Gastroparesis

New Study Links GLP-1 Agonists to Serious GI AEs

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Popular glucagon-like peptide-1 receptor agonists are associated with serious gastrointestinal adverse effects such as pancreatitis, gastroparesis and bowel obstruction, according to the results of a large retrospective study.

These agents “have potential serious side effects, and prescribers should be aware of them and feel comfortable managing adverse events [AEs] and understanding appropriate dosing strategies,” said Eduardo Grunvald, MD, the director of the weight management program at the University of California, San Diego, and lead author of the 2022 American Gastroenterological Association guidelines on drug therapy for obesity, who was not involved in the research.

In the study, researchers at the University of British Columbia evaluated patients prescribed the GLP-1 agonists semaglutide (Ozempic/Wegovy, Novo Nordisk) and liraglutide (Victoza/Saxenda, Novo Nordisk) for weight loss, comparing their effects with those of naltrexone-bupropion (Contrave, Currax), a weight-loss agent with a different mechanism of action.

The researchers used a random sample of 16 million patients from the PharMetrics Plus database between 2006 and 2020, a timeframe that covers the FDA approvals for weight-loss indication with liraglutide in 2014 and semaglutide in 2021. They ensured every case had an obesity code in the 90 days before or up to 30 days after entry into the study. Patients with a diabetes diagnosis or an antidiabetic drug code were excluded.

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The results, published in JAMA (2023 Oct 5. doi:10.1001/jama.2023.19574), suggested that use of semaglutide and liraglutide for weight loss is associated with an increased risk for pancreatitis (adjusted hazard ratio [aHR], 9.09; 95% CI, 1.25-66.00), gastroparesis (aHR, 3.67; 95% CI, 1.15-11.90) and bowel obstruction (aHR, 4.22; 95% CI, 1.02-17.40) compared with naltrexone-bupropion. The incidence of pancreatitis per 1,000 patients was higher for both GLP-1 agonists relative to naltrexone-bupropion (semaglutide, 4.6 per 1,000; liraglutide, 7.9 per 1,000; and naltrexone-bupropion, 1.0 per 1,000). The incidence of gastroparesis—an AE that could not only cause nausea and vomiting, among other symptoms, but also could affect endoscopic procedures (see box)—was also higher for the GLP-1 agonists (semaglutide, 9.1/1,000; liraglutide, 7.3/1,000; and naltrexone-bupropion, 3.1/1,000). The incidence of bowel obstruction was higher in patients on liraglutide (8.1/1,000) than semaglutide (zero) or naltrexone-bupropion (1.7/1,000).

AGA Says Don’t Unilaterally Stop GLP-1 Agonists Before Endoscopy

Before endoscopy, clinicians should review the effects of glucagon-like peptide-1 receptor agonist medications on a patient-by-patient basis and not unilaterally stop GLP-1 agonist medications due to their links to GI adverse events, according to a new clinical practice update from the American Gastroenterological Association (Clin Gasterol Hepatol 2023 Nov 7. doi:10.1016/j.cgh.2023.11.002).

The clinical practice update follows accumulating research that GLP-1 agonist drugs used for weight loss are linked to GI side effects such as delayed gastric emptying and gastroparesis in certain patients. Anesthesiologists have reported instances of incomplete gastric emptying after fasting in patients taking semaglutide, and the American Society of Anesthesiologists (ASA) released guidance in June 2023 recommending that these medications be held before elective surgeries (see related commentary).

However, the AGA guideline authors stressed that stopping these agents before endoscopic procedures should be individualized based on the patient’s current symptoms. “While GLP-1 [receptor agonists] might slow gastric emptying in some patients, there is overall insufficient evidence for ‘blanket statements’ on how to manage patients taking these medications who require endoscopy,” noted Andrew Wang, MD, the director of interventional endoscopy at the University of Virginia, in Charlottesville, who co-authored the new AGA guidance, in an AGA press release.

