Rybelsus, a brand name for semaglutide, is an oral medication used primarily to manage type 2 diabetes. As with any medication, understanding its side effects and potential risks is crucial for both patients and healthcare providers.

One of the concerns raised with the use of Rybelsus is whether it causes gastroparesis, a condition that affects stomach motility. This article aims to explore the relationship between Rybelsus and gastroparesis, providing an in-depth analysis based on the latest scientific research and clinical data.

Key Findings

  • Gastroparesis is a condition characterized by delayed gastric emptying without a mechanical obstruction, leading to symptoms like nausea, vomiting, bloating, early satiety, and abdominal pain.
  • Various causes of gastroparesis include idiopathic origins, diabetes mellitus, postsurgical complications, viral infections, rheumatological and autoimmune diseases, and medications affecting gastric motility.
  • GLP-1 receptor agonists, including Rybelsus, are known to slow gastric emptying, which can potentially lead to gastroparesis. Case studies have linked semaglutide and other GLP-1 agonists to gastroparesis in both diabetic and non-diabetic patients.
  • Post-market surveillance and reports to the FDA’s Adverse Event Reporting System have noted symptoms of gastroparesis among users of Rybelsus and other GLP-1 agonists.
  • Comparative studies show that individuals using GLP-1 agonists are more likely to develop gastroparesis compared to those using other medications, with semaglutide having a higher frequency of reported cases.
  • Factors contributing to gastroparesis in diabetic patients include diabetic neuropathy, hyperglycemia, altered gastric smooth muscle function, autonomic dysfunction, and changes in the enteric nervous system.
  • Experts suggest careful patient selection and monitoring when prescribing GLP-1 medications, considering the potential risks of gastroparesis. Stopping the medication often resolves symptoms.
  • Despite the potential risk of gastroparesis, Rybelsus offers significant benefits for type 2 diabetes management, including effective blood sugar control, weight loss, and cardiovascular benefits. Monitoring and individualized strategies can help mitigate risks.

Understanding Gastroparesis

Gastroparesis is characterized by delayed gastric emptying without a mechanical obstruction, which means there is no physical blockage persisting for at least three months. This delay causes symptoms like:

  • Nausea
  • Vomiting
  • Bloating
  • Early satiety (feeling full quickly)
  • Abdominal pain

Delays in stomach emptying happen because the stomach muscles and nerves don’t work properly. This involves a complex interaction between the nervous systems, stomach muscles, specific cells in the stomach and intestine that act like pacemakers, and the valve between the stomach and small intestine. Additionally, people with gastroparesis also have changes in their stomach’s immune response and inflammatory markers.

Causes and Risk Factors

The causes of gastroparesis are very diverse, with over 90 different reasons identified. Here are the main causes:

  • Idiopathic: This accounts for one-third of all cases and is more likely to affect women, white individuals, and those with symptoms like abdominal pain and feeling full quickly.
  • Diabetes mellitus (DM): People with diabetes are at higher risk of developing gastroparesis, accounting for around 30% of cases, especially if they have had the disease for a long time (at least ten years), have other nerve complications, and have poor blood sugar control. In fact, up to 50% of diabetics with poor glucose control may experience this condition. Additionally, high blood sugar can slow stomach emptying, even in individuals who are not diabetic.

According to a study, diabetic gastroparesis affects about 4.8% of individuals with type 1 diabetes, 1% of those with type 2 diabetes, and 0.1% of those without diabetes. While there is a stronger link between type 1 diabetes and gastroparesis, the higher prevalence of type 2 diabetes means that gastroparesis is more commonly observed in type 2 diabetics.

  • Postsurgical: Injury to the vagus nerve during surgery or changes in stomach anatomy can affect stomach emptying. The vagus nerve plays a key role in how the stomach moves its contents, connecting to over 70% of the nerves in its muscle layer.

Gastroparesis often occurs after surgeries involving the esophagus, stomach, duodenum, or pancreas, especially if these surgeries damage the vagus nerve. It can develop immediately after surgery or even years later. Surgeries like Nissen fundoplication, gastrectomy, and procedures on the pancreas are linked to gastroparesis. Some gynecological surgeries can also cause this condition.

