptible to dehydration, nutritional deficiency and sarcopenia.

A dietary protocol for patients using GLP-1s should address not only what patients eat, but also how they eat. “Food consumption is not about loading the body with sustenance,” says Hill. “It is a planned and routine action that allows us to give thought to our choices around food and connect with it on a more personal level.  Therefore, how we eat becomes as relevant as what we eat.”

Consuming meals at regular intervals—three meals a day, with no snacking or fasting—helps compensate for suppressed appetite and promotes optimal nutrient delivery to the body. Research on patients taking GLP-1s suggests habits like eating slowly without distractions, consuming smaller portions and increasing the frequency of meals may lessen the severity and duration of adverse effects.^{5, 6, 7, 8}

While limited evidence exists to support specific nutritional recommendations, recently released guidelines emphasize protein to sustain muscle health, as well as whole, nutrient-rich foods and a reduced intake of simple carbs, processed foods and sugar. Easily digestible foods, such as simply prepared whole vegetables, decrease the risk of gastrointestinal distress. A combination of soluble and insoluble fibers is crucial, but fiber can exacerbate feelings of fullness. Incorporate moderate fiber from whole foods sources as tolerated, to support digestion and GI motility.^{9, 10}

Besides correcting nutrient deficiencies and alleviating side effects, strategic dietary changes improve insulin sensitivity, stabilize blood glucose and enhance the overall usefulness of GLP-1 medications. Dietary protein appears to boost the metabolic effects of GLP-1, and foods containing both protein and calcium—like dairy products—have been shown to promote GLP-1 release. Soluble fiber also appears to stimulate endogenous GLP-1 production, and studies suggest diets higher in monounsaturated fats and omega-3s, lower in saturated fat, may heighten GLP-1 secretion.^{11, 12, 13}

Lifestyle considerations.

In addition to dietary interventions, a targeted exercise regimen is essential to preserve muscles, increase insulin sensitivity and glucose control, support weight loss, improve body composition, protect cardiovascular health and enhance the effectiveness of GLP-1 medications.^{14, 15}

Even modest weight loss and calorie restriction are associated with a decrease in lean mass, impaired muscle strength, lower metabolic rate, and reduced cardiac mass and VO2max. Exercise protects against these repercussions—critical for patients taking GLP-1s. Resistance training in particular increases muscle mass, strength and function, and even modest, consistent training has been shown to significantly build muscle mass over time. In other research, exercise combined with GLP-1s was found to reduce metabolic syndrome severity, abdominal obesity and inflammation, potentially decreasing cardiometabolic risk more than GLP-1 treatment alone.^{16, 17, 18, 19, 20}

In the long term, resistance training boosts basal metabolic rate, and a combination of exercise and GLP-1s can help patients maintain healthy body composition and lower the risk of rebound weight gain after medication is discontinued. Research suggests exercise improves weight maintenance and body composition during GLP-1 treatment, and in one study, a supervised exercise program allowed better maintenance of body weight and body composition one year after treatment termination.^{21, 22}

Mental and emotional wellness are equally critical. While the impact of GLP-1 drugs on psychiatric manifestations is not well known, a range of adverse mood changes have been noted. GLP-1 is shown to influence brain regions involved in emotional regulation, and one animal study found GLP-1 agonists induced anxiety immediately after the start of treatment. Other research links GLP-1 agonists with a significantly higher risk of specific psychiatric effects, including depression, anxiety and suicidal behaviors. In one trial, GLP-1 treatment was associated with a 98 percent increased risk of any psychiatric disorders, and patients on GLP-1s exhibited a 108 percent higher risk for anxiety, a 195 percent increased risk of major depression and a 106 percent elevated risk for suicidal behavior.^{23, 24, 25}

Supplemental support.

