Tirzepatide for refractory post-fundoplication dumping syndrome: A case report

Abstract

BACKGROUND

Dumping syndrome (DS), initiated by rapid gastric emptying leading to gastrointestinal and vasomotor symptoms, is a known complication of gastric surgery. While this is well recognized after gastric surgery procedures, it tends to be underrecognized after fundoplication. Recommended pharmacotherapy for DS has had varying responses. We present a case of post-fundoplication DS successfully treated with tirzepatide, a dual glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic peptide agonist.

CASE SUMMARY

We report a case of a 36-year-old female who developed hunger pain, diarrhea, and fatigue 6 months after a laparoscopic herniorrhaphy with fundoplication for hiatal hernia (HH) and gastroesophageal reflux disease. These symptoms developed while her reflux symptoms were concurrently improving. Physical examination, routine laboratory tests, imaging, and upper endoscopy were unremarkable. Esophagogastroduodenoscopy with wireless pH monitoring showed an intact fundoplication without HH, and her pH study showed significantly improved acid parameters compared with those prior to surgery. A nuclear gastric emptying study showed 50% emptying at 30 minutes and 90% at 54 minutes, consistent with DS. Tirzepatide therapy, initiated for the management of concomitant obesity, incidentally led to the resolution of DS symptoms. The subsequent discontinuation of tirzepatide, after achieving her weight goal, resulted in the recurrence of symptoms. Considering this, the patient was restarted on tirzepatide, and she is clinically doing well.

CONCLUSION

Our case highlights DS as a potential complication of fundoplication and offers insight into GLP-1-based therapies for refractory DS.

Key Words: Dumping syndrome; Fundoplication; Tirzepatide; Glucagon-like peptide-1 agonist; Glucose-dependent insulinotropic peptide agonist; Gastric emptying; Case report

Core Tip: This report discusses a case of post-fundoplication dumping syndrome (DS), an underrecognized complication of para-esophageal herniorrhaphy, treated with tirzepatide. While an exaggerated incretin response can induce DS, glucagon-like peptide-1 (GLP-1) receptor and glucose-dependent insulinotropic peptide receptor agonists have demonstrated benefits in treating refractory cases. Our case underscores the importance of recognizing post-fundoplication DS and the potential of GLP-1-based therapies for refractory cases. Our patient’s symptoms recurrence during tapering, despite stable weight, highlights tirzepatide’s pharmacological potential in DS. This represents one of the first reported uses of tirzepatide post-fundoplication, resulting in DS resolution.

INTRODUCTION

Dumping syndrome (DS) is a complex cascade initiated by the rapid delivery of hyperosmolar gastric contents into the small intestine, resulting in a myriad of gastrointestinal (GI) and vasomotor symptoms[1]. DS is most commonly seen after surgery involving gastric resection and anastomosis, which bypasses the normal sphincter function of the pyloric channel. Clinically significant disease has been reported in 5%-10% of patients undergoing bariatric surgery[1]. Although uncommon, DS can also be seen following fundoplication. While the pyloric channel is preserved in such cases, the rapid gastric emptying is thought to be a result of reduced fundal accommodation and vagal nerve dysfunction[2,3].

Dietary modification remains the initial step in managing this condition. Medications, including acarbose and somatostatin, have been used in cases of persistent DS, with limited and often ineffective results[4] (Table 1). Few centers have begun to explore the utility of glucagon-like peptide-1 (GLP-1) receptor agonists as treatment modalities for select patients with refractory DS[5]. Here we present the case of a 36-year-old female with DS secondary to a Toupet fundoplication successfully managed with tirzepatide, a dual GLP-1 receptor and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist. The use of such medications underscores a paradoxical yet clinically significant novelty for this medication that has not previously been studied in this context.

Table 1 Mechanism of action of pharmacotherapies used for dumping syndrome.

