2 days ago
In Real World, Women More Likely to Have Issues With GLP-1s
If it weren't for post hoc analyses and findings from curious academic labs, the substantial list of biological differences that separates the sexes would still be relegated to the shadows. That list — including research from the fields of neurology, cardiology, immunology, oncology, endocrinology — shows that the longtime presumption of men and women reacting as one to diagnoses, disease progression, and treatment should be considered, scientifically speaking, passé.
But in the world of clinical trials, it has been and still is mostly a sexless, homogenous world. One reason: Stratifying by sex in a trial would not be cheap. 'Doing that up front would cost millions more,' said Antonella Santuccione Chadha, MD, PhD, founder and CEO of the Women's Brain Foundation and a former member of the EU Commission Directorate-General for Health and Food Safety.
A significant issue is under enrollment of women in randomized trials, meaning the percentage of women enrolled isn't in line with the percentage of women with a particular disease in the real world — so signals that indicate an adverse event are not picked up. From a systems perspective, women do not clear drugs through their kidneys as quickly as men, and women maintain a higher blood concentration of the medication. 'Women may be overmedicated,' Neurologist Irving Zucker and others wrote in a 2020 analysis of 86 medications.
This can lead to adverse events (AEs). And they do.
' Women experience adverse drug reactions nearly twice as often as men, yet the role of sex as a biological factor in the generation of [these reactions] is poorly understood,' Zucker wrote in that study, published in the journal Biology of Sex Differences , which showed that pharmacokinetics 'strongly linked' sex differences in adverse drug events.
Antonella Santuccione Chadha, MD, PhD
Among the 86 medications was the GLP-1 receptor agonist (GLP-1 RA), liraglutide. It was found to be biased toward women with regard to headache, vomiting, nausea.
There are little stratified data in the GLP-1 RA receptor clinical trials, let alone appropriate enrollment percentages, as compared to real world disease prevalence. Considering that these medications are being used in patients with diabetes, obesity and overweight, cardiovascular problems, and likely in the future, to mitigate Alzheimer disease advancement, it likely would help to know how sex affects these drugs.
So the question is: How can general practitioners determine what treatment is right for patients, especially their female patients, when so little evidence is based on sex?
'The side effects are very real and important to track,' said Sadiya S. Khan, MD, MSc, professor of cardiovascular epidemiology, and associate professor, medicine medical social sciences, preventive medicine, at the Feinberg School of Medicine at Northwestern University, Chicago.
'The truth about GLP-1 agonists is that you have to personalize it for the patient in front of you,' said Martha Gulati, MD, MS, professor of cardiology at Cedars-Sinai Heart Institute. Efficacy has to be balanced with the potential for side effects. 'Every individual will be slightly different.'
Sex Differences of Note
In its natural state, GLP-1 is found in many areas of the body, including the brain. It has multiple purposes, including gastric emptying, food intake inhibition, and neuroprotective effects on lung and cardiovascular systems. But in its natural state, GLP-1 has a short half-life, hence the pharmaceutical drive for analogues.
As a class, these analogues, primarily the injectables, have been much ballyhooed for their ability to treat diabetes, induce weight loss, and reduce the risk for cardiovascular events. One recent study also demonstrated how the GLP-1 RAs can mitigate cognition issues.
These analyses show how the GLP-1 RAs work at the stratified population level:
In this study, women, who generally have a smaller stature than men, had higher concentrations (32%) of the tested medication than men; patients with diabetes had lower amounts of medication than those with normal blood glucose levels or prediabetes.
In a new analysis of FAERS, the FDA's adverse event reporting system, among reports of neurologic related events in GLP-1 agonists, 46.25% occurred within 30 days of the start of treatment. The report, based on complaints filed from 2004 to 2025, found that 11.58% of the 250,014 listed were neurologic in nature. Women reported 65% of the 28,953 neurologic AEs events; most came from consumers. The top AEs reported were dizziness, tremor, and dysgeusia.
Women who had taken semaglutide, liraglutide, and tirzepatide reported 65% of the 372 psychiatric events found in the EudraVigilance database, between January 1, 2021, and May 30, 2023.
