Spotlight on: Glucagon-like peptide-1 receptor agonists (and the potential benefits beyond weight loss…)

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a class of medications that have long been used to treat type 2 diabetes mellitus (T2DM). More lately, certain GLP-1RAs have been approved by the FDA for other uses, such as weight loss and maintenance. Ongoing research indicates that they may also have other beneficial effects on health. Ozempic (a semaglutide) is perhaps one of the most well-known of these, being in the spotlight recently for its popularity among celebrities for its weight loss effects. However, despite many advantages, GLP-1RAs also come with their own set of risks and side effects ranging from mild to serious. This article aims to provide an overview of how GLP-1RAs work, the associated and potential benefits, and risks.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs)

This class of drugs was designed to mimic glucagon-like peptide 1 (GLP-1), a peptide hormone, that is produced naturally by the body. While its most widely cited effect is on glucose control, GLP-1 also has numerous other functions in the body. GLP-1 is produced by, and activated in various cells of the pancreas, digestive tract, heart muscle, skeletal muscle, liver, central nervous system, and immune system (1).  After a meal, GLP-1 levels rise and stimulate insulin production and release, suppress glucagon secretion, delay gastric emptying, and increase glucose metabolism and satiety (2).

However, GLP-1 produced by the body has a short half-life (about 1-2 minutes before it is degraded) (3). This short half-life has led to the development of GLP-1RAs (and other drugs that inhibit its metabolism) which allow for a sustained release and can be regularly administered. As a result, GLP-1RAs are regularly prescribed for managing T2DM and obesity. Examples of GLP-1RAs include exenatide, liraglutide, dulaglutide, and semaglutide (Ozempic is one of the brand names semaglutide is sold under). While each of these varies slightly in their effectiveness, as a whole, taking GLP-1RAs leads to superior glucose control, prolonged feelings of fullness, and reduced food intake resulting in substantial weight loss (4).

Other possible benefits of GLP-1RAs

The following will outline other aspects of health (beyond managing glucose and obesity) where GLP-1RAs have been implicated to be beneficial. It should be noted that in most cases the findings are not conclusive so should be read with this in mind. Additionally, GLP-1RAs have been historically predominantly prescribed for those with T2DM, and only very recently obesity, which often comes with one or many other health issues. Consequently, most of the studies are focused on these patients, and I was unable to find any studies on healthy individuals. Finally, different GLP-1RAs offer varying degrees of benefits for specific health outcomes, so it is important to talk to your medical practitioner in order to determine which one is superior in treating your specific health concern.

Cardiovascular health

Strict blood glucose management has been associated with a reduced risk of cardiovascular events. Maintaining stable blood glucose levels can offset the adverse effects of high blood glucose (hyperglycaemia) and help reduce the risk of cardiovascular diseases in those with diabetes (5,6). As we have learned, GLP-1RAs are very successful in stabilising and helping maintain blood glucose levels in those with T2DM. Additionally, by mimicking the effects of GLP-1 produced in the body, GLP-1RAs stimulate GLP-1 receptors, including those in heart muscle cells and blood vessels (7). As a consequence, GLP-1 RAs are associated with blood pressure reduction, lipid levels reduction, and endothelial function improvement (3).

Studies on GLP-1RA and cardiovascular outcomes consistently support these effects; predominantly demonstrating a reduced incidence of non-fatal heart attacks, stroke, and cardiovascular-related deaths (3). Big trials such as the LEADER, SUSTAIN-6, and REWIND studies have shown that in high-risk individuals with T2DM taking a GLP-1RA (liraglutide) had a reduced risk of major adverse cardiac events (MACE) by 13% (8). The SUSTAIN-6 trial found that the participants had a reduced risk of MACE (26%); mainly through reducing their nonfatal stroke risk. (43. Similarly, the REWIND study found a reduced risk of nonfatal strokes in participants. (3). As a consequence, semaglutide has recently been approved to reduce the risk of cardiovascular events in patients with CVD and T2DM.

Liver health

There is a well-established relationship between non-alcoholic fatty liver disease and T2DM which is not surprising due to the role of the liver in glucose regulation. The term “non-alcoholic fatty liver disease” encompasses individuals with liver disease ranging from hepatic steatosis to steatohepatitis and cirrhosis, in the absence of significant alcohol intake or the presence of other secondary causes of steatosis (9). Treatment with GLP-1RAs seems to be promising in improving non-alcoholic fatty liver disease in individuals with T2DM (10).

