Side Effects of GLP-1 Drugs

November 26, 2024

What are GLP-1 RA drugs?

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are a class of medications that mainly help manage blood sugar (glucose) levels in people with type 2 diabetes. Some GLP-1 RA drugs can also help with obesity [1, 2, 3]. They mimic the action of the natural hormone GLP-1, which is released by the intestine in response to food intake.

These medications are relatively new. The U.S. Food and Drug Administration (FDA) approved the first GLP-1 RA drug (exenatide) in 2005.

GLP-1 RA drugs alone can’t treat type 2 diabetes or obesity. Both conditions require other treatment strategies, including lifestyle and dietary changes.

GLP-1 RA drugs are most often injectable medications, meaning you inject a liquid medication with a needle and syringe. You give the shots in the fatty tissue just under your skin (subcutaneous injection). Areas of your body you can give the injections to include your belly, outer thighs, upper buttocks and the backs of your arms.

Other names for this medication class include:

Glucagon-like peptide-1 agonists.

GLP-1 receptor agonists.

Incretin mimetics.

GLP-1 analogs.

GLP-1 drugs.

How do GLP-1 RA drugs work?

To understand how GLP-1 RA drugs work, it helps to understand how the natural GLP-1 hormone works in your body. GLP-1 is normally released from the intestinal cells in response to the presence of nutrients in the digestive system, especially carbohydrates including glucose. In individuals with type 2 diabetes, there may be a deficiency or impaired function of GLP-1.

GLP-1 hormone plays several roles in glucose control and body weight management [4, 5].

Stimulates insulin release from your pancreas: Insulin is an essential hormone that helps your body use the food you eat for energy. It lowers the amount of glucose (sugar) in your blood. If you don’t have enough insulin, your blood sugar increases, leading to diabetes.

Inhibits glucagon secretion: Glucagon is a hormone your body uses to raise your blood sugar levels when necessary. GLP-1 prevents more glucose from going into your bloodstream.

Slows stomach emptying: Slower digestion means that your body absorbs less nutrients and releases less glucose (sugar) from the food you eat into your bloodstream.

Suppresses appetite and increases satiety: GLP-1 affects areas of your brain that processes hunger and satiety. You feel fuller, so you eat less, and thus you lose weight.

GLP-1RA drugs are synthetic substances that mimic natural GLP-1 hormones. GLP-1 RA drugs bind to GLP-1 receptors to trigger the effects of the GLP-1 hormone. The higher the dose of the GLP-1 RA drugs, the more extreme the effects. In other words, GLP-1 RA drugs trick your body to think there are natural GLP-1 hormones while there are none.

While GLP-1RA drugs have shown effectiveness in the management of type 2 diabetes and obesity, they come with limitations [5]. Most importantly, GLP-1RA drugs essentially hijack the body’s natural GLP-1 signaling, tricking the body to think there is sufficient GLP-1 secretion in the presence of GLP-1RA. This has caused undesirable dependence of GLP-1RA for type 2 diabetes and obese patients.

Studies have shown that patients regained the vast majority of their lost weight within 12 months after stopping GLP-1RA drugs, and their glucose levels increased back as well. Even during the process of weight loss, much of the lost weight was muscle, which unfortunately was not the weight you wanted to lose.

Instead of enhancing the body's own natural response to nutrient intake, GLP-1RA drugs likely further mess up with the body’s natural regulatory and feedback mechanisms, especially in type 2 diabetes patients who are already suffering from the deficiency or defect of natural GLP-1 hormone.

What are the side effects of GLP-1 RA drugs?