Pharmacotherapy	Mechanism of action in dumping syndrome
α-glucosidase inhibitor (e.g., acarbose)	Competitively inhibits intestinal α-glucosidases, which delays the breakdown of complex carbohydrates into monosaccharides. This reduces glucose absorption, thereby decreasing postprandial glucose spikes and the subsequent effects of hyperinsulinemia
Uncooked cornstarch	A complex carbohydrate with a low glycemic index that is slowly digested and absorbed offers a gradual release of glucose. This supports maintaining euglycemia and prevents post-meal hypoglycemic episodes
Calcium channel blockers (e.g., nifedipine)	Inhibit voltage-gated calcium channels on pancreatic β-cells, reducing calcium influx inside the cell. This suppresses insulin secretion and helps reduce hyperinsulinemic responses to post-meal glucose elevations
Nondiuretic benzothiadiazine derivative (diazoxide)	Activates ATP-sensitive potassium channels on pancreatic β-cells, causing membrane hyperpolarization. This action inhibits voltage-dependent calcium channels, reducing insulin secretion and countering hyperinsulinemic hypoglycemia
Somatostatin analogues (e.g., octreotide)	Binds to somatostatin receptors, inhibiting insulin secretion and other gastrointestinal hormones like incretins. This decreases postprandial insulin release and slows gastric emptying, thereby preventing hypoglycemia
Avexitide	Glucagon-like peptide receptor (GLP-1) antagonists that reduce postprandial insulin and GLP-1 secretion and increase glucagon

GLP-1: Glucagon-like peptide-1.

CASE PRESENTATION

Chief complaints

A 36-year-old female presented to the gastroenterology clinic with abdominal discomfort, diarrhea, generalized weakness, and hunger pain. Abdominal discomfort and diarrhea began within 30-45 minutes after meals, whereas generalized weakness and hunger pain occurred within 1-3 hours after meals.

History of present illness

The patient's symptoms began 4 years prior to presentation, approximately 6 months after undergoing laparoscopic paraoesophageal herniorrhaphy and fundoplication for hiatal hernia (HH) and gastroesophageal reflux disease (GERD). These symptoms developed while her reflux symptoms were concurrently improving. She had been evaluated by her primary care provider and an outside gastroenterology practice prior to our assessment. One of these evaluations showed a low-normal glucose level of 74 mg/dL. She was advised to start conservative measures, including dietary changes to eat small, frequent meals high in protein and fiber. However, diarrhea, abdominal pain, and fatigue were resistant to these measures, which also included gradually increasing doses of proton pump inhibitors (PPIs).

History of past illness

The patient had a longstanding history of class II obesity, GERD, and HH lasting over 10 years. Her symptoms were resistant to conservative treatment, including dietary changes and gradually increasing doses of PPIs. Due to persistent symptoms despite maximum medical therapy, she underwent laparoscopic paraesophageal herniorrhaphy and fundoplication four years ago.

Personal and family history

The patient denied any previous related symptoms, smoking, or alcohol use. She also denied any family history of GI disorders or endocrine disease.

Physical examination

Upon visiting our clinic, the patient appeared chronically ill but remained hemodynamically stable throughout the evaluation. The patient’s body mass index (BMI) was calculated at 36 kg/m², indicating class II obesity.

Laboratory examinations

Routine laboratory investigations, including a complete metabolic panel, complete blood count, and blood sugar levels, were within normal limits.

Imaging examinations

A computed tomography scan of the abdomen and pelvis was unrevealing. Further evaluation with an esophagogastroduodenoscopy (EGD) with wireless pH monitoring revealed an intact fundoplication without HH. The pH study revealed significantly improved acid parameters compared to those prior to surgery, with acid exposure decreasing from 7.1% to 1.6%, the longest reflux duration decreasing from 32.1 minutes to 13.6 minutes, and the DeMeester score decreasing from 21.1 to 6.4. Subsequently, she underwent a nuclear study, which showed abnormally rapid gastric emptying: 50% at 30 minutes and 90% at 54 minutes.

FINAL DIAGNOSIS

The patient was diagnosed with DS due to the absence of structural abnormalities on EGD and her rapid gastric emptying times.

TREATMENT

During the course of this evaluation, the patient was started on subcutaneous tirzepatide therapy for the management of obesity. Her initial dose was 2.5 mg weekly, which was subsequently increased to 5 mg weekly after 8 weeks. Interestingly, the patient noted that her symptoms resolved when she initiated tirzepatide therapy, and she no longer experienced diarrhea, weakness, and hunger pain. No episodes of tirzepatide-related hypoglycemic episodes were documented. The patient lost 50 pounds over the next 7 months. After reaching her target BMI of 26 kg/m², she began tapering her tirzepatide dose, during which her symptoms gradually recurred and ultimately returned to their pre-treatment severity upon complete discontinuation, suggesting that this benefit was not solely from weight loss, but perhaps also from the mechanistic properties of GLP-1 agonism leading to delayed gastric emptying. Following a negative repeat EGD, she was restarted on a weekly 2.5 mg subcutaneous injection of tirzepatide.

