October 5, 2023

expert reaction to study looking at risk of gastrointestinal adverse events with GLP-1 agonists (e.g. semaglutide or liraglutide) when used for weight loss

A study published in JAMA looks at the risk of gastrointestinal adverse effects when taking semaglutide or liraglutide weight loss drugs. 

Prof Penny Ward, independent pharmaceutical physician, and Visiting Professor in Pharmaceutical Medicine at King’s College London, said:

“A short report in today’s JAMA evaluated the risk of uncommon but potentially severe gastrointestinal adverse events associated with Semaglutide and liraglutide used for weight loss compared to a control group taking bupropion and naltrexone combination appetite suppressant therapy for the same reason.  The authors used data from a random population of patients apparently receiving treatment for obesity derived from a large US healthcare database prior to the date at which the GLP-1 receptor agonists were first licensed for obesity management.

“In total 5411 patients were identified from a total database population of 16 million, the majority (4144/5411) were prescribed liraglutide, while similar but much smaller numbers of patients received treatment with either semaglutide or bupropion/naltrexone (613 and 634 respectively).  Baseline characteristics suggested some imbalances between the groups with respect to other medical conditions particularly hyperlipidaemia (which was present in more than half of the patients taking semaglutide compared to approx 23% and 12% in the liraglutide and bupropion/naltrexone groups respectively), alcohol use and smoking behaviours.  These features might have affected the risk of pancreatitis and biliary disease in the observed patient groups.

“The incidence of the events of interest (pancreatitis, biliary disease, bowel obstruction and gastroparesis (slow stomach emptying)) were expressed as incidence per 1000 patient years of use of the respective medicine.  Of interest, the cited rate of pancreatitis in patients receiving GLP-1 receptor agonists was 4.6/1000 person years for semaglutide compared to 7.9/1000 person years for liraglutide.  The rates of pancreatitis quoted in the US prescribing information for these agents, based on clinical trials which may have excluded patients at greater risk of this disorder compared to the general population investigated in this study, are 1-2/1000 person years.  Biliary effects were more commonly reported in patients receiving liraglutide than either semaglutide or bupropion/naltrexone, where the incidence rates were comparable.

“Similarly gastroparesis was observed more frequently in patients taking GLP-1 receptor agonists than bupropion/naltrexone while bowel obstruction was mostly observed among patients receiving liraglutide.  Slowed gastric emptying is a class effect among GLP-1 receptor agonists.

“The results of this study are consistent with effects observed in clinical trials in obese patients, but suggest that the incidence of pancreatitis in particular may be higher than expected.  Care must be taken in prescribing these agents for weight management and patients developing acute abdominal or back pain with nausea/vomiting should be counselled to seek medical advice while doctors should consider the possibility of pancreatitis and biliary disease in patients presenting with these symptoms while taking these medicines for weight management.

“This study was not designed to assess all of the possible side effects of the various treatments investigated and while the bupropion/naltrexone combination was relatively free of GI effects in this study, these agents depress appetite via a central action in the brain and have been associated with significant psychiatric side effects which may be more severe in older patients.  All of this information suggests that these agents should be used with care and only among patients at greatest risk of poor health or obesity related complications that have been appropriately counselled about their risks.”

Prof Carel Le Roux, Professor of Metabolic Medicine, Ulster University; and Professor of Experimental Pathology, University College Dublin, said:

“This important paper confirms the safety signals hinted at in previous randomized controlled trials.  The limitations of the paper are acknowledged but do not detract from the value of the robust data.  Patients should be informed of the low risk of serious complications such as pancreatitis, gastroparesis, and bowel obstruction before they start semaglutide or liraglutide.”

Dr Simon Cork, Senior Lecturer in Physiology, Anglia Ruskin University, said:

“This study uses a large national (US) database of prescription and diagnoses of patients undergoing outpatient treatment.  The study has looked at patients who have been prescribed GLP-1 agonists (the class of drugs to which semaglutide (Wegovy/Ozempic) and liraglutide (Saxenda) belong) specifically for weight loss.  As a consequence, the number of individuals taking these two drugs is relatively low (only 613 for semaglutide), which is a result of these drugs not being licenced for the treatment of obesity for very long.  Nevertheless the data is reliable and of high quality.