Along with diet and lifestyle interventions, a strategic supplement protocol is crucial to preserve muscle mass, offset nutrient deficiencies and address gastrointestinal effects from GLP-1 drugs. Three key areas to emphasize:

1. Preserve muscles. The impact of GLP-1s on muscle mass, health and function is a serious concern, and studies show a significant portion of weight lost during GLP-1 treatment can be attributed to muscle mass. Research demonstrates notable reductions in lean mass in patients taking GLP-1s, especially in trials with a larger number of patients, and in some studies, reductions in lean mass ranged between 40 percent and 60 percent as a proportion of total weight lost.^{26, 27, 28}

Research suggests the lower protein intake associated with GLP-1 treatment is not sufficient to sustain muscle health. But because of the appetite-suppressing effect of GLP-1s, substantially increasing protein is challenging. Hydrolyzed collagen protein provides a complete protein source and as a protein shake, delivers concentrated protein that patients can tolerate without feeling overly satiated. Well-designed collagen supplements also contain high amounts of branched chain amino acids, vital for muscle maintenance. Collagen protein may improve body composition and increases muscle strength, especially in combination with resistance training. Hydrolyzed collagen protein that includes whole food fiber, healthy fats, phytochemicals and other bioactive nutrients further supports gastrointestinal and metabolic health for patients using GLP-1 agonists.^{29, 30, 31, 32}

2. Correct for micronutrient deficiencies. Nutrient deficiencies are an established consequence of caloric restriction, and research links a reduction in overall dietary intake during GLP-1 treatment with micronutrient shortfalls. Even marginal micronutrient deficiencies impair physiological functions and processes at a cellular level [CAN LINK TO TRUGEN MICRONUTRIENT STORY] and are associated with diminished cognitive function, altered immune response and a higher risk for diabetes, osteoporosis, macular degeneration and heart disease. Micronutrient deficiencies are also strongly implicated in the development and progression of several types of cancer, heart failure and increased all-cause mortality. A balanced multi that provides a full spectrum of vitamins and minerals can correct for micronutrient shortfalls seen in GLP-1 treatment. Choose a carefully formulated supplement that contains the appropriate levels of vitamins and minerals in bioavailable forms, as well as trace elements, phytochemicals and other biologically active compounds. ^{33, 34, 35, 36, 37, 38}

3. Support GI motility. GLP-1s significantly slow gut motility, leading to nausea, vomiting, bloating and abdominal discomfort. Certain natural ingredients have been shown to promote healthy gut motility, support peristaltic actions and offset adverse GI effects. A comprehensive formula shown to target multiple pathways related to GI motility, including smooth muscle contraction frequency and function, gastric emptying and bile secretion, can ease patients’ discomfort, safely. Science-backed ingredients to look for:

• • Ginger contains bioactive compounds shown to regulate dysmotility throughout the gastrointestinal tract and stimulate both gastric emptying and antral contractions.^{39, 40, 41, 42}
  • Artichoke extract is high in phenolic compounds and antioxidants known to stimulate bile acid secretion, potentially reducing symptoms related to cholestasis and improving nausea, fullness, discomfort and bloating. In combination with ginger, artichoke extract has been shown to promote gastric emptying and ease gastrointestinal discomfort and indigestion.^{43, 44, 45, 46, 47}
  • 5-HTP supplementation increases levels of 5-HI, a compound that activates L-type calcium channels of smooth muscle cells, thereby enhancing gut motility. Experimental models suggest 5-HTP supplementation also restores depleted serotonin levels in enteric neurons, normalizing impaired gut motility and stimulating contractions in the duodenum, jejunum and large intestine.^{48, 49, 50, 51, 52}
  • Magnesium supports peristalsis throughout the GI tract and is a cofactor for multiple neurotransmitters in the enteric nervous system, which largely regulates peristalsis. In studies, magnesium has been shown to significantly decrease post-operative gastrointestinal symptoms such as nausea, vomiting and constipation. Because low magnesium intake can be exacerbated by reduced appetite and medications used to treat gastrointestinal symptoms, it’s especially vital for patients taking GLP-1s.^{53, 54, 55, 56, 57, 58, 59}