OUTCOME AND FOLLOW-UP

After reinitiating tirzepatide at 2.5 mg weekly, the patient was followed in the clinic at 3 months, 6 months, and 9 months. During this period, she reported improved fatigue and no significant abdominal discomfort or diarrhea. Notably, symptom relapse with discontinuation of tirzepatide, followed by symptom resolution with reinitiation, and stable weight further support the conclusion that the therapeutic benefit may be attributable to tirzepatide's pharmacologic effects rather than to weight loss alone.

DISCUSSION

DS is a well-known complication of gastric surgery. However, post-fundoplication DS is often underrecognized, making it difficult to ascertain its true incidence[6]. While the anatomy of the gastric outlet is preserved during fundoplication, rapid gastric emptying is thought to result from functional issues, including reduced fundal accommodation and vagal nerve dysfunction[2,3,7]. As highlighted earlier, the abnormally rapid gastric transit triggers a complex cascade initiated by the rapid delivery of large volumes of hyperosmolar gastric content to the small intestine. Primarily, this hyperosmolar content causes fluid to shift from the intravascular compartment into the intestinal lumen, resulting in early cardiovascular and GI symptoms[8]. Additionally, distension of the small intestine stimulates the release of various GI hormones, including vasoactive agents, GLP-1s, and GIPs. Elevated levels of these incretins play a crucial role in stimulating insulin secretion and can theoretically lead to hypoglycemia[9].

One important consideration in this case is the absence of documented hypoglycemia. Our patient reported abdominal discomfort and diarrhea within an hour after meals, symptoms that are characteristic of early dumping symptoms. She also described generalized weakness and hunger pain 1-3 hours after meals, which may be suggestive of late DS. However, given the absence of documented hyperinsulinemic hypoglycemia, a definitive diagnosis of late DS could not be made. Given the objective evidence of positive gastric emptying on nuclear testing, her clinical phenotype could be viewed within a broader spectrum of mixed DS or post-fundoplication rapid gastric emptying rather than an isolated early or late DS. This limitation should be considered when interpreting the clinical response observed in this case.

The first-line approach to managing DS involves dietary and lifestyle modifications to promote gastric retention. Patients are advised to consume small, frequent meals with high protein and fiber content[4]. Further dietary modifications include separating liquids and solids and avoiding carbohydrates. When conservative measures fail, medications such as acarbose, calcium channel blockers, sodium-glucose cotransporter-1/2 inhibitors, diazoxide, or somatostatin analogs have been used with variable results[4] (Table 1). Treatment options beyond this are limited.

Few centers have begun to explore the utility of GLP-1 receptor agonists as treatment modalities for select patients with refractory DS. Ironically, while an exaggerated incretin response is considered a key factor in the secondary cascade of DS, there is growing interest in the off-label use of these agents in treatment-refractory DS. Tirzepatide should, in theory, exacerbate the symptoms and hypoglycemia of DS given the role of this secondary cascade. However, tirzepatide may potentially improve DS by regulating enteric motility, reducing antral contractions, and increasing pyloric tone, thereby slowing the hyperosmolar loading of the small intestine and resulting in symptom improvement[10]. In patients with vagal nerve dysfunction and/or altered anatomy from bariatric surgery, or reduced fundal accommodation from fundoplication, rapid nutrient exposure in the small intestine could trigger excessive endogenous insulinotropic gut hormone-based secretion and amplify autonomic activation and responses of the enteric nervous system[11]. Sustained exogenous GLP-1 receptor (and GIP receptor) agonism may serve as a “hormonal clamp” that stabilizes excessive postprandial GLP receptor activation and reduces the exaggerated sympathetic signaling and enteroendocrine fluctuations typical of dumping physiology by providing continuous receptor stimulation at stable pharmacologic levels[11,12]. This could help alleviate symptoms such as postprandial discomfort, diarrhea, and palpitations, even without causing overt hypoglycemia. Most studies attribute the potential benefits of incretins in DS to GLP-1 agonism, whereas the role of GIP agonism remains poorly understood. However, it appears that GIP agonism does not seem to negate these effects and may also affect postprandial hormonal balance[12].

