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A study published in Nature Medicine looks at the health risks and benefits linked to GLP-1 receptor agonists.
Prof Naveed Sattar, Professor of Cardiometabolic Medicine/Honorary Consultant, University of Glasgow, said:
“This is an observational study so cannot be considered anywhere near definitive, and such evidence will generally not influence clinical guidelines. Even so, a few of the suggested benefits have been confirmed in randomised trials (myocardial infarction, stroke, heart failure), whereas MOST others require future assessment to confirm or refute. The same goes for suggested risks, some of which make clear sense (e.g. more nausea and vomiting) and have been seen in trials, but many others have not, and findings could simply reflect unmeasured confounding. Hence, interesting but the findings fall well below the level evidence that comes from gold standard placebo controlled randomised trials. Fortunately, large scale randomised trials with GLP-1RA-based therapies that yield greater weight loss are ongoing and several will report out in the next 1-4 years. Such trials will lead us much closer to the truth.”
Prof Sir Stephen O’Rahilly FRS FMedSci, Professor of Clinical Biochemistry and Medicine and Director of the Wellcome-MRC Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, said:
“Studies such as these have to be interpreted very cautiously as the people studied have not been randomly allocated to GLP1 receptor agonist treatment, so any difference between those taking and not taking the class of drug could potentially be attributable to factors other than the drug. As the data comes from the UK Veterans Administration it is heavily skewed to older white males.
“That said , the study provides useful reassurance about the safety of this class of drugs. The expected benefits on heart disease, stroke and other cardiovascular and most kidney diseases are clearly seen. There is also a reassuring reduction in the incidence of several cancers, including pancreatic. Importantly, as there has been discussion in the media about possible adverse effects of the drugs on mental health, the group taking the drug had a lower incidence of schizophrenia, alcohol and drug use disorders, and less suicidal ideation. In terms of other disorders affecting the brain there was a small but statistically significant reduced risk of seizures and of dementia in those taking GLP1RAs.
“In terms of the list of conditions and/ or symptoms that are reported to be increased by GLP1 receptor agonists, as expected gastrointestinal upset of various kinds is most common adverse effect. The small but significant increase in people with low blood pressure and with kidney stones are likely attributable to the fact that a combination of diarrhoea and reduced oral intake can lead some people to become somewhat fluid-depleted. The most surprising finding is an increase in a range of symptoms relating to joint pain. It is possible that the increased physical activity that is made possible when people lose substantial amounts of weight could result in the appearance of joint symptoms that were previously masked by inactivity. On the other hand, the fact that receptors for GLP1 are present on subsets of immune cells means that until we have deeper knowledge, the effects of these drugs on inflammatory responses are somewhat unpredictable. While some inflammatory disorders may be assisted by these drugs others might conceivably be exacerbated. Further research is needed.
“Overall the results of this study, which followed over 200,000 people with diabetes who were treated with GLP1RAs and compared them to over 1.5 million people on other forms of diabetes treatment, is reassuring regarding the risk/benefit ratio for the long term use of GLP1RAs in people with diabetes. Future studies of people treated with these drugs for obesity, without accompanying diabetes, are awaited with interest.”
‘Mapping the effectiveness and risks of GLP-1 receptor agonists’ by name of Xie et al. was published in Nature Medicine at 16:00 UK time on Monday 20th January.
DOI: 10.1038/s41591-024-03412-w
Declared interests
Prof Naveed Sattar “has consulted for several companies that make diabetes medicines but also contributed to several lifestyle trials.
“For Novo Nordisk: have consulted for company in advisory boards but not on any of their weight loss drug trial committees; am on steering committee for ZEUS trial but this is not a weight loss trial product but anti-inflammatory. Do not have any shares either for any product in health etc.
“N.S. declares consulting fees and/or speaker honoraria from Abbott Laboratories, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, and Sanofi; and grant support paid to his university from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics.”
Prof Sir Stephen O’Rahilly “I have received remuneration from several pharmaceutical companies for scientific advice given relating to the development of drugs for metabolic diseases. In the past 3 years this has not included any of the companies manufacturing GLP-1RAs”