References

1. Pierce Logan, MA. “On the Increase in Use of GLP-1s.” Bioethics article: Indiana School of Medicine, June 27, 2024.
2. Annika Kim Constantino. “Ozempic, Wegovy drug prescriptions hit 9 million, surge 300% in under three years.” CNBC Health and Science. September 27, 2023.
3. Aldhaleei WA et al. Glucagon-like Peptide-1 Receptor Agonists Associated Gastrointestinal Adverse Events: A Cross-Sectional Analysis of the National Institutes of Health All of Us Cohort. Pharmaceuticals (Basel). 2024 Feb 2;17(2):199.
4. Sodhi M et al. Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss. JAMA. 2023 Nov 14;330(18):1795-1797.
5. He L et al. Pharmacovigilance study of GLP-1 receptor agonists for metabolic and nutritional adverse events. Front Pharmacol. 2024 Jul 8;15:1416985.
6. Dash S. Opportunities to optimize lifestyle interventions in combination with glucagon-like peptide-1-based therapy. Diabetes Obes Metab. 2024 Sep;26 Suppl 4:3-15.
7. Cuenca A et al. Clinical Recommendations to Manage Gastrointestinal Adverse Events in Patients Treated with Glp-1 Receptor Agonists: A Multidisciplinary Expert Consensus. J Clin Med. 2022 Dec 24;12(1):145.
8. Bettadapura S et al. Changes in food preferences and ingestive behaviors after glucagon-like peptide-1 analog treatment: techniques and opportunities. Int J Obes (Lond). 2024 Mar 7.
9. Almandoz JP et al. Nutritional considerations with antiobesity medications. Obesity (Silver Spring). 2024 Sep;32(9):1613-1631.
10. Christensen S et al. Dietary intake by patients taking GLP-1 and dual GIP/GLP-1 receptor agonists: A narrative review and discussion of research needs. Obes Pillars. 2024 Jul 25;11:100121.
11. Mietlicki-Baase EG et al. Daily supplementation of dietary protein improves the metabolic effects of GLP-1-based pharmacotherapy in lean and obese rats. Physiol Behav. 2017 Aug 1;177:122-128.
12. Watkins JD et al. Protein- and Calcium-Mediated GLP-1 Secretion: A Narrative Review. Adv Nutr. 2021 Dec 1;12(6):2540-2552.
13. Bodnaruc AM et al. Nutritional modulation of endogenous glucagon-like peptide-1 secretion: a review. Nutr Metab (Lond). 2016 Dec 9;13:92.
14. van Dijk JW, van Loon LJ. Exercise strategies to optimize glycemic control in type 2 diabetes: a continuing glucose monitoring perspective. Diabetes Spectr. 2015 Jan;28(1):24-31
15. Norton L et al. Exercise training improves fasting glucose control. Open Access J Sports Med. 2012 Nov 16;3:209-14.
16. Weiss EP et al. Effects of Weight Loss on Lean Mass, Strength, Bone, and Aerobic Capacity. Med Sci Sports Exerc. 2017 Jan;49(1):206-217.
17. Bosy-Westphal A et al. Contribution of individual organ mass loss to weight loss-associated decline in resting energy expenditure. Am J Clin Nutr. 2009;90(4):993–1001.
18. Fyfe JJ et al. Minimal-Dose Resistance Training for Improving Muscle Mass, Strength, and Function: A Narrative Review of Current Evidence and Practical Considerations. Sports Med. 2022 Mar;52(3):463-479.
19. Borde R et al. Dose-Response Relationships of Resistance Training in Healthy Old Adults: A Systematic Review and Meta-Analysis. Sports Med. 2015 Dec;45(12):1693-720.
20. Sandsdal RM et al. Combination of exercise and GLP-1 receptor agonist treatment reduces severity of metabolic syndrome, abdominal obesity, and inflammation: a randomized controlled trial. Cardiovasc Diabetol. 2023 Feb 25;22(1):41.