  • Viral infections: Postinfectious gastroparesis, caused by viruses, is typically temporary, with full recovery being common. The most frequently identified viruses are Norwalk virus and rotavirus, but Epstein-Barr virus, cytomegalovirus, and Varicella Zoster virus can also cause long-term issues with stomach movement.
  • Rheumatological diseases: Conditions like amyloid neuropathy and systemic sclerosis (scleroderma) can cause gastroparesis.
  • Autoimmune diseases: These might be treated with plasmapheresis to remove autoantibodies.
  • Medications: Various drugs can impact gastric motility, including painkillers like opioids, immunosuppressants such as cyclosporine, antipsychotic drugs from the phenothiazine class, medications that mimic dopamine, hormone therapies including octreotide, alpha-2 adrenergic agonists, antidepressants like tricyclics, calcium channel blockers, GLP-1 agonists or their analogs (including semaglutide, liraglutide, exenatide, dulaglutide, and tirzepatide), mood stabilizers such as lithium, and the hormone progesterone.

Clinical Evidence Linking Rybelsus to Gastroparesis

GLP-1 receptor agonists, including Rybelsus, are known to slow gastric emptying as part of their therapeutic effect. By delaying gastric emptying, these medications help reduce the rapid increase in blood sugar levels after eating a meal. However, this mechanism also raises concerns about the potential development of gastroparesis.

Patient Case Studies

Case reports provide valuable insights into the potential side effects of GLP-1 receptor agonists and highlight the need for careful management and monitoring of patients on these medications. Here are some case examples involving GLP-1 receptor agonists, including semaglutide, the active ingredient in Rybelsus:

Case Study 1: Semaglutide-Induced Gastroparesis without Diabetes

A 53-year-old woman with a history of depression, moderate obesity, and obstructive sleep apnea came to the hospital with nausea and abdominal pain for three weeks. She had been using a weekly injection of 0.5 mg semaglutide for weight loss over the past four months, which helped her lose around 40 pounds. She did not increase the dose as she was happy with the initial results. Her other medications included alprazolam, methocarbamol, desvenlafaxine, and bupropion.

Concerned about a possible abdominal obstruction, doctors ordered a CT scan of her abdomen and pelvis, which showed no obstruction or other acute issues. Further tests ruled out diabetes, blockage causes, and autoimmune diseases.

The patient was treated with IV ondansetron for nausea and was able to tolerate a semisolid diet. An endoscopy the next day showed a normal esophagus but retained semisolid food in the stomach, leading to the procedure being stopped. She was then placed on a clear liquid diet and prepped for another endoscopy the following day, which still showed retained food in the stomach.

The finding of food remaining in the stomach for over 24 hours suggested gastroparesis. Doctors believed this was caused by her use of semaglutide and advised her to stop taking it. They did not perform a gastric emptying study, usually the gold standard for diagnosing gastroparesis, because they were confident in the diagnosis based on her symptoms and endoscopy findings. One month after stopping semaglutide, the patient reported a significant improvement and complete resolution of her nausea.

Case Study 2: Semaglutide-Induced Gastroparesis with Diabetes

A 52-year-old woman, who has had type 2 diabetes for 10 years, came to the clinic because she had been experiencing pain in her upper abdomen after meals for the last seven months. This pain was also accompanied by feelings of fullness, bloating, and nausea.

Various medications were tried to relieve her symptoms, including proton pump inhibitors (which reduce stomach acid) and antispasmodics (anticholinergics, which reduce muscle spasms), but none of them worked.

Her lab tests and a CT scan of her abdomen didn’t show any abnormalities. Her HbA1c, a measure of blood sugar control over the past few months, was 5.7%, indicating well-controlled diabetes. Previous upper and lower endoscopies didn’t show any blockages, and a biopsy ruled out Heliobacter pylori (a bacteria that can cause stomach problems).

A hepatobiliary iminodiacetic acid (HIDA) scan, which checks gallbladder function, showed no issues, and an abdominal Doppler blood flow study ruled out median arcuate ligament syndrome (a condition that can cause abdominal pain).

During a detailed discussion of her medical history, it was discovered that she had started taking semaglutide about a month before her symptoms began. A 4-hour gastric emptying study (GES), which measures how quickly food leaves the stomach, showed that 24% of the food remained in her stomach after four hours. Normally, less than 10% should remain, indicating that she had delayed gastric emptying or gastroparesis.

