Unintended Benefit of GLP-1 Treatment for Obesity: Resolution of Chronic Systemic Mastocytosis Symptoms

| May 1, 2023

by George Woodman, MD, FACS, FASMBS; Alexander Wells, BS; Gregory A. Hanissian, MD; and Guy Voeller, MD

Dr. Woodman is with Baptist Memorial Hospital–Memphis in Memphis, Tennessee, and Methodist Hospital Germantown in Germantown, Tennessee. Mr. Wells is a medical student at the University of Tennessee Health Sciences Center in Memphis, Tennessee. Dr. Hanissian is with Hanissian Allergy in Germantown, Tennessee. Dr. Voeller is with Baptist Health Sciences University in Memphis, Tennessee. 

Funding: No funding was provided for this article.

Disclosures: The authors have no conflicts of interest relevant to the contents of this article.

Bariatric Times. 2023;20(5–6):20–22.

Abstract

This case report outlines a patient with a history of aggressive systemic mastocytosis with minimal benefit from standard treatment options who began semaglutide treatment for medical weight loss and had immediate resolution of chronic disabling symptoms.

Keywords: Obesity, GLP-1 agnoist, semaglutide, Ozempic, mastocytosis, mast cell disease, mast cells, weight loss, adipose tissue, inflammatory state

The obesity epidemic has necessitated the search for effective treatments for the disease. Today, there are multiple options, including both surgical and nonsurgical therapies. There has been an exponential increase in the use of glucagon-like peptide 1 (GLP-1) agonists or GLP-1 analogues to treat obesity, as either primary weight loss treatment, preoperative optimization for weight loss surgery, or secondary rescue after bariatric surgery. These medications, initially used within the realm of Type 2 diabetes management, have effectively given us a proven and reliable medical treatment for obesity with tolerable side effects in most patients. They may also be used as part of a multimodal approach to obesity management by making use of one of the most important, beneficial effects of GLP-1, promotion of satiety. The increase in prescription of GLP-1 agonists will undoubtedly also unveil unknown interactions and side effects, one of which we will present herein.

Systemic mastocytosis is a heterogeneous group of diseases that almost exclusively affects adults and is defined by the proliferation and accumulation of clonal mast cells in various tissues.1 Diagnostic criteria are multiple but primarily based on the presence of dense aggregates of mast cells on tissue specimens. Treatment is based on symptomatic relief and prevention of the disease’s clinical manifestation of mediator release. Treatments can be largely ineffective in certain patients and have mild benefits only in patients who subsequently develop progressive reactions to various stimuli, and this directly affects their daily lives.

Case Presentation

This case involves 56-year-old female patient with a history of chronic obesity (body mass index [BMI]: 30–35kg/m2), hypertension, polycystic ovary syndrome, gastroesophageal reflux disease, and a surgical history of total knee replacement. She had suffered with the complex symptoms related to systemic mast cell disease for most of her life. The diagnosis was definitively made with an endoscopic colon biopsy, revealing an increased mast cell infiltrate and chronically elevated histamine and tryptase levels, four years ago. She was also identified on bone marrow sample as having an abnormal karyotype with a pericentric inversion of chromosome 11. Her symptoms included severe recurring rashes and flushing, diarrhea, itching, easy bruising, headaches, and progressive anaphylactoid allergy-like reactions to numerous medications and situations that have been unsuccessfully treated with medication. Some medication allergies that she developed include reactions to diphenhydramine, codeine, oxycodone, famotidine, pantoprazole, simvastatin, propofol, and various tapes; she also developed multiple food allergies, including, but not limited to, milk products, tree nuts, eggs, and cumin. All of these allergies developed during her adulthood.

She received treatment and had either minimal relief or mild improvement with multiple medications, including, but not limited to, albuterol inhalers, levocetirizine, midostaurin, and benzonatate. She has also been evaluated by allergists and immunologists, without significant symptomatic relief, although follow-up with these physicians was less than optimal. Her description of her general overall health was that she “felt miserable every day due to recurring rashes, flushing, itching, and headaches.”

She was referred to our medical weight loss program for assistance in losing weight prior to undergoing hiatal hernia repair for symptoms of chronic reflux, dysphagia, esophagitis, and pathologic findings consistent with Barrett’s esophagus.