21. Jensen SBK et al. Healthy weight loss maintenance with exercise, GLP-1 receptor agonist, or both combined followed by one year without treatment: a post-treatment analysis of a randomised placebo-controlled trial. EClinicalMedicine. 2024 Feb 19;69:102475.
22. Lundgren JR et al. Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined. N Engl J Med. 2021 May 6;384(18):1719-1730.
23. Manoharan SVRR, Madan R. GLP-1 Agonists Can Affect Mood: A Case of Worsened Depression on Ozempic (Semaglutide). Innov Clin Neurosci. 2024 Jun 1;21(4-6):25-26.
24. Chen W et al. Psychiatric adverse events associated with GLP-1 receptor agonists: a real-world pharmacovigilance study based on the FDA Adverse Event Reporting System database. Front Endocrinol (Lausanne). 2024 Feb 6;15:1330936.
25. Kornelius E et al. The risk of depression, anxiety, and suicidal behavior in patients with obesity on glucagon like peptide-1 receptor agonist therapy. Sci Rep. 2024; 14, 24433.
26. Wilding JPH et al. STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021 Mar 18;384(11):989-1002.
27. Bikou A et al. A systematic review of the effect of semaglutide on lean mass: insights from clinical trials. Expert Opin Pharmacother. 2024 Apr;25(5):611-619.
28. Neeland IJ et al. Changes in lean body mass with glucagon-like peptide-1-based therapies and mitigation strategies. Diabetes Obes Metab. 2024 Sep;26 Suppl 4:16-27.
29. Holwerda AM, van Loon LJC. The impact of collagen protein ingestion on musculoskeletal connective tissue remodeling: a narrative review. Nutr Rev. 2022 May 9;80(6):1497-1514.
30. Kirmse M et al. Prolonged Collagen Peptide Supplementation and Resistance Exercise Training Affects Body Composition in Recreationally Active Men. Nutrients. 2019 May 23;11(5):1154.
31. Oertzen-Hagemann V et al. Effects of 12 Weeks of Hypertrophy Resistance Exercise Training Combined with Collagen Peptide Supplementation on the Skeletal Muscle Proteome in Recreationally Active Men. Nutrients. 2019 May 14;11(5):1072.
32. Jendricke P et al. Specific Collagen Peptides in Combination with Resistance Training Improve Body Composition and Regional Muscle Strength in Premenopausal Women: A Randomized Controlled Trial. Nutrients. 2019 Apr 20;11(4):892.
33. Zhang W et al. Requirements for essential micronutrients during caloric restriction and fasting. Front Nutr. 2024 Feb 28;11:1363181.
34. Gropper SS. The role of nutrition in chronic disease. Nutrients. 2023 Jan 28;15(3):664.
35. Awuchi CG et al. Nutritional diseases and nutrient toxicities: A systematic review of the diets and nutrition for prevention and treatment. Int J Adv Res 2020;6:1-46.
36. Ames BN. Low micronutrient intake may accelerate the degenerative diseases of aging through allocation of scarce micronutrients by triage. Proc Natl Acad Sci U S A. 2006 Nov 21;103(47):17589-94.
37. Ames B et al. Are vitamin and mineral deficiencies a major cancer risk? Nat Rev Cancer. 2002; 2, 694–704.
38. Rehman S et al. Micronutrient deficiencies and cardiac health. Front Nutr. 2022 Oct 14;9:1010737.
39. Abidi C et al. Dose-dependent Action of Zingiber officinale on Colonic Dysmotility and Ex Vivo Spontaneous Intestinal Contraction Modulation. Dose Response. 2022 Sep 15; 20(3):15593258221127556.
40. Abdel-Aziz H et al. Mode of action of gingerols and shogaols on 5-HT3 receptors: binding studies, cation uptake by the receptor channel and contraction of isolated guinea-pig ileum. Eur J Pharmacol. 2006 Jan 13;530(1-2):136-43.