After identifying that semaglutide might be causing the delayed gastric emptying and related symptoms, the medication was stopped for six weeks. During this period, the patient’s symptoms resolved. A repeat GES was performed, and the results showed a significant improvement in gastric emptying, indicating that the delay in GE had been resolved. Specifically:

Before stopping semaglutide:

  • 1 hour: 93% retention (normal <90% and >30%)
  • 4 hours: 24% retention (normal <10%)

After stopping semaglutide for 6 weeks:

  • 1 hour: 77% retention (normal <90% and >30%)
  • 4 hours: 6% retention (normal <10%)

These results confirmed that stopping semaglutide normalized gastric emptying and resolved the patient’s symptoms.

Case Study 3: Dulaglutide-Induced Gastroparesis with Diabetes

A healthcare professional uses a glucometer to check a patient's blood sugar level.

A 57-year-old woman with a 16-year history of type 2 diabetes came to the clinic because she had been experiencing abdominal bloating, nausea, and vomiting for the past year. Her blood tests showed a high HbA1C level of 8.2%, indicating poorly controlled diabetes. Previous tests, including an upper endoscopy and colonoscopy, showed no blockages or other issues, but she had never undergone a GES.

About 15 months ago, she started taking dulaglutide, also a GLP-1 receptor agonist. A 4-hour GES was performed, and 35% of the food remained in her stomach, indicating gastroparesis. As a result, she stopped taking dulaglutide for four weeks. During this time, her symptoms gradually improved. A repeat GES was performed, which showed that her gastric emptying had returned to normal.

In all three cases, symptoms improved, and gastric emptying normalized after stopping the medication, suggesting a link between GLP-1 receptor agonists and gastroparesis. However, for patients with diabetes, it is particularly challenging because both diabetes and GLP-1 receptor agonists can cause delayed gastric emptying.

Post-Market Surveillance

Since its approval, post-market surveillance has been critical in identifying rare or long-term side effects. Reports to the FDA’s Adverse Event Reporting System (FAERS) and other pharmacovigilance databases have noted symptoms of gastroparesis among users of Rybelsus and other GLP-1 agonists.

FAERS, a publicly accessible post-marketing safety database, collects adverse event reports, medication error reports, and product quality complaints from health professionals, pharmaceutical manufacturers, lawyers, and patients worldwide.

A study investigated the association between semaglutide and gastrointestinal adverse events. Researchers identified cases using both the generic name (semaglutide) and trade names (Ozempic, Rybelsus, and Wegovy), resulting in 11,326 semaglutide-related gastrointestinal events in 5,442 patients from the FAERS database.

The most frequently reported gastrointestinal adverse events were:

  • nausea
  • vomiting
  • diarrhea
  • constipation
  • upper abdominal pain
  • abdominal pain
  • pancreatitis

Many of these are symptoms consistent with gastroparesis. Furthermore, the data for impaired gastric emptying associated with semaglutide revealed 48 reported cases. The Reporting Odds Ratio (ROR) is 11.83, with a 95% confidence interval ranging from 8.88 to 15.75, indicating a strong statistical association between semaglutide and impaired gastric emptying. Although no deaths were reported, the condition is significant enough to be classified as an important medical event.

Comparative Studies

Comparative studies between different GLP-1 receptor agonists can provide insight into the risk of gastroparesis. For example, a study in JAMA Network compared the effects of semaglutide, liraglutide, and bupropion-naltrexone on the risk of gastrointestinal adverse events, including gastroparesis.

Results revealed that individuals using GLP-1 agonists are 3.67 times more likely to develop gastroparesis compared to those using bupropion-naltrexone. For semaglutide, gastroparesis was reported at a frequency of about 10 cases per 1,000 users and 7 cases per 1,000 users of liraglutide.

Mechanisms Behind Gastroparesis in Diabetic Patients

Does Rybelsus Cause Gastroparesis? An In-Depth Analysis

The mechanisms behind gastroparesis in diabetic patients are multifaceted. Understanding the underlying causes of gastroparesis in diabetic patients involves examining the following factors:

Neuropathy

Diabetic neuropathy is a major contributing factor to gastroparesis. Chronic high blood sugar levels can damage the vagus nerve, which controls the movement of food through the digestive tract. When the vagus nerve is impaired, the coordinated muscular contractions (peristalsis) necessary for moving food from the stomach to the intestines become erratic or slow down, leading to delayed gastric emptying.