The patient’s presenting weight was 202 pounds at 5 feet 4 inches, for a BMI of 34.6kg/m2. She was not considering weight loss surgery. She was started on standard Ozempic® (semaglutide; Novo Nordisk A/S; Bagsvaerd, Denmark) dosing at 0.25mg subcutaneously each week. At her first follow-up appointment one month after starting therapy, her weight was 193 pounds (still with significant hunger cravings), so her dosing was increased to 0.5mg. However, she incidentally reported that immediately after taking her first dose of semaglutide, her symptoms related to mast cell disease began decreasing dramatically, and after two weeks, she was symptom-free for the first time in years. She noted that the chronic rashes, which she had been struggling with for over 20 years, had completely resolved. 

When she presented for her two-month follow-up appointment, her weight was 190 pounds and her semaglutide dosing was maintained at 0.5mg. This patient said that she “felt like a new person and has never felt better.” Chronic fatigue was one of her primary symptoms, and she had complete resolution of fatigue within weeks. She has not had any allergic-type reactions to typical stimuli. She has not undergone any specific testing to date, and these reports are largely subjective; however, her rashes are not detectable on physical exam. After two months of treatment, she is free of all her previous symptoms of rashes, flushing, itching, and headaches, which had affected her for more than two decades.

She has not been allergy tested again to date. As of six months after the start of her treatment, she remains symptom-free, outside of a transient minor flushing episode during a stressful family situation.

Discussion

Systemic mast cell disease, or systemic mastocytosis, is a rare disorder that is caused by excess mast cells that have built up in various anatomic locations and organs within one’s body. There is no cure for mastocytosis, so the goal is symptomatic relief and control of mediator release. When discharged, mast cells release substances that can cause a wide variety of inflammatory-type reactions. Specific symptoms depend on where mast cells have excessively developed.2–4 Symptoms can range from minor to anaphylactic reactions.

GLP-1 treatment for weight loss is becoming very common and has recently gained approval by the United States (US) Food and Drug Administration (FDA) for isolated chronic weight management, after initially being approved for glucose control in Type 2 diabetes. Semaglutide is a GLP-1 receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with Type 2 diabetes.5 Dosing is performed subcutaneously in the abdomen, thigh, or upper arm. Single-use pens deliver stairstep dosing. Dosing is increased based on the patient’s response and subjective feelings of satiety. Many patients have negative reactions, such as nausea, vomiting, abdominal pain, diarrhea, constipation, and reflux, among others,2 limiting its use to those that can tolerate these symptoms or who are symptom-free.

GLP-1 is a physiological hormone that has multiple actions on glucose, mediated by the GLP-1 receptors.5 Semaglutide lowers fasting and postprandial blood glucose and reduces body weight. It works primarily by reducing appetite as the GLP-1 agonists target brain receptors regulating appetite.6

Symptomatic relief of some of the symptoms related to mastocytosis could potentially be subjective. For example, resolution of chronic fatigue is difficult to quantitate and could also be multifactorial and improved secondary to an improved diet plan and acute weight loss. However, physical resolution of chronic rashes is a concrete finding. Our patient had chronic and exacerbating rashes over her arms and back with flushing that involved much of her body surface area for years. These physical symptoms resolved completely in two weeks after two doses of semaglutide. She also had chronic diarrhea as her primary gastrointestinal symptom, and this resolved completely in two weeks as well.

Obesity is a chronic disease and known to be a low-grade inflammatory state. Divoux et al7 evaluated the contribution of mast cells to the inflammatory status of white adipose tissue. Mast cells are found in areas of local inflammation and might play a significant role in obesity itself or obesity-related disease. Divoux et al concluded there was a close relationship between mast cells and components of adipose tissue alterations in obesity. They postulated that mast cells appear to be cellular actors of adipose tissue inflammation and contribute to the interactions between immune cells that accumulate with obesity.7

One possible mechanism of action that could explain this patient’s almost immediate response to this GLP-1 agonist is that the GLP-1 receptor is a G-protein coupled receptor that is not only expressed in tissues, such as the pancreas (β– and α-cells), brain, bowel, heart, kidney, and vascular system, but also in a variety of cells of the immune system. It has been identified in human T and B lymphocytes, variant natural killer T cells, immature lymphocytes subsets, and the CD4+CD25+ (T-regulatory) subsets. It is expressed on human macrophages, eosinophils, and neutrophils.8 The GLP-1 receptor has known immunomodulatory roles.9 Wang et al3 showed that a GLP-1 analogue attenuated the accumulation of mast cells around pulmonary vessels, demonstrating another instance of the potential anti-inflammatory effects of GLP-1.