41. Hu ML et al. Effect of ginger on gastric motility and symptoms of functional dyspepsia. World J Gastroenterol. 2011 Jan 7;17(1):105-10. .
42. Wu KL et al. Effects of ginger on gastric emptying and motility in healthy humans.  Eur J Gastroenterol Hepatol. 2008 May;20(5):436-40.
43. Olas B. An Overview of the Versatility of the Parts of the Globe Artichoke (Cynara scolymus L.), Its By-Products and Dietary Supplements. Nutrients. 2024 Feb 22;16(5):599.
44. Kirchhoff R et al. Increase in choleresis by means of artichoke extract. Phytomedicine. 1994 Sep;1(2):107-15.
45. Lazzini S et al. The effect of ginger (Zingiber officinalis) and artichoke (Cynara cardunculus) extract supplementation on gastric motility: a pilot randomized study in healthy volunteers. Eur Rev Med Pharmacol Sci. 2016;20(1):146-9.
46. Giacosa A et al. The Effect of Ginger (Zingiber officinalis) and Artichoke (Cynara cardunculus) Extract Supplementation on Functional Dyspepsia: A Randomised, Double-Blind, and Placebo-Controlled Clinical Trial. Evid Based Complement Alternat Med. 2015;2015:915087.
47. Drobnic F et al. Efficacy of artichoke and ginger extracts with simethicone to treat gastrointestinal symptoms in endurance athletes: a pilot study. Minerva Gastroenterol (Torino). 2022 Mar;68(1):77-84.
48. Waclawiková B et al. Gut bacteria-derived 5-hydroxyindole is a potent stimulant of intestinal motility via its action on L-type calcium channels. PLoS Biol. 2021 Jan 22;19(1):e3001070.
49. Israelyan N et al. Effects of Serotonin and Slow-Release 5-Hydroxytryptophan on Gastrointestinal Motility in a Mouse Model of Depression. Gastroenterology. 2019 Aug;157(2):507-521.e4.
50. Siegle ML et al. 5-Hydroxytryptophan modulates postprandial motor patterns of canine proximal small intestine. Can J Physiol Pharmacol. 1990 Dec;68(12):1495-502.
51. Keating DJ, Spencer NJ. What is the role of endogenous gut serotonin in the control of gastrointestinal motility? Pharmacol Res. 2019 Feb;140:50-55.
52. Najjar SA et al. Serotonergic Control of Gastrointestinal Development, Motility, and Inflammation. Compr Physiol. 2023 Jun 26;13(3):4851-4868.
53. Paul RJ, Rüegg JC. Role of magnesium in activation of smooth muscle. Am J Physiol. 1988 Oct;255(4 Pt 1):C465-72.
54. D’Angelo EK et al. Magnesium relaxes arterial smooth muscle by decreasing intracellular Ca2+ without changing intracellular Mg2+. J Clin Invest. 1992 Jun;89(6):1988-94.
55. Spasov AA et al. Features of central neurotransmission in animals in conditions of dietary magnesium deficiency and after its correction. Neurosci Behav Physiol. 2009 Sep;39(7):645-53.
56. Wood JD. Enteric nervous system, serotonin, and the irritable bowel syndrome. Curr Opin Gastroenterol. 2001 Jan;17(1):91-7.
57. Nazarinasab M et al. Investigating the effect of magnesium supplement in patients with major depressive disorder under selective serotonin reuptake inhibitor treatment. J Family Med Prim Care. 2022 Dec;11(12):7800-7805.
58. Moradian ST et al. Oral magnesium supplementation reduces the incidence of gastrointestinal complications following cardiac surgery: a randomized clinical trial. Magnes Res. 2017 Feb 1;30(1):28-34.
59. Gommers LMM et al. Mechanisms of proton pump inhibitor-induced hypomagnesemia. Acta Physiol (Oxf). 2022 Aug;235(4):e13846.