Be Aware of Lesser-Known Downsides to GLP-1 Weight Loss

Medscape

22-05-2025

ORLANDO, Florida — Extreme fatigue, bone loss, and abdominal pain are real-world adverse events noted with the use of glucagon-like peptide 1 receptor agonists (GLP-1s) that may not have been apparent from the clinical trials.
In a wide-ranging 'meet the professor' lecture at the American Association of Clinical Endocrinology (AACE) Annual Meeting 2025, obesity expert W. Timothy Garvey, MD, the Charles E. Butterworth, Jr. professor and university professor at the University of Alabama (UAB) and director of the UAB Diabetes Research Center at Birmingham, Alabama, said these phenomena all point to the importance of close clinical management of people taking GLP-1s and to the dangers of online prescribing of these medications.
'You can't engage in complications-centric obesity care unless you evaluate the patient for complications, which doesn't happen with online availability of prescriptions,' said Garvey.
In one example, he said, 'there are individuals who are very responsive to low [GLP-1] doses who lose a lot of weight on submaximal doses and may lose too much weight on maximal doses…Weight loss has to be actively managed. This increasing practice of online availability of prescriptions without evaluation by a healthcare professional is such a substandard way to treat a chronic disease. I think our patients deserve better.'
Garvey described a concerning 'fatigue syndrome' he's seen in about 1 in 10 patients with rapid and/or excessive weight loss. He also presented evidence that bone loss may be a greater concern than muscle loss with GLP-1s, particularly in postmenopausal women. And, he noted, at least some real-world data suggest that abdominal pain might be a more common GLP-1 adverse effect of these medications than the often-mentioned nausea and vomiting.
Asked to comment, session moderator Jaime Almandoz, MD, associate professor of internal medicine and medical director of the Weight Wellness Program at the University of Texas Southwestern Medical Center, Dallas, told Medscape Medical News , 'we really don't have good clinical guidelines on what is too much weight loss or what puts people at risk for frailty, fractures, and other adverse outcomes…I think we need better data to create better evidence-informed guidelines around risk stratification prior to treatment, given the wide indications for treatment the high prevalence of high [body mass index].'
Almandoz noted these are new concerns in the era of second-generation GLP-1s, ie, semaglutide and the dual glucose-dependent insulinotropic polypeptide tirzepatide. 'Until recently, we have not been in a situation where we're worried about people losing too much weight with pharmacotherapy.'
'Fatigue Syndrome' Seen After Rapid or Progressive Weight Loss
Garvey described a phenomenon he's encountered in about 1 in 10 people who experience rapid weight loss or progressive weight loss without a plateau. These individuals lose their appetites to the point where they can't eat more even when advised to do so by a healthcare professional. Symptoms include fatigue, listlessness, and/or weakness; low energy for life activities; and cognitive clouding, all of which can compromise home or work activities.
The solution is to decrease the GLP-1 dose or discontinue it entirely, but some patients may resist. 'They can be so happy they're losing weight, they kind of lose perspective…That's why it takes active management by a healthcare professional to recognize this,' Garvey said.
Patients also need to be counseled about appropriate nutrition and water intake. 'These patients aren't drinking enough water…Some with this syndrome are eating less than 800 calories a day. They're not getting enough protein and iron and calcium, which we don't get enough of in our diets anyway. So, nutrition is important,' Garvey said.
Almandoz, who authored a review paper on nutritional considerations with anti-obesity medications, said he's seen this fatiguing phenomenon as well. 'When you look at the quality of the average American diet, which is not meeting requirements, you can imagine that without recommendations for optimizing dietary quality…you may not be meeting nutritional needs.'
He added, 'there may be a dehydration issue, where people are experiencing satiety for food, but also for fluids, and they may then be chronically dehydrated as part of it too…So pushing nutritional quality, volume, intake, fiber, things that will not only help to mitigate side effects but also optimizing outcomes beyond weight reduction is important.'
But, Almandoz noted, ongoing monitoring may be a challenge. 'There's lack of guidance with regard to how we should do a functional assessment to make sure that things are improving and not worsening. I think there are ways in which you can do this with through history-taking or functional measures, but many busy clinical practices have not instituted measures to assess and track function as part of obesity care.'
Is Bone Loss More Worrisome Than Muscle Loss?