A few other cases of DS managed with GLP-1- based therapy have been described in the literature (Table 2). Among these, only one case was secondary to a fundoplication, but in that case, liraglutide was used. The improvement in DS with tirzepatide therapy supports the hypothesis that dual GLP-1/GIP receptor agonists may offer a promising therapeutic avenue for DS. While our patient’s weight loss may have coincided with symptomatic improvement, several factors suggest that weight reduction alone may not fully explain her therapeutic response. Symptom resolution occurred shortly after starting tirzepatide (at low doses of 2.5-5 mg weekly), well before significant weight loss, and these symptoms returned to pre-treatment levels during dose tapering and discontinuation, even though her body weight remained stable. Additionally, her symptoms improved again after restarting tirzepatide at a low maintenance weekly dose of 2.5 mg, with no noticeable changes in her weight throughout the 9-month follow-up period. This pattern suggests that other pharmacodynamic effects of tirzepatide, beyond its weight loss effect, could have contributed to the therapeutic benefits observed in our patient (Table 3). As shown in Figure 1, there appears to be a temporal relationship between tirzepatide use and symptom severity over the study period, with the patient’s symptoms improving shortly after treatment initiation, recurring after discontinuation despite a stable BMI, and improving again after reinitiation, while BMI remained largely unchanged during the 9-month follow-up period. Nevertheless, given the limitations of a single-case report, these findings should be considered hypothesis-generating rather than evidence of a causal relationship. The only other reported case of tirzepatide use in DS was documented by Stortz and Lawler[12]. They described a patient in whom tirzepatide use was associated with symptom resolution following sleeve gastrectomy[12]. The patient’s GI symptoms improved shortly after starting weekly doses of 2.5 mg of tirzepatide, which were then increased to 5 mg, coinciding with reductions in postprandial glycemic levels. However, the report focused on symptom evaluation and glucose levels without an objective assessment of gastric emptying, and it did not review the patient’s symptoms for possible recurrence after tirzepatide was discontinued.

Figure 1 Temporal relationship of tirzepatide use, symptom severity, and body mass index. Symptom severity improved with tirzepatide initiation and re-initiation, worsened after dose reduction and discontinuation, and paralleled changes in drug exposure. Body mass index decreased during treatment and subsequently stabilized. BMI: Body mass index.

Table 2 Comprehensive comparison of our case and published dumping syndrome cases treated with glucagon-like peptide-1 analogs.

Ref.	Age/gender	Surgery type	Timing of symptom onset	Primary symptoms	Documented hypoglycemia	Failed prior therapies	Incretin therapy used	Initial dose	Maximum dose	Symptom response	Response to discontinuation	Follow-up duration
Our case	36/female	Toupet 270° fundoplication	6 months post-operation	Hunger pain, diarrhea, fatigue	No	Dietary modification	Tirzepatide	2.5 mg weekly	5 mg weekly	Complete resolution	Symptom recurrence	7 months before taper
Chiappetta and Stier[10]	52/female	Toupet fundoplication	12 months post-operation	Palpitations, nausea, sweating	Yes (nadir 35 mg/dL)	Dietary modification	Liraglutide	0.6 mg daily	1.2 mg daily	Significant improvement	Not attempted	Not specified
Ding et al[11]	53/male	Distal gastrectomy	16 months post-operation	Palpitations, sweating, dizziness	Yes (nadir 1.8 mmol/L)	Acarbose, diet	Beinaglutide	0.1 mg twice daily	0.1 mg twice daily	Complete resolution	Not attempted	1 month
Stortz and Lawler[12]	46/female	Sleeve gastrectomy	Approximately 8 months post-operation	Bloating, diarrhea, confusion	Yes (30-50 mg/dL)	Dietary modification	Tirzepatide	2.5 mg weekly	5 mg weekly	Complete resolution	Not reported	1.5 years

Table 3 Timeline of clinical course from symptom onset through tirzepatide treatment and follow-up.