GLP-1RA have a strong association with improvements in hepatic steatosis, attributed to their ability to improve insulin signalling pathways and fatty acid metabolism (in addition to the weight loss benefits that help control this condition) (11,12). This theory is supported by recent studies that found improvements in markers in participants diagnosed with non-alcoholic steatohepatitis and reduced liver fat content (13,14,15).

Neuroprotection

Endogenous GLP-1 is thought to have neuroprotective effects by reducing inflammation, stimulating nerve growth, and affecting lipid metabolism (16,17). In addition to its role in glucose regulation, GLP-1 can cross the blood-brain barrier and promotes synaptic function, enhances neurogenesis, reduces apoptosis, and protects neurons from oxidative stress (18). Accordingly, it has been questioned whether GLP-1RAs can have neuroprotective effects.

While research in this area is still very much evolving, GLP-1Ras have shown potential in early-phase trials and animal models in a range of neurodegenerative conditions including Alzheimer’s Disease, Parkinson’s Disease, and other neurodegenerative conditions (18,19). Post hoc analysis in the REWIND study suggests that long-term GLP-1RA therapy (specifically dulaglutide) might reduce cognitive impairment in people with T2DM (20). GLP-1RAs have also been suggested by several small studies to help in Parkinson’s disease. In mice, semaglutide was found to reduce motor impairment and protect certain neurons (21). Similarly, small studies in humans suggest that treatment with a GLP-1RA (extended-release exenatide) may improve motor impairment in patients with Parkinson’s Disease (22,23,24).

Kidney health

Recent studies indicate that GLP-1RA may help prevent the onset and progression of DKD. Chronic kidney disease is among the most common complications of T2DM and is associated with an increased risk of all-cause and cardiovascular mortality in patients with diabetes. (25). At least half of patients with T2DM will develop DKD (26). Hyperglycaemia plays a critical role in DKD initiation through altered ratios of glucose metabolites, fatty acids, and amino acids, modifications of mitochondrial respiratory chain function, and uncoupling of the respiratory chain proteins (27).

GLP-1RAs may offer beneficial effects on traditional risk factors for chronic kidney disease, for example through glycaemic control, lowering blood pressure, decreasing insulin levels, cardiovascular benefits, and causing weight loss (28). However, the potential mechanisms are multiple and not completely understood, most having been demonstrated in experimental animals only (25).

Potential side effects and risks of GLP1-RAs

Mild gastrointestinal effects

GLP-1 RAs have been well-established to cause several mild gastrointestinal adverse effects including, abdominal pain, nausea, vomiting, constipation, diarrhoea, and delayed gastric emptying (29). Those taking the GLP-1RA liraglutide, dulaglutide, and semaglutide have been found particularly susceptible to these side effects (29). It is suggested that a slow escalation of dose, smaller portion sizes, stopping eating if nauseated, and avoiding spicy or fatty meals can help manage these effects (20)

Thyroid cancer

Concerns have been raised regarding an increased risk of thyroid C-cell cancer. Thyroid C-cells express GLP-1 receptors, and when bound by GLP-1 stimulate cell growth and calcitonin production. GLP-1 receptors are also expressed in papillary thyroid carcinoma cells (and to a greater extent than in normal human thyroid cells) (30). Accordingly, several mechanisms have been proposed for an association between GLP-1RAs and thyroid cancer however, none to my knowledge have been established in experimental studies. Additionally, while some (but not all) observational data has suggested an association, many of these studies have been criticised for not accounting for certain factors that potentially amplify the connection (31,32).

Until recently, it would appear that a link between GLP-1RAs and thyroid cancer is weak at best. However, a recent meta-analysis of predominantly large randomised control trials (RCTs), published in November 2023 suggests that GLP-1RA treatment may be associated with a moderate increase in thyroid cancer risk (30). While the results are far from conclusive, it warrants further study and is something to be considered when making the decision to start GLP-1RA treatment.

Pancreatitis and pancreatic cancer

Concerns were raised following several publications in the mid-2000s that suggest that those taking GLP-1RAs were at an increased risk for pancreatitis and pancreatic cancer (33,34).