GLP-1RA drugs have many unwanted side effects [6, 7, 8, 9], including but not limited to the following. The most common side effects of GLP-1 agonists include:

Loss of appetite.
Nausea
Vomiting
Diarrhea
Constipation

Other common side effects include:

Muscle loss.
Dizziness
Mild tachycardia (increased heart rate).
Infections
Headaches
Indigestion (stomach upset).
Injection site itching, redness, swelling.
Pancreatitis, an inflammation of the pancreas that causes abdominal pain.
Gastroparesis, sometimes called stomach paralysis, in which movement of food out of the stomach is slowed or stopped.
Bowel obstruction, a blockage that keeps food from passing through the intestines.
Gallstone attacks and bile duct blockage.
Medullary thyroid cancer.
Acute (sudden) kidney injury.
Worsening diabetes-related retinopathy.

Of special note, GLP-1 RA drugs aren’t safe to take during pregnancy. Animal and human studies have shown that these medications cause developmental abnormalities in the fetus [10].

The side effects of GLP-1 RA drugs are substantial, so much so that, on August 2, 2023, Jaclyn Bjorklund, a 44-year-old woman from Louisiana, filed a lawsuit against Novo Nordisk, the company behind Ozempic and Wegovy, and Eli Lilly, who make Mounjaro, another GLP-1 drug. Bjorklund lost 150 pounds while taking the two drugs and sued the manufacturer for failing to warn her about serious adverse gastrointestinal effects.

"Ozempic face" as a side effect of GLP-1 RA drugs?

One side effect that has taken over social media is "Ozempic face," where skin on the face sags and wrinkles. "Ozempic face" was coined in reference to one of these drugs, though the term is misleading because this can be a side effect of any GLP-1 RA drug or any other cause of rapid weight loss.

The rapid loss of fat in the face can cause:

a hollowed look to the face

changes in the size of the lips, cheeks, and chin

wrinkles on the face

sunken eyes

sagging jowls around the jaw and neck.

If weight is lost in a more gradual way, these changes may not be as noticeable. It's the faster pace of weight loss that occurs that can make facial changes more obvious.

“Ozempic face” is only one part of the story, neglecting a much more important and relevant fact: rapid or sudden weight loss is simply not sustainable, as all subjects regained the weight they lost in less than a year after stopping GLP-1 RA drugs [11].

Natural GLP-1 signaling product vs synthetic GLP-1 RA drugs? Your choice.

While GLP-1RA drugs have shown effectiveness in the management of type 2 diabetes and obesity, they come with limitations and unwanted adverse effects. GLP-1RA drugs essentially hijack the body’s natural GLP-1 signaling, tricking the body to think there is sufficient GLP-1 secretion in the presence of GLP-1RA.

On the other hand, products that boost the endogenous secretion and activity of natural GLP-1 compared to GLP-1RA drugs offer obvious advantages in the treatment of type 2 diabetes and obesity.

Physiological regulation: Agents that stimulate the endogenous production of GLP-1 work in harmony with the body's natural regulatory mechanisms. They enhance the body's own response to nutrient intake, potentially leading to a more physiologically regulated glucose metabolism.

Tissue selectivity: Endogenous GLP-1 release is tightly regulated and occurs in response to nutrient stimuli. This natural regulation may lead to more selective GLP-1 action in tissues that play a role in glucose homeostasis, such as the pancreas and gastrointestinal tract.

Reduced risk of hypoglycemia: Endogenous GLP-1 release is glucose-dependent, meaning it occurs in response to elevated blood glucose levels. This glucose-dependent action reduces the risk of hypoglycemia compared to some GLP-1RA drugs that have a more sustained and sometimes glucose-independent effect.

Natural feedback mechanisms: Stimulating the endogenous production of GLP-1 allows the body to maintain its natural feedback mechanisms. GLP-1RA drugs, being synthetic and exogenous, may not integrate as seamlessly into the body's regulatory processes.

Preservation of the incretin axis: Agents that boost endogenous GLP-1 production preserve the incretin axis, the physiological system involving hormones like GLP-1 that enhance insulin secretion in response to nutrient intake. Preserving this axis may have broader metabolic benefits.