Dr. Wang and his co-authors recommend that endoscopists proceed with planned endoscopies in patients on GLP-1 agonists who have followed standard fasting instructions and who do not have nausea, vomiting, dyspepsia or abdominal distension. Instead of stopping medications, they recommend that some patients can be put on a liquid` diet the day before an endoscopy. If patients have symptoms that suggest retained gastric contents but providers cannot delay an endoscopic procedure, they recommended that gastroenterologists consider rapid sequence intubation, although they noted this may not be an available option in ambulatory or office-based procedure settings.

Philip Schoenfeld, MD, MSEd, MSc (Epi), and Sonali Paul, MD, MS, reviewed a recent JAMA study on GLP-1 agent side effects (see main story) in in the November 15 issue of Evidence-Based GI and discussed the study and the issues related to holding GLP-1 agents for endoscopic procedures in an accompanying audio summary.

Pointing to differing stances the ASA and GI societies have taken, Dr. Paul, an assistant professor of medicine at the University of Chicago School of Medicine, said, “I know the anesthesia guidelines came out and said that we should be holding these meds and I know our own GI societies came out and said there isn’t enough evidence right now.” But, she added, at her institution, the anesthesiologists “said they won’t actually perform anesthesia for our procedures if a patient is on a GLP-1. For someone is on daily GLP-1, they recommend holding it the day of and the day before and for the folks who are on it weekly, they should be held the week before.” Given the need to work with anesthesiologists on many of these cases, she said, “at this point, we are going with what our anesthesia colleagues tell us.”

Dr. Schoenfeld, the chief (emeritus) of the Gastroenterology Section at the John D. Dingell VA Medical Center, in Detroit, agreed, saying “If you’re going to do propofol with your anesthesia colleagues, and their guidelines say that [these drugs need to be held], then you have to comply with that.” However, he said, “based on what our own GI societies have said, if I’m doing a colonoscopy on somebody who’s on semaglutide and they haven’t held it for a week, I still feel comfortable going ahead and just using [midazolam] and fentanyl in an open endoscopy setting for those patients.” But, he added, “That’s something each endoscopist will have to decide for themself.”

—Meaghan Lee Callaghan and Sarah Tilyou

The incidence of biliary disease per 1,000 patients was similar in all groups, although slightly higher in those taking liraglutide (semaglutide, 11.7/1,000; liraglutide, 18.6/1,000; and naltrexone-bupropion, 12.6/1,000).

The researchers noted that a main limitation was the study’s observational nature, and while they included only GLP-1 agonist users with a record of obesity, they indicated it is uncertain whether GLP-1 agonists were used specifically for weight loss in each case.

Underscoring the implications of these potential AEs, Dr. Grunvald said “these adverse events are rare, but given the potential number of people that will use them, absolute numbers of serious adverse events will not be trivial.” Nevertheless, he added, “I also strongly believe, based on emerging data and my own clinical experience, the overall benefits outweigh these risks in general.”

In an audio summary discussion in the November 15 issue of Evidence-Based GI, Sonali Paul, MD, MS, an assistant professor of medicine at the Center for Liver Diseases at the University of Chicago School of Medicine, also pointed to the importance of these potential AEs because of the growing use of the GLP-1 agents. She noted that some of the GI side effects of these drugs, such as nausea, often can be mitigated with dosing strategies and other methods. But she expressed concern about the finding related to pancreatitis. “The pancreatitis signal is definitely real,” she said. “If I have a patient that is on a GLP-1 and develops pancreatitis, I think for me, and for most of my endocrine colleagues, that’s a case where we stop the GLP-1 and we don’t rechallenge.”