Time point	Clinical phase	Key clinical & diagnostic details	Surgical context	Tirzepatide dose	Symptom status	BMI (kg/m2)
4 years prior	Index surgery	Laparoscopic paraesophageal herniorrhaphy for hiatal hernia and reflux	Toupet 270° fundoplication	N/A	Reflux symptoms present	36
Approximately 3.5 years prior (6 months post-procedure)	Symptom onset	Postprandial abdominal discomfort, diarrhea, generalized weakness, hunger pain; reflux improved	Post-fundoplication	N/A	DS symptoms (8-9/10)	36
3 months prior	Initial evaluation	Persistent symptoms despite dietary modification and proton pump inhibitor therapy	Post-fundoplication	N/A	DS symptoms (8-9/10)	36
2 months prior	Diagnostic work-up	CT abdomen/pelvis unremarkable; endoscopy with wireless pH showed intact fundoplication and reduced acid exposure (1.6%); gastric emptying study confirmed rapid emptying	Post-fundoplication	N/A	DS symptoms (8-9/10)	36
Month 0	Diagnosis & treatment initiation	Dumping syndrome diagnosed; tirzepatide initiated for obesity management	Post-fundoplication	2.5 mg weekly	Improving DS symptoms (6/10)	36
Month 2 (week 8)	Dose escalation	Dose increased due to good tolerability and partial symptom response	Post-fundoplication	5 mg weekly	Minimal DS symptoms (2/10)	34-35
Months 3-7	Maintenance phase	Continued therapy with progressive weight loss	Post-fundoplication	5 mg weekly	Minimal DS symptoms (1-2/10)	26-34
Month 7	Target BMI achieved	Approximately 50-lb weight loss achieved; target BMI reached	Post-fundoplication	5 mg weekly	Minimal DS symptoms (1-2/10)	26
Months 8-9	Dose tapering & discontinuation	Gradual dose reduction and discontinuation; symptoms gradually recurred despite stable weight	Post-fundoplication	5 mg to 2.5 mg to 0 mg	Progressive DS symptoms (2-6/10)	26 (stable)
Month 9	Post-discontinuation reassessment	Repeat endoscopy unremarkable; full symptom recurrence with stable BMI	Post-fundoplication	0 mg	Severe DS symptoms (8/10)	26.5 (stable)
Month 11	Treatment reinitiation	Tirzepatide restarted at lower maintenance dose	Post-fundoplication	2.5 mg weekly	Improving DS symptoms (2-6/10)	26 (stable)
Months 12-20	Follow-up/sustained remission	Sustained symptom resolution at 3- and 6-month follow-up; no adverse effects	Post-fundoplication	2.5 mg weekly	Minimal DS symptoms (1-2/10)	26 (stable)

BMI: Body mass index; N/A: Not available; DS: Dumping syndrome; CT: Computed tomography.

Although our patient reported no side effects with tirzepatide use, the long-term safety of tirzepatide remains an important consideration for off-label use in DS. These side effects are typically dose-dependent and more common during initiation or dose escalation. They include GI side effects such as nausea (13%-26%), diarrhea (11%-21%), and vomiting (5%-13%), which could theoretically worsen or overlap with DS symptoms[13,14]. While the risk of hypoglycemia with tirzepatide monotherapy is generally considered low, it remains a theoretical concern when combined with insulin or other secretagogues, especially given tirzepatide’s role in the secondary cascade of DS[13]. In practice, these risks can be minimized with several strategies: (1) Starting with standardized titrations at 2.5 mg weekly for 4 weeks, then increasing by 2.5 mg every 4 weeks as tolerated, is recommended[15]; (2) Dose reduction should be considered for patients experiencing significant symptoms; (3) When tirzepatide is used alongside insulin or secretagogues, planned dose adjustments of these medications can reduce the risk of hypoglycemia[15]; and (4) Patients should be educated to recognize these side effects, especially during initiation and dose escalations[16].

The proposed mechanisms for DS resolution with tirzepatide in our patient are supported by observed clinical effects; however, they remain hypothetical and have not been experimentally validated. Therefore, the therapeutic benefit observed in this case should be considered preliminary evidence warranting additional investigation. Furthermore, symptom severity and treatment response were assessed using patient-reported scores rather than a validated DS severity score or glucose monitoring, which could be subject to reporting bias.

CONCLUSION

Our case underscores the recognition of post-fundoplication DS and the use of GLP-1 therapies for refractory DS. While clinical decisions should rarely be based on individual case reports or case series, there appears to be a strong argument to consider tirzepatide or other GLP-1 receptor agonists in select cases of refractory DS. Furthermore, conducting randomized trials with larger patient cohorts and extended follow-up periods is needed to determine the optimal dosing, efficacy, and long-term safety profile of tirzepatide in post-fundoplication DS.

ACKNOWLEDGEMENTS

We gratefully acknowledge all members of the West Virginia University Gastroenterology and Internal Medicine teams who contributed to the patient's care.