Hidden Risks of GLP-1 Weight Loss Medications: What Patients and Doctors Need to Know

Hidden Side Effects of GLP-1 Medications: Fatigue, Bone Loss, and Abdominal Pain

As GLP-1 receptor agonists like semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound) continue to dominate headlines as groundbreaking treatments for obesity and type 2 diabetes, emerging real-world data has revealed several lesser-known adverse effects. These include profound fatigue, notable bone loss, and persistent abdominal pain—side effects that may not have been fully appreciated in clinical trials.

In a powerful keynote during the 2025 American Association of Clinical Endocrinology (AACE) Annual Meeting, Dr. W. Timothy Garvey, one of the field’s most respected authorities, emphasized the need for responsible prescribing and thorough patient monitoring. As the Charles E. Butterworth, Jr. Endowed Professor and Director of the University of Alabama at Birmingham (UAB) Diabetes Research Center, Dr. Garvey highlighted the potential dangers of unsupervised use and online prescriptions of GLP-1-based medications.

You cannot practice complications-focused obesity medicine without assessing patients for those complications,” Garvey stated. “Online prescribing entirely bypasses that necessary clinical evaluation.

Why Proper Medical Supervision Is Crucial for GLP-1 Use

One of the key messages from Dr. Garvey’s presentation was that not all patients respond the same way to GLP-1 medications. Some individuals are hyper-responsive to low doses, experiencing rapid and sometimes excessive weight loss even at submaximal dosages. Without medical oversight, these patients risk losing more weight than is healthy, with possible cascading effects on physical and cognitive health.

“Weight loss isn’t just about seeing the number on the scale go down. It must be clinically managed,” said Garvey. “The rise in online prescribing—where patients receive medication without a full work-up—is a substandard way to treat a complex, chronic disease.”

The Rise of “Fatigue Syndrome” in GLP-1 Users

One concerning clinical pattern Garvey has observed involves a fatigue syndrome that appears in roughly 1 in 10 patients undergoing rapid or unchecked weight loss on GLP-1 medications. This syndrome is marked by:

• Profound tiredness
• Loss of motivation and energy
• Cognitive clouding (“brain fog”)
• Diminished physical function at home or work

Interestingly, this is not just physical fatigue but a full-body slowdown—both mental and muscular. The affected patients often have such a reduced appetite that they cannot increase their caloric intake, even when guided by a healthcare provider.

They’re so pleased with their weight loss that they don’t recognize the toll it’s taking,” Garvey explained.

To reverse this, clinicians may need to lower the GLP-1 dosage or even discontinue it altogether, despite patient resistance.

Malnutrition and Dehydration: The Hidden Risks of Appetite Suppression

This fatigue syndrome is closely tied to poor dietary intake and insufficient hydration. Patients are frequently consuming fewer than 800 calories per day—levels typically only recommended in supervised medical weight loss programs. Compounding the problem is a marked reduction in water intake due to suppressed thirst mechanisms.

This results in:

• Protein deficiency
• Low iron and calcium levels
• Chronic dehydration
• Electrolyte imbalances

These patients simply aren’t eating or drinking enough to meet their physiological needs,” Garvey noted.

Dr. Jaime Almandoz, who co-authored a review on nutritional management during anti-obesity treatment, echoed these concerns. He stressed that the average American diet is already nutritionally poor, and GLP-1-induced appetite suppression may exacerbate this deficiency unless clinicians actively guide nutritional planning.

Without professional support, patients are unlikely to meet basic macronutrient and micronutrient needs,” Almandoz warned.

He also pointed to fluid intake as a growing issue. “Many are dehydrated but don’t realize it—satiety affects both food and liquid consumption.”

Lack of Functional Assessment in Obesity Clinics

Despite the growing popularity of GLP-1 medications, there is a lack of standard guidelines for monitoring functional outcomes such as muscle strength, activity levels, or frailty risk. Almandoz called this an “unmet need” in modern obesity treatment.

We must assess if patients are thriving, not just shrinking,” he emphasized.

Muscle vs. Bone: Which Loss Is More Concerning?

