The Risks of GLP-1s (Glucagon-Like Peptides)— and Safer, Natural Options

James Odell, OMD, ND, LAc

This article reviews the mechanism of action and formulation of synthetic GLP-1 receptor agonists, their history, potential benefits, adverse effects, contraindications, drug interactions, and natural alternatives.

In 2017, worldwide approximately 500 million individuals were affected by type 2 diabetes, corresponding to over 6% of the world’s population. Since then, type 2 diabetes has accelerated to epidemic proportions.  The rising prevalence of obesity and metabolic dysfunction associated with environmental toxicity is tied to insulin resistance, impaired insulin secretion, progressive failure of β-cells, and a reduction in β-cell mass. 74% of American adults are overweight or obese. 50% of American children are overweight. 

Causes of Metabolic Dysfunction

Indeed, dietary issues of processed food, excess sugar consumption (corn syrup), depleted soil nutrients, problems with sulfur metabolism, a dramatic increase in food, air, and water toxicity, and a sedentary lifestyle are all co-causes. 

There are some other causes of metabolic dysfunction too. Genetic predisposition, chronic inflammation, chronic stress, and elevated cortisol, poor sleep patterns, environmental toxins, gut health and microbiome imbalance, aging, hormonal imbalances, and certain medications also contribute to this epidemic.

For example, several genetic variations, particularly in genes related to GLP-1 receptors, proglucagon production, and insulin secretion pathways, can impact GLP-1 levels and function. These genetic differences may affect how efficiently GLP-1 regulates insulin release, glucose metabolism, and overall metabolic health. Testing for these SNIPS can help in identifying individuals who may be more or less responsive to therapies that target GLP-1, such as GLP-1 receptor agonists used in diabetes treatment.

Complications of Diabetes

The chronic complications of diabetes comprise both macrovascular diseases (those affecting the large blood vessels), with a markedly increased risk of death and disability from coronary heart disease, stroke, peripheral vascular disease, and microvascular disease (those affecting the small blood vessels), resulting in retinopathy, nephropathy, and neuropathy. Diabetes is the primary medical cause of blindness in developed countries, as well as a major cause of end-stage renal failure. Thus, there is an intensive pharmaceutical drive for novel therapies for diabetes. 

GLP-1’s Mechanism of Action and Benefits 

Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene that is expressed in these cells. GLP-1 is released in response to meal intake and is rapidly metabolized and inactivated by the enzyme dipeptidyl peptidase IV even before the hormone has left the gut.

The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, thereby contributing to limiting postprandial glucose excursions. It also inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the "ileal brake" mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. GLP-1 declines as we age.

Because of these actions, GLP-1 or GLP-1 receptor agonists are currently being marketed as therapy for type 2 diabetes. Decreased secretion of GLP-1 may contribute to the development of obesity, and exaggerated secretion may be responsible for postprandial reactive hypoglycemia. 

Incretins are a group of hormones released from the gut that stimulate insulin secretion in response to food intake, enhancing glucose-dependent insulin release and playing a role in regulating blood sugar levels. Bayliss and Starling first described the connection between the pancreas, the gut, and incretin hormones in the early twentieth century.1 When the incretin hormone glucagon-like peptide-1 (GLP-1) was subsequently shown to account for up to 70% of insulin secretion in response to nutrient intake, its potential as a therapeutic target in type 2 diabetes was realized.2 However, while the insulin secretory response could be restored with pharmacological levels of native GLP-1 in patients with type 2 diabetes, a short half-life limited its therapeutic use.3, 4

GLP-1 not only increases insulin secretion, but also increases β-cell proliferation and survival, suppresses glucagon secretion, delays gastric emptying, and suppresses appetite. All these actions contribute to a potential anti-diabetic effect. However, native GLP-1 has a very short half due to its rapid breakdown by the enzymes dipeptidyl peptidase IV and ectopeptidases. 