Hyperglycemia

Persistent hyperglycemia has direct and indirect effects on gastric motility. High blood sugar levels can alter the release of gastrointestinal hormones that regulate motility, such as motilin and ghrelin. Furthermore, hyperglycemia can lead to oxidative stress and inflammation, which can further damage nerve cells and smooth muscle in the gastrointestinal tract.

Altered Gastric Smooth Muscle Function

Hyperglycemia and resultant oxidative stress can directly affect the smooth muscle cells in the stomach, impairing their contractility. This can result in weakened gastric peristalsis and contribute to the delayed emptying observed in gastroparesis. Changes in the interstitial cells of Cajal, which are essential for generating the electrical impulses that coordinate smooth muscle contractions, are also implicated.

Autonomic Dysfunction

Diabetes can cause autonomic neuropathy, which affects the autonomic nervous system that regulates involuntary bodily functions, including gastric motility. Autonomic dysfunction can lead to abnormal gastric reflexes and impaired coordination between different parts of the digestive tract, exacerbating the symptoms of gastroparesis.

Changes in the Enteric Nervous System

The enteric nervous system, sometimes referred to as the “second brain,” plays a critical role in controlling gastrointestinal motility. Diabetic patients may experience dysfunction within this system due to nerve damage, affecting the communication between the gut and the brain, further disrupting normal gastric emptying processes.

Impact of Medications

Certain medications used to manage diabetes and its complications can also affect gastric motility. For example, GLP-1 agonists, which are used to improve blood glucose control, can slow gastric emptying as a side effect, potentially exacerbating gastroparesis symptoms in diabetic patients.

Further research into these mechanisms continues to be essential for developing targeted therapies to address this challenging condition.

Expert Insights on Rybelsus and Gastroparesis

Experts and leading medical organizations offer valuable insights and guidelines for the use of Rybelsus in managing type 2 diabetes, especially considering its potential risk of gastroparesis.

Dr. Andres Acosta on GLP-1 Medications

Dr. Andres Acosta, a gastroenterologist at the Mayo Clinic, recognizes the general safety of GLP-1 medications like Ozempic and Wegovy but cautions about serious gastrointestinal side effects, such as nausea, vomiting, and delayed gastric emptying. He suggests that some side effects may result from rapid weight loss rather than the medication itself and calls for larger randomized controlled trials to better understand these risks, including gastroparesis.

Dr. Shauna Levy on Prescribing Practices

Dr. Shauna Levy, an obesity medicine specialist, reviewed recent study findings and stated she would not change her prescribing practices for GLP-1 medications like semaglutide. She emphasizes the importance of these medications being regulated by a physician who can monitor patients closely and stop the medication if severe side effects occur. Dr. Levy believes that the rare side effects do not outweigh the health risks associated with obesity and stresses careful patient history and monitoring.

Dr. Michael Camilleri on Gastroparesis Risks

Dr. Michael Camilleri, another gastroenterologist at the Mayo Clinic, conducted a study with liraglutide that showed dramatically slowed digestion compared to a placebo, correlating with weight loss.

Over time, patients seemed to adjust, and symptoms like nausea and vomiting eased. However, he emphasized that the delayed gastric emptying effect of these drugs is not well-recognized, suggesting that some patients with borderline slow gastric emptying might develop full-blown gastroparesis when starting GLP-1 agonists.

Dr. Renuka George on Surgical Risks

Dr. Renuka George, the director of the regional anesthesiology fellowship at the Medical University of South Carolina, raised significant concerns about the risks of stomach paralysis in patients taking GLP-1 agonists, especially during surgery. She shared an instance where a patient who had fasted correctly still had a full stomach due to the medication.

This situation poses a risk of aspiration, where stomach contents enter the lungs, potentially leading to severe complications or extended ventilation. To mitigate these risks, the American Society of Anesthesiologists recommends stopping these medications one week before surgery, although this advice is based on limited scientific evidence. Ongoing studies aim to provide more precise guidelines for managing these risks effectively.