GLP-1 agonists have a variety of anti-inflammatory effects. For example, in an mouse model with obesity and asthma, treatment with a GLP-1 receptor agonist reduced airway hyperresponsiveness and eosinophilic airway inflammation via suppression of NLRP3 inflammasome activity and interleukin (IL)-1β.10 In a study of control subjects and subjects with asthma, a GLP-1 analogue significantly decreased expression of eosinophil-surface activation markers following lipopolysaccharide (LPS) stimulation and decreased eosinophil production of the T helper 2 (Th2) cytokines IL-4 and IL-13, and IL-8 (neutrophil chemotactic factor).9, 11 The drug exenatide, a GLP-1 receptor agonist, drives macrophages to increase production of IL-10, an anti-inflammatory cytokine, and decreases both tumor necrosis factor (TNF)-α and IL-1β in cultured human monocytes and macrophages.14 Additionally, in patients with Type 2 diabetes uncontrolled on metformin, who were randomized to semaglutide versus empaglifozin, not only was semaglutide superior in reducing hemoglobin A1c, but patients on semaglutide had a significant reduction in C-reactive protein (mean: 1.85 vs. 2.65, p<0001).15

Conclusion

As a single case report, this information is clearly limited in its scope. Further testing of this individual has been encouraged, and further investigation and data will be needed before any specific recommendations can be made about a definitive link between GLP-1 agonist treatment and resolution of systemic mastocytosis. This particular case, however, could shed light on an intriguing treatment option to mast cell disease and a potential mechanism of action to better treat this disease’s crippling symptomatology.

At the time of this patient’s treatment, semalgutide was used off-label. However, semaglutide weekly injection is now approved by the FDA for weight management.

References

  1. Zanotti R, Tanasi I, Crosera L, et al. Systemic mastocytosis: multidisciplinary approach. Mediterr J Hematol Infect Dis. 2021;13(1):e2021068. 
  2. Krystel-Whittemore M, Dileepan KN, Wood JG. Mast cell: a multi-functional master sell. Front Immunol. 2016;6:620.
  3. Wang J, Yu M, Xu J, et al. Glucagon-like peptide-1 (GLP-1) mediates the protective effects of dipeptidyl peptidase IV inhibition on pulmonary hypertension. J Biomed Sci. 2019;26(1):6. 
  4. Akin C, Metcalfe DD. Systemic mastocytosis. Annu Rev Med. 2004;55:419–432.
  5. Medication Guide: Ozempic. Novo Nordisk A/S. 2017. https://www.novo-pi.com/ozempic.pdf#guide. Accessed 22 Mar 2023.
  6. Mahapatra MK, Karuppasamy M, Sahoo BM. therapeutic potential of semaglutide, a newer GLP-1 receptor agonist, in abating obesity, non-alcoholic steatohepatitis and neurodegenerative diseases: a narrative review. Pharm Res. 2022;39(6):1233–1248. 
  7. Divoux A, Moutel S, Poitou C, et al. Mast cells in human adipose tissue: link with morbid obesity, inflammatory status, and diabetes. J Clin Endocrinol Metab. 2012;97(9):E1677–E1685.
  8. Bendotti G, Montefusco L, Lunati ME, et al. The anti-inflammatory and immunological properties of GLP-1 receptor agonists. Pharmacol Res. 2022;182:106320. 
  9. Mitchell PD, Salter BM, Oliveria JP, et al. Glucagon-like peptide-1 receptor expression on human eosinophils and its regulation of eosinophil activation. Clin Exp Allergy. 2017;47(3):331–338. 
  10. Hur J, Kang JY, Kim YK, et al. Glucagon-like peptide 1 receptor (GLP-1R) agonist relieved asthmatic airway inflammation via suppression of NLRP3 inflammasome activation in obese asthma mice model. Pulm Pharmacol Ther. 2021;67:102003. 
  11. Yang F, Zeng F, Luo X, et al. GLP-1 receptor: a new target for sepsis. Front Pharmacol. 2021;12:706908. 
  12. Bułdak Ł, Machnik G, Bułdak RJ, et al. Exenatide (a GLP-1 agonist) expresses anti-inflammatory properties in cultured human monocytes/macrophages in a protein kinase A and B/Akt manner. Pharmacol Rep. 2016;68(2):329–337. Erratum in: Pharmacol Rep. 2017;69(2):376. Erratum in: Pharmacol Rep. 2019;71(5):985–986. 
  13. Rodbard HW, Rosenstock J, Canani LH, et al. Oral semaglutide versus empagliflozin in patients with Type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial. Diabetes Care. 2019;42(12):2272–2281.  

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