History of the Peptide GLP-1

In 1980, gastroenterologist Jean-Pierre Raufman started working at the NIH, testing guinea pig pancreases with venom from animals like bees, wasps, snakes, frogs, and lizards. This research on the digestive system and pancreas explored if there was any specific insect and animal venom that could trigger the pancreas to release more insulin and digestive enzymes. He found that the venom that elicited the most digestive enzymes came from the Gila monster, a large orange and black lizard from the southwestern U.S. Essentially, he discovered a hormone-like molecule called exendin-4. This molecule was like a human hormone called glucagon-like peptide-1 (GLP-1), which helps regulate blood sugar levels.  Raufman and his colleagues published their findings, and others followed.5, 6, 7, 8, 9, 10, 11 He continued his work with another researcher in New York on the molecule exendin-4 and found that this peptide was like human GLP-1.

Gila Monster

Endocrinologist Daniel Drucker at the University of Toronto heard about this discovery, because he was already interested in GLP-1, but did not know about the Gila monster’s saliva containing a similar but more stable molecule. Scientists like Drucker, have long been researching human diabetes treatment based on synthetic GLP-1, but unsuccessfully, because the synthetic GLP-1 would quickly break down or the subject would become ill if they got too much of it too quickly. With the new “copy-cat” molecular design of Gila monster’s GLP-1, researchers discovered a much longer-lasting and effective peptide. 

Exenatide was the first GLP-1 receptor agonist to receive FDA approval in 2005 for the management of type 2 diabetes mellitus, and since then, multiple similar medications have been developed. Currently, several GLP-1 receptor agonists are employed in the treatment of type 2 diabetes.12 Ozempic, also known by its generic name semaglutide, received FDA approval for the management of type 2 diabetes mellitus in 2017.13 Recently, semaglutide has also been approved for use in patients with obesity and is sold under the name WegovyTM.14

Today, millions of people have prescriptions for GLP-1 receptor agonist medications like Ozempic. The upside is both oral and subcutaneous forms have shown effectiveness in improving glycemic control, weight loss, and reducing cardiovascular risks associated with diabetes mellitus.GLP-1 receptor agonists have also shown potential in being used as a therapeutic strategy in Alzheimer’s disease due to its anti-neuroinflammatory effects15 and even being used to treat polycystic ovary syndrome.16, 17 

The Risks of GLP-1s - Adverse Effects, Contraindications, and Interactions

If you encounter a Gila monster in the desert, it is wise to proceed with extreme caution. GLP-1 receptor agonists should also be approached with just as much caution as this class of drugs is associated with some very concerning adverse effects. Those include gastrointestinal complications, acute pancreatitis, acute kidney injury, acute gallbladder injury, nonarteritic anterior ischemic optic neuropathy, and diabetic retinopathy. Contraindications of GLP-1 receptor agonists include a history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, and pregnancy. Drug interactions to consider with semaglutide therapy include those also used in diabetes treatment, like metformin, as well as anti-psychotics. 

Gastrointestinal Side Effects

Most people know that GLP-1 receptor agonist medications like Ozempic and Wegovy can cause relatively minor side effects like nausea, delayed gastric emptying, reduced intestinal motility, constipation, and in some cases diarrhea.  These are well-known side effects of this drug class.18, 19, 20

Ozempic Face

Facial fat serves as a protective function and affects facial aesthetics and elasticity. Weight loss can cause dermatological changes and shrinking because the fat that stretches and cushions the skin is no longer in place. The skin of the face also loses its ability to retract after an episode of rapid weight loss due to reduced levels of elastin and collagen, which are essential for structural integrity. That is to say, this peptide can cause the loss of collagen, an important structural protein. As a result, people taking Ozempic or semaglutide may report the following facial symptoms:

• increased signs of aging, such as more lines and wrinkles

• loss of fat, which can lead the skin to become loose and sag, throughout the body, especially the face

• a hollowed-out facial appearance

• lipodystrophy, which affects how the body accumulates and stores fat

Pancreatic Adverse Events: Pancreatitis and Pancreatic Cancer

Within years of the introduction of GLP-1 receptor agonists, these agents were linked to the occurrence of acute pancreatitis and even suggested a rare potential to cause pancreatic cancer.21, 22, 23, 24 Additionally, a handful of preclinical studies in animals showed that GLP-1 receptor agonists induce pancreatic inflammation, cellular proliferation, and intra-epithelial neoplasia.25, 26, 27 Most case reports indicate acute pancreatitis as a side effect shortly after Semaglutide exposure. However, there is a case occurring after four years of use.28 Although pancreatic adverse events as a result of medication side effects are difficult to assess, in 2014 the FDA and the EMA concluded that a “causal association between incretin-based drugs and pancreatitis or pancreatic cancer is inconsistent with the current data.”29 However, that assessment is now over ten years old and should be reviewed again, as many acute pancreatic cases have been reported since then. It appears the risk of developing pancreatic adverse events while taking a GLP-1 receptor agonist is low, but real. 

Acute Kidney Injury

Initial case reports suggested that GLP-1RA treatment could cause acute kidney injury in certain high-risk patients.30 Mechanistically, this was explained by dehydration caused by nausea, vomiting, and diarrhea. Also, very recently it was shown that the GLP-1 receptor agonist, dulaglutide decreased fluid intake and can result in fluid and electrolyte loss.31 Furthermore, GLP-1 receptor agonists can potentially further compromise fluid homeostasis by increasing renal sodium excretion.32 Combined, this could potentially induce renal failure, especially in frail patients or those with medication such as renin–angiotensin–aldosterone system inhibitors, non-steroidal anti-inflammatory drugs, or diuretic drugs.

Diabetic Retinopathy and Blinding Eye Disease

Diabetic retinopathy is a leading cause of vision impairment and blindness. GLP-1 receptor agonists have been associated with a higher rate of diabetic retinopathy complications vs placebo.33, 34 An increase in diabetic retinopathy complications, defined as a composite of the need for retinal photocoagulation or treatment with intravitreal agents or vitreous hemorrhage or diabetes-related blindness, was reported for semaglutide compared to placebo.35 An increase in diabetic retinopathy complications has been observed in high-risk patients, and the data are consistent with the phenomenon of early worsening of pre-existing diabetic retinopathy, secondary to an initial, rapid improvement in glycemic control.36 

New studies also indicate a connection between semaglutide use and increased risk for a blinding eye disease called non-arteritic anterior ischemic optic neuropathy (NAION).37, 38, 39 NAION, happens when blood flow to the optic nerve is blocked, causing sudden, painless loss of vision in one eye. 

Natural Alternatives for Increasing GLP-1s

The question is always whether the benefits of taking a GLP-1 receptor agonist outweigh the risks of GLP-1s. For those who seek a more natural bioregulatory method of increasing GLP1, there are excellent alternatives to the drugs. 

• Using Probiotics - The intestine naturally produces GLP-1, which plays multiple roles in metabolic health. Unfortunately, GLP-1 can decrease with age and lifestyle. It can also be depleted from a corruption of the intestinal microbiome. Hence, repair of the intestinal microbiome with specific probiotic organisms has shown to be an effective method of increasing GLP-1. 

 Obesity and type 2 diabetes is related to gut dysbiosis as an imbalance between energy consumption and expenditure favors the prevalence of pathogenic bacteria.37, 38 

Not only can dysbiosis result in insulin resistance but the disruption of the integrity of the intestinal mucosa drives the development of inflammatory bowel diseases, such as ulcerative colitis and Crohn’s disease, which are chronic idiopathic inflammatory diseases characterized by an exaggerated immune response to gut microbiota, resulting in tissue damage.39

Akkermansia muciniphila is a Gram-negative anaerobic mucus-layer-degrading bacterium that colonizes the intestinal mucosa of humans. Metagenomic data have shown an inverse correlation between the abundance of A. muciniphila and diseases such as inflammatory bowel disease, obesity, and diabetes. Thus, in recent decades, the potential of this bacterium as an immunomodulatory probiotic for autoimmune and chronic inflammatory diseases has been explored in experimental models. Corroborating these human correlation data, it has been reported that A. muciniphila slows down the development and progression of diabetes, obesity, and IBD in mice.40, 41 

The mechanisms by which A. muciniphila regulates obesity and glucose levels have not yet been completely elucidated. A previous study showed that A. muciniphila was able to increase thermogenesis and the secretion of glucagon-like peptide-1 (GLP-1) reduce the expression of proteins involved in adipose cell differentiation, and the gene expression of glucose and fructose transporters in the jejunum, suggesting that A. muciniphila reduces carbohydrate absorption.42, 43

Akkermansia muciniphila is commercially available. It is often formulated together with Clostridium butyricum and Bifidobacterium infantis which also boost GLP-1.

• Eat More Fiber-Rich Foods - Foods that are high in soluble fiber, such as fruits, vegetables, legumes, oats, and whole grains, can help increase GLP-1 secretion. Fiber slows down digestion and can stimulate the release of GLP-1, contributing to improved blood sugar control and satiety.

• Consume Healthy Fats - Healthy fats, especially those from monounsaturated and polyunsaturated fats, such as avocados, olive oil, nuts, seeds, and fatty fish (like salmon and mackerel), have been shown to stimulate GLP-1 release. These fats help with digestion and can support the body's metabolic functions.

• Eat Protein-Rich Meals - Consuming protein-rich foods like lean meats, fish, eggs, dairy, tofu, and legumes can naturally stimulate GLP-1 secretion. Protein helps improve satiety, keeping you fuller for longer and supporting balanced blood sugar levels.

• Intermittent Fasting - Some studies suggest that intermittent fasting or time-restricted eating may enhance the natural release of GLP-1. By giving your digestive system regular periods of rest, you may encourage a better hormonal response to food intake.

Eating at regular intervals, rather than consuming large, irregular meals, may also help maintain consistent GLP-1 secretion.

• Exercise Regularly - Physical activity, particularly aerobic exercise (like walking, jogging, or cycling) and resistance training (like weightlifting), has been shown to boost GLP-1 levels. Exercise helps improve insulin sensitivity and can lead to higher post-meal GLP-1 secretion.

  
  

• Stay Hydrated - Drinking enough water throughout the day helps support overall metabolic health, and hydration can indirectly support the secretion of GLP-1 and other beneficial hormones involved in digestion and blood sugar regulation.

• Consume Fermented Foods - Probiotic-rich foods like yogurt, kefir, kimchi, sauerkraut, and kombucha can support gut health and help enhance GLP-1 release. A healthy gut microbiome is thought to influence the body's hormonal responses, including GLP-1 secretion.

• Consume Caffeine (in Moderation) - Some research suggests that caffeine, typically found in coffee and tea, may increase GLP-1 secretion. However, the effects are generally mild, so moderation is key to avoid any potential negative effects from excessive caffeine intake.

• Include Resistant Starch in Your Diet - Resistant starch, which is found in foods like green bananas, potatoes that are cooled after cooking, and certain legumes, is not digested in the small intestine but instead ferments in the colon. This fermentation process can stimulate GLP-1 release.

• Add More Spices like Cinnamon and Turmeric - Certain spices, like cinnamon and turmeric, contain compounds that may have a positive effect on GLP-1 levels. Cinnamon, in particular, has been studied for its role in improving insulin sensitivity and stimulating GLP-1 secretion.

• Maintain a Moderate Carbohydrate Intake - Avoiding excessive carbohydrate intake, particularly from high glycemic index foods (like refined sugars and processed grains), can prevent blood sugar spikes and may help maintain a healthy GLP-1 response. Pairing carbohydrates with fiber and protein can improve GLP-1 secretion and prevent insulin resistance.

Conclusions:

The prevalent use of GLP-1 receptor agonists has been successful in treating type 2 diabetes and obesity but carries several adverse risks, which are consistently downplayed. Long-term usage of this drug class has not been thoroughly researched. The pharmaceutical industry claims these agents have an overall beneficial risk/benefit profile for the treatment of patients with type 2 diabetes. However, for those wishing to treat prediabetes and type 2 diabetes with a more natural approach, there are probiotic strains that have been shown to increase GLP-1, such as A. muciniphila as well as other lifestyle modifications.

These lifestyle modifications include eating a fiber-rich, balanced diet with healthy fats, lean proteins, and fermented foods while maintaining a regular exercise routine. Staying hydrated and incorporating specific spices and foods like resistant starch may also provide benefits.

References

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