It’s well known that weight loss—regardless of method—typically involves the loss of both fat mass and lean mass. With GLP-1 medications, roughly two-thirds of the lost weight is fat, while the remaining third is lean body mass (which includes muscle and bone). While clinicians often worry about muscle loss, Dr. Garvey suggested that the real concern may be hidden in the bones.

“Some loss of muscle mass is physiologically expected,” he explained. “You don’t need as much muscle to carry a lighter body. But the bone issue may be more insidious.”

A 2024 JAMA review questioned whether loss of lean body mass with GLP-1s is clinically significant, especially if physical function remains intact. Supporting this, a study of HIV-positive patients using semaglutide showed improved quality of life and no decline in physical capacity, despite muscle mass reduction.

However, bone density may tell a different story.

Alarming Data on Bone Mineral Density (BMD)

Garvey referenced a 2011 study involving postmenopausal women who lost weight through exercise. The troubling finding: bone density decreased during weight loss and failed to rebound even after weight regain—especially in critical areas like the spine and hips.

A more recent trial involving 195 individuals with obesity (but not diabetes) compared liraglutide alone versus liraglutide plus exercise. Only the combination group preserved bone mineral density. Those using liraglutide alone lost significant bone mass at sites associated with fracture risk.

“This raises the question: are GLP-1 users—especially older women—at higher long-term fracture risk?” Garvey asked.

A safety analysis from the SELECT cardiovascular outcomes trial showed no overall difference in fracture rates between semaglutide and placebo. However, subgroup analyses found higher rates of hip and pelvic fractures among women and those over age 75 using semaglutide.

Dr. Almandoz emphasized that as more older adults begin using GLP-1s for cardiovascular benefits, the risk of bone complications could become more pronounced.

“Everyone focuses on muscle loss, but we should be paying closer attention to bones,” he said.

Ongoing Pharmaceutical Innovation to Mitigate Muscle and Bone Loss

Pharmaceutical companies are now developing therapies to preserve muscle mass during weight loss. Promising agents include:

Azelaprag (a muscle growth stimulator)
Bimagrumab and Apitegromab (myostatin inhibitors)
Taldefgrobep and KER-065
REGN-1033 + REGN-2477 (monoclonal antibody combinations)

In parallel, amylin-based medications in development may also help preserve bone density while supporting fat loss.

Is Abdominal Pain More Common Than Nausea?

Perhaps the most surprising new finding relates to gastrointestinal side effects. Traditionally, GLP-1s are associated with nausea, vomiting, and diarrhea. However, recent real-world data challenge that narrative.

A cross-sectional analysis from the NIH’s “All of Us” cohort, involving over 10,000 GLP-1 users, showed:

• Abdominal Pain: 60%
• Constipation: 30%
• Diarrhea: 30%
• Nausea/Vomiting: Only fourth-most reported

“This really surprised me,” said Garvey. “Abdominal pain was the top symptom. We didn’t see this in the trials to the same extent.”

In contrast, the STEP 1 randomized controlled trial of semaglutide 2.4 mg reported:

• Nausea: 44.2%
• Diarrhea: 31.5%
• Vomiting: 24.8%
• Constipation: 23.4%
• Abdominal Pain: Only 10%

This discrepancy underscores the importance of gathering and acting on post-marketing surveillance data. It also calls attention to the limitations of clinical trial environments, which may not fully capture long-term or subtle adverse effects experienced in the real world.

Final Thoughts: A Need for Active Management and Evidence-Based Care

GLP-1 receptor agonists are powerful tools in the treatment of obesity and metabolic disease, offering life-changing results for many patients. But as their popularity grows, so do the responsibilities of clinicians and the risks of misuse.

Key takeaways include:

Fatigue, bone loss, and abdominal pain are real-world side effects needing more attention.
Medical supervision is non-negotiable for responsible GLP-1 prescribing.
Nutritional and functional monitoring must become standard parts of obesity care.
Older adults and postmenopausal women may require extra caution due to bone-related risks.
Abdominal pain could be more prevalent than we thought and deserves screening.

As the landscape of obesity treatment evolves, so too must our protocols, risk assessments, and patient education efforts. We owe it to our patients not only to help them lose weight—but to ensure they thrive in the process.

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