Computational modeling of drug dissolution in the human stomach: Effects of posture and gastroparesis on drug bioavailability

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ABSTRACT

The oral route is the most common choice for drug administration because of several advantages, such as convenience, low cost, and high patient compliance, and the demand and investment in research and development for oral drugs continue to grow. The rate of dissolution and gastric emptying of the dissolved active pharmaceutical ingredient (API) into the duodenum is modulated by gastric motility, physical properties of the pill, and the contents of the stomach, but current in vitro procedures for assessing dissolution of oral drugs are limited in their ability to recapitulate this process. This is particularly relevant for disease conditions, such as gastroparesis, that alter the anatomy and/or physiology of the stomach. In silico models of gastric biomechanics offer the potential for overcoming these limitations of existing methods. In the current study, we employ a biomimetic in silico simulator based on the realistic anatomy and morphology of the stomach (referred to as “StomachSim”) to investigate and quantify the effect of body posture and stomach motility on drug bioavailability. The simulations show that changes in posture can potentially have a significant (up to 83%) effect on the emptying rate of the API into the duodenum. Similarly, a reduction in antral contractility associated with gastroparesis can also be found to significantly reduce the dissolution of the pill as well as emptying of the API into the duodenum. The simulations show that for an equivalent motility index, the reduction in gastric emptying due to neuropathic gastroparesis is larger by a factor of about five compared to myopathic gastroparesis.

What Is Gastroparesis?

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stomach-310730_640Gastroparesis (also called delayed gastric emptying) is a progressive disorder that causes food to remain in the stomach for longer than normal periods. Because the nerves that move food through the digestive tract are damaged, the muscles do not work as they normally would.  As a result, food often sits in the stomach undigested.  So what are the signs and symptoms of gastroparesis?  Lets take a closer look!

Symptoms Of Gastroparesis:

The following are the most common symptoms associated with gastroparesis:

  • vomiting of undigested food
  • early fullness after a small meal
  • weight loss
  • nausea
  • bloating
  • stomach spasms
  • blood glucose levels that are hard to stabilize
  • heartburn 
  • loss of appetite
  • acid reflux

What Causes Gastroparesis:

Per the Mayo Clinic, it’s not always clear what leads to gastroparesis. In many cases, gastroparesis is believed to be caused by damage to a nerve that controls the stomach muscles (vagus nerve).

The vagus nerve helps manage the complex processes in your digestive tract, including signaling the muscles in your stomach to contract and push food into the small intestine. A damaged vagus nerve can’t send signals normally to your stomach muscles. This may cause food to remain in your stomach longer, rather than move normally into your small intestine to be digested.

The vagus nerve can be damaged by diseases, diabetes in particular, or by surgery to the stomach or small intestine.

How Is Gastroparesis Diagnosed:

Gastroparesis is diagnosed by upper gastrointestinal x -rays, and a gastroscopy, which allows the doctor to look into the stomach with a scope that contains a tiny camera. Other tests may be initiated.

All of these will help rule out other diseases such as ulcers, gastritis, and stomach cancer.

It is thought that as many as 50% of diabetics may show signs of gastroparesis, but only a small percentage of those people develop symptoms that need intervention.

Gastroparesis Treatments:

Treatment begins with a renewed commitment to tight blood glucose control as hyperglycemia aggravates gastroparesis. As we are all well aware, this is easier said than done as food is absorbed at unpredictable times, making control difficult (story of our lives, right!).

High blood glucose levels can slow stomach emptying and that adds to the problem. If you take insulin, you may be asked to up the number of injections you take daily or even increase your basal rates if you use an insulin pump. You will also have to check your blood glucose levels more frequently after you eat to help bring them down sue to the increase of insulin.

Your doctor may also suggest that you eat small meals throughout the day rather than a few larger ones as this helps your stomach from becoming overfilled. You will be told to cut back on fatty foods because fat slows stomach emptying. You may also need to cut back on difficult-to-digest foods such as legumes, lentils, and citrus fruits. Food difficult to digest, may form “tumors of food” known as bezoars. These bezoars will worsen symptoms of fullness, nausea, and abdominal discomfort, and they can be very difficult for a doctor to remove.