In a new JAMA article discussing the management of GLP-1 events, neurologic issues are not mentioned, just common gastrointestinal ailments, including nausea. In the huge study published in February confirming semaglutide 2.4 mg safety in overweight, obesity, cardiovascular disease but not diabetes, the sexes were segregated in listing fractures, poisoning, and procedural events but not in serious cardiac and nervous system disorders.
article discussing the management of GLP-1 events, neurologic issues are not mentioned, just common gastrointestinal ailments, including nausea. In the huge study published in February confirming semaglutide 2.4 mg safety in overweight, obesity, cardiovascular disease but not diabetes, the sexes were segregated in listing fractures, poisoning, and procedural events but not in serious cardiac and nervous system disorders. The inclusion criteria for the still-running Evoke trials, which is testing oral semaglutide's efficacy in early-stage symptomatic Alzheimer's disease (AD), have no breakdown of the 1840 participants by sex, either in or the peer-reviewed summary. AD affects women significantly more than men. Efforts to reach an investigator were not successful.
With regard to diabetes, it seems the sexes have more differences than commonalities, according to a 2023 study in Diabetologia , the journal of the European Association for the study of diabetes. One review found men: are younger at diagnosis; have a lower BMI and a lower risk factor burden, including hypertension and more weight gain; have a lower relative risk for cardiovascular complications and death; and get guideline recommended care more than women.
Sadiya S. Khan, MD, MSc
'Across their lifetime, changes in sex hormones mean that women experience greater variations in the risk of cardiometabolic disease, including type 2 diabetes,' the Austria-based authors wrote. A Danish study reviewing more than 200,000 cases in the country's national registry reached similar conclusions.
A cause for concern: Population trends show that more women are obese or severely obese, particularly among those older than 60 years.
Clinical Discussion
Prescribing women GLP-1 RAs takes some planning, Gulati and Khan said. Conversations about what to expect are critical, especially about potential AEs.
Gulati said women respond better to these medications, especially if they are premenopausal. These physicians, both preventive cardiologists, discuss the benefits, including lower hypertension, weight reduction, and better glycemic control. Advice includes eating small meals, avoiding greasy food, and eating lots of fiber because constipation is no fun. And patients have to be prepared for the side effects.
'I have this oatmeal spiel,' Gulati said. One patient, she said, insisted on eating greasy food until the AEs won out. 'She started improving her diet and she got the results she wanted…If they get something you told them about, they know more.'
Gulati, president-elect of the American Society for Preventive Cardiology, said some women won't be able to go up to the highest dosage because of the AEs.
Khan said the AEs increase as the GLP-1 RA dosage increases. She said that in real life, 80% of people taking a GLP-1 RA stop because of the side effects. 'It's about going slow and seeing if people can benefit.'
At least one premarketing clinical study claimed that dose adjustment by sex wasn't necessary.
Robert Kushner, MD, the lead investigator on the semaglutide obesity study, said in a JAMA podcast that more than 30% of patients, at least in the phase 3 trials, stopped using semaglutide because of nausea, constipation, diarrhea, and vomiting. His advice paired with that of Khan and Gulati.
Most, if not all, of this conversation could be avoided if sex-based evidence was generated in preclinical research and then used to shape the trial, said Santuccione Chadha.
By investing more money in the beginning of the trial to determine sex-based differences, there would be a 'higher return on investment across the chain.' There would be fewer side effects and more adherence to drugs, the GLP-1s included. But with the current method of research, 'What happens is that there are unexpected side effects, more adverse events in the female population, who also get more serious events.'
Gulati agreed more planning is needed prior to trial enrollment. 'Honestly? I think it is because of a lack of prestudy planning. Who do we want, and where will we get them?' If the trial is underpowered, 'you can't look at sex differences.'
The fact that the GLP-1 RAs have proven effective in so many body systems now has more specialists prescribing these medicines. Khan said interdisciplinary care is critical, so it's necessary to have a point person. 'We are realizing this, who is owning responsibility, who is comfortable with it.'