Long-term safety profile: As agents enhancing endogenous GLP-1 production work with the body's natural processes, they may have a favorable long-term safety profile. Mimicking the body's own regulatory mechanisms may be associated with fewer long-term concerns.

A cautious and controversial question: Could GLP-1 RA drugs be the next “Opioid Crisis”?

GLP-1 drugs topic has been so hot that there have been a lot of discussions around their side effects and even dangers. There has been a cautious and controversial question for everyone to think about: could GLP-1 drugs be next “opioid crisis”?

GLP-1 drugs are certainly different from opioid painkillers, as they work via different pathways and produce different effects in the human body. There are also some differences between their market dynamics.

Let us first briefly examine the most recent opioid crisis in USA (YES, there have been multiple opioid crises), without getting to the technical details [12, 13]. The opioid crisis in the United States has evolved over several decades, caused by multisystem failure. According to Centers for Disease Control and Prevention (CDC), chief among them is the profit-motivated big pharma fraudulently inflated their benefits and downplayed their potential harms (especially addiction), which fueled overprescription of opioid painkillers by the medical community [14]. Lack of proper and timely regulations from regulatory bodies such as FDA is another important factor [15].

Opioid painkillers are synthetic molecules mimicking natural opiates that the human body naturally produces. Opioid painkillers were only approved for dying cancer patients suffering from severe cancer-related pains. In the 1970s, big pharma began aggressively marketing opioid painkillers as safe and effective treatment options for chronic pain for average persons. Drugs like oxycodone and hydrocodone were promoted as non-addictive or less addictive than previously believed. The medical community increasingly prescribed opioids for chronic pain management, leading to a significant increase in opioid prescriptions.

Though large evidence showed the strong addiction of opioid painkillers in the late 1990s, big pharma reassured the medical community that patients would not become addicted to prescription opioids. This led to another surge in opioid prescriptions. The introduction of OxyContin (extended-release oxycodone) in 1996 by Purdue Pharma further fueled the rise in opioid prescribing. OxyContin was marketed as a humane long-acting pain reliever with a lower risk of addiction.

As opioid prescriptions increased, so did rates of opioid misuse, addiction, and overdose deaths. Many individuals who became addicted to prescription opioids transitioned to using heroin, which was cheaper and more readily available. The number of overdose deaths involving prescription opioids and heroin began to rise dramatically.

The opioid crisis took a deadlier turn with the proliferation of illicitly manufactured fentanyl and other synthetic opioids. Fentanyl, a potent synthetic opioid, began to appear in the illicit drug supply, often mixed with heroin or pressed into counterfeit pills. The introduction of fentanyl significantly increased the risk of overdose deaths due to its potency and unpredictable presence in street drugs.

Despite the mounting data clearly showing the deadliness of these opioid drugs over a decade, the US Government did not declare the opioid epidemic a public health emergency until October 16, 2017.

GLP-1 RA drugs are certainly different from opioid painkillers, as they work via different pathways and produce different effects in the human body. However, it is worthy to note that the current scheme and event progression of GLP-1 RA drugs are strikingly similar to the early history of the most recent opioid crisis: benefits were heavily promoted and even exaggerated but risks were muffled by profit-driven big pharma; even worse, though severely lacking long-term safety data, big pharma are aggressively expanding GLP-1 RA drugs’ indications, trying to use them on more common patients.

After all, many if not all the systems that failed Americans and created the opioid crisis are still the same: profit-driven big pharma and American medical system, revolving doors between FDA and big pharma, slow reacting regulatory bodies such as FDA, etc [15]. Considering the gaining popularity and aggressive expansion of GLP-1 RA drugs, many experts in the field are alarmingly concerned and are calling for stricter regulation from FDA and slower introduction of GLP-1 RA drugs into more common patients.

History never repeats itself, but it always rhymes!

Could GLP-1 RA drugs be the next “Opioid Crisis”?

Only time will tell.

Scientific References

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