Now comes the difficult decision for people with diabetes who suffer from diarrhea or constipation who are advised to eat a high fiber diet. It may seem that the advice to avoid indigestibles contradicts that suggestion. Indigestibles are not exactly the same as high fiber foods, although indigestibles are almost always examples of high-fiber foods. You may have to decide which problem – the stomach symptoms, or the diarrhea and constipation is worse, when deciding whether or not to eat a high-fiber diet.

Drug treatments are also another option that you can discuss with your physician especially for those of you with significant symptoms.

Novel radiation-free test to aid diagnosis of gastroparesis

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The US Food and Drug Administration (FDA) has approved gastric emptying breath test (GEBT) to aid the diagnosis of gastroparesis.

GEBT measures carbon-13, a naturally existing non-radioactive form of carbon-12, in a patient’s breath. Gastric scintingraphy, the standard diagnostic test for gastroparesis, uses radioactive material and requires specialist training. “[GEBT] can be performed in any clinical setting since it does not require the health care professionals administering the test to undergo special training or to take special precautions related to radiation emitting compounds,” as no radioactive materials are used said Dr. Alberto Gutierrez, director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health.

The approval is based on study data of 115 participants who underwent both GEBT and gastric scintigraphy. Performed over a 4-hour period following an overnight fast, GEBT measured the ratio of carbon-13 to carbon-12 in breath samples at multiple points, which is then compared to the baseline measure. Participants consumed a carbon-13 enriched meal containing scrambled egg-mix and Spirulina platensis. GEBT and scintigraphy results agreed 73-97 percent of the time.

Gastroparesis interferes with normal digestion causing severe nausea and vomiting, dehydration, and malnutrition. Diabetes is the most common cause of gastroparesis. Other causes include infections, internal surgery, neurological disease like Parkinson’s disease, and endocrine disorders like hypothyroidism.

GEBT is not advisable for patients with an allergy to Spirulina, egg, milk or wheat, or certain lung diseases or conditions that cause small bowel malabsorption.

Wireless Motility Capsule Versus Other Diagnostic Technologies for Evaluating Gastroparesis and Constipation: A Comparative Effectiveness Review..

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To systematically review the evidence comparing wireless motility capsule (WMC) with other diagnostic tests used for the evaluation of gastroparesis and slow-transit constipation, in terms of diagnostic accuracy, accuracy of motility assessment, effect on treatment decisions, effect on patient-centered outcomes, harms, and effect on resource utilization. Data sources. We searched Medline ® and Embase ® from inception through July 2012. Additionally, we scanned reference lists of relevant articles and queried experts. Review methods. We included studies in any language that compared WMC with other diagnostic tests among patients with suspected gastroparesis or slow-transit constipation. Two reviewers independently assessed articles for eligibility, serially abstracted data from relevant articles, independently evaluated study quality, and graded the strength of the evidence (SOE). We summarized results qualitatively rather than quantitatively because of the heterogeneity of studies. Results. We included 12 studies (18 publications). Seven studies evaluated diagnosis of gastric emptying delay; we found low SOE that WMC alone was comparable to scintigraphy for diagnostic accuracy, accuracy of motility assessment, effect on treatment decisions, and effect on resource utilization. Sensitivity of WMC compared with gastric scintigraphy ranged from 59 to 86 percent and specificity ranged from 64 to 81 percent. We found two studies evaluating WMC as an add-on to other testing. The SOE was low for diagnostic accuracy and for the accuracy of motility assessment by WMC in combination with other modalities. The addition of WMC increased diagnostic yield. Nine studies analyzed colon transit disorders and provided moderate SOE for diagnostic accuracy, accuracy of motility assessment, and harms. WMC was comparable to radiopaque markers (ROM), with concordance ranging between 64 percent and 87 percent. Few harms were reported. The evidence was insufficient to justify conclusions about effects of WMC on treatment decisions and resource utilization. Conclusions. WMC is comparable in accuracy to current modalities in use for detection of slowtransit constipation and gastric emptying delay, and is therefore another viable diagnostic modality. Little data are available to determine the optimal timing of WMC for diagnostic algorithms.

Source: AHRQ Comparative Effectiveness Review.