“As part of the study, the authors compared adverse events associated with patients taking semaglutide or liraglutide for weight loss compared with bupropion-naltrexone (another, non-GLP-1 based weight loss drug).  They identified that GLP-1 agonists were associated with an increased risk of developing bowel obstruction, gastroparesis (slowed stomach emptying) and a 4x increased risk of developing pancreatitis in those taking semaglutide compared with bupropion-naltrexone.

“The results from this study highlight how important it is that patients access these drugs only through trusted medical professionals, and only with ongoing support and monitoring.  It is vital that regulation is tightened to ensure that these drugs are only prescribed under the right circumstances.

“Whilst the likelihood of developing these conditions is still rare, when scaled up to the numbers who could potentially be prescribed these drugs we could start to see many people experiencing adverse effects from their use.

“That being said, it’s important to look at this in the proper context.  Obesity significantly increases the risk of developing cardiovascular disease, type 2 diabetes, cancer, gallbladder disease and stroke.  These risks fall dramatically with clinically meaningful and sustained weight loss.  For the overwhelming majority of patients for whom these drugs are targeted (those with the most severe forms of obesity), the benefits of weight loss far outweigh the risks.”

‘Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss’ by Mohit Sodhi et al. was published in JAMA at 16:00 UK time on Thursday 5 October 2023.

DOI: 10.1001/jama.2023.19574

Declared interests

Dr Simon Cork: “No CoI to declare.”

Prof Penny Ward: “I am semi retired but am owner and director of PWG Consulting (Biopharma) Ltd, advising companies on drug and device development.  I am a previous employee of Roche (which developed Orlistat as an oral weight reducing treatment) and of GSK (which markets this agent as an over the counter weight reducing treatment under the brand name Alli).”

Prof Carel Le Roux: “Carel was a co-author on SURMOUNT-2 (https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01200-X/fulltext

Professor of Metabolic Medicine, Ulster University; and Professor of Experimental Pathology, University College Dublin:

“Grants or contracts from any entity:

Irish Research Council – Payments to my institution;

Health Research Board – Payments to my institution;

Science Foundation Ireland – Payments to my institution;

Anabio – Payments to my institution.

Royalties or licenses:

None.

Consulting fees:

NovoNordisk – Global Advisory Board;

Eli Lilly – Global Advisory Board;

Johnson&Johnson – Global Advisory Board.

Boehringer Ingelheim – Global Advisory Board;

GI Dynamics – Global Advisory Board;

Herbalife – Global Advisory Board;

Altimmune – Global Advisory Board;

Irish Life Health – Advisory Board.

Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events:

NovoNordisk – Payments to me for presentations;

Herbalife – Payments to me for presentations;

Johnson&Johnson – Payments to me for presentations;

Eli Lilly – Payments to me for presentations;

Boehringer Ingelheim – Payments to me for presentations;

Rhythm Pharmaceuticals – Payments to me for presentations;

Currax Pharmaceuticals – Payments to me for presentations.

Payment for expert testimony:

None.

Support for attending meetings and/or travel:

NovoNordisk – Payments to me;

Herbalife – Payments to me;

Johnson&Johnson – Payments to me;

Eli Lilly – Payments to me;

Boehringer Ingelheim – Payments to me.

Patents planned, issued or pending:

None.

Participation on a Data Safety Monitoring Board or Advisory Board:

None.

Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid:

Irish Society for Nutrition and Metabolism – Unpaid.

Stock or stock options:

Keyron – Previous Chief medical officer and Director of the Medical Device Division of Keyron in 2021.  Both of these were unremunerated positions.  Previous investor in Keyron, which develops endoscopically implantable medical devices intended to mimic the surgical procedures of sleeve gastrectomy and gastric bypass.  The product has only been tested in rodents and none of Keyron’s products are currently licensed.  They do not have any contracts with other companies to put their products into clinical practice.  No patients have been included in any of Keyron’s studies and they are not listed on the stock market.  ClR was gifted stock holdings in September 2021 and divested all stock holdings in Keyron in September, 2021.  He continues to provide scientific advice to Keyron for no remuneration.

Beyond BMI – Private obesity clinic providing obesity care.

Receipt of equipment, materials, drugs, medical writing, gifts or other services:

None.

Other financial or non-financial interests:

None.”