Reddit Discussions on Rybelsus and Gastroparesis

Users of Reddit shared their opinions and concerns on the potential risks of Rybelsus related to stomach paralysis. Here are some of the subreddit discussions:

User hoppy999 raised concerns about Rybelsus and stomach paralysis, noting the lawsuits related to Ozempic. PurplestPanda responded, stating, “Your major risks for Rybelsus are pancreatitis, gall bladder or kidney issues, and vision problems if you’re diabetic. Stomach paralysis is such a remote possibility, it’s not worth worrying about.

Another user, Briartell, added, “My husband’s doctor explained that those developing gastroparesis were likely to have undiagnosed GI conditions, which semaglutide can exacerbate.

For more details, you can view the full discussion here:

Posts from the semaglutide
community on Reddit

In another Reddit thread, user jujubeans1998 voiced worries about the potential side effects of Rybelsus, including stomach paralysis, gallbladder issues, and thyroid cancer. User DitzyShroom responded, reassuring that stomach paralysis is incredibly rare and gallbladder issues are common with weight loss. Thyroid cancer was only observed in preclinical mouse studies. Another user, Cmdr_Toucon, expressed more concern about the negative health effects of obesity than the potential side effects of the medication.

For more details, check out the full discussion here:

Anyone else worried about the upcoming issues?
byu/jujubeans1998 inSemaglutide

Balancing Benefits and Risks

As with any medication, it’s crucial to weigh the benefits of Rybelsus against potential risks, including the risk of developing or worsening gastroparesis.

Benefits of Rybelsus

Despite the potential risk of gastroparesis, Rybelsus offers significant benefits for patients with type 2 diabetes, including:

  • Effective Blood Sugar Control: In the PIONEER program, once-daily oral semaglutide 14 mg reduced HbA1c by 1.0–1.4%, significantly more than sitagliptin or empagliflozin, and comparable to liraglutide after 26 weeks.
  • Weight Loss: Many patients experience weight loss while taking Rybelsus, which can benefit overall health and improve insulin sensitivity, further aiding in diabetes management. During clinical trials, oral semaglutide resulted in more weight loss than sitagliptin, liraglutide, and empagliflozin. For instance, in the PIONEER 1 trial, participants on the 7 mg dose of oral semaglutide lost 2.0-2.2 lbs, while those on the 14 mg dose experienced weight loss of 5.1-5.7 lbs. Other trials showed positive results as well, specifically:
  • PIONEER 2: Oral semaglutide demonstrated superior efficacy at week 52 compared to empagliflozin (10.4 lbs vs. 8.4 lbs). Additionally, reductions in waist circumference were consistently greater with oral semaglutide.
  • PIONEER 3: The estimated mean changes from baseline in body weight at week 26 for 3 mg, 7 mg, and 14 mg oral semaglutide vs. sitagliptin are 2.6 lbs, 4.9 lbs, and 6.8 lbs vs. 1.3 lbs.
  • PIONEER 4: At week 26 (policy estimand), oral semaglutide resulted in superior weight loss compared to both liraglutide (9.7 lbs vs. 6.8 lbs) and placebo (9.7 lbs vs. 1.1 lbs). When using the trial product estimand, oral semaglutide resulted in about 3.3 lbs greater weight loss than liraglutide and approximately 8.8 lbs greater weight loss than placebo.
  • PIONEER 5: Participants taking oral semaglutide experienced a mean weight loss of 7.5 lbs, whereas those on placebo had 2.0 lbs, based on treatment policy estimand. Under the trial product estimand, participants on oral semaglutide lost 8.2 lbs, while those on placebo lost 2.4 lbs.
  • Cardiovascular Benefits: The PIONEER 6 trial demonstrated that oral semaglutide is not only safe for patients with type 2 diabetes who are at high cardiovascular risk but also significantly reduces the risk of death from heart problems and other causes.

Risk Mitigation Strategies

By implementing individualized strategies, healthcare providers can help patients achieve optimal outcomes while minimizing risks. Some effective approaches include:

  • Individualized Assessment: Each patient’s medical history, including any pre-existing gastrointestinal conditions, should be thoroughly evaluated. Those with a history of gastroparesis or significant gastrointestinal issues may need to consider alternative treatments.
  • Monitoring and Adjustment: Regular monitoring of blood sugar levels, weight, and gastrointestinal symptoms is essential. If symptoms of gastroparesis develop, the healthcare provider may need to adjust the dosage or consider switching to a different medication.
  • Lifestyle and Dietary Modifications: Implementing dietary changes, such as eating smaller, more frequent meals and avoiding high-fat and high-fiber foods, can help manage gastroparesis symptoms if they occur while taking Rybelsus.
  • Shared Decision-Making: Patients should be involved in the decision-making process, understanding both the potential benefits and risks of Rybelsus. Open communication with healthcare providers about any side effects or concerns is crucial for optimal management.