Garvey noted that with the second-generation (GLP-1) medications, people lose about two-thirds fat mass and one third fat-free mass, also called lean body mass. The trajectory of loss of lean body mass with increasing body weight loss is about the same whether weight loss is due to diet, anti-obesity medications, or bariatric surgery.
But, he said, while loss of muscle mass is often cited as a concern with these medications, 'I think the weight loss we're seeing with a decrease in muscle masses is physiologic in a sense. It's what you would expect with having to carry around a decreased body mass. You don't need as much muscle to do that. So you will get some muscle loss on that basis, regardless.'
He cited a 2024 review paper in JAMA questioning whether the loss of fat-free mass with GLP-1s is actually clinically relevant. And a study published in Clinical Infectious Diseases found that among people with HIV treated with semaglutide for metabolic dysfunction–associated steatotic liver disease, there was no significant change in physical function despite significant muscle loss.
'All of the questionnaires show increased quality of life, increased physical activity, so weakness associated with muscle loss doesn't seem to be a big clinical problem. That doesn't mean there aren't subgroups we need to pay more attention to, such as those with sarcopenia, but generally speaking it's not a big clinical problem,' Garvey said.
Nonetheless, he noted, 'that hasn't stopped Pharma from trying to find ways to preserve muscle mass during weight loss.' Drugs are in development to induce muscle growth stimulation, such as azelaprag, and block inhibitors of muscle growth, including bimagrumab, apietgromab, taldefgrobep, REGN-1033+REGN-2477, and KER-065. 'So, a lot of development there is afoot.'
At the same time, bone loss may be an underappreciated issue. In a 2011 study of 23 postmenopausal women who lost weight via exercise, bone mineral density was lost with the weight loss but didn't increase when they regained the weight. 'They didn't regain bone mass in the lumbar spine, total hip, or trochanter…It's kind of disturbing.'
In a more recent clinical trial of 195 individuals with obesity but not diabetes, those randomly assigned to exercise plus liraglutide lost weight with preserved bone mineral density, whereas those on liraglutide alone had reduced bone mineral density at clinically relevant sites despite similar weight loss. 'Exercise may help a little bit…Does this translate into increased fracture risk? We don't know, but there are a couple of hints here,' Garvey said.
In a follow-up safety evaluation of the SELECT cardiovascular outcomes trial of semaglutide 2.4 mg vs placebo in people with overweight/obesity, there was no overall difference in fractures, but in subanalyses, women and those older than 75 years both had higher hip and pelvic fracture rates with semaglutide.
'Bone loss may be a longer-term outcome adverse event that we need to think more about, particularly perhaps in postmenopausal females,' Garvey said.
Almandoz agreed. 'As we get wider indications for cardiovascular risk reduction, particularly in older adults, this may be a problem…People talk about the lean mass all the time, but I think the bone is a unique angle that we need to keep an eye on.'
He added that other agents in development for treating obesity, including amylin-based therapies, may confer bone protection.
Is Pain More Common Than Nausea/Vomiting?
While nausea and vomiting are famously associated with GLP-1 use, a cross-sectional analysis of real-world data from more than 10,000 individuals in the National Institutes of Health All of US Cohort found that nausea/vomiting was only the fourth most frequently reported symptom associated with the medication use. The most common was abdominal pain, reported by nearly 60% of people taking semaglutide or any of the first-generation GLP-1 medications. Constipation and diarrhea were second and third, respectively, both around 30%.
'These patients are continuing to have these [gastrointestinal] symptoms long term…I was kind of surprised to see abdominal pain. I hadn't seen a lot of that,' Garvey said.
In the STEP 1 trial of semaglutide 2.4 mg in adults with overweight or obesity, abdominal pain was reported by about 10% with the drug, as opposed to 44.2% with nausea, 31.5% with diarrhea, 24.8% with vomiting, and 23.4% with constipation. 'So, just something to be aware of,' Garvey said.
Garvey served on advisory boards, conducted clinical trials, and/or served on data monitoring committees for Boehringer Ingelheim, Eli Lilly and Company, Novo Nordisk, Pfizer, Fractyl Health, Inc., Alnylam Pharmaceuticals, Inc., Inogen, Zealand Pharma, Allurion, Carmot Therapeutics/Roche, Terns Pharmaceuticals, Neurocrine Biosciences, Keros Therapeutics, Gan & Lee Pharmaceuticals, Regeneron, Epitomee, Neurovalens, Viking Therapeutics, Inc., and the Milken Family Foundation. Almandoz had received consulting fees from AbbVie, Boehringer Ingelheim, Eli Lilly and Company, Nestlé, Novo Nordisk, and Wave Life Sciences.