However, more recent meta-analyses did not demonstrate an association of GLP-1RAs with pancreatitis or pancreatic cancer (35,36). Two additional large cohort studies published support these findings also (37,38). Three more recent meta-analyses of RCTs reported no association between GLP-1RA use and pancreatitis (39,40). So, it appears at the moment claims that taking GLP-1RAs can lead to pancreatic issues have not been substantiated.

Depression

There exists evidence suggesting an association between the use of GLP-1 RAs and depression. In the USA, there have been 60 reports of suicidal thoughts from patients on semaglutide since 2018 and 70 from those on liraglutide since 2010 (41). While these reports are not proof of causation, several government bodies are investigating their safety in this context, and depression has been labelled as a potential side effect of several GLP-1RA. Among many potential mechanisms, it is proposed that GLP-1 seems to decrease the rewarding effects of food intake by affecting dopaminergic systems in the brain (42).

However, the evidence is far from conclusive. Independent of GLP-1RAs, there exists a possible link between weight change and suicide, for example, in individuals who undergo bariatric surgery the suicide rate is notably higher than that of the general population. Bariatric surgery and GLP-1RAs have been shown to produce similar amounts of weight loss, which poses the question of whether they could elicit similar depressive effects. Several theories have been proposed to explain the potential link between weight loss and suicide, including hormonal changes involving ghrelin and reduced triglyceride levels (43.44). Alternatively, as a drug that is commonly prescribed to treat T2DM, it is possible that the comorbidities of this condition, number of medications, duration of use, and body size could also be participating in the negative mental health effects in these individuals.

Body composition

It is well established that when body weight is reduced through dietary energy restriction, not all of the weight lost is fat, with approximately 25% to 33% estimated to be lean body mass (notably skeletal muscle) (45,46). Given the importance of skeletal muscle, this loss is far from ideal and needs to be minimised as much as possible. While predominantly, individuals taking GLP-1RAs still lose more fat than muscle, it would seem that the potential for skeletal muscle loss is greater than other forms of weight loss. In fact some studies found that the participants lost up to 50% of their fat-free mass (47). The accelerated decline in skeletal muscle and the associated increased risk of sarcopenia are particularly concerning, especially since individuals prescribed these therapies are typically already at higher risk for physical frailty, such as those with T2DM and/or obesity.

Therefore, it is important to implement other lifestyle changes to preserve or enhance skeletal muscle. Strength training should be emphasised, alongside consuming ample dietary protein. It is important to understand that even though individuals taking GLP-1RAs are inclined to eat less, the body’s protein requirements stay the same. Therefore ensuring optimal protein intake is crucial.

What about natural alternatives?

Certain food, drinks, and supplements have been promoted to contain naturally occurring compounds that result in more GLP-1 production than is normal, one of the more popular ones being yerba mate. Such products are often promoted as “nature’s Ozempic” or natural alternatives to GLP-1RAs. However, while there is some evidence that certain compounds can increase GLP-1, the increases are very unlikely to produce the kind of appetite-suppressive effect that would lead to any significant weight loss (48). GLP-1RA drugs increase GLP-1 to a magnitude that would be impossible to do naturally. Additionally, the short half-life of endogenous GLP-1 means that any magnitude of increase would be degraded too quickly to be of any significant benefit.

Conclusion

GLP-1RAs have been breakthrough drugs in the treatment of T2DM and obesity, and are indicated to offer numerous health benefits beyond weight loss. GLP-1RAs have demonstrated potential benefits in cardiovascular health, liver health, and neuroprotection, and may play a role in reducing the risk of chronic kidney disease. However, these drugs also come with potential risks and side effects, including gastrointestinal issues, thyroid cancer, pancreatitis, depression, and the loss of lean body mass. As ongoing research continues to uncover the full scope of GLP-1RAs' effects and risks, it is crucial for individuals to consult with their healthcare providers to weigh the benefits and risks of these treatments based on their specific health needs.

*Disclaimer*

The information presented in this article is for educational purposes only and based on my interpretation of the research. Individuals with specific health concerns or dietary restrictions should consult with qualified healthcare professionals or registered dietitians for personalised guidance and recommendations tailored to their individual needs and circumstances.

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