Final Thoughts

Rybelsus, like other GLP-1 receptor agonists, has a well-documented impact on gastric emptying, which can raise concerns about gastroparesis. However, the clinical evidence linking Rybelsus directly to gastroparesis is not definitive.

While gastrointestinal symptoms are common, severe cases of gastroparesis appear to be relatively rare. Balancing the benefits of improved glycemic control and weight loss with the potential risks requires careful patient selection and monitoring. Ongoing research and post-market surveillance will continue to shed light on this important issue, helping healthcare providers make informed decisions to optimize patient outcomes.

Frequently Asked Questions

Does Rybelsus cause joint pain?

No. Rybelsus does not commonly cause joint pain. The primary side effects include gastrointestinal issues such as nausea, vomiting, diarrhea, and abdominal pain.

How long does Rybelsus stay in your system?

Blood concentrations of semaglutide stabilize and become consistent after 4 to 5 weeks of regular administration, meaning they no longer exhibit significant fluctuations. Semaglutide remains in the system for an extended period, approximately 4 to 5 weeks following the final dose.

How does Rybelsus cause weight loss?

Semaglutide mimics the action of a hormone called GLP-1 (glucagon-like peptide-1), which influences areas of the brain that regulate appetite and food intake. This reduces hunger and helps people feel full sooner, leading to a lower calorie intake. Additionally, Rybelsus slows down the rate at which food leaves the stomach, extending the feeling of fullness after eating and reducing overall food consumption.

Does Rybelsus cause stomach pain?

Yes, stomach (abdominal) pain is a common side effect of Rybelsus, particularly when starting the medication or increasing the dose.

Does Rybelsus cause acid reflux?

While acid reflux is not a commonly listed side effect, gastrointestinal issues such as nausea, vomiting, and abdominal discomfort can potentially contribute to acid reflux in some patients.

Does Rybelsus cause pancreatitis?

Rybelsus has been associated with an increased risk of pancreatitis. Patients are advised to discontinue use and seek medical attention if they experience severe abdominal pain that does not go away.

Why does Rybelsus make you nauseous?

Nausea is a common side effect of Rybelsus because it slows gastric emptying and affects gastrointestinal motility. This effect is often temporary and may diminish as the body adjusts to the medication.

Can Rybelsus cause vomiting?

Yes, vomiting is a common side effect of Rybelsus, particularly during the initial phase of treatment or dose escalation.

Does Rybelsus cause indigestion?

Indigestion, or dyspepsia, is not commonly reported. However, the gastrointestinal side effects of Rybelsus, such as nausea and abdominal pain, can mimic indigestion symptoms.

Why does Rybelsus cause diarrhea?

Diarrhea is a common side effect of Rybelsus due to its effect on slowing gastric emptying and altering gastrointestinal motility?. By affecting the gut’s motility, Rybelsus can disrupt the usual rhythm and contractions of the intestines, resulting in diarrhea. This alteration helps increase the sensation of fullness but can also lead to digestive discomfort and loose stools. Furthermore, semaglutide activates receptors in the gut that can lead to changes in how the intestines absorb water and electrolytes, potentially causing diarrhea.

Does Rybelsus cause loss of appetite?

Yes. During clinical trials, 6-9% of participants taking Rybelsus experienced a decreased appetite, which is one of the mechanisms through which it helps with weight loss.

Can a non-diabetic take Rybelsus?

Rybelsus is specifically approved for the treatment of type 2 diabetes and its safety and efficacy in non-diabetic individuals have not been established.

Can insulin cause gastroparesis?

Insulin itself does not cause gastroparesis, but poor blood glucose control in diabetics can contribute to the development of this condition.

Does Rybelsus cause glycosuria?

Glycosuria, or glucose in the urine, is not a common side effect of Rybelsus. It primarily works by lowering blood glucose levels rather than affecting renal glucose reabsorption.

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