Dealing With Unexpected Effects of GLP-1s
By April Hopcroft
Nausea and stomach problems are well-known side effects of GLP-1s, but you may be less familiar with other pros and cons of these powerful medications.
With more and more people using GLP-1 receptor agonists for diabetes and weight management, healthcare providers are becoming more aware of ways – both positive and negative – these medications impact the body.
Drug labels clearly warn GLP-1 users about unpleasant gastrointestinal side effects including nausea, vomiting, diarrhea, and constipation. However, recent research has indicated that GLP-1s can also affect skin, muscle mass, and emotional well-being. We spoke to experts to better understand these often overlooked effects.
Changes in mental health
GLP-1s and other incretin medications can have a range of effects on a person’s mental and emotional well-being.
As a starting point, it’s important to recognize the bidirectional relationship between excess weight and depression, said Dr. Jaime Almandoz, associate professor of medicine and medical director of the Wight Wellness Program at UT Southwestern Medical Center. That is, people with obesity have a higher risk of developing depression, and people with depression are also more likely to have excess weight.
Even though obesity and depression often occur together, clinical trials typically exclude people with severe depression. Thus, it’s possible many people at high risk of developing obesity are not benefitting from GLP-1s. Of course, it’s also possible that these medications could worsen depressive symptoms in people with obesity who already have severe depression.
So far, clinical trials haven’t shown that these medications directly worsen psychiatric illness, added Dr. W. Timothy Garvey, professor of medicine at the University of Alabama at Birmingham. While the FDA has concluded that there is no evidence that GLP-1s cause suicidal ideation, researchers are continuing to carefully evaluate any changes in mental health.
Improved quality of life
Almandoz emphasized that many of his patients have reported significant improvements in quality of life after starting weight loss medications. Many of these improvements are likely related to better mobility, exercise endurance, and cardiovascular conditioning.
“Patients will tell me that there have been changes in their status like, ‘This is the first time I was able to get up off the ground when playing with my grandchildren without help,’” Almondoz said. “Or ‘I can cross my legs comfortably now and I haven’t been able to do that for years.’”
“It is often a confluence of little things that contribute to improvement in overall quality of life and how people feel about themselves,” Almandoz said.
Potential to reduce addiction
Although research is in its early stages, there are signs that GLP-1s may be useful in reducing cravings for things other than food. It’s possible these medications could help manage addiction and substance use.
Both Garvey and Almandoz described accounts from people who reported that they consume less alcohol since starting a GLP-1. Almandoz noted that this applied to a range of people, including those who drink socially, as well as those with a diagnosis of alcohol use disorder. Reduced cravings can be attributed to how GLP-1s affect the reward system in the brain, though the exact mechanism is not well understood.
Almandoz noted that some of his patients who struggled with shopping or gambling addictions described improvements in these impulse-control conditions, too.
Fatigue syndrome
Some people experience extreme fatigue when starting GLP-1s. In a minority of patients, Garvey has seen fatigue syndrome set in following rapid or profound weight loss. Symptoms of fatigue syndrome include feeling tired and rundown, cognitive impairment, and a general loss of joie de vivre.
“Fatigue means different things to different people,” Almandoz said. “Whether it means low energy, low desire, or lack of pleasure in something, it’s important to tease out through a thorough history of what it means to each person.”
To provide context for these symptoms, Almandoz emphasized that newer incretin medications lead to significant weight loss. For instance, in clinical trials with tirzepatide (marketed as Mounjaro or Zepbound), over half of the participants lost more than 20% of their body weight.
“What we’re talking about is potentially achieving bariatric surgery level weight loss in a year’s time,” he said.
Weight loss at the magnitude of bariatric surgery in such a short period triggers several changes as the body adapts and tries to “preserve” body weight. These can include changes to the nervous system and feedback mechanisms involved in appetite signaling, which could reduce caloric intake and result in fatigue.
In terms of addressing fatigue syndrome, Garvey said most people respond well to lowering the medication dose and a few will require at least temporary discontinuation.
Reduced inflammation
GLP-1s have also been shown to reduce inflammation, which can positively impact many different body systems. For instance, Gene Holcombe, who has been living with type 2 diabetes for 25 years, said he noticed improvements in his psoriatic arthritis after taking Mounjaro (tirzepatide, a dual GIP/GLP-1 receptor agonist).
“I had really bad arthritis and inflammation in my joints, and psoriasis on my elbows and knees,” he said. The inflammation was so bad that it often hurt to pick things up and use his hands. “That has completely cleared, and I don’t need to take Humira [a medication for psoriasis] anymore.”
Reducing the total number of medications one takes is yet another way that GLP-1s can improve quality of life. In addition to seeing improvements in his psoriasis and psoriatic arthritis, Holcombe was also able to stop taking his other diabetes medications.
Previously, he was taking metformin, insulin, and Jardiance each day. After starting Mounjaro (tirzepatide, a dual GIP/GLP-1 receptor agonist), Holcombe’s A1C fell from nearly 7% to around 5.5%. As a result, he was able to eliminate all of his other diabetes medications and now only takes a once-weekly Mounjaro injection.
“If I could go from taking five to six diabetes medications down to taking one injection every week, I’m all in on that,” Holcombe said.
Hair and skin changes
Hair thinning or hair loss (alopecia) has long been linked to weight loss and can occur with GLP-1 medications.
“It’s common to lose hair during stress or major weight loss,” Almandoz explained. “Hair is made from protein. If we’re not meeting our nutritional needs like protein intake, the body can reallocate its resources, leading to hair loss.”
Fortunately, Almandoz said this kind of hair thinning is usually reversible once weight stabilizes.
Rapid weight loss can also lead to changes in the skin. Weight loss usually involves the loss of some subcutaneous fat, which adds texture and elasticity to the skin.
“We don’t choose where we store fat or lose fat from,” Almandoz said. “Fat loss from the face as part of a weight loss journey can lead to changes in appearance that attract comments about people looking different or unhealthy.”
Almandoz recommended optimizing nutritional status and protein intake to help prevent or address hair and skin changes. If you’re concerned about these changes, it’s also a good idea to ask your healthcare provider to assess your risk for nutritional deficiencies.
Loss of muscle mass
When people lose weight through dieting, medication, or bariatric surgery, about one-third of the weight lost is lean mass, Almandoz explained. Lean mass includes muscle, organs, and bone.
Loss of lean mass presents two challenges. First, with less muscle mass, the body burns fewer calories. This causes the metabolic rate to decrease, meaning people need to eat fewer calories to maintain the same weight. The skeletal muscle – the “main furnace in the body that determines our metabolic rate,” said Almandoz – becomes more efficient and requires fewer calories. Without continued dietary changes to further reduce caloric intake, some people experience a weight plateau or even weight regain.
At the other end of the spectrum, some people who take medications for weight loss struggle to get proper nutrition and may experience malnutrition. GLP-1s are powerful appetite suppressants, so many people find themselves eating fewer calories over time.
It’s important to be mindful of diet quality given the reductions in caloric intake that accompany GLP-1-based medications with an emphasis on calcium, iron, and protein, noted Garvey.
A balanced diet and resistance training can prevent muscle loss
When you reduce calorie intake, it’s important to re-evaluate your diet and make sure you’re getting enough nutrients. Almandoz also noted the importance of eating regularly throughout the day.
For instance, eating protein at just one meal might no longer be enough to meet your energy needs. Without enough protein, the body may “cash out its savings” and start breaking down muscle mass for fuel, Almandoz said.
Indeed, Holcombe said he began losing muscle in addition to fat after increasing his Mounjaro dose to the 10 mg level. After consulting with his endocrinologist and reducing his dose to 5 mg, plus increasing his protein intake, Holcombe said he has been able to maintain glycemic control without losing muscle mass.
Likewise, a lack of calcium can lead the body to start breaking down bones, which causes osteoporosis. This is especially concerning for those who are older and more prone to frailty, fatigue, and falls.
It’s therefore important to continue eating a balanced diet with enough calcium, protein, and other nutrients even after weight loss.
Both Almandoz and Garvey recommended incorporating resistance activity into your exercise routine to increase muscle strength. Examples of resistance exercises include using free weights, resistance bands, or even your own body weight (squats, push-ups, etc.).
The bottom line
While there are no magic solutions to address the effects of GLP-1 medications, there are strategies to reduce bothersome effects.
Regarding gastrointestinal symptoms, even something as simple as switching the time of dosing from morning to bedtime can be helpful, Garvey noted. Less is known about the timing of dosing on muscle loss and skin and hair changes. Always seek advice from your healthcare provider if you’re experiencing unpleasant side effects.
It’s important to remember that everyone responds differently to medications: some people may experience a lot of side effects, while others could experience none at all.
“It’s a wide spectrum of health – not one size fits all,” said Almandoz.
Above all, Garvey emphasized that it’s important to consider the right amount of weight loss for your health.
“It’s not just losing as much weight as you can,” he said. “It’s losing the weight that brings you to good health, treats complications, and improves quality of life that’s important.”
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