Semaglutide Overdose in a Diabetic Patient: Suicidal Behavior and Multiorgan Failure

Introduction

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as Semaglutide have become prominent in managing type 2 diabetes mellitus (T2DM) and obesity due to their effectiveness in controlling blood sugar levels and promoting weight loss [1–3]. The widespread promotion of Semaglutide for weight management has led to a significant increase in its prescription for both approved and for off-label uses [1,2,4]. After its initial approval by the US Food and Drug Administration (FDA) for managing type 2 diabetes mellitus (T2DM) and facilitating long-term weight management [4], concerns have emerged regarding a potential link between GLP-1 RAs administration and an elevated risk of suicidal behavior [5,6]. However, to the best of our knowledge, documented suicidal behavior or severe adverse effects following a Semaglutide overdose are notably absent from the available literature. Here, we describe an exceedingly rare case of Semaglutide self-administered overdose effect and provide a focused review of the literature on this topic.

Case Report

A 67-year-old man presented to the emergency room with a 2-week history of progressive weakness, loss of appetite, and epigastric pain, which evolved into massive watery, bloody diarrhea and melena. Additionally, he reported a syncopal episode the day before hospitalization. On physical examination, he looked pale, had blood pressure of 79/36, pulse 94/min, and body temperature of 36.6°C. The main laboratory findings were hypoglycemia, severe anemia, and acute kidney injury. Further investigation revealed cholestatic type liver function impairment, with bilirubin up to 2.5 mg/dL (norm<1.1) and liver enzymes 3 times higher than normal. Additionally, elevated blood lipase and amylase levels were found. After receiving isosmotic fluids and packed cells, he was stable enough to undergo upper-gastrointestinal (GI) endoscopy. Two clean-based duodenal ulcers with no active bleeding were found in the duodenal bulb (Figure 1A). An abdominal CT scan with contrast material revealed a 5-mm stone in the dilated pancreatic duct. Under prolonged conservative management, his condition gradually improved, and kidney function, liver tests, and pancreatic enzymes returned to normal. Moreover, the duodenal ulcers almost completely resolved (Figure 1B). The patient’s medical background included overweight (weight 75 kg, height 1.7 m, BMI=26) and T2DM, routinely treated with insulin and Semaglutide (1 mg/week, initiated 1 year before the current hospitalization) and ischemic heart disease treated by daily aspirin (100 mg/day). He was further screened for other health risks and was considered a non-smoker, without excessive alcohol consumption, and as having no recent substance abuse or mental disorders history according to his interviews with medical staff including a physician, nurse, dietitian, and social worker. Upon further questioning, the patient recalled feeling moody in the past weeks due to separation from his partner, and injecting his accumulated monthly Semaglutide prescription of 8 mg all at once 14 days before hospital admission. Investigating his background revealed no history of major depression disorder (MDD) or other psychiatric diagnosis or self-harm. As the patient improved more, he was discharged to recover at home.

Discussion

We report a unique case of a patient self-injecting an overdose of Semaglutide. He reported being dysphoric prior to the event and injecting an overdose 8 times greater than his approved single injection dose of 1 mg/week. Notably, the Semaglutide application pen is very safely designed and the maximum dose available for a single injection is the approved weekly dose [1,5]. Overdosing is possible only by multiple injections up to the pre-filled monthly amount. Since the Semaglutide treatment was initiated >1 year before the event and the patient was experienced in self-injecting, overdosing as an expression of suicidal behavior may be considered [6]. Due to the excessive amount of the drug, not only did he experience various well-known adverse reactions, he also developed uncommon life-threatening adverse effects, including acute kidney injury, gastrointestinal bleeding, ischemic necrosis of the upper-gastrointestinal (GI) tract, and biliary pancreatitis [7]. This is most likely due to the high dosage and the drug half-life.

It is not yet fully understood how GLP-1 RAs overdose harms the GI system. However, updated explanations can be offered. Some GI adverse events include abdominal pain, nausea, vomiting, constipation, diarrhea, delayed gastric emptying, and pancreatitis [8]. A recent study linked GLP-1 RAs to pancreatitis, gastroparesis, and bowel obstructions [9]. Medications such as Semaglutide simulate gut hormones [10]. Accordingly, we hypothesized that our patient’s overdose caused the above-mentioned adverse effects. GI-related adverse effects of GLP-1 RAs include nausea, vomiting, constipation, and diarrhea, even at prescribed doses [9,10]. This suggests that multiorgan failure should be excluded in Semaglutide-treated patients presenting with an abrupt onset of acute illness.

Recently, growing numbers of studies have found an association between GLP-1 RAs and possible self-injury thoughts [11], but a recent report found no causal link between GLP-1 RAs and suicidality [5]. Although it is possible that an unreported history of ADD, self-harm, and previous other mental health events could have contributed to suicidal behavior [12], the current case report may serve as evidence of GLP-1 RAs overdose that raises suspicions regarding self-overdosing this medication in attempting suicide. Thus, in our opinion, the causal relationship between self-harm and suicidality and GLP-1 RAs administration should be further investigated, especially in the light of the very broad use of GLP-1 RAs [1,3]. Given an approximate 7-day half-life in humans [13], Semaglutide serum levels should be included in such investigations to confirm overdose. This investigation is also needed as individuals with morbid obesity and T2DM might be at increased risk of developing ADD, which in turn can also lead to a higher risk of self-harm [11]. We also suggest measuring blood levels of Semaglutide (or its possible marker) to better elaborate causality among patients suspected as self-injury by Semaglutide overdose in future relevant cases. If true, psychiatric evaluation is required to determine intent.

In summary, the current case report may be considered suicidal behavior to self-inject an overdose 8 times greater than approved for a single injection for 6 reasons: (1) Semaglutide treatment began more than 1 year before the event; (2) The patient was experienced in self-injecting; (3) A single injection is limited to the weekly recommended dose; (4) If multiple injections exceed the pre-filled monthly amount, an overdose might occur; (5) Semaglutide application by pen is very safe; and (6) He reported being dysphoric prior to the event.

Conclusions

Screening patients taking GLP-1 RAs, such as Semaglutide, for common mental disorders is recommended. Further, we suggest that patients on Semaglutide with acute illness be evaluated